Exercise training-induced M. HAROLD

LAUGHLIN

AND

coronary vascular adaptation RICHARD

M. MCALLISTER

Department of Veterinary Biomedical Sciences, Department Center, University of Missouri, Columbia, Missouri 65211

of Physiology,

and The D&on

Research

LAUGHLIN, M. HAROLD, AND RICHARD ing-induced coronary vascular adaptation.

M. MCALLISTER. JZxercise trainJ. Appl. Physiol. 73(6): 22092225,1992.-Aerobic exercisetraining inducesan increasein coronary vascular transport capacity. This increasedtransport capacity is the result of increases in both blood flow capacity and capillary exchange capacity. These functional changesare the result of two major types of adaptive responses,structural vascular adaptation and altered control of vascular resistance. Structural vascular adaptation occurs in responseto exercise training in at least two forms, increasesin the cross-sectionalarea of t,he proximal coronary arteries and angiogenesis.Angiogenesishasbeendemonstrated in that training causesmoderate cardiac hypertrophy while maintaining or increasing capillary density and increasing arteriolar density. Training-induced changesin coronary vascular control have beenshownto include altered coronary responsesto vasoactive substances,changesin endothelium-mediated vasoregulation, and alterations in the cellular-molecular control of intracellular free Ca2+in both endothelial and vascular smooth musclecellsisolated from coronary arteries of exercise-trained animals. The signal or signalsfor these adaptive responsesremain unknown. The hypothesis that the adaptive strategy entails maintenance of normal shear stressin coronary arterial vesselsis discussed.We proposethat as a result of training-induced structural vascular adaptations and alterations in the control of vascular resistance,shear stressthroughout the coronary vasculature is returned to the level present in sedentary animals.The signal for adaptation may be peak shearstressduring exerciseand/or average shear stressover a 24-h period of time. endothelium; endothelial cell; capillary; microcirculation; prostaglandins; norepinephrine; potassium; coronary blood flow; propranolol; vascular smooth muscle;endothelin; acetylcholine; adenosine;isoproterenol

IN BODY BUILDING, eXf3rCk training programs, and aerobic activities is high in our society. Many individuals are motivated to initiate and continue in such INTEREST

activities because of a belief that a life-style that includes a moderate level of physical activity reduces the risk of cardiovascular disease. The hypothesis that increased levels of physical activity ameliorate coronary disease may be traced to the work of Morris et al. (87). This hypothesis has been extensively investigated since that time (14, 31,41,43,46-48,103). Although it has not yet been established that exercise training ameliorates coronary disease, Powell et al. (99) concluded, in a comprehensive review of the literature, that physical activity is inversely and causally related to the incidence of coronary diseasein humans. The efficacy of exercise training in prevention and/or treatment of coronary disease could 0X1-7567/92

$2.00

be the result of 1) training-induced alterations in the atherosclerotic disease process, and/or 2) primary alterations in the coronary vascular bed. The purpose of this review is to focus on the second of these possibilities, that the efficacy of exercise training in prevention and/or treatment of coronary disease is due, at least in part, to primary training-induced alterations that improve coronary vascular function. The hypothesis that coronary vascular function is enhanced by exercise training is considered first. This is followed by consideration of how training-induced vascular adaptation is accomplished (i.e., what is changed) and the potential cellular mechanisms involved. The primary function of the coronary circulation is to supply cardiac cells with nutrients and remove metabolic products. Coronary vascular transport consists of at

Copyright 0 1992 the American Physiological Society

2209

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2210 TABLE

BRIEF REVIEW

1. Effects of exercise training

on coronary blood floul capacity

Species

Age

Type uf Training

Dog

A

Run

Stone (123)

Dog

A

Run

Barnard et al. (5)

Dog

A

Run

Yipintsoi et al. (138)

Rat

yg

Swim

Carey et al. (19)

Dog

A

Run

Liang et al.

Dog

A

Run

Breisch et al. (16)

Pig

A

Run

Cohen (24)

Dog

A

Run

Penpargkul and Scheuer (96) Spear et al. 1119)

Rat

yg

Swim

150 miniday, 5 days/wk, 10 wk

Cardiac function

Y

Rat

yg

Run

26.8 m/min,

NM

Laughlin et al. (76)

Dog

References

Program Studies

Bove et al. (15)

(82)

reporting

8 mph, 4%, 75 miniday, 5 days/wk, 8wk ?, 75 minIday, 5 days/wk, 8wk ?, 2 h/day, 5 days/wk, 12-18 wk 150 miniday, 5 days/wk, 10 wk 8 mph, lO%, 50 minlday, 5 days/wk, 8wk ?, 90 miniday, 5 days/wk, 12 wk 70-80% max, 6U min /day, 5 days/wk, 12 wk Greyhound compared with mongrels Studies

Schaible and Scheuer (113)

15%,

A

Run

Efficacy of Program

Training

reporting

unchanged

Hypertrophy blood

fluw capacity

Method of Vasodilation in trained

Maximal

Measured

Vasodilation

Parameter

Hemodynamic Control

animals

HR, SMVo,

Y

t Cardiac work

No

CBF

Poor

HR

Y

t Heart rate and RH

NO

CBFV

Good

SMvo,, HR, vo2 nlax NM

Y

Maximal exercise

No

CBF

Adequate

Y

Hypoxia

Questionable

CBF

Poor

HR

N

Ado-iv

Questionable

CBF

Poor

HR

N

Ado-iv

No

CBF

Poor

VO, max, HR

Y

Adoiv during maximal exercise

Questionable

CBF

Poor

NM

Y

Ado-ia

Yes

CBF

Good

t Cardiac work

No

CBF

Good

Y

Hypoxia

Questionable

CBF

Poor

SMVo,

Y

RH

No

CBF

Adequate

HR, cardiac function

Y

t Cardiac work

No

CBF

Good

HR, cardiac function

Y

t Cardiac work

No

CBF

Good

NM

N

Ado-ia

Yes

CBF

Good

NM

N

WR

No

CBF vs. HR

Poor

SMvo,

N

Ado-ia

Yes

CBF

Good

Cardiac function

Y

Ado-ia

Yes

CBF

Good

SMVo,

N

Ado-ia

Yes

CBF

Good

increased

blood

flow

capacity

in trained

animals

60

miniday, 5 days/wk, 18 wk 10-20 km/h, l&20%,

Rat

A

Swim

Rat

A

Run

&heel et al. (114)

Dog

A

Run

Liang and Stone (83) Laughlin

Dog

A

Run

Dog

A

Run

75 miniday, 5 days/wk, lo wk 150 minIday, 5 days/wk, 8 wk 20 m/min, lO%, 150 minfday, 5 days/wk, 8wk 3.6 mph, 25%, 45 min/day, 5 days/wk, 6wk ?, 60 min/day, 5 days/wk, 4wk 6 mph, lo2O%, 75

(74)

Buttrick et al. (18)

Rat

yg

Swim

Laughlin and Tomanek (79)

Dog

A

Run

min’day, 5 days/wk, 12-20 wk 150 min/day, 5 days/wk, 8-10 wk 6 mph, lo-20%,

75

min/day, 5 days/wk, 12-20 wk

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2211

BRIEF REVIEW TABLE

l-continued

Species

Age

Type of Training

Laughlin et al. (78)

Pig

A

Run

DiCarlo et al. (37) Baur et al. (8)

Dog

A

Run

Rat

Yg

Run

References

Training Program Studies

reporting

4-6 mph, 0%, 85 min/day, 5 days/wk, 16-20 wk ?, 5 days/wk, 4 wk 27 m/min, lo%, 60 miniday, 5 days/wk, 16 wk

Efficacy of Program increased

blood

Hypertrophy flow capacity

in trained

Method of Vasodilation animals

Maximal Vasodilation

Measured Parameter

Hemodynamic Control

(continued)

Y

Ado-ia

Yes

CBF

Good

NM

N

Ado-ia

Yes

CBF

Good

NM

N

Hypoxia and dipyridamole

Questionable

CBF

Good

SMVo, HR

,

In many investigations involving rats the age was estimated from the body weight. Training programs are described as intensity (run = speed and grade), duration of training sessions, frequency of training sessions, and duration of training in weeks. Hypertrophy refers to presence of cardiac hypertrophy. A, adult; Yg, young; HR, training bradycardia; SM~O,, skeletal muscle oxidative capacity; vo2 max,whole body maximal 0, consumption; NM, training efficacy was not measured in the study; cardiac function, improved cardiac function was measured in trained groups; Y, hypertrophy present; N, no hypertrophy. RH, reactive hyperemia induced by coronary occlusion; Ado, adenosine infusion; CBF, coronary blood flow; CBFV, coronary blood flow velocity; CBF vs. HR, relationship between CBF and heart rate.

least two steps or processes, convective transport of blood to and through the capillaries and transcapillary exchange between blood and tissue (103). Because of this, Laughlin (73) proposed that it was best to estimate coronary transport capacity with indexes of both processes, blood flow capacity and capillary exchange capacity. Blood flow capacity can best be estimated by measuring blood flow as a function of perfusion pressure during maximal vasodilation (i.e., generating a blood flow vs. perfusion pressure relationship during maximal vasodilation) (78). Capillary exchange capacity can be estimated from measurements of the permeability-surface area product (PS) (112) for various solutes and/or capillary filtration coefficient for water (73, 74, 78, 79). Current information indicates that exercise training of large mammals induces adaptive changes in the coronary circulation that improve the ability of this vascular bed to transport nutrients to and metabolites away from cardiac myocytes. Blood Flow Capacity Studies of the effects of exercise training on coronary blood flow capacity have found either an unchanged blood flow capacity (5, 13, 15, 16, 19, 82, 113, 115, 122, 123, 138) or an increase in coronary blood flow capacity (18,37, 74, 76,78,79,83,113,119). Disagreement among investigations concerning the effects of training on blood flow capacity may be related to the fact that the effects of exercise training on coronary blood flow capacity can be influenced by I) species differences, 2) adequacy and type of exercise training used, 3) the age of the animal at the time exercise training is initiated, and 4) the method used to estimate coronary blood flow capacity. Models of exercise tmining. In this review, an animal is considered endurance exercise trained if repeated bouts of dynamic exercise have resulted in one or more of the following adaptations: increased skeletal muscle oxidative capacity and/or whole body maximal 0, consumption, increased exercise tolerance, training bradycardia, cardiac hypertrophy, increased maximal cardiac output, and/or improved cardiac function (12,28,39,117,129). It

is well known in exercise science that many adaptations induced by exercise training are specific to the type of contractile activity involved in training bouts (12). This is especially true of adaptations within skeletal muscle tissue (12). However, training specificity also exists in training-induced adaptations of the cardiovascular system. For example, the cardiovascular adaptations induced by rhythmic exercise (walking, running, swimming, or cycling) are different from those induced by resistance training or weight lifting. Rhythmic exercise produces a complex form of stress on the heart. During exercise, heart rate, total cardiac work, and myocardial 0, consumption are all increased (110). In addition, the cells of the heart and coronary circulation are exposed to increased levels of norepinephrine, epinephrine, and other neurohumoral agents and to an altered intracellular chemical environment. Chronic exposure to acute bouts of rhythmic exercise stress is known to result in training bradycardia, increased whole body maximal 0, consumption, increased maximal cardiac output, cardiac hypertrophy, increased cardiac stroke volume, increased rates of left ventricular pressure development, and improvements in other indexes of cardiac function (4, 12, 39, 43, 108, 116, 128). In light of these training-induced cardiac adaptations, it is not surprising that the hypothesis that exercise training induces adaptive changes in the coronary circulation was conceived. Because we have chosen to focus on aerobic exercise training, which is believed to ameliorate coronary heart disease in humans, an important concern is whether the animal studies included in our deliberations used training protocols that evoke adaptations similar to those induced by aerobic training in humans. For example, the model of swim training rats in tanks does not mimic human responses (12). Also, weight training does not induce the cardiac adaptations indicated above (57, 65). Even the treadmill-trained rat model does not mimic many of the cardiac adaptations seen in humans and large mammals (77,117). It is important that experimental quality control include measurements of several parameters known to demonstrate training-induced adapta-

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2212

BRIEF REVIEW

tion to assure a training effect has been obtained that is comparable to the classic human response. Table 1 presents 20 studies of the effects of exercise training on coronary blood flow capacity. It can be seen that one-third of these studies did not have an independent measure documenting the efficacy of the training program (NM, efficacy of program). It is surprising that this is such a common weakness among studies of the effects of exercise training on the coronary circulation. Finally, as discussed below (STRUCTURAL CORONARY VASCULAR ADAPTATION), it is well established that coronary structural vascular adaptation in rats is blunted in mature animals. Thus some coronary vascular adaptations induced by exercise training in immature rodents may not reflect the type of coronary vascular adaptation induced in mature humans and other large mammals. Approaches to measurement of coronary blood flow capacity. Several methods have been used to estimate coronary blood flow capacity. Definitive interpretation of the results of several experimental approaches employed to estimate coronary blood flow capacity is difficult because of 1) complex hemodynamic determinants of myocardial 0, consumption and coronary resistance, 2) use of indirect indexes of coronary flow capacity, and 3) nonrigorous definitions of key concepts. For example, some investigators have used intravenous administration of drugs to induce “maximal coronary vasodilation” to estimate coronary blood flow capacity. The interpretation of these experiments is complicated by the systemic effects of intravenous vasodilators, including decreases in arterial pressure and increases in heart rate and contractility. These hemodynamic effects are generally greater in trained subjects than in controls (16,19,82). As a result, coronary blood flows and/or calculated coronary resistances measured under these conditions are not only determined by minimal coronary vascular resistance but by a combination of vascular resistance, coronary perfusion pressure, altered diastolic time for coronary flow, and extravascular compressive resistance (24,58,74,78,79). Procedures utilized to estimate coronary blood flow capacity should include control of key hemodynamic parameters that determine heart work and myocardial metabolic rate (arterial pressure, sympathetic tune to the heart, venous return, circulating catecholamines, arterial 0, content, coronary perfusion pressures, and heart rate) to ensure that measurements are made under comparable conditions in both trained and control animals so that coronary resistance is the major determinant of blood flow. Indirect measures of blood flow capacity that have been used to investigate the effects of training on coronary transport capacity include 1.) measurements of reactive hyperemic blood flow (76), 2) measurements of blood flow during “maximal” exercise (5, 15, 16, 136), and 3) measurements of coronary blood flow as a function of heart rate and diastolic coronary resistance (82). These measurements are only indirect estimates of blood flow capacity rather than definitive indexes of blood flow capacity. As a result, changes in these estimates of blood flow capacity could be due to training-induced alterations in metabolic vascular control mechanisms, neuro-

humoral factors, and/or extravascular cardiac compression or diastolic time intervals. Finally, the phrases “maximal blood flow,” “maximal vasodilation,” and “minimal coronary resistance” are not used in a rigorous or uniform manner by all investigators (58, 78, 79, 114). Precise definition of these phrases and consideration of appropriate methods for assessing coronary blood flow capacity are necessary. The phrase “maximal coronary blood flow” should be used to refer to a specific blood flow value measured during maximal vasodilation at a defined, physiological coronary perfusion pressure (90-120 mmHg). If maximal blood flow is to be estimated, control of perfusion pressure is essential because once maximal vasodilation has been produced, both blood flow and resistance are directly related to coronary arterial pressure (58,67,68). A truly maximal blood flow cannot be determined because the coronary vessels will continue to distend with increasing pressures until the vasculature is damaged by overdistention (78, 79). Therefore, blood flow capacity can best be estimated by measuring blood flow as a function of perfusion pressure, during maximal vasodilation. The mathematical expression describing the relationship between blood flow and perfusion pressure can then be compared between control and trained groups. Even the term maximal vasodilation is misused in the literature. Maximal correctly refers to the maximal response, as that seen at (and beyond) the plateau in a dose-response curve. As such, it is a unique, reproducible value for each vasodilator agent in a given vascular bed. However, this is not what all investigators mean by the term maximal vasodilation. For example, Liang et al. (82) used systemic infusions of adenosine to produce coronary vasodilation in conscious dogs. Maximal vasodilation was defined as dilation sufficient to produce a coronary flow velocity equal to the peak flow velocity measured during a reactive hyperemia after a 10-s occlusion. Warltier et al. (134) have shown that vasodilation induced with several vasodilators produces greater coronary blood flows than flow measured during even the greatest peak reactive hyperemic flow, and it has been reported that even severe myocardial ischemia does not produce maximal coronary vasodilation (17). Therefore, maximal vasodilation was probably not attained in the study of Liang et al. (82). Table 1 presents a summary of published investigations of the effects of exercise training on coronary blood flow capacity. In forming Table 1, the animal models used, the programs employed in training, and the methods used to measure coronary blood flow capacity were critically evaluated. Each study was assessed by evaluating the quality of training and adequacy of coronary blood flow capacity measurements. Examination of studies reporting an unchanged coronary blood flow capacity in trained subjects reveals that only the study of Cohen (24) avoided complications of changes in myocardial 0, consumption and extravascular resistance effects by using intracoronary infusion of vasodilator drugs. Cohen (24) also clearly demonstrated maximal adenosine vasodilation in mongrel dogs and greyhounds but found no difference in coronary blood flow capacity. However, as

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BRIEF REVIEW

pointed out by Cohen, the cardiac hypertrophy of greyhounds is partially determined by genetic factors and partially related to the animal’s level of physical activity. As a result, it is tenuous to relate these observations to what may happen with exercise training in other mammals. It has been reported that during submaximal exercise, coronary blood flow is less in exercise-trained dogs than in untrained dogs and that during exercise at maximal intensities coronary blood flow is greater than or equal to that seen in untrained dogs (5, 82, 123). Similarly, Breisch et al. (16) reported that transmural coronary blood flow during exercise at intensities producing maximal heart rates was not significantly different in trained and untrained pigs and that transmural coronary blood flows were similar in trained and control pigs during systemic infusion of adenosine during exercise at this intensity. It is difficult to definitively interpret the results of these conscious animal experiments because critical hemodynamic factors were not adequately controlled. As a result, coronary blood flows may have been influenced, at least in part, by factors other than coronary resistance (58, 67, 68, 78, 79, 100, 115). DiCarlo et al. (37) avoided complications of changes in myocardial 0, consumption and extravascular resistance effects and minimized changes in mean arterial pressure by using intracoronary infusion of vasodilator drugs in conscious dogs. DiCarlo et al. also used dose-response curves to establish maximal vasodilation with adenosine and ,&adrenergic agonists. Thus their estimates of coronary blood flow capacity are excellent (Table 1). Maximal vasodilation with adenosine and P-adrenergic agonists caused greater vasodilation in dogs that had been exercise trained for 4 wk than in sedentary dogs. These results indicate that coronary blood flow capacity is increased in exercise-trained dogs. It is possible, however, that the effects of a 4-wk training program are not the same as those from more prolonged training programs. Among the studies finding increased coronary blood flow capacity, the studies of Buttrick et al. (US), Scheel et al. (ll4), and DiCarlo et, al. (37) clearly established maximal vasodilation and conducted the measurements under comparable hemodynamic conditions in control and trained subjects. Also, Laughlin and colleagues have reported that exercise-trained dogs (74, 79) and miniature swine (78) have an increased coronary transport capacity in that both blood flow capacity and capillary diffusion capacity were observed to be greater in exercisetrained animals compared with sedentary controls. In these studies (74,78,79), the determinants of myocardial 0, demand, diastolic time, and extravascular resistance were comparable in trained and sedentary animals. As a result, it is likely that the greater blood flow measured in coronary vascular beds of exercise-trained animals was the result of lower minimal coronary vascular resistance. In conclusion, a review of available data indicates that the results of the more rigorously controlled studies of exercise training have consistently found greater coronary blood flow capacity in exercise-trained subjects. As summarized in Table 1, these studies were judged to be better on the basis of the following characteristics: 1) adequate training programs were employed and exercise

2213

training was established by independent measures of training effectiveness, 2) maximal vasodilat5on was clearly established, 3) direct measurements of blood flow capacity were obtained, and 4) hemodynamic factors were comparable in sedentary control and exercisetrained animals during flow capacity measurements. Evaluation of current studies in the literature with these criteria supports the conclusion that exercise training induces an increase in coronary blood flow capacity. Capillary Diffusion Capacity

There have been only four investigations that measured an index of functional capillary diffusion capacity in exercise-trained subjects (74,75,78,79). The results of these studies indicate that the capillary PS product for EDTA, measured during maximal vasodilation with adenosine, is greater in the hearts of exercise-trained dogs (74,79) and miniature swine (78). These results are consistent with the report of Barnard et al. (6) that exercise training results in increases in potential 0, supply and improves the supply-demand balance at any given cardiac work load. An increase in capillary diffusion capacity could result from an increase in capillary permeability and/or increased capillary surface area available for exchange. Capillary surface area available for exchange could be increased due to capillary proliferation, i.e., angiogenesis, which is discussed in detail in STRUCTURALCORONARYVASCULARADAPTATION.

A training-induced increase in functional capillary surface area available for exchange does not require angiogenic increases in capillary density (no. of capillaries/ mm2 of myocardium) or other anatomically measurable changes in the capillary bed. For example, if the control of the microvascular bed is altered by exercise training so that the distribution of blood flow through the perfused exchange vessels is more closely matched to each capillary’s exchange capacity (PS), capillary exchange would be improved and measurements of PS would be increased without a change in the total amount of capillary surface area per gram of myocardium (79). Also, it has been demonstrated that capillary diffusion capacity in-

creases as a function of flow in a maximally vasodilated coronary bed. This phenomenon appears to be due to flow-related increases in hydrostatic pressure in the microcirculation, causing recruitment of more capillaries and/or microvascular exchange area (79,106). If this notion is correct, it is possible that exercise training alters the distribution of resistance in the coronary vascular bed so that at any given coronary perfusion pressure the microvascular pressure is higher. It is also possible that the response of the coronary microvasculature to adenosine and other vasoactive agents is altered by training so that at a given coronary perfusion pressure, higher microvascular pressures exist, resulting in more capillary exchange area exposed to blood. Finally, because PS is generally a function of flow, it is also possible that, PS is higher after exercise training simply because flow is higher. We recently concluded that the most reasonable explanation for the increased maximal PS in the trained heart is a change in the distribution of blood flow in the

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2214

BRIEF REVIEW

capillary bed, resulting

in a better match of capillary PS and capillary blood flow and/or more effective recruitment of functioning microvascular (capillary) surface area in the coronary circulation (78,79). The hypothesis that exercise training induces alterations in the control of coronary blood flow and its distribution through the microvascular exchange areas is discussed in detail below. In conclusion, one of the cardiovascular adaptations induced by exercise training is an increase in coronary vascular transport capacity. The increase in transport capacity of the coronary circulation involves increases in both coronary blood flow capacity and coronary capillary diffusion capacity. Potential mechanisms for traininginduced coronary vascular adaptations deserve detailed consideration. Mechanisms for vascular adaptation induced by prolonged increases in metabolic rate in striated muscle tissue can be grouped into two major categories, structural adaptations and adaptations in the control of vascular resistance. Structural vascular adaptations generally involve growth of vessels, such as increased length and/or diameters of existing vessels, as well as increases in the number of vessels per unit myocardium (i.e., angiogenesis). Adaptive changes in vascular control can be the result of altered neurohumoral control of the vascular bed and/or altered local vascular control. There is evidence that exercise training modifies metabolic control, myogenic responses, and produces intrinsic changes in vascular smooth muscle cells and/or endothelial cells. STRUCTURAL

CORONARY

VASCULAR

ADAPTATION

The concept that exercise training results in increases in coronary vessel size and/or numbers has been popular since the corrosion-cast studies of Tepperman and Pearlman (125) in 1961. Tepperman and Pearlman filled the coronary vasculature of exercise-trained and sedentary control rats with a casting material. After the casting material had cured, the myocardium was digested away and the weight of the coronary vascular cast was determined. They found that the amount of coronary vascularization, as represented by coronary cast weight relative to heart weight, was greater in exercise-trained animals. Several other studies of exercise-trained rodents report similar results (57,122). The casting material used in these studies generally provides a measure of the total amount of precapillary vasculature but does not, provide information about where in the coronary arterial vascular bed changes have occurred (62, 126). These techniques have rarely been used to study coronary vascular adaptation in exercise-training studies using large mammals. Studies that have used histological methods and/or in vivo imaging techniques to examine the effects of exercise training on coronary vascular structure are summarized in Table 2. Examination of these results reveals that among the studies of small mammals, experiments that have used swim training have generally reported increases in coronary vascularization and cardiac hypertrophy. The results from treadmill training are not as definitive (Table 2). Available information, in general, supports the notion that exercise training induces struc-

tural vascular adaptation lar tree (Table 2).

throughout

the coronary vascu-

Proximul Coronary Arteries

Histological measurements of coronary artery diameters have demonstrated that exercise training induces enlargement of proximal coronary arteries of rats (54,55, 80, 122, 125), monkeys (70), and humans (31). Angiographic measures of proximal coronary artery size in dogs also indicate that exercise training results in enlargement of coronary arteries (14, 137). In addition, echocardiographic estimates indicate that human athletes have enlarged coronary arteries (95). Training-induced enlargement in proximal coronary arteries appears to regress if subjects cease exercise training (80, 137). It appears that the normal relationship between left ventricular mass and coronary artery size (91) is maintained in exercise-trained humans (95). However, Bove and Dewey (14) reported that when coronary artery cross-sectional area was expressed per gram of myocardium perfused by the artery, trained dogs had larger cross-sectional area-to-myocardial mass ratios than sedentary control dogs. Such a net increase in relative size of proximal coronary arteries may contribute to the increased coronary blood flow capacity and decreased minimal coronary resistance present in exercise-trained animals. Coronary Collateral Vessels Eckstein (41) first reported that exercise training of dogs in which coronary stenosis was surgically induced led to increases in the rate of growth of coronary collaterals. Several other investigations, employing different models of coronary disease, have also found that exercise training increases the rate of coronary collateral development. For example, Cohen et al. (26) and Bloor et al. (11) reported training-induced enhancement of coronary collaterals in dogs and pigs, respectively, with a fixed coronary stenosis. Heaton et al. (56), Neil1 and Oxendine (go), and Scheel et al. (114) reported that training enhanced the development of collaterals in hearts of dogs with progressive coronary occlusions (ameroid constrictors). Roth et al. (107) reported that initiating exercise training after gradual coronary occlusion had been completed (ameroid constrictor) also resulted in an increase in collateral blood flow. In contrast, exercise training appears to have no effect on coronary collateral growth in normal coronary vascular beds. Exercise training has been found to have no effect on collateral circulation of normal coronary vascular beds in dogs (25,26,114), pigs (111,135), and rats (69). Thus available data clearly indicate that exercise training enhances the development of coronary collateral circulation in hearts with stenosed and/or occluded coronary arteries but does not appear to have an effect on the coronary collateral circulation in animals with normal coronary arteries. Small Coronary Arteries and Arterioles

Most coronary vascular resistance is considered to reside in the small arteries and arterioles of the microcirculation. Breisch et al. (16) and White et al. (136) have reported that exercise training of miniature swine and

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TABLE

2. Investigations

Reference Leon and Bloor m-0 Tomanek (131)

Wyatt and Mitchell (137) Carlsson et al. (20) Wachtlova et al. (133) Kramsch et al. (70) Tharp and Wagner

of exercise training-induced

Species

Age

Type of Training

Rat

yg

Swim

5

60 miniday

10 wk

NM

Yes

Perfusion

Rat

yg yg

Swim Run

2 6

10 wk 12 wk

NM HR

No No

Perfusion fixation Ink perfusion (Pelikan ink)

0

Run

6

60 min/day 1.0-1.5 mph, 8% grade, 40-50 miniday

12 wk

HR

No

A

Run

6

12 wk

HR

No

A

Run

5

12 wk

HR

Dog

Frequency, days/wk

structural vascular adaptation

Rat

yg

Swim

6

Rabbit

A

Run

Monkey

A

Run

3

Rat

yg

Run

3-5

A

Run

Pig

A

Rat

Spontaneous

Session Duration and Intensity

4-8 mph, 1 h/day

lo%,

1 h/day Wild

vs. caged

Pelliccia et al. (95)

In many acid-Schiff;

Human

investigations CSA, coronary

Efficacy Training

of

Cardiac Hypertrophy

Proximal Arteries

Technique fixation

Arterioles

Angiographic histological

and

Capillaries

f CSA

f C/F

-

f C/F t C/F t CND

CSA

s120

Yes performance

t CSA

f C/F CND t C/F+-+ CND - CND

2 wk

NM

?

[3H]thymidine

t Labeling

?

N/A

Yes

PAS

t CND

Yes

Angiographic and histological Ink perfusion (Pelikan ink)

2-3.5 km/h, 1 h/day 18.8-26.8 m/min

42 mo

HR

8 wk

Body

5

lo-20 km/min, lo-20% grade, 75 min/day

Run

5

yg

Run

5

yg

Run

5

A

Run

Mixed

60 miniday, 70-85% max 60 min/day, 13.4 m/min, 7.5% grade 90 m/day, 26.8 m/min, 15% grade Human athletes

involving artery

rats the age was estimated from the body cross-sectional area; C/F, capillary-to-fiber

(126)

Laughlin and Tomanek (7% Breisch et al. (16) Anversa et al. (2)

Training Duration

stain

t CSA

weight

Yes

18 wk

SMVo,, performance, HR

No

Perfusion

fixation

12 wk

f vo

Yes

Perfusion

fixation

7wk

NM

No t RVW

Perfusion

fixation

- CND - C/F t CND

7wk

NM

Yes

Perfusion

fixation

f CND

Performance

Yes

Echocardiographic

Years

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weight. Efficacy of training programs as reported ratio; CND, capillary numerical density; AND,

in the publications arteriolar numerical

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old; PAS, periodic

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BRIEF REVIEW

domestic pigs causes increases in morphometrically determined arteriolar numerical densities. Coronary arterioles were defined as vessels with at least three layers of vascular smooth muscle and with diameters >35 pm and 4% pm. Coronary arteriolar density of the trained pigs was 40% greater than in control pigs (16). Arteriolar length density was also increased by 40% in trained pigs. To predict the impact of these changes in the size and number of coronary resistance vessels on total and regional coronary blood flow and coronary blood flow capacity is difficult. However, these data indicate that exercise training may induce changes in vascular control vessels of the coronary microcirculation. These and similar changes in other microvascular control vessels could have important functional significance on control of coronary blood flow and capillary exchange. Coronary Capillary (and/or Microvascular Exchange) Vessels

There have been a number of studies that have measured the number of coronary capillaries per mass of myocardium. The large amount of interest may be due to the fact that the idea of a training-induced increase in capillarization is attractive in that such a change could contribute to increases in both blood flow capacity and capillary exchange capacity. There are many reports in the literature presenting capillary density (no. of capillaries/mm2 of tissue) and other morphometric indexes of myocardial capillarization in exercise-trained animals (2, 62, 115, 127). Many of these studies were conducted on swim-trained or treadmill-trained rats (Table 2). The results of these rat studies indicate that training results in either increases in capillarization or maintenance of normal levels of capillarization. Although it is clear that exercise training can produce increases in myocardial capillarization (2,62,1X5,127), it appears that this phenomenon can be best demonstrated in young animals. Two studies that compared the effects of treadmill exercise on coronary capillary density in young (prepubescent) and old (postpubescent) rats found that capillary density only increased significantly when training commenced at an early age (66, 131). Most investigators have failed to find increased capillarization with exercise training when training was commenced with adult animals (16,79). Exercise-trained mature dogs have generally been found to have normal numbers of capillaries per mass of myocardium (79, 137). Also, Breisch et al. (16) and White et al. (136) have recently demonstrated that exercise training of adult miniature swine and domestic swine, respectively, does not produce increases in myocardial capillarization. Because exercise training often produces moderate levels of cardiac hypertrophy, it appears that, even in adults, training produces angiogenesis of new capillaries at a rate matched to cardiac hypertrophy. If this were not so, capillarization would decrease with the development of hypertrophy (2,79). Thus currently available information indicates that some rat models of exercise training (swim) may be associated with increases in the amount of capillary surface area per gram of myocardium. However, it appears that results from studies of capillarization in exercise-trained dogs and pigs that were mature

at the commencement of training are at odds with the notion that training-induced increases in capillary exchange capacity are due to increased capillarization. Small Coronary Veins and Venules

There appears to be no information training on these coronary vessels.

on the effects of

Interaction of Exercise Training-Induced Structural Vascular Adaptation in the Coronary Circulation and Other Types of Cardiac Hypertrophy

The data summarized in Table 2 clearly indicate that training-induced cardiac hypertrophy is not associated with a decrease in the relative amount of capillaries per gram of myocardium (capillary density). Thus capillary density and capillary-to-fiber ratios are consistently unchanged or increased in the hearts of trained animals. This indicates that angiogenesis of new capillaries is matched to the increase in cardiac mass in training-induced cardiac hypertrophy. This is not true in all forms of cardiac hypertrophy (22). For example, cardiac hypertrophy induced by hypertension or cardiac valvular lesions is generally associated with decreases in coronary blood flow capacity and capillary density (18,22,30,101, 132). Thyroxine-induced cardiac hypertrophy appears to be similar to training-induced hypertrophy in that the growth of the coronary vascular system is matched to the increased myocardial mass (22, 23). It is interesting that the decrement in capillary density, a characteristic of hypertension-induced cardiac hypertrophy, is prevented by exercise t’raining of young (6 wk of age) rats (30) but not by the exercise training of adult rats with established cardiac hypertrophy (101, 132). ADAPTATIONS CONTROL

OF CORONARY MECHANISMS

VASCULAR

Support for the notion that exercise training induces alterations in coronary vascular control exists in at least three forms. First, there is considerable evidence that systemic cardiovascular control systems are altered by exercise training. It is reasonable to expect that altered control of the coronary vascular bed would be one component of altered cardiovascular control. Second, a number of investigations have directly examined vascular control mechanisms in coronary circulations of trained animals. Finally, there are a number of studies that have applied a variety of in vitro techniques to examine vascular control mechanisms in the coronary circulation. Systemic Cardiovascular Regulatory Systems

Space does not allow a detailed review of the effects of endurance exercise training on systemic cardiovascular regulatory systems. The reader is referred to several excellent reviews on these topics (102, 108, 117, 118, 130). DiBello et al. (33) have reported that during recovery from bouts of exercise total peripheral resistance is less in trained subjects. These altered responses may be related to the frequently reported training-induced attenuation in arterial baroreflex function. For example, Bed-

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BRIEF REVIEW

ford and Tipton (9) reported an attenuation of the arterial baroreflexes in trained rats. DiCarlo and Bishop (3436) also reported attenuated baroreflex function and modified reflex responses to activation of cardiac vagal afferents in exercise-trained rabbits. Gwirtz et al. (49) reported similar alterations in arterial baroreflex control in exercise-trained dogs. In addition, it has been reported that plasma catecholamine concentrations are lower in exercise-trained humans (27, 29, 53) and dogs (14) and that exercise training can alter adrenergic receptor numbers and/or receptor-second messenger coupling in cardiovascular tissues (117). Training-induced alterations of coronary vascular control mechanisms may be one component of these well-established alterations in cardiovascular control mechanisms. However, limited evidence exists to support this hypothesis. Akurohumord

Control

Gwirtz and Stone (50) and Liang and Stone (83) reported that exercise training alters neural control of the coronary circulation. Also, Bove and Dewey (14) reported diminished phenylephrine-induced vasoconstrictor responses of proximal coronary arteries in intact anesthetized exercise-trained dogs. The vasodilator response of the intact coronary circulation of anesthetized exercise-trained dogs to a-adrenergic blockade with prazosin was reported to be enhanced compared with control dogs (74). DiCarlo et al. (37) reported that exercise training for 4 wk resulted in enhanced coronary resistance vessel sensitivity to both a- and P-adrenergic agents and to adenosine. Finally, Laughlin and Tomanek (79) reported that blockade of cu-adrenergic receptors produced a larger increase in coronary plasma flow in exercisetrained pigs than in controls and that adenosine produced greater coronary vasodilation in exercise-trained pigs. Integration of the results of these studies (14,37,50, 79, 83) supports the notion that exercise training alters neurohumoral control of the coronary circulation. However, these studies shed little light on mechanisms for these changes and what impact they may have on coronary function in vivo. It has been established that exercise training alters cardiac function and neurohumoral influences on the heart. As a result, whether changes observed in experiments conducted on intact coronary vascular beds are the result of alterations in neural, humoral, or metabolic influences on the heart or the result of primary alterations in the control of coronary vascular resistance is difficult to determine. If exercise training alters the control of the coronary circulation, the changes could be the result of altered central control mechanisms, local control mechanisms, or both. Local Coronary Vascular Control

Local vascular control phenomena are regulatory responses that can be demonstrated in isolated perfused tissues that are removed from all neural or humoral influences. Examples of these phenomena in the coronary circulation include reactive hyperemia (the increase in blood flow above resting levels that is observed after a coronary occlusion), autoregulation of coronary blood flow (the tendency to maintain blood flow constant de-

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spite altered perfusion pressures), and active hyperemia (the increase in blood flow induced by increased metabolic activity). Local vascular control is paramount in the coronary circulation (44). Thus the coronary vascular bed demonstrates exquisite autoregulation of blood flow and reactive hyperemic responses. The consistent relationship between myocardial 0, consumption and coronary blood flow is central to understanding coronary physiology and function. Because local vascular control is the primary control system in the coronary circulation, it is likely that any training-induced change in control of the coronary vascular bed will include alterations in local control. Three popular theories for local control of coronary blood flow are metabolic control, myogenic control, and flow-induced vasodilation. A4etabolic control mechanisms. The metabolic theory of blood flow control holds that metabolic processes release one or more vasoactive metabolites in proportion to metabolic rate. As a result, any increase in metabolic rate will release more metabolites, causing vasodilation and increased blood flow, whereas decreases in metabolic rate will release less metabolites, resulting in vasoconstriction and decreased blood flow. Two observations suggest that metabolic control of the coronary vascular bed is altered by exercise training: 1) the relationship between heart rate (during atria1 pacing) and coronary blood flow is shifted to the left (higher flow) in exercise-trained dogs (123), and 2) diastolic coronary resistance is lower at any given heart rate in exercise-trained dogs (83). Also consistent with the hypothesis that exercise training alters local metabolic control of coronary blood flow, reactive hyperemic responses produced by a 10-s coronary occlusion have been shown to be augmented in exercisetrained dogs compared with control dogs (76). Spear et al. (119) have reported an increased sensitivity to hypoxia in the coronary circulation of exercise-trained rats, further evidence that local metabolic control phenomena are altered in the coronary circulation of exercise-trained animals. However, the effects of insufficient 0, supply on coronary blood flow may not be altered by exercise training, since Yipintsoi et al. (138) found no differences between myocardial blood flow responses to acute hypoxia and volume loading in exercise-trained rats compared with sedentary controls. If metabolic vascular control is altered by exercise training, this could be the result of alterations in the relationship between metabolic rate and the release of vasoactive metabolites or of alterations in the response of coronary resistance vessels to vasoactive metabolites. Although it does not appear that exercise training alters cardiac metabolic enzyme systems (77), there is evidence that exercise training alters the vasodilator sensitivity of the coronary circulation to adenosine, one metabolite believed to be important in local control of the coronary circulation (44). Laughlin and co-workers (74, 79) reported an increased sensitivity to adenosine in the coronary vascular beds of exercise-trained dogs. DiCarlo et al. (37) reported similar results from experiments in conscious exercise-trained dogs. Also, Laughlin et al. (78) reported that adenosine produced greater coronary blood flow in exercise-trained miniature swine than in sedentary control swine. Finally, as discussed below, Olt-

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BRIEF REVIEW

man et al. (93) have reported that segments of coronary artery isolated from exercise-trained pigs are more sensitive to adenosine than are vessel rings from sedentary control pigs. These in vivo and in vitro observations support the hypothesis that exercise training changes the sensitivity of coronary resistance vessels to vasoactive metabolites. Myogenic corztrol mechanisms. The myogenic control theory states that local vascular responses are the result of the response of vascular smooth muscle to mechanical stimuli imparted to the blood vessels. Although the hypothesis that exercise training alters myogenic vascular control in the coronary circulation has not been directly tested, the fact that; exercise-trained dogs have altered reactive hyperemic responses is consistent with this hypothesis (76). On the other hand, Laughlin and coworkers reported normal autoregulation of coronary blood flow in exercise-trained dogs (74, 79) and miniature swine (78). Thus there is no definitive evidence indicating that training alters myogenic control of the coronary circulation. Fbw-induced uasodilation. Dilation observed in arteries that appears to be the direct result of increases in blood flow is called flow-induced vasodilation. Flow-induced vasodilation has been demonstrated in both coronary (59,72) and femoral (64,98) arteries and is believed to be caused by a local (within the blood vessel wall) mechanism. Most evidence indicates that flow-induced vasodilation is dependent on the presence of a normal endothelium in the artery (64, 72,98, 109). Kuo et al. (71) recently demonstrated flow-induced vasodilation in isolated coronary resistance vessels. Flowinduced vasodilation has not been studied in coronary arteries or arterioles of exercise-trained animals. However, the reports of enhanced sensitivity to vasodilator agents (37,74,78,79) could be explained with this theory. If exercise training produced an enhancement of flow-induced vasodilation in the coronary microcirculation, then this would be expected to work synergistically with a vasodilator, like adenosine, so that with a given dose of adenosine, a greater amount of vasodilation would be produced. The hypothesis that exercise training alters flow-induced vasodilation in the coronary circulation remains to be tested. Contractile Behavior of Isolated Coronary Arteries

Control of coronary blood flow and its distribution is accomplished via modulation of total and regional vascular resistances. Vascular resistance is determined by the level of contractile activity in arterial vascular smooth muscle in the coronary arteries. Oltman et al. (93) recently investigated the contractile behavior of epicardial coronary arteries isolated from exercise-trained miniature swine. Intrinsic contractile responses of coronary arteries were evaluated in vitro using rings of left circumflex coronary arteries. The results indicated that lengthdependent passive and active tension of proximal coronary arteries was not altered by exercise training. Concentration-response relationships for isometric contractions evoked with KCl, prostaglandin Fza, acetylcholine, and endothelin were similar in arteries from seden-

tary and exercise-trained pigs. In contrast, arteries from trained pigs developed 47% less maximal tension in response to norepinephrine. Concentration-response vasodilator responses evoked by isoproterenol and forskolin were similar in arteries from sedentary and exercisetrained pigs. However, arteries from exercise-trained animals were more sensitive to the vasodilator actions of sodium nitroprusside and adenosine. The alterat

Exercise training-induced coronary vascular adaptation.

Aerobic exercise training induces an increase in coronary vascular transport capacity. This increased transport capacity is the result of increases in...
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