Br. J. clin. Pharmac. (1992), 33, 333-336
Role of vagal activity in the cardiovascular responses to phenylephrine in man MITCHELL A. H. LEVINE* & FRANS H. H. LEENEN Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
The effects of phenylephrine on blood pressure (BP), left ventricular function and total peripheral resistance (TPR) were evaluated in six normotensive male volunteers before and after vagal blockade with atropine. Before atropine, phenylephrine dose-related increased TPR, systolic and diastolic BP and decreased cardiac output by decreases in both stroke volume and heart rate. Post-atropine, the BP (but not TPR) responses to phenylephrine were markedly potentiated, related to an increase in stroke volume despite the higher afterload. Thus vagal tone may regulate cardiac output via effects on both heart rate and venous return. Keywords otl-adrenoceptor stimulation blood pressure LV function vagal tone
Introduction
The aol-adrenoceptor agonist phenylephrine causes arterial constriction, increasing systolic and diastolic blood pressure (BP). The mechanisms by which cardiac output are altered by phenylephrine are less clear because of the numerous factors involved, including changes in preload and afterload, inotropic and chronotopic responses to changes in autonomic tone and direct stimulation of a,-receptors in ventricular myocardium (Bruckner et al., 1984; Smyth et al., 1969; Woodman & Vatner, 1986). Although the effects of atropine on the phenylephrine-induced decrease in heart rate have been well documented, the role of changes in vagal tone in the effects of phenylephrine on left ventricular performance and peripheral resistance has not been assessed in man. We therefore investigated the cardiovascular effects of phenylephrine before and after vagal blockade with atropine.
Methods
Subjects Six healthy male volunteers 23 ± 0.4 years old and weighing 70 ± 3 kg participated in the study. Subjects were not on any medications, and were instructed to refrain from alcohol and caffeine ingestion 24 h prior to study. All subjects were non-smokers. Written informed consent was provided by all subjects.
Experimental protocol The study was performed as a single-blind trial, with each subject receiving a phenylephrine infusion before and after the administration of intravenous atropine. On the study day, after a 12 h overnight fast, a standardized liquid breakfast was given. An indwelling venous catheter was inserted in a forearm and was kept patent with heparin (5,000 iu 30 ml-1). Subjects remained supine from the period following breakfast until completion of the study day. After a supine rest period of 60 min, phenylephrine HCI was administered at incremental rates (each for 5 min), 0.42, 0.82, 1.10 and 1.60 ,ug kg-' min-'. At 90, 120 and 150 min, atropine sulphate was administered in a sequence of intravenous dosages (0.02, 0.01 and 0.01 mg kg-'). Following the third dose of atropine, the phenylephrine infusion was repeated, this time at rates of 0. 11, 0.21 and 0.42 ,ug kg-' min-'. For safety reasons, increases in systolic or diastolic BP were limited to 30 mmHg above the initial baseline values (i.e. before the first phenylephrine infusion). Heart rate and BP were monitored every 2 min prior to the administration of phenylephrine and at 3, 4 and 5 min at each rate of phenylephrine. The means of these values during each period were used for statistical analysis. Heart rate was derived from the electrocardiogram recorded by a Hewlett-Packard 78351A monitor and BP was measured automatically using a Roche Arteriosonde 1225 (Hunyor et al., 1978) on the arm opposite the venous catheter.
*Present address: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
Correspondence: Dr Frans H. H. Leenen, Hypertension Unit, University of Ottawa Heart Institute, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9
333
334
M. A. H. Levine & F. H. H. Leenen
Left ventricular (LV) echocardiograms were obtained with the subjects in the supine position, turned 30 degrees on their left side, using a Toshiba Sonolayer SSH-60A echo machine with a 3.75 MHz transducer in conjunction with a Toshiba Line scan recorder LSR20B. M-mode echocardiograms were obtained under 2-D guidance and tracings were recorded at a paper speed of 50 mm s-1. Measurements were made to the nearest millimetre for at least four cardiac cycles during quiet respiration and the means used for analysis. All echocardiograms in a patient were obtained by the same research assistant with the patient in the same position, in the same intercostal area and in the same LV area, just below the tip of the mitral leaflets. Measurements were made by the same observer and were obtained according to the guidelines of the American Society of Echocardiography (Sahn et al., 1978). LV echocardiograms were obtained at baseline and at the end of each infusion rate of phenylephrine. The following parameters were measured or calculated in a blinded manner: LV end-diastolic and LV endsystolic dimension and volume; cardiac output; stroke volume; ejection fraction; LV end-systolic stress and total peripheral resistance (TPR).
25 20
I
E E
15 10
0-
CO
cl)
251 20
'a E E
15
10
-
m
5
Analysis of data
0
Cardiovascular parameters for different drug exposure states were compared by analysis of variance. Pulse interval and systolic blood pressure response to phenylephrine were evaluated by linear regression analysis. Data are presented as mean ± s.e. mean.
5
-1
0.1
1
10
Phenyleph'rine (,ug kg -' min -' ) Figure 1 Log-dose response curves for changes in systolic and diastolic blood pressure, pre-atropine (0) and post-
atropine (A). Plotted points represent mean ± s.e. mean for individual phenylephrine dosages (0.11, 0.21, 0.42, 0.82, 1.1, and 1.6 ,ug kg-' min-'). Results
BP and heart rate response to phenylephrine
Phenylephrine induced the expected dose related increases in systolic BP and R-R interval. The regression lines of R-R interval to systolic BP for the phenylephrine infusion showed a pre-atropine slope of 9.85 ± 2.12 ms/mmHg and a post-atropine slope of 2.44 ± 0.03 ms/mmHg (P < 0.001 for difference in slope). The phenylephrine dose-response curves for systolic and diastolic BP were shifted to the left after atropine (Figure 1). Cardiovascular response to phenylephrine 0.42 pLg kg-' min-, pre- vs post-atropine: The systolic and diastolic BP responses to phenylephrine 0.42 ,u g kg-1 min-' were significantly (P < 0.01) greater post-atropine than pre-atropine (Table 1). In contrast, the increase in TPR was not larger post- vs pre-atropine, but the decline in cardiac output (CO) greater (P < 0.05) pre-atropine than post-atropine. The two components of CO stroke volume and heart rate responded differently. Whereas heart rate was decreased by phenylephrine both pre- and postatropine, stroke volume declined pre-atropine and was increased post-atropine (P < 0.05, pre vs post) by -
phenylephrine, explaining the different responses of CO. LV emptying, as assessed by ejection fraction decreased pre- and post-atropine by 2-3%. Indicators of preload and afterload - LV end-diastolic volume and end-systolic stress - both increased with this dose of phenylephrine post-atropine (P < 0.05, pre vs post) but not pre-atropine.
Cardiovascular responses to atropine Atropine markedly increased heart rate. Since stroke volume showed only a minor (NS) fall, cardiac output increased markedly as well. This increase in cardiac output was associated with modest increases in systolic and diastolic BP, whereas calculated TPR decreased (Table 1). All these changes were already present after the first dose of atropine (data not shown).
Discussion The a1l-adrenoceptor agonist phenylephrine increases TPR via arteriolar vasoconstriction and may increase LV filling via effects on venous tone (Woodman & Vatner, 1986). A positive inotropic effect also may occur (Bruckner et al., 1984; Curiel et al., 1989).
Short report
335
Table 1 Cardiovascular parameters at baseline, changes from baseline with phenylephrine (0.42 ,ug kg-' min-1), baseline after atropine, and changes with phenylephrine after atropine which reflect additional changes beyond the effects of atropine alone
Systolic BP (mmHg) Diastolic BP
Baseline after atropine
Baseline
Changes by phenylephrine
109 ± 2
4±1
67 ± 2
4± 1
77 ± 4**
52 ± 3
-5 ± 3
90 ± 3**
-4 ± 1
89 ± 7
Changes by phenylephrine after atropine 17 ± 2b
115 ± 3*
17 ± 4b
(mmHg) Heart rate
(beats min-') 97 ± 9 Stroke volume (ml) 5.0 ± 0.5 Cardiac output (1 min-1) Total peripheral 32 ± 2 resistance (units) LV end diastolic volume (ml) End systolic stress (g cm-2)
137 ± 14
-0.6 ± 0.2
-10 ± 2 9 ± 3a
-7.9 ± 0.5** -0.1 ± 0.3a
7±3
22 ± 2*
4± 1
-2 ± 3
133 ± 11
16 ± 4a
55 ± 3
15 ± 3a
51 ± 4
2±2
Data represent mean ± s.e. mean (n = 6) * P < 0.05, ** P < 0.01 for comparison of the two baselines ap < 0.05, bp < 0.01 for comparison of the phenylephrine effects.
However, with an intact autonomic nervous system the effect of these haemodynamic effects on BP will be blunted via a baroreflex-mediated increase in vagal tone and decrease in sympathetic activity. Moreover, the associated increase in afterload may decrease LV
emptying. In the present study, phenylephrine alone indeed induced the expected dose-related increase in TPR, and in BP. However, the increase in BP was clearly blunted by the fall in cardi'ac output, since after atropine there is a substantial potentiation of the BP response to phenylephrine, with no potentiation of the TPR response but also no decrease in cardiac output. The differential response of cardiac output does not appear to be due to differences in afterload, since end-systolic wall-stress - if anything - increased more post- vs preatropine. Any positive inotropic effect of the a1l-adrenoceptor agonist would have decreased at the higher heart rates after atropine (Curiel et al., 1989). The major difference thus appears to be related to the vagal blockade. The increase in R-R interval which accompanied the rise in BP with phenylephrine alone was markedly blunted following atropine, confirming the adequacy of the vagal blockade (Smyth et al., 1969). However, after atropine phenylephrine still decreased absolute heart rate, suggesting that this component relates to the reflex withdrawal of sympathetic tone, which is not affected by atropine. Cardiac output was therefore maintained after atropine because of modest increases in stroke volume with percentage-wise less decrease in heart rate. Vagal blockade may do this via two mechanisms. First there is some evidence for a negative inotropic effect arising from
an increase in vagal tone (De Geest et al., 1975; Higgins et al., 1973), although cholinergic innervation of ventricular myocardium is limited (Kent et al., 1974). Atropine may have prevented this effect. Moreover, the increase in heart rate per se may have some inotropic effect (Mahler et al., 1974). Secondly, atropine alone markedly increased heart rate but did not decrease LV end-diastolic volume and stroke volume indicating that venous return increased commensurate with the increase in heart rate resulting in the marked increase in cardiac output. These results would suggest that vagal tone is involved in regulating not only heart rate, but also in venous return (presumably via venous effects), the effects in concert increasing or decreasing cardiac output. It is thus possible that after atropine the venoconstriction induced by phenylephrine is not masked by the reflex increase in vagal tone and results in maintenance/increase of stroke volume. In summary, the present study shows that in man the reflex increase in vagal tone markedly blunts the increase in BP expected from the vasoconstriction caused by phenylephrine. Vagal tone may regulate cardiac output via effects on both heart rate and venous return.
This research was supported by an operating grant from the Heart and Stroke Foundation of Ontario. MAHL was supported by a Pfizer Fellowship in Clinical Pharmacology from the Canadian Society for Clinical Pharmacology. FHHL is career Investigator of the Heart and Stroke Foundation of Ontario. We thank Ms F. Browning and Ms K. Gaebel for their assistance.
336
M. A. H. Levine & F. H. H. Leenen
References Bruckner, R., Meyer, W., Mugge, A., Schmitz, W. & Scholz, H. (1984). Alpha-adrenoceptor-mediated positive inotropic effect of phenylephrine in isolated human ventricular myocardium. Eur. J. Pharmac., 99, 345-347. Curiel, R., Perez-Gonzalez, J., Brito, N., Zerpa, R., Tellez, D., Cabrera, J., Curiel, C. & Cubeddu, L. (1989). Positive inotropic effects mediated by a1 adrenoceptors in intact human subjects. J. cardiovasc. Pharmac., 14, 603-615. De Geest, H., Levy, M. N., Zieske, H. & Lipman, R. I. (1965). Depression of ventricular contractility by stimulation of the vagus nerves. Circ. Res., 17, 222-235. Higgins, C. B., Vatner, S. F. & Braunwald, E. (1973). Parasympathetic control of the heart. Pharmac. Rev., 25, 119-155. Hunyor, S. N., Flynn, J. M. & Cochineas, C. (1978). Comparison of performance of various sphygmomanometers with intra-arterial blood pressure readings. Br. med. J., 2, 159-162. Kent, K. M., Epstein, S. E., Cooper, J. & Jacobowitz, D. M. (1974). Cholinergic innervation of the canine and human ventricular conducting system. Circulation, 50, 948-955.
Mahler, F., Yoran, C. & Ross, J. (1974). Inotropic effect of tachycardia and poststimulation potentiation in the conscious dog. Am. J. Physiol., 227, 569-575. Sahn, D. J., DeMaria, A., Kisslo, J. & Weyman, A. (1978). The committee of standardization of the American Society of Echocardiography: recommendations regarding quantification in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation, 58, 1072-1083. Smyth, H. S., Sleight, P. & Pickering, G. W. (1969). Reflex regulation of arterial pressure during sleep in man: a quantitative method of assessing baroreflex sensitivity. Circ. Res., 24, 109-121. Woodman, 0. L. & Vatner, S. F. (1986). Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog. J. Pharmac. exp. Ther., 237, 86-91.
(Received 15 July 1991, accepted 27 November 1991)
Role of vagal activity in the cardiovascular responses to phenylephrine in man MITCHELL A. H. LEVINE* & FRANS H. H. LEENEN Hypertension Unit, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
The effects of phenylephrine on blood pressure (BP), left ventricular function and total peripheral resistance (TPR) were evaluated in six normotensive male volunteers before and after vagal blockade with atropine. Before atropine, phenylephrine dose-related increased TPR, systolic and diastolic BP and decreased cardiac output by decreases in both stroke volume and heart rate. Post-atropine, the BP (but not TPR) responses to phenylephrine were markedly potentiated, related to an increase in stroke volume despite the higher afterload. Thus vagal tone may regulate cardiac output via effects on both heart rate and venous return. Keywords otl-adrenoceptor stimulation blood pressure LV function vagal tone
Introduction
The aol-adrenoceptor agonist phenylephrine causes arterial constriction, increasing systolic and diastolic blood pressure (BP). The mechanisms by which cardiac output are altered by phenylephrine are less clear because of the numerous factors involved, including changes in preload and afterload, inotropic and chronotopic responses to changes in autonomic tone and direct stimulation of a,-receptors in ventricular myocardium (Bruckner et al., 1984; Smyth et al., 1969; Woodman & Vatner, 1986). Although the effects of atropine on the phenylephrine-induced decrease in heart rate have been well documented, the role of changes in vagal tone in the effects of phenylephrine on left ventricular performance and peripheral resistance has not been assessed in man. We therefore investigated the cardiovascular effects of phenylephrine before and after vagal blockade with atropine.
Methods
Subjects Six healthy male volunteers 23 ± 0.4 years old and weighing 70 ± 3 kg participated in the study. Subjects were not on any medications, and were instructed to refrain from alcohol and caffeine ingestion 24 h prior to study. All subjects were non-smokers. Written informed consent was provided by all subjects.
Experimental protocol The study was performed as a single-blind trial, with each subject receiving a phenylephrine infusion before and after the administration of intravenous atropine. On the study day, after a 12 h overnight fast, a standardized liquid breakfast was given. An indwelling venous catheter was inserted in a forearm and was kept patent with heparin (5,000 iu 30 ml-1). Subjects remained supine from the period following breakfast until completion of the study day. After a supine rest period of 60 min, phenylephrine HCI was administered at incremental rates (each for 5 min), 0.42, 0.82, 1.10 and 1.60 ,ug kg-' min-'. At 90, 120 and 150 min, atropine sulphate was administered in a sequence of intravenous dosages (0.02, 0.01 and 0.01 mg kg-'). Following the third dose of atropine, the phenylephrine infusion was repeated, this time at rates of 0. 11, 0.21 and 0.42 ,ug kg-' min-'. For safety reasons, increases in systolic or diastolic BP were limited to 30 mmHg above the initial baseline values (i.e. before the first phenylephrine infusion). Heart rate and BP were monitored every 2 min prior to the administration of phenylephrine and at 3, 4 and 5 min at each rate of phenylephrine. The means of these values during each period were used for statistical analysis. Heart rate was derived from the electrocardiogram recorded by a Hewlett-Packard 78351A monitor and BP was measured automatically using a Roche Arteriosonde 1225 (Hunyor et al., 1978) on the arm opposite the venous catheter.
*Present address: Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
Correspondence: Dr Frans H. H. Leenen, Hypertension Unit, University of Ottawa Heart Institute, Ottawa Civic Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9
333
334
M. A. H. Levine & F. H. H. Leenen
Left ventricular (LV) echocardiograms were obtained with the subjects in the supine position, turned 30 degrees on their left side, using a Toshiba Sonolayer SSH-60A echo machine with a 3.75 MHz transducer in conjunction with a Toshiba Line scan recorder LSR20B. M-mode echocardiograms were obtained under 2-D guidance and tracings were recorded at a paper speed of 50 mm s-1. Measurements were made to the nearest millimetre for at least four cardiac cycles during quiet respiration and the means used for analysis. All echocardiograms in a patient were obtained by the same research assistant with the patient in the same position, in the same intercostal area and in the same LV area, just below the tip of the mitral leaflets. Measurements were made by the same observer and were obtained according to the guidelines of the American Society of Echocardiography (Sahn et al., 1978). LV echocardiograms were obtained at baseline and at the end of each infusion rate of phenylephrine. The following parameters were measured or calculated in a blinded manner: LV end-diastolic and LV endsystolic dimension and volume; cardiac output; stroke volume; ejection fraction; LV end-systolic stress and total peripheral resistance (TPR).
25 20
I
E E
15 10
0-
CO
cl)
251 20
'a E E
15
10
-
m
5
Analysis of data
0
Cardiovascular parameters for different drug exposure states were compared by analysis of variance. Pulse interval and systolic blood pressure response to phenylephrine were evaluated by linear regression analysis. Data are presented as mean ± s.e. mean.
5
-1
0.1
1
10
Phenyleph'rine (,ug kg -' min -' ) Figure 1 Log-dose response curves for changes in systolic and diastolic blood pressure, pre-atropine (0) and post-
atropine (A). Plotted points represent mean ± s.e. mean for individual phenylephrine dosages (0.11, 0.21, 0.42, 0.82, 1.1, and 1.6 ,ug kg-' min-'). Results
BP and heart rate response to phenylephrine
Phenylephrine induced the expected dose related increases in systolic BP and R-R interval. The regression lines of R-R interval to systolic BP for the phenylephrine infusion showed a pre-atropine slope of 9.85 ± 2.12 ms/mmHg and a post-atropine slope of 2.44 ± 0.03 ms/mmHg (P < 0.001 for difference in slope). The phenylephrine dose-response curves for systolic and diastolic BP were shifted to the left after atropine (Figure 1). Cardiovascular response to phenylephrine 0.42 pLg kg-' min-, pre- vs post-atropine: The systolic and diastolic BP responses to phenylephrine 0.42 ,u g kg-1 min-' were significantly (P < 0.01) greater post-atropine than pre-atropine (Table 1). In contrast, the increase in TPR was not larger post- vs pre-atropine, but the decline in cardiac output (CO) greater (P < 0.05) pre-atropine than post-atropine. The two components of CO stroke volume and heart rate responded differently. Whereas heart rate was decreased by phenylephrine both pre- and postatropine, stroke volume declined pre-atropine and was increased post-atropine (P < 0.05, pre vs post) by -
phenylephrine, explaining the different responses of CO. LV emptying, as assessed by ejection fraction decreased pre- and post-atropine by 2-3%. Indicators of preload and afterload - LV end-diastolic volume and end-systolic stress - both increased with this dose of phenylephrine post-atropine (P < 0.05, pre vs post) but not pre-atropine.
Cardiovascular responses to atropine Atropine markedly increased heart rate. Since stroke volume showed only a minor (NS) fall, cardiac output increased markedly as well. This increase in cardiac output was associated with modest increases in systolic and diastolic BP, whereas calculated TPR decreased (Table 1). All these changes were already present after the first dose of atropine (data not shown).
Discussion The a1l-adrenoceptor agonist phenylephrine increases TPR via arteriolar vasoconstriction and may increase LV filling via effects on venous tone (Woodman & Vatner, 1986). A positive inotropic effect also may occur (Bruckner et al., 1984; Curiel et al., 1989).
Short report
335
Table 1 Cardiovascular parameters at baseline, changes from baseline with phenylephrine (0.42 ,ug kg-' min-1), baseline after atropine, and changes with phenylephrine after atropine which reflect additional changes beyond the effects of atropine alone
Systolic BP (mmHg) Diastolic BP
Baseline after atropine
Baseline
Changes by phenylephrine
109 ± 2
4±1
67 ± 2
4± 1
77 ± 4**
52 ± 3
-5 ± 3
90 ± 3**
-4 ± 1
89 ± 7
Changes by phenylephrine after atropine 17 ± 2b
115 ± 3*
17 ± 4b
(mmHg) Heart rate
(beats min-') 97 ± 9 Stroke volume (ml) 5.0 ± 0.5 Cardiac output (1 min-1) Total peripheral 32 ± 2 resistance (units) LV end diastolic volume (ml) End systolic stress (g cm-2)
137 ± 14
-0.6 ± 0.2
-10 ± 2 9 ± 3a
-7.9 ± 0.5** -0.1 ± 0.3a
7±3
22 ± 2*
4± 1
-2 ± 3
133 ± 11
16 ± 4a
55 ± 3
15 ± 3a
51 ± 4
2±2
Data represent mean ± s.e. mean (n = 6) * P < 0.05, ** P < 0.01 for comparison of the two baselines ap < 0.05, bp < 0.01 for comparison of the phenylephrine effects.
However, with an intact autonomic nervous system the effect of these haemodynamic effects on BP will be blunted via a baroreflex-mediated increase in vagal tone and decrease in sympathetic activity. Moreover, the associated increase in afterload may decrease LV
emptying. In the present study, phenylephrine alone indeed induced the expected dose-related increase in TPR, and in BP. However, the increase in BP was clearly blunted by the fall in cardi'ac output, since after atropine there is a substantial potentiation of the BP response to phenylephrine, with no potentiation of the TPR response but also no decrease in cardiac output. The differential response of cardiac output does not appear to be due to differences in afterload, since end-systolic wall-stress - if anything - increased more post- vs preatropine. Any positive inotropic effect of the a1l-adrenoceptor agonist would have decreased at the higher heart rates after atropine (Curiel et al., 1989). The major difference thus appears to be related to the vagal blockade. The increase in R-R interval which accompanied the rise in BP with phenylephrine alone was markedly blunted following atropine, confirming the adequacy of the vagal blockade (Smyth et al., 1969). However, after atropine phenylephrine still decreased absolute heart rate, suggesting that this component relates to the reflex withdrawal of sympathetic tone, which is not affected by atropine. Cardiac output was therefore maintained after atropine because of modest increases in stroke volume with percentage-wise less decrease in heart rate. Vagal blockade may do this via two mechanisms. First there is some evidence for a negative inotropic effect arising from
an increase in vagal tone (De Geest et al., 1975; Higgins et al., 1973), although cholinergic innervation of ventricular myocardium is limited (Kent et al., 1974). Atropine may have prevented this effect. Moreover, the increase in heart rate per se may have some inotropic effect (Mahler et al., 1974). Secondly, atropine alone markedly increased heart rate but did not decrease LV end-diastolic volume and stroke volume indicating that venous return increased commensurate with the increase in heart rate resulting in the marked increase in cardiac output. These results would suggest that vagal tone is involved in regulating not only heart rate, but also in venous return (presumably via venous effects), the effects in concert increasing or decreasing cardiac output. It is thus possible that after atropine the venoconstriction induced by phenylephrine is not masked by the reflex increase in vagal tone and results in maintenance/increase of stroke volume. In summary, the present study shows that in man the reflex increase in vagal tone markedly blunts the increase in BP expected from the vasoconstriction caused by phenylephrine. Vagal tone may regulate cardiac output via effects on both heart rate and venous return.
This research was supported by an operating grant from the Heart and Stroke Foundation of Ontario. MAHL was supported by a Pfizer Fellowship in Clinical Pharmacology from the Canadian Society for Clinical Pharmacology. FHHL is career Investigator of the Heart and Stroke Foundation of Ontario. We thank Ms F. Browning and Ms K. Gaebel for their assistance.
336
M. A. H. Levine & F. H. H. Leenen
References Bruckner, R., Meyer, W., Mugge, A., Schmitz, W. & Scholz, H. (1984). Alpha-adrenoceptor-mediated positive inotropic effect of phenylephrine in isolated human ventricular myocardium. Eur. J. Pharmac., 99, 345-347. Curiel, R., Perez-Gonzalez, J., Brito, N., Zerpa, R., Tellez, D., Cabrera, J., Curiel, C. & Cubeddu, L. (1989). Positive inotropic effects mediated by a1 adrenoceptors in intact human subjects. J. cardiovasc. Pharmac., 14, 603-615. De Geest, H., Levy, M. N., Zieske, H. & Lipman, R. I. (1965). Depression of ventricular contractility by stimulation of the vagus nerves. Circ. Res., 17, 222-235. Higgins, C. B., Vatner, S. F. & Braunwald, E. (1973). Parasympathetic control of the heart. Pharmac. Rev., 25, 119-155. Hunyor, S. N., Flynn, J. M. & Cochineas, C. (1978). Comparison of performance of various sphygmomanometers with intra-arterial blood pressure readings. Br. med. J., 2, 159-162. Kent, K. M., Epstein, S. E., Cooper, J. & Jacobowitz, D. M. (1974). Cholinergic innervation of the canine and human ventricular conducting system. Circulation, 50, 948-955.
Mahler, F., Yoran, C. & Ross, J. (1974). Inotropic effect of tachycardia and poststimulation potentiation in the conscious dog. Am. J. Physiol., 227, 569-575. Sahn, D. J., DeMaria, A., Kisslo, J. & Weyman, A. (1978). The committee of standardization of the American Society of Echocardiography: recommendations regarding quantification in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation, 58, 1072-1083. Smyth, H. S., Sleight, P. & Pickering, G. W. (1969). Reflex regulation of arterial pressure during sleep in man: a quantitative method of assessing baroreflex sensitivity. Circ. Res., 24, 109-121. Woodman, 0. L. & Vatner, S. F. (1986). Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog. J. Pharmac. exp. Ther., 237, 86-91.
(Received 15 July 1991, accepted 27 November 1991)
