The following is the abstract the subsequent letter:
of the article discussed in
BARNARD,JOSEPH
W., ROBERTA. WARD, W. KEITH ADAND AUBREY E. TAYLOR. Characterization of thrmnboxane and prostacyclin effects on pulmonary vascular resistance. J. KINS,
Appl. Physiol. 72(5): 1845-1853, 1992.-Although thromboxane and prostacyclin (PGI,) have long been describedas major controllers of pulmonary vascular resistance, little has been reported on the characteristics of the interactions between the two arachidonic acid products. The current study usessegmental vascular resistance and compliancemeasurementsto evaluate the actions of thromboxane and PGI, in isolated blood-perfused rat lung. The thromboxane analogue U-46619 increases pulmonary vascular resistance by increasing only small artery resistance and decreases pulmonary vascular compliance in the
middle compartment. Among the vascular effects of U-46619 are a maximum increasein resistance (Rmax,-,,,,) of 60.3 k 15.6cmH,O l 1-l 9min 100 g-l and a concentration required for 50% of maximum increase (Ko5u-46619) of 1.60 t 0.85 nM for small artery resistance, a n&mum vascular compliance ) of -0.93 t 0.58 cmH,O, and a K, 5u 4661Qof 1.10 t CCminu-46619 1.60 nM for middle compartment compliance:kmilar results were obtained for total resistance and total compliance. The effects of PGI, on thromboxane-induced resistanceand compliance changes were evaluated using K,,,,, , Rmax,,, , and at each dose of thromboxane. ‘PGI, was more2effecCm=PGIz l
tive in reversing the thromboxane constriction at higher concentrations of thromboxane. These data showthat the absolute concentration of PGI, and thromboxane and not a simpleratio of thromboxane to PGI, determines vascular tone.
Pulmonary vascular responsesto thromboxane and prostacyclin
5?o the Editor: We read wit,h interest the paper by Barnard et al. concerning the interaction between thromboxane-induced pulmonary vasoconstriction and prostacyclin-induced pulmonary vasodilation in isolated perfused rat lungs. However, we disagree with their conclusion that the dose of PGI, that effectively reversed the pulmonary responses to thromboxane was the same regardless of the concentration of thromboxane. This conclusion is based on the concentration required for 50% maximal effect given in Table 2. These values range from 22 t 11 to 242 t 209 pM w&h such a wide range of variability (e.g., 218 t 502 PM) that it is difficult to understand how any firm conclusions can be drawn from these data. Furthermore, there is a substantial body of evidence that supports the opposite position, that PGI, causes dose-dependent pulmonary vasodilation in many species (l-3, 5), including patients with primary pulmonary hypertension (7,8). Thus we strongly disagree with the conclusion that “relatively high concentrations of PGI, will not be more effective than relatively low concentrations in treating pulmonary hypertension.” Indeed, patients with primary pulmonary hypertension re-
ceiving continuous PGI,
infusion require progressively higher doses to achieve the same reduction in pulmonary vascular resistance (8). Another concern we have with their paper is the omission of pertinent references. For example, in the introduction the authors state that “although thromboxane is a pulmonary venoconstrictor in canine, ovine, and feline lungs, the site of action of PGI, in the pulmonary circulation has not been determined in any of these species.” There were no references cited as evidence for the thromboxane-induced venoconstriction, although a number of reports on thromboxane’s sites of act,ion in the pulmonary circulation exist (2, 4, 6, 10). In addition, the dilator action of PGI, has been determined during thromboxane-induced constriction (5, 9, 10). We documented pulmonary venoconstriction in isolated perfused lungs from newborn lambs in response to a stable thromboxane A, anafogue that was attenuated by infusion of PGI, (10). Additionally, we observed that both pulmonary arterial and double occlusion pressures were significantly reduced by infusion of PGI, alone (9). Thus it seems somewhat inaccurate to state that the site of action to PGI, has not been determined, when clearly we and others have done so.
REFERENCES 1. CASSIN, S., I. WINIKOR, M. TED, J. PHILIPS, J. FRISINGER, J. JORDAN, AND C. GIBBS, Effects of prostacyclin on fetal pulmonary circulation. Pediatr. Pharmac0L. 1: 197-207, 1981. 2 HYMAN, A. L., B. M. CHAPNICK, P. J. KADOWITZ, W. E. M. LANDS, C. G. CRAWFORD, J. FRIED, AND J. BARTON. unusual pulmonary
vasodilator activity of 13,14-dehydroprustacyclin methyl ester: comparison with endoperoxides and other prostanoids. Proc. NC&. Acad. Sci. USA 74: 5711-5715, 1977. 3 KADOWITZ, P. J., B. M. CHAPNICK, L. P, FEIGEN, A. L. HYMAN, P. K. NELSON, AND E. W. SPANNHAKJZ. Pulmonary and systemic vasodilator effects of the newly discovered prostaglandin, PGI,. J. A&. Physiol. 45: 408-413, 1978. 4. KADOWITZ, P. J., C. A. GRUETTER, II. B. MCNAMARA, R. R. GORMAN, E. W. SPANNHAKE, AND A. L. HYMAN. Comparative effects of
endoperoxide PGH, and an analog on the pulmonary vascular bed. J. Appl. Physiol. 42: 953-958, 1977. 5. KADOWITZ, P. J., C. A. GRUETTER, E. W. SPANNHAKE, AND A. L. HYMAN. Pulmonary vascular responses to prostaglandins. Federation Proc. 40: 1991-1996, 1981. 6. KADOWITZ, P. J., AND A. L. HYMAN. Influence of a prostaglandin
endoperoxide
analogue on the canine pulmonary
vascular bed.
Ckc. Res. 40: 282-287, 1977. 7. RUBIN, L. J., 3. M. GROVES, J. T. REEVES, HANDEL, AND A. E. CATO. Prostacyclin-induced
vasodilation
in primary pulmonary
M. FROSOLONO, F. acute pulmonary hypertension. Circulation 66:
334-338,1982. 8, RUBIN, L. J., W. B. WILLIAMS,
J. MENDOZA, M. HOOD, M. MIGNON, R. BARST, J. H. DIEHL, J. CROW, AND W. LONG. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Ann. Intern. Med. 112: 485-491,1990. K., M. L. TOD, K. G. PIER, AND L. J. RUBIN. Effects of 9. YOSHIMURA, 2717
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2718
LETTERS
TO THE EDITOR
a throlmboxane AZ analogue and prostacyclin on lung fluid balance in newborn lambs. Circ. Res. 65: 1409~1416,1989. 10. YOSHIMWRA, K., M. L. TOD, K. G. PIER, AND L. J. RUBIN. Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs. J. AppZ. Physiol. 66: 929-935, 1989.
Mary L. Tod and Lewis J. Rubin Division of Pulmonary and Critical Care Medicine Departments of Medicine and Physiology University of Marylund School of Medicine Baltimore, Maryland 21201
more effective in reducing the vasoactive effects of thromboxane. Interestingly, one of the references suggested by Tod and Rubin (8) supports our results. Unfortunately we had not located this publication when our paper was submitted, or we certainly would have discussed this paper in detail. In their study, which was conducted in newborn lamb lungs, a thromboxane analogue was used to increase pulmonary arterial pressure in a dose-dependent manner. As the concentration of the analogue was increased, the same amount of prostacyclin (0.4 pg kg-‘. min-l) caused a progressively greater attenuation of the absolute increase in vascular resistance (Fig. 1 in Ref. 8). Because we do not have access to the original data, we can only estimate values directly from their graphical data to calculate the effects of prostacyclin on thromboxane constriction as follows: when the dose of the thromboxane analogue was increased from 1 to 3, to 10, and to 30 pg, the vasodilation produced by 0.4 pg kg-‘. min-1 prostacyclin decreased arterial pressure by -0.2 mmHg (40% attenuation), by ml.6 mmHg (61% attenuation), by -3.9 mmHg (59% attenuation), and at the highest analogue dose (30 pg) by -5.2 mmHg (44% attenuation). Their data also indicate that prostacyclin does not become less effective in dilating the thromboxane-induced pressure increases at higher thromboxane concentrations but remains relatively constant within the concentration range studied. We surmise from the second point raised by the letter, stating that “a substantial body of evidence that supports the opposite position, that prostacyclin causes l
REPLY
To the Editor: We would like to respond to the letter by Tod and Rubin in which they disagree with the conclusions in our paper. They assert that our evaluation of prostacyclin’s effect on thromboxane-mediated vascular constriction was unfounded because of the large variability in the values of concentration of prostacyclin required to produce one-half its maximal effect (K, 5 PG12)shown in Table 2. To address this issue, we have p&ted the average data included in that table. Figure 1 shows the K&s for prostacyclin at each concentration of the thrombdxane analogue. As shown, the more variable values of K 0.5,PGIz only occurred at the low concentrations of the thromboxane analogue because only slight increases in vascular resistance (not significant) and compliance decreases resulted. Figure 1 clearly demonstrates no tento increase. In fact, it remains essendency for K05PG12 tially unchakied, indicating that prostacyclin becomes 800
1 E 23 6001 t-a
800
Total Resistance
600
1
800 -
E e
l
800
Total Compliance
600 -
0.0
600
0.5
1.0
1.5
2.0
U46619 (nM)
2.5
3.0
IT
SmallArtery Resistance
1
0.0
Middle CompartmentCompliance
0.5
1.0
1.5
2.0
2.5
3.0
U46619 (nM)
FIG. 1. Concentration of prostacyclin required to produce one-half its maximal effect on thromboxane-induced vasoconstriction and compliance decreases (K0.5,PG!z ) at each concentration of a thromboxane analogue (U-46619) for total and small artery resistances and total and middle compartment compliances in rat lungs. Data are taken from Table 2 in Ref. 4. Note that variable values occur only at low concentrations of U-46619 in both resistance and compliance groups. Note also that high values are also onlv r>resent at lowest concentrations of IJ-46W3.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 14, 2019.
LETTERS
TO
THE
2719
EDITOR
ent species are known to respond differently to various vasoconstrictors and dilators. However, we do apologize to Drs. Tod and Rubin for not selecting their choice of references; however, it is not always possible to quote all the literature on any subject, and any omission was not intended.
dose-dependent pulmonary vasodilation in many species ” indicates that they did not fully understand our ZGyg An important conclusion from our study is that prostacyclin is a dose-dependent vasodilator but that the dose dependence does not greatly change as the amount of vasoconstriction increases. When we calculated the K 0.5,PG12 values from dose-response curves for prostacyclin at each individual dose of thromboxane, prostacyclin of course produced a dose-dependent vasodilation, as clearly shown in our data contained in Fig. 4. We did not purposefully omit pertinent references as stated by Tod and Rubin, but we are grateful to have an opportunity to discuss these papers in this letter. Their studies show that thromboxane constricts pulmonary veins in buffer-perfused newborn lamb lungs (9) and pulmonary arteries in blood-perfused lamb lungs (8). Other studies mentioned in their letter for canine and feline lungs are not appropriate references to show this effect. Reference 5 did not evaluate the site of vasoconstriction. Reference 6 shows constriction of veins >2-3 mm in canine lungs and also in vessels upstream from the large veins, i.e., almost the whole lung. Also, helical strips of pulmonary veins of 2- to 3-cm diameter constricted with thromboxane, but blood vessels of other sizes were not studied. Reference 7 also did not localize the vascular site of the constriction associated with thromboxane. However, Barman et al. (1, 2) clearly demonstrated that a thromboxane analogue (U-46619) only constricted the venuus side of the canine lung, which was referenced in the discussion of our paper. Tod and Rubin are correct in stating that prostacyclin causes venous dilation in the presence of thromboxane in newborn lambs (9). However, the next statement that “both pulmonary arterial and double occlusion pressures were significantly reduced by infusion of prostacyclin alone” (8) is misleading as written in their letter. Prostacyclin infusion after the thromboxane analogue did not attenuate the venoconstriction and, in effect, only attenuated arterial constriction. They also chose not to discuss these data in their letter, although they stated in their paper that “the elevation of the Ppa was due mainly to vasoconstriction upstream from PC” (9). Had we referred to this article, our conclusion would have been that thromboxane is primarily an arterial constrictor in blood-perfused newborn lamb lungs and that prostacyclin dilates the arterial vessels, which had been preconstricted by thromboxane, similar to our findings in rat lungs. It is interesting to note that their paper is strengthened by our work, although their studies did not do dose-response curves in the same fashion as presented in our paper. We think that dose-response curves should always be done when responses of the lungs’ vascular system to various dilators and constrictors are evaluated and that the K&s and maximum effects should be evaluated when possible. A simple measure of segmental vascular resistances will also allow the sites of action of various vasoactive substances to be identified. Finally, one must not mix apples and oranges when interpreting data collected in different fashions or compare resistance
chain-length glucosepolymer (GP) and solublestarch (SS). Six endurance-trained subjectsingested 1,200 ml of either GP or SS while cycling for 90 min at 70% of maximal oxygen consumption (VO2max).Whereas the calculated total CHO oxidation (GP 266.8 t- 41.9 g; SS 263.6 t 28.9 g) and the volume emptied from the stomach (GP 813 t 130 ml; SS 919 t 116 ml) were similar, the appearanceof the 14Clabel in plasmaoccurred more rapidly from ingestedSS than from GP (P < 0.001).This resulted in a significantly greater rate of SS oxidation than that from GP (SS 105.9 -+ 21.9 g, GP 49.6 k 10.2 g; P < 0.001). Exogenous CHO oxidation from GP accounted for 19% of total
studies in rats and dogs, because vascular beds of differ-
CHO oxidation,
REFERENCES
BARMAN,~.A., E. SENTENO,S.SMITH, AND A. E. TAYLOR.Acetylcholine’s effect on vascular resistance and compliance in the pulmonary circulation. J. Appl. Pltysiol. 67: 1495-1503, 1989. 2. BARMAN, S. A., AND A. E. TAYLOR. Histamine’s effect on pulmonary vascular resistance and compliance at elevated tone. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H618-H625, 1989. 3. BARNARD, J. W., S. A. BARMAN,W. K. ADKINS,G. L. LONGENECKER, ANDA. E. TAYLOR.Sustained effects of endothelin-1 on the rabbit, dog and rat pulmonary circulation. Am. J. Physiol. 261 (Heart 1.
Circ. Physiol.
30): H479-H486,
1991.
4. BARNARD, J. W.,R. A. WARD,AND A.E. TAYLOR.Characterization of thromboxane and prostacyclin effects on pulmonary vascular resistance. J. Appl. Physiol. 72: 1845-1853, 1992. 5. HYMAN, A. L., B, M. CHAPNICK, P. J. KADOWITZ, W. E. M. LANDS, C. G. CRAWFORD, J. FRIED, AND J. BARTON.Unusual pulmonary vasodilator activity of 13,14-dehydroprostacyclin methyl ester: comparison with endoperoxides and other prostanoids. Pm. AM. Acad. Ski. USA
74: Wll-5715,1977.
6. KADOWITZ, P. J., C. A. GRUETTER, D. B. MCNAMARA, R. R. GORMAN,E.W. SPANNHAKE,AND A.L. HYMAN.Comparative effectsof endoperoxide PGH, and an analog on the pulmonary vascular bed. J. Appl.
Physiol. P.
42: 953-958,
1977.
7. KADOWITZ,
J., C. A. GRUETTER, E. W. SPANNHAKE,AND HYMAN.Pulmonary vascular responses to prostaglandins. tion Proc. 40: 1991-1996,
A. L. Federa-
1981.
8, YOSHIMURA, K., M. L. TOD, K. G. PIER, AND L, J. RUBIN. Effects of a thromboxane A, analogue and prostacyclin on lung fluid balance in newborn lambs. Circ. Res. 65: 1409-1416, 1989. 9. YOSHIMURA, K., M. L. TOD, K. G. PIER, AND L. J. RUBIN. Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs. J. Appl. Physiol. 66: 929-935, 1989.
Joseph W. Barnard, Robert A. Ward, and Aubrey E. Taylor Department of Physiology College of Medicine University of South Alabama Mobile, Alabama 36688
The following is the abstract of the article discussed in the subsequent letter: HAWLEY,JOHN A., STEVEN C.DENNIS,BARRY J. LAIDLER, ANDREWNBOSCH, TIMOTHYD.NOAKES,ANDFREDBROUNS.
High rates of exogenous carbohydrate oxidatiun from starch ingested during prolonged exercise. J. Appl. Physiol. 71(5): 18011806, 1991.-This study compared the gastric emptying and oxidation of two 15% carbohydrate (CHO) solutions: a 22-
whereas
the corresponding
value for SS was
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2720
LETTERS
TO
40%. This study suggests that the oxidation of SS and GP solutions ingested during exercise at 70% Vogrnax is not limited by gastric emptying. Rather, it appears to be either the rate of digestion or absorption of these solutions that determines their utilization.
Exogenous starch oxidation using 14Clubelirzg
To the Editor: A recent paper by Hawley et al. (3) compared the oxidation rate of 180 g of a 22-chain-long glucose polymer to that of starch during 90 min of exercise at 70% maximal oxygen consumption (VO, max) in trained triathletes [oxygen consumption (Tjo2) = 3.43 l/mm]. The substrates were ingested as a solution (glucose polymer) or as a suspension (starch) in 1,200 ml of water. [The authors refer to the starch as “soluble starch (SS),” but this is a misnomer as such a concentration starch is not soluble in water.] 14C was used as tracer. Gastric emptying was similar for both carbohydrates, but the appearance of 14C in the blood and in expired CO, was much faster with starch than with the glucose polymer. The average oxidation rates over the 90 min of exercise were 0.6 and 1.3 g of glucose/min for the glucose polymer and starch, respectively (1 g of glucose polymer or starch provides ~1.1 g of glucose). The oxidation rate of starch reported appears very high. We have shown that the oxidation rate of exogenous carbohydrates during exercise is related to VO, in liters per minute (0.062 + 0.173 h2, r = 0.617) (5). For VO, between 3.4 and 3.5 l/min, the average oxidation rate estimated using this equation and actually observed by Wagenmakers et al. (6) does not exceed 0.7 g/min. In addition, the difference between the oxidation rate reported by Hawley et al. (3) for starch and that of glucose reported from the same laboratory [
of the article discussed in
BARNARD,JOSEPH
W., ROBERTA. WARD, W. KEITH ADAND AUBREY E. TAYLOR. Characterization of thrmnboxane and prostacyclin effects on pulmonary vascular resistance. J. KINS,
Appl. Physiol. 72(5): 1845-1853, 1992.-Although thromboxane and prostacyclin (PGI,) have long been describedas major controllers of pulmonary vascular resistance, little has been reported on the characteristics of the interactions between the two arachidonic acid products. The current study usessegmental vascular resistance and compliancemeasurementsto evaluate the actions of thromboxane and PGI, in isolated blood-perfused rat lung. The thromboxane analogue U-46619 increases pulmonary vascular resistance by increasing only small artery resistance and decreases pulmonary vascular compliance in the
middle compartment. Among the vascular effects of U-46619 are a maximum increasein resistance (Rmax,-,,,,) of 60.3 k 15.6cmH,O l 1-l 9min 100 g-l and a concentration required for 50% of maximum increase (Ko5u-46619) of 1.60 t 0.85 nM for small artery resistance, a n&mum vascular compliance ) of -0.93 t 0.58 cmH,O, and a K, 5u 4661Qof 1.10 t CCminu-46619 1.60 nM for middle compartment compliance:kmilar results were obtained for total resistance and total compliance. The effects of PGI, on thromboxane-induced resistanceand compliance changes were evaluated using K,,,,, , Rmax,,, , and at each dose of thromboxane. ‘PGI, was more2effecCm=PGIz l
tive in reversing the thromboxane constriction at higher concentrations of thromboxane. These data showthat the absolute concentration of PGI, and thromboxane and not a simpleratio of thromboxane to PGI, determines vascular tone.
Pulmonary vascular responsesto thromboxane and prostacyclin
5?o the Editor: We read wit,h interest the paper by Barnard et al. concerning the interaction between thromboxane-induced pulmonary vasoconstriction and prostacyclin-induced pulmonary vasodilation in isolated perfused rat lungs. However, we disagree with their conclusion that the dose of PGI, that effectively reversed the pulmonary responses to thromboxane was the same regardless of the concentration of thromboxane. This conclusion is based on the concentration required for 50% maximal effect given in Table 2. These values range from 22 t 11 to 242 t 209 pM w&h such a wide range of variability (e.g., 218 t 502 PM) that it is difficult to understand how any firm conclusions can be drawn from these data. Furthermore, there is a substantial body of evidence that supports the opposite position, that PGI, causes dose-dependent pulmonary vasodilation in many species (l-3, 5), including patients with primary pulmonary hypertension (7,8). Thus we strongly disagree with the conclusion that “relatively high concentrations of PGI, will not be more effective than relatively low concentrations in treating pulmonary hypertension.” Indeed, patients with primary pulmonary hypertension re-
ceiving continuous PGI,
infusion require progressively higher doses to achieve the same reduction in pulmonary vascular resistance (8). Another concern we have with their paper is the omission of pertinent references. For example, in the introduction the authors state that “although thromboxane is a pulmonary venoconstrictor in canine, ovine, and feline lungs, the site of action of PGI, in the pulmonary circulation has not been determined in any of these species.” There were no references cited as evidence for the thromboxane-induced venoconstriction, although a number of reports on thromboxane’s sites of act,ion in the pulmonary circulation exist (2, 4, 6, 10). In addition, the dilator action of PGI, has been determined during thromboxane-induced constriction (5, 9, 10). We documented pulmonary venoconstriction in isolated perfused lungs from newborn lambs in response to a stable thromboxane A, anafogue that was attenuated by infusion of PGI, (10). Additionally, we observed that both pulmonary arterial and double occlusion pressures were significantly reduced by infusion of PGI, alone (9). Thus it seems somewhat inaccurate to state that the site of action to PGI, has not been determined, when clearly we and others have done so.
REFERENCES 1. CASSIN, S., I. WINIKOR, M. TED, J. PHILIPS, J. FRISINGER, J. JORDAN, AND C. GIBBS, Effects of prostacyclin on fetal pulmonary circulation. Pediatr. Pharmac0L. 1: 197-207, 1981. 2 HYMAN, A. L., B. M. CHAPNICK, P. J. KADOWITZ, W. E. M. LANDS, C. G. CRAWFORD, J. FRIED, AND J. BARTON. unusual pulmonary
vasodilator activity of 13,14-dehydroprustacyclin methyl ester: comparison with endoperoxides and other prostanoids. Proc. NC&. Acad. Sci. USA 74: 5711-5715, 1977. 3 KADOWITZ, P. J., B. M. CHAPNICK, L. P, FEIGEN, A. L. HYMAN, P. K. NELSON, AND E. W. SPANNHAKJZ. Pulmonary and systemic vasodilator effects of the newly discovered prostaglandin, PGI,. J. A&. Physiol. 45: 408-413, 1978. 4. KADOWITZ, P. J., C. A. GRUETTER, II. B. MCNAMARA, R. R. GORMAN, E. W. SPANNHAKE, AND A. L. HYMAN. Comparative effects of
endoperoxide PGH, and an analog on the pulmonary vascular bed. J. Appl. Physiol. 42: 953-958, 1977. 5. KADOWITZ, P. J., C. A. GRUETTER, E. W. SPANNHAKE, AND A. L. HYMAN. Pulmonary vascular responses to prostaglandins. Federation Proc. 40: 1991-1996, 1981. 6. KADOWITZ, P. J., AND A. L. HYMAN. Influence of a prostaglandin
endoperoxide
analogue on the canine pulmonary
vascular bed.
Ckc. Res. 40: 282-287, 1977. 7. RUBIN, L. J., 3. M. GROVES, J. T. REEVES, HANDEL, AND A. E. CATO. Prostacyclin-induced
vasodilation
in primary pulmonary
M. FROSOLONO, F. acute pulmonary hypertension. Circulation 66:
334-338,1982. 8, RUBIN, L. J., W. B. WILLIAMS,
J. MENDOZA, M. HOOD, M. MIGNON, R. BARST, J. H. DIEHL, J. CROW, AND W. LONG. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Ann. Intern. Med. 112: 485-491,1990. K., M. L. TOD, K. G. PIER, AND L. J. RUBIN. Effects of 9. YOSHIMURA, 2717
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2718
LETTERS
TO THE EDITOR
a throlmboxane AZ analogue and prostacyclin on lung fluid balance in newborn lambs. Circ. Res. 65: 1409~1416,1989. 10. YOSHIMWRA, K., M. L. TOD, K. G. PIER, AND L. J. RUBIN. Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs. J. AppZ. Physiol. 66: 929-935, 1989.
Mary L. Tod and Lewis J. Rubin Division of Pulmonary and Critical Care Medicine Departments of Medicine and Physiology University of Marylund School of Medicine Baltimore, Maryland 21201
more effective in reducing the vasoactive effects of thromboxane. Interestingly, one of the references suggested by Tod and Rubin (8) supports our results. Unfortunately we had not located this publication when our paper was submitted, or we certainly would have discussed this paper in detail. In their study, which was conducted in newborn lamb lungs, a thromboxane analogue was used to increase pulmonary arterial pressure in a dose-dependent manner. As the concentration of the analogue was increased, the same amount of prostacyclin (0.4 pg kg-‘. min-l) caused a progressively greater attenuation of the absolute increase in vascular resistance (Fig. 1 in Ref. 8). Because we do not have access to the original data, we can only estimate values directly from their graphical data to calculate the effects of prostacyclin on thromboxane constriction as follows: when the dose of the thromboxane analogue was increased from 1 to 3, to 10, and to 30 pg, the vasodilation produced by 0.4 pg kg-‘. min-1 prostacyclin decreased arterial pressure by -0.2 mmHg (40% attenuation), by ml.6 mmHg (61% attenuation), by -3.9 mmHg (59% attenuation), and at the highest analogue dose (30 pg) by -5.2 mmHg (44% attenuation). Their data also indicate that prostacyclin does not become less effective in dilating the thromboxane-induced pressure increases at higher thromboxane concentrations but remains relatively constant within the concentration range studied. We surmise from the second point raised by the letter, stating that “a substantial body of evidence that supports the opposite position, that prostacyclin causes l
REPLY
To the Editor: We would like to respond to the letter by Tod and Rubin in which they disagree with the conclusions in our paper. They assert that our evaluation of prostacyclin’s effect on thromboxane-mediated vascular constriction was unfounded because of the large variability in the values of concentration of prostacyclin required to produce one-half its maximal effect (K, 5 PG12)shown in Table 2. To address this issue, we have p&ted the average data included in that table. Figure 1 shows the K&s for prostacyclin at each concentration of the thrombdxane analogue. As shown, the more variable values of K 0.5,PGIz only occurred at the low concentrations of the thromboxane analogue because only slight increases in vascular resistance (not significant) and compliance decreases resulted. Figure 1 clearly demonstrates no tento increase. In fact, it remains essendency for K05PG12 tially unchakied, indicating that prostacyclin becomes 800
1 E 23 6001 t-a
800
Total Resistance
600
1
800 -
E e
l
800
Total Compliance
600 -
0.0
600
0.5
1.0
1.5
2.0
U46619 (nM)
2.5
3.0
IT
SmallArtery Resistance
1
0.0
Middle CompartmentCompliance
0.5
1.0
1.5
2.0
2.5
3.0
U46619 (nM)
FIG. 1. Concentration of prostacyclin required to produce one-half its maximal effect on thromboxane-induced vasoconstriction and compliance decreases (K0.5,PG!z ) at each concentration of a thromboxane analogue (U-46619) for total and small artery resistances and total and middle compartment compliances in rat lungs. Data are taken from Table 2 in Ref. 4. Note that variable values occur only at low concentrations of U-46619 in both resistance and compliance groups. Note also that high values are also onlv r>resent at lowest concentrations of IJ-46W3.
Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (130.070.008.131) on January 14, 2019.
LETTERS
TO
THE
2719
EDITOR
ent species are known to respond differently to various vasoconstrictors and dilators. However, we do apologize to Drs. Tod and Rubin for not selecting their choice of references; however, it is not always possible to quote all the literature on any subject, and any omission was not intended.
dose-dependent pulmonary vasodilation in many species ” indicates that they did not fully understand our ZGyg An important conclusion from our study is that prostacyclin is a dose-dependent vasodilator but that the dose dependence does not greatly change as the amount of vasoconstriction increases. When we calculated the K 0.5,PG12 values from dose-response curves for prostacyclin at each individual dose of thromboxane, prostacyclin of course produced a dose-dependent vasodilation, as clearly shown in our data contained in Fig. 4. We did not purposefully omit pertinent references as stated by Tod and Rubin, but we are grateful to have an opportunity to discuss these papers in this letter. Their studies show that thromboxane constricts pulmonary veins in buffer-perfused newborn lamb lungs (9) and pulmonary arteries in blood-perfused lamb lungs (8). Other studies mentioned in their letter for canine and feline lungs are not appropriate references to show this effect. Reference 5 did not evaluate the site of vasoconstriction. Reference 6 shows constriction of veins >2-3 mm in canine lungs and also in vessels upstream from the large veins, i.e., almost the whole lung. Also, helical strips of pulmonary veins of 2- to 3-cm diameter constricted with thromboxane, but blood vessels of other sizes were not studied. Reference 7 also did not localize the vascular site of the constriction associated with thromboxane. However, Barman et al. (1, 2) clearly demonstrated that a thromboxane analogue (U-46619) only constricted the venuus side of the canine lung, which was referenced in the discussion of our paper. Tod and Rubin are correct in stating that prostacyclin causes venous dilation in the presence of thromboxane in newborn lambs (9). However, the next statement that “both pulmonary arterial and double occlusion pressures were significantly reduced by infusion of prostacyclin alone” (8) is misleading as written in their letter. Prostacyclin infusion after the thromboxane analogue did not attenuate the venoconstriction and, in effect, only attenuated arterial constriction. They also chose not to discuss these data in their letter, although they stated in their paper that “the elevation of the Ppa was due mainly to vasoconstriction upstream from PC” (9). Had we referred to this article, our conclusion would have been that thromboxane is primarily an arterial constrictor in blood-perfused newborn lamb lungs and that prostacyclin dilates the arterial vessels, which had been preconstricted by thromboxane, similar to our findings in rat lungs. It is interesting to note that their paper is strengthened by our work, although their studies did not do dose-response curves in the same fashion as presented in our paper. We think that dose-response curves should always be done when responses of the lungs’ vascular system to various dilators and constrictors are evaluated and that the K&s and maximum effects should be evaluated when possible. A simple measure of segmental vascular resistances will also allow the sites of action of various vasoactive substances to be identified. Finally, one must not mix apples and oranges when interpreting data collected in different fashions or compare resistance
chain-length glucosepolymer (GP) and solublestarch (SS). Six endurance-trained subjectsingested 1,200 ml of either GP or SS while cycling for 90 min at 70% of maximal oxygen consumption (VO2max).Whereas the calculated total CHO oxidation (GP 266.8 t- 41.9 g; SS 263.6 t 28.9 g) and the volume emptied from the stomach (GP 813 t 130 ml; SS 919 t 116 ml) were similar, the appearanceof the 14Clabel in plasmaoccurred more rapidly from ingestedSS than from GP (P < 0.001).This resulted in a significantly greater rate of SS oxidation than that from GP (SS 105.9 -+ 21.9 g, GP 49.6 k 10.2 g; P < 0.001). Exogenous CHO oxidation from GP accounted for 19% of total
studies in rats and dogs, because vascular beds of differ-
CHO oxidation,
REFERENCES
BARMAN,~.A., E. SENTENO,S.SMITH, AND A. E. TAYLOR.Acetylcholine’s effect on vascular resistance and compliance in the pulmonary circulation. J. Appl. Pltysiol. 67: 1495-1503, 1989. 2. BARMAN, S. A., AND A. E. TAYLOR. Histamine’s effect on pulmonary vascular resistance and compliance at elevated tone. Am. J. Physiol. 257 (Heart Circ. Physiol. 26): H618-H625, 1989. 3. BARNARD, J. W., S. A. BARMAN,W. K. ADKINS,G. L. LONGENECKER, ANDA. E. TAYLOR.Sustained effects of endothelin-1 on the rabbit, dog and rat pulmonary circulation. Am. J. Physiol. 261 (Heart 1.
Circ. Physiol.
30): H479-H486,
1991.
4. BARNARD, J. W.,R. A. WARD,AND A.E. TAYLOR.Characterization of thromboxane and prostacyclin effects on pulmonary vascular resistance. J. Appl. Physiol. 72: 1845-1853, 1992. 5. HYMAN, A. L., B, M. CHAPNICK, P. J. KADOWITZ, W. E. M. LANDS, C. G. CRAWFORD, J. FRIED, AND J. BARTON.Unusual pulmonary vasodilator activity of 13,14-dehydroprostacyclin methyl ester: comparison with endoperoxides and other prostanoids. Pm. AM. Acad. Ski. USA
74: Wll-5715,1977.
6. KADOWITZ, P. J., C. A. GRUETTER, D. B. MCNAMARA, R. R. GORMAN,E.W. SPANNHAKE,AND A.L. HYMAN.Comparative effectsof endoperoxide PGH, and an analog on the pulmonary vascular bed. J. Appl.
Physiol. P.
42: 953-958,
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7. KADOWITZ,
J., C. A. GRUETTER, E. W. SPANNHAKE,AND HYMAN.Pulmonary vascular responses to prostaglandins. tion Proc. 40: 1991-1996,
A. L. Federa-
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8, YOSHIMURA, K., M. L. TOD, K. G. PIER, AND L, J. RUBIN. Effects of a thromboxane A, analogue and prostacyclin on lung fluid balance in newborn lambs. Circ. Res. 65: 1409-1416, 1989. 9. YOSHIMURA, K., M. L. TOD, K. G. PIER, AND L. J. RUBIN. Role of venoconstriction in thromboxane-induced pulmonary hypertension and edema in lambs. J. Appl. Physiol. 66: 929-935, 1989.
Joseph W. Barnard, Robert A. Ward, and Aubrey E. Taylor Department of Physiology College of Medicine University of South Alabama Mobile, Alabama 36688
The following is the abstract of the article discussed in the subsequent letter: HAWLEY,JOHN A., STEVEN C.DENNIS,BARRY J. LAIDLER, ANDREWNBOSCH, TIMOTHYD.NOAKES,ANDFREDBROUNS.
High rates of exogenous carbohydrate oxidatiun from starch ingested during prolonged exercise. J. Appl. Physiol. 71(5): 18011806, 1991.-This study compared the gastric emptying and oxidation of two 15% carbohydrate (CHO) solutions: a 22-
whereas
the corresponding
value for SS was
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LETTERS
TO
40%. This study suggests that the oxidation of SS and GP solutions ingested during exercise at 70% Vogrnax is not limited by gastric emptying. Rather, it appears to be either the rate of digestion or absorption of these solutions that determines their utilization.
Exogenous starch oxidation using 14Clubelirzg
To the Editor: A recent paper by Hawley et al. (3) compared the oxidation rate of 180 g of a 22-chain-long glucose polymer to that of starch during 90 min of exercise at 70% maximal oxygen consumption (VO, max) in trained triathletes [oxygen consumption (Tjo2) = 3.43 l/mm]. The substrates were ingested as a solution (glucose polymer) or as a suspension (starch) in 1,200 ml of water. [The authors refer to the starch as “soluble starch (SS),” but this is a misnomer as such a concentration starch is not soluble in water.] 14C was used as tracer. Gastric emptying was similar for both carbohydrates, but the appearance of 14C in the blood and in expired CO, was much faster with starch than with the glucose polymer. The average oxidation rates over the 90 min of exercise were 0.6 and 1.3 g of glucose/min for the glucose polymer and starch, respectively (1 g of glucose polymer or starch provides ~1.1 g of glucose). The oxidation rate of starch reported appears very high. We have shown that the oxidation rate of exogenous carbohydrates during exercise is related to VO, in liters per minute (0.062 + 0.173 h2, r = 0.617) (5). For VO, between 3.4 and 3.5 l/min, the average oxidation rate estimated using this equation and actually observed by Wagenmakers et al. (6) does not exceed 0.7 g/min. In addition, the difference between the oxidation rate reported by Hawley et al. (3) for starch and that of glucose reported from the same laboratory [
