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The local effect of glyceryl trinitrate, nitrite, papaverine, and atropine upon coronary vascular resistance
The local nitrite, upon
effect
of glyceryl
papaverine, coronary
and vascular
trinitrate, atropine resistance
Edward D. Frohlich, M.D. fwry B. Scott, M.S. Fort h-nox, h-y.
T
he literature is abundant with studies concerned with the effects of various vasoactive substances on the coronary vascular bed.‘-‘j None, however, permit a comparison by weight and molarity of the local, steady-state effects of the active principle of glyceryl trinitrate, sodium nitrite, papaverine hydrochloride, and atropine sulfate. In addition, the factor of tonicity and its effects on vascular resistance were not seriously considered. Therefore, the present study was designed to quantitate the local vascular effects of the active principle of glyceryl trinitrate, sodium nitrite, papaverine hydrochloride, and atropine sulfate on the coronary vasculature. This was done by measuring coronary perfusion pressure at constant coronary blood flow during intracoronary infusion of isotonic solutions of these agents at rates which provided therapeutic blood concentrations. Materials
and
methods
The study included a total of 18 mongrel dogs anesthetized with sodium pentobarbital (35 mg. per kilogram) and anticoagulated with heparin (5 mg. per kilogram). The preparation has been described in detail in an earlier communication.7 The heart was exposed through the right From the Environmental Received for publication
362
Medicine Division, Aug. 7, 1961.
fourth intercostal space. A rotating disc blood oxygenator, blood heat exchanger, and blood pump were interposed between the left femoral artery and plastic cannulae which were inserted into the superior and inferior venae cavae via the right atrium. The body was thus perfused with oxygenated blood at an average rate of 95 ml. per kilogram per minute, and body temperature was maintained at 37” C. A second pump, interposed between the right femoral artery and the ascending aorta, perfused the coronary vascular bed. By cross-clamping the aorta and pulmonary artery 3 cm. from the heart the output of this pump was thus diverted through the entire coronary circulation. Flow rate was held constant at an average value of 92 ml. per minute (50 to 125 ml. per minute). Coronary venous blood was collected from the right side of the heart with a cannula threaded through the tricuspid valve in such a way as to render the valve incompetent. This blood was returned to the venous limb of the perfusion circuit. Blood from the left side of the heart (from arterioluminal, Thebesian, and bronchial vessels) was collected with another cannula inserted into the left atrium and ventricle through a superior pulmonary vein. A resistance-wire pressure transducer
U. S. Army
Medical
Research
Laboratory,
Fort
Knox,
KY.
Volwne
63
h-umber
Study on glyceryl trinitrate,
3
papaverine,
and atropine
363
Results
120 1 ATROPINE
SOab9,F=92)
60 Na NITRITE h=S,F=S9)
50
4o0
nitrite,
\
L
I 0.5
I 1.0 INFUSION
I 1.5 RATE
I 2.0 (ml./min.l
I 2.5
I
3.0
Fig. 1. Coronaryperfusionpressureasa function of infusionrate of active principle. F, Averageblood flow in milliliters per minute; n, numberof dogs. was utilized to measure pressure in the coronary perfusion tubing just prior to entrance into the ascending aorta. Isotonic solutions, as determined by the Fiske osmometer, of glyceryl trinitrate, sodium nitrite, papaverine hydrochloride, and atropine sulfate were infused into the coronary perfusion circuit at rates of 0.2, 0.5, 0.8, 1.2, 1.6, 2.1, and 2.6 ml. per minute, in that order (Table I). Each rate was maintained for 30 seconds. Coronary perfusion pressure and electrocardiogram were recorded continuously. Pressure, heart rate, and Q-T interval were obtained at the end of each 30-second period, at which time the pressures were stable. Since the rate of blood flow through the coronary vascular bed was held constant and pressure in the right heart remained atmospheric, changes in resistance were therefore directly proportional to changes in coronary artery pressure. The proportion of time spent by the ventricles in systole was calculated from the formula shown below:
Per cent of a minute qxrt
Dose-responseefects. Coronary vascular pressure decreased as a function of the infusion rate of solutions of glyceryl trinitrate, sodium nitrite, and papaverine hydrochloride in each animal (Fig. 1). Infusion of atropine sulfate failed to produce a regular change in pressure. At the maximal infusion rate of 2.6 tnl. per minute, glyceryl trinitrate decreased average coronary perfusion pressure by 21.2 per cent, whereas sodium nitrite, papaverine hydrochloride, and atropine sulfate reduced resistance by 34.0,35.1, and 4.7 per cent, respectively (Table II). Table II presents the change in pressure as a function of the atnount of active principle infused per minute. It may be seen that, on a weight basis, glyceryl trinitrate is by far the most active agent. Table III presents the number of milligrams and moles of each active principle per minute necessary to reduce coronary perfusion pressure by 12 and 20 per cent. From this comparison the active principle of these agents may be ranked according to their potency-in the order: glyceryl trinitrate, papaverine, and nitrite. Electrocardiographic effects. The effects of these substances on the heart rate and Q-T interval allow inferences to be made concerning coronary vessel transmural pressures.8 Table IV compares perfusion pressure, heart rate, Q-T interval, and the proportion of time spent by the ventricles in sl-stole during the control period and during the slowest and most rapid rates of infusion. Glyceryl trinitrate, nitrite, and papaverine failed to change significantly the proportion of a minute spent in systole. Atropine at the maximal infusion rate increased the heart rate, Q-T interval, and the proportion of time spent by the ventricles in systole by 22, 3, and 21 per cent, respectively. Discussion
These studies indicate that, in this prepara,tion, isotonic solutions of glyceryl trinitrate, sodium nitrite, and papaverine
Q-T Interval X HR in systole = -__6O
x 100.
364
Frohlich
and Scott
Table I. Osmolarity dog
and concentration
Solution
of solutions
Osmolarity (mOsnz./Rg.)
Glyceryl trinitrate Sodium nitrite Atropine sulfate Papaverine hydrochloride
Table II. Reduction principle Glyceryl
in
&nitrate
Presszzre change (75 of control)
0.02 0.05 0.08 0.12 0.16 0.21 0.26
- 2.6 -12.3 -17.6 -19.4 -19.4 -20.3 -21.2
into the coronary vascular
perfusion
coronary
0.10 10.87 2.00 3.25
pressure
as
Nitrite
i Ilzfzzsion rate (nzg./nzin.)
a
1.45 3 63 5.80 8.70 11.60 15.23 18.85
- 3.2 - 8.7 -15.3 -18.6 -25.2 -29.6 --.3&O
Infusion rate (mg./nzin.)
function
Table III. Comparison of amounts of active principle duce equal reduction in coronary perfusion pressure
infusion
of
Infz4sion rate (mg./wzin.)
-12.0 -19.4 -24.0 -28.7 -32.1 --33..1 --35.1
rate of active
d tropine
!
Presszire change (‘;I of control),
0.29 0.74 1.18 1 .76 2 3.5 3.09 3.82
the
of
0.10 7.25 1.70 1.47
Papaverine
Pressure change (7; of control)
bed
Concentration oJ artiae principle (nzg./ml. 1
Concentration (nzg./nzl. )
30.5 31.5 312 276
---.-----.-, Infusion rate (mg./min.)
in&ced
Prcss11re
(s,
0.34 0.85 1.36 2.01 2.72 3.57 4.42
by weight and molarity
change 0f control) +0.9 -0.9 -1 .8 -2.8 -3.7 -1.8 -2.9
necessary to
pro-
I Agent
__~_.~.
12 per cuzt reduction ~__~ ~~~_ ~~~~~ ._
mg./nzin. Glyceryl trinitrate Nitrite Papaverine
0.05 1.89 0.29
hydrochloride produced a decrease in coronary vascular resistance as a function of the rate of steady-state infusion of the active principle. Atropine sulfate produced no apparent change in the vascular resistance. Although the formulation of an exact potency ratio between various drugs from dose-response curves is difficult, it is possible to arrive at a general approximation of their respective relationships. From the
moles/min. 2.2 x 1.2 x 8.6X
10-T 10-1 10-i
20 per cent reduction __~~ wzg./nzin. 0.12 9.3.5 0.76
moles/mi?z. 5.3 x ‘.0X 2.2x
10-7 10-d 10~~”
data in Tables II and III, on a weight basis, glyceryl trinitrate is 98 times as potent as the nitrite anion when coronary vascular resistance is reduced by 12 per cent, and 88 times as potent when resistance is clecreased by 20 per cent. On a molar basis, however, glyceryl trinitrate is 545 and 377 times as potent when resistance is reduced by 12 and 20 per cent, respectively. Glyceryl trinitrate is 6 times as active as papaverine, on a weight basis, at both the
Study on glyccryl trinitrate,
12 and 20 per cent reduction levels. When a molar comparison is made, glyceryl trinitrate is 4 times as potent as papaverine, whether the resistance is decreased by 12 or 20 per cent. Therefore, at two different infusion levels, at which significant decrease in coronary vascular resistance is produced, there is essentially no difference in the reLltionships of potency of these drugs. Hence, on a comparison of weight, glyceryl trinitrate is approximately 90 times as potent as nitrite, and 6 times as active as papaverine. When this comparison is expressed on a molecular basis, however, the organic glyceryl trinitrate is approxinlately 4.50 times as potent as the inorganic nitrite anion, and 4 times the strength of papaverine. This relationship is also apparent from the curves in Fig. 1. The fall in coronary vascular resistance most likely resulted from an increase in the caliber of the vessels. Resistance to blood flow through a vascular bed is determined by blood viscosity and vessel geometry.g Blood viscosity did not change significantly during administration of these agents because the maxitnal infusion rate of the solutions diluted the blood by only 2.6 per cent. Furthermore, changes in viscosity due to reorientation of the red blood cells in the flowing stream need not be seriously considered since flow rate was l-able IV. Efect infusion
Agent
Control Glyceryl Glyceryl
of active principles
Infusion rate (ml./min.)
nitrite,
papavcrine,
and atropint,
365
held constant and pressures and flows were well above the range in which this “phenomenon” occurs.*O Because intramyocardial pressure was not measured, it cannot be stated with certainty whether the dilation was active, due to a change in the contractile state of the smooth muscle within the vessel wall, or passive, due to an increase in vessel transmural pressure subsequent to a decrease in intramyocardial pressure. The absence of a change in the per cent of a minute spent in electrical systole suggests that intramyocardial pressure was not altered b, changes in the relationship of mechanical systole to diastole, but does not provide information regarding the strength of myocardial contraction. Passive dilation due to dehydration of the vessel wall need not be considered because all solutions infused were isosmotic to plasma. Thus, glyceryl trinitrate, nitrite, and papaverine produce coronary vascular dilation when administered locally over the concentration ranges which might occur during therapy. The fact that atropine increased the proportion of a minute spent in systole, without significantly changing perfusion pressure, suggests that atropine also dilates coronary vessels. Previous studies” have shown that the sodium ion produces no change in coronary vascular resistance. Hence, the dilation
upon several parameters
Coronary pressure (mm. Hg)
at minimal
Heurt ratr (beats/win.)
and ~maximal rates oj
Q-T interzal (sec.)
j i /
Time in systole (72)
0 0.2 0.6
113 110 89
128 127 120
.27 .27 .28
54 54 53
Control Nitrite Nitrite
0 0.2 0.6
92 88 60
116 116 113
31 31 .32
41 42 42
Control Papaverine Papaverine
0 0.2 0.6
108 95 70
134 134 130
.31 .31 .35
66 65 69
Control Atropine Atropine
0 0.2 0.6
103 107 100
116 117 142
.28 .28 .29
56 56 68
-
trinitrate trinitrate
366
Am. Hart J. March, 1962
Frohlich and Scott
produced by sodium nitrite must have been due to the nitrite anion. The chloride and sulfate ions also failed to alter coronary vascular resistance.” Therefore, the dilation produced by papaverine hydrochloride and atropine sulfate solutions was due to the active cationic principles, papaverine and atropine. Although a vasoactive agent may lower vascular resistance when administered locally, it does not necessarily follow that this substance will increase blood flow when given intravenously. If the agent when administered systemically produces vasodilation in other vascular beds, and thus lowers aortic pressure, coronary blood flow might not change. In fact, coronary perfusion may even decrease despite a fall in coronary vascular resistance. Conclusions
and
D. Jacobson for their kind assistance in the preparation of this paper. REFERENCES 1
2
3
4.
.5
summary
The local effect of isotonic solutions of glyceryl trinitrate, sodium nitrite, papaverine hydrochloride, and atropine sulfate on coronary vascular resistance in the beating, nonworking heart was studied in dogs during cardiopulmonary bypass. Evidence is presented which indicates that glyceryl trinitrate, nitrite, papaverine, and, possibly, atropine produce coronary vasodilation. On a weight basis, glyceryl trinitrate was 90 times as potent as the inorganic nitrite anion and 6 times as active as papaverine. On a molar basis, however, the ratios were 450 and 4, respectively. We wish to express our appreciation to Dr. Francis J. Haddy, Dr. John C. Krantz, and Dr. Eugene
and comments
6.
7.
8.
9. 10.
11.
Krantz, J. C., Jr., Carr, C. J., Forman, S. E., and Cone, N.: Alkyl nitrites. VI. A contribution to the mechanism of action of organic nitrites, J. Pharmacol. & Exper. Therap. 70:323, 1940. Boyer, N. H., and Green, H. D.: The effects of nitrites and xanthines on coronary inflow and blood pressure in anesthetized dogs, -4~. HEART J. 21:199, 1941. Eckenhoff, J. E., and Hafkenschiel, J. H.: The effect of nikethamide on coronary blood llow and cardiac oxygen metabolism, J. Pharmacol. & Exper. Therap. 91:362, 1947. Wills, J. H.: Effects of sodium nitrite and certain organic “nitrates” on blood pressures in the rat, Proc. Sot. Exper. Biol. & Med. 65:161, 1947. \Vinder, C. V., and Kaiser, M. E.: Relative experimental coronary vasodilation potencies and toxicities of papaverine, theophylline, and a papaverine-theophylline molecular association compound, J. Pharmacol. & Exper. Therap. 93:86, 1948. Nuki, B., and Takeya, N.: Pharmacology of the coronary circulation, J. Philippine M. .\. 32: 312, 1956. Scott, J. B., Hardin, R. A., and Haddy, F. J.: Effect of cardiac cooling on coronary vascular resistance in normothermic dogs, Am. J. Physiol. 199:163, 1960. Scott, J. B., Hardin, R. A., and Haddy, F. J.: The effect of epinephrine and norepinephrine upon coronary vascular resistance in the dog, :Zm. J. Physiol. (in press). Haddy, F. J.: Peripheral vascular resistance (Editorial), AM. HEART J. 60:1, 1960. Haynes, R. H., and Burton, A. C.: Role of the non-Newtonian behavior of blood in hemodynamics, Am. J. Physiol. 197:943, 1959. Frohlich. E. D., Scott, J. I3., Hardin, R. A., and Haddy, F. J.: Effect of cations on coronary vascular resistance, Clin. Res. 9:139, 1961.
effect
of glyceryl
papaverine, coronary
and vascular
trinitrate, atropine resistance
Edward D. Frohlich, M.D. fwry B. Scott, M.S. Fort h-nox, h-y.
T
he literature is abundant with studies concerned with the effects of various vasoactive substances on the coronary vascular bed.‘-‘j None, however, permit a comparison by weight and molarity of the local, steady-state effects of the active principle of glyceryl trinitrate, sodium nitrite, papaverine hydrochloride, and atropine sulfate. In addition, the factor of tonicity and its effects on vascular resistance were not seriously considered. Therefore, the present study was designed to quantitate the local vascular effects of the active principle of glyceryl trinitrate, sodium nitrite, papaverine hydrochloride, and atropine sulfate on the coronary vasculature. This was done by measuring coronary perfusion pressure at constant coronary blood flow during intracoronary infusion of isotonic solutions of these agents at rates which provided therapeutic blood concentrations. Materials
and
methods
The study included a total of 18 mongrel dogs anesthetized with sodium pentobarbital (35 mg. per kilogram) and anticoagulated with heparin (5 mg. per kilogram). The preparation has been described in detail in an earlier communication.7 The heart was exposed through the right From the Environmental Received for publication
362
Medicine Division, Aug. 7, 1961.
fourth intercostal space. A rotating disc blood oxygenator, blood heat exchanger, and blood pump were interposed between the left femoral artery and plastic cannulae which were inserted into the superior and inferior venae cavae via the right atrium. The body was thus perfused with oxygenated blood at an average rate of 95 ml. per kilogram per minute, and body temperature was maintained at 37” C. A second pump, interposed between the right femoral artery and the ascending aorta, perfused the coronary vascular bed. By cross-clamping the aorta and pulmonary artery 3 cm. from the heart the output of this pump was thus diverted through the entire coronary circulation. Flow rate was held constant at an average value of 92 ml. per minute (50 to 125 ml. per minute). Coronary venous blood was collected from the right side of the heart with a cannula threaded through the tricuspid valve in such a way as to render the valve incompetent. This blood was returned to the venous limb of the perfusion circuit. Blood from the left side of the heart (from arterioluminal, Thebesian, and bronchial vessels) was collected with another cannula inserted into the left atrium and ventricle through a superior pulmonary vein. A resistance-wire pressure transducer
U. S. Army
Medical
Research
Laboratory,
Fort
Knox,
KY.
Volwne
63
h-umber
Study on glyceryl trinitrate,
3
papaverine,
and atropine
363
Results
120 1 ATROPINE
SOab9,F=92)
60 Na NITRITE h=S,F=S9)
50
4o0
nitrite,
\
L
I 0.5
I 1.0 INFUSION
I 1.5 RATE
I 2.0 (ml./min.l
I 2.5
I
3.0
Fig. 1. Coronaryperfusionpressureasa function of infusionrate of active principle. F, Averageblood flow in milliliters per minute; n, numberof dogs. was utilized to measure pressure in the coronary perfusion tubing just prior to entrance into the ascending aorta. Isotonic solutions, as determined by the Fiske osmometer, of glyceryl trinitrate, sodium nitrite, papaverine hydrochloride, and atropine sulfate were infused into the coronary perfusion circuit at rates of 0.2, 0.5, 0.8, 1.2, 1.6, 2.1, and 2.6 ml. per minute, in that order (Table I). Each rate was maintained for 30 seconds. Coronary perfusion pressure and electrocardiogram were recorded continuously. Pressure, heart rate, and Q-T interval were obtained at the end of each 30-second period, at which time the pressures were stable. Since the rate of blood flow through the coronary vascular bed was held constant and pressure in the right heart remained atmospheric, changes in resistance were therefore directly proportional to changes in coronary artery pressure. The proportion of time spent by the ventricles in systole was calculated from the formula shown below:
Per cent of a minute qxrt
Dose-responseefects. Coronary vascular pressure decreased as a function of the infusion rate of solutions of glyceryl trinitrate, sodium nitrite, and papaverine hydrochloride in each animal (Fig. 1). Infusion of atropine sulfate failed to produce a regular change in pressure. At the maximal infusion rate of 2.6 tnl. per minute, glyceryl trinitrate decreased average coronary perfusion pressure by 21.2 per cent, whereas sodium nitrite, papaverine hydrochloride, and atropine sulfate reduced resistance by 34.0,35.1, and 4.7 per cent, respectively (Table II). Table II presents the change in pressure as a function of the atnount of active principle infused per minute. It may be seen that, on a weight basis, glyceryl trinitrate is by far the most active agent. Table III presents the number of milligrams and moles of each active principle per minute necessary to reduce coronary perfusion pressure by 12 and 20 per cent. From this comparison the active principle of these agents may be ranked according to their potency-in the order: glyceryl trinitrate, papaverine, and nitrite. Electrocardiographic effects. The effects of these substances on the heart rate and Q-T interval allow inferences to be made concerning coronary vessel transmural pressures.8 Table IV compares perfusion pressure, heart rate, Q-T interval, and the proportion of time spent by the ventricles in sl-stole during the control period and during the slowest and most rapid rates of infusion. Glyceryl trinitrate, nitrite, and papaverine failed to change significantly the proportion of a minute spent in systole. Atropine at the maximal infusion rate increased the heart rate, Q-T interval, and the proportion of time spent by the ventricles in systole by 22, 3, and 21 per cent, respectively. Discussion
These studies indicate that, in this prepara,tion, isotonic solutions of glyceryl trinitrate, sodium nitrite, and papaverine
Q-T Interval X HR in systole = -__6O
x 100.
364
Frohlich
and Scott
Table I. Osmolarity dog
and concentration
Solution
of solutions
Osmolarity (mOsnz./Rg.)
Glyceryl trinitrate Sodium nitrite Atropine sulfate Papaverine hydrochloride
Table II. Reduction principle Glyceryl
in
&nitrate
Presszzre change (75 of control)
0.02 0.05 0.08 0.12 0.16 0.21 0.26
- 2.6 -12.3 -17.6 -19.4 -19.4 -20.3 -21.2
into the coronary vascular
perfusion
coronary
0.10 10.87 2.00 3.25
pressure
as
Nitrite
i Ilzfzzsion rate (nzg./nzin.)
a
1.45 3 63 5.80 8.70 11.60 15.23 18.85
- 3.2 - 8.7 -15.3 -18.6 -25.2 -29.6 --.3&O
Infusion rate (mg./nzin.)
function
Table III. Comparison of amounts of active principle duce equal reduction in coronary perfusion pressure
infusion
of
Infz4sion rate (mg./wzin.)
-12.0 -19.4 -24.0 -28.7 -32.1 --33..1 --35.1
rate of active
d tropine
!
Presszire change (‘;I of control),
0.29 0.74 1.18 1 .76 2 3.5 3.09 3.82
the
of
0.10 7.25 1.70 1.47
Papaverine
Pressure change (7; of control)
bed
Concentration oJ artiae principle (nzg./ml. 1
Concentration (nzg./nzl. )
30.5 31.5 312 276
---.-----.-, Infusion rate (mg./min.)
in&ced
Prcss11re
(s,
0.34 0.85 1.36 2.01 2.72 3.57 4.42
by weight and molarity
change 0f control) +0.9 -0.9 -1 .8 -2.8 -3.7 -1.8 -2.9
necessary to
pro-
I Agent
__~_.~.
12 per cuzt reduction ~__~ ~~~_ ~~~~~ ._
mg./nzin. Glyceryl trinitrate Nitrite Papaverine
0.05 1.89 0.29
hydrochloride produced a decrease in coronary vascular resistance as a function of the rate of steady-state infusion of the active principle. Atropine sulfate produced no apparent change in the vascular resistance. Although the formulation of an exact potency ratio between various drugs from dose-response curves is difficult, it is possible to arrive at a general approximation of their respective relationships. From the
moles/min. 2.2 x 1.2 x 8.6X
10-T 10-1 10-i
20 per cent reduction __~~ wzg./nzin. 0.12 9.3.5 0.76
moles/mi?z. 5.3 x ‘.0X 2.2x
10-7 10-d 10~~”
data in Tables II and III, on a weight basis, glyceryl trinitrate is 98 times as potent as the nitrite anion when coronary vascular resistance is reduced by 12 per cent, and 88 times as potent when resistance is clecreased by 20 per cent. On a molar basis, however, glyceryl trinitrate is 545 and 377 times as potent when resistance is reduced by 12 and 20 per cent, respectively. Glyceryl trinitrate is 6 times as active as papaverine, on a weight basis, at both the
Study on glyccryl trinitrate,
12 and 20 per cent reduction levels. When a molar comparison is made, glyceryl trinitrate is 4 times as potent as papaverine, whether the resistance is decreased by 12 or 20 per cent. Therefore, at two different infusion levels, at which significant decrease in coronary vascular resistance is produced, there is essentially no difference in the reLltionships of potency of these drugs. Hence, on a comparison of weight, glyceryl trinitrate is approximately 90 times as potent as nitrite, and 6 times as active as papaverine. When this comparison is expressed on a molecular basis, however, the organic glyceryl trinitrate is approxinlately 4.50 times as potent as the inorganic nitrite anion, and 4 times the strength of papaverine. This relationship is also apparent from the curves in Fig. 1. The fall in coronary vascular resistance most likely resulted from an increase in the caliber of the vessels. Resistance to blood flow through a vascular bed is determined by blood viscosity and vessel geometry.g Blood viscosity did not change significantly during administration of these agents because the maxitnal infusion rate of the solutions diluted the blood by only 2.6 per cent. Furthermore, changes in viscosity due to reorientation of the red blood cells in the flowing stream need not be seriously considered since flow rate was l-able IV. Efect infusion
Agent
Control Glyceryl Glyceryl
of active principles
Infusion rate (ml./min.)
nitrite,
papavcrine,
and atropint,
365
held constant and pressures and flows were well above the range in which this “phenomenon” occurs.*O Because intramyocardial pressure was not measured, it cannot be stated with certainty whether the dilation was active, due to a change in the contractile state of the smooth muscle within the vessel wall, or passive, due to an increase in vessel transmural pressure subsequent to a decrease in intramyocardial pressure. The absence of a change in the per cent of a minute spent in electrical systole suggests that intramyocardial pressure was not altered b, changes in the relationship of mechanical systole to diastole, but does not provide information regarding the strength of myocardial contraction. Passive dilation due to dehydration of the vessel wall need not be considered because all solutions infused were isosmotic to plasma. Thus, glyceryl trinitrate, nitrite, and papaverine produce coronary vascular dilation when administered locally over the concentration ranges which might occur during therapy. The fact that atropine increased the proportion of a minute spent in systole, without significantly changing perfusion pressure, suggests that atropine also dilates coronary vessels. Previous studies” have shown that the sodium ion produces no change in coronary vascular resistance. Hence, the dilation
upon several parameters
Coronary pressure (mm. Hg)
at minimal
Heurt ratr (beats/win.)
and ~maximal rates oj
Q-T interzal (sec.)
j i /
Time in systole (72)
0 0.2 0.6
113 110 89
128 127 120
.27 .27 .28
54 54 53
Control Nitrite Nitrite
0 0.2 0.6
92 88 60
116 116 113
31 31 .32
41 42 42
Control Papaverine Papaverine
0 0.2 0.6
108 95 70
134 134 130
.31 .31 .35
66 65 69
Control Atropine Atropine
0 0.2 0.6
103 107 100
116 117 142
.28 .28 .29
56 56 68
-
trinitrate trinitrate
366
Am. Hart J. March, 1962
Frohlich and Scott
produced by sodium nitrite must have been due to the nitrite anion. The chloride and sulfate ions also failed to alter coronary vascular resistance.” Therefore, the dilation produced by papaverine hydrochloride and atropine sulfate solutions was due to the active cationic principles, papaverine and atropine. Although a vasoactive agent may lower vascular resistance when administered locally, it does not necessarily follow that this substance will increase blood flow when given intravenously. If the agent when administered systemically produces vasodilation in other vascular beds, and thus lowers aortic pressure, coronary blood flow might not change. In fact, coronary perfusion may even decrease despite a fall in coronary vascular resistance. Conclusions
and
D. Jacobson for their kind assistance in the preparation of this paper. REFERENCES 1
2
3
4.
.5
summary
The local effect of isotonic solutions of glyceryl trinitrate, sodium nitrite, papaverine hydrochloride, and atropine sulfate on coronary vascular resistance in the beating, nonworking heart was studied in dogs during cardiopulmonary bypass. Evidence is presented which indicates that glyceryl trinitrate, nitrite, papaverine, and, possibly, atropine produce coronary vasodilation. On a weight basis, glyceryl trinitrate was 90 times as potent as the inorganic nitrite anion and 6 times as active as papaverine. On a molar basis, however, the ratios were 450 and 4, respectively. We wish to express our appreciation to Dr. Francis J. Haddy, Dr. John C. Krantz, and Dr. Eugene
and comments
6.
7.
8.
9. 10.
11.
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