Comparison of the acute hemodynamic and coronary vasodilating effects between nicorandil and glyceryl trinitrate.

Acute hemodynamic and coronary vasodilating effects of nicorandol (SG-75, Sigmat; CAS 65141-46-0) and glyceryl trinitrate (GTN, nitroglycerin) were examined in 20 subjects under cardiac catheterization and coronary arteriography. Nicorandil 4 mg i.v. produced significant increases in heart rate, cardiac index and stroke volume index and significant decreases in systolic, diastolic and mean blood pressure, pulmonary capillary wedge pressure, left ventricular enddiastolic pressure, systemic vascular resistance and total pulmonary resistance. Degree of percent changes in these parameters by nicorandil were similar to that by GTN 0.3 mg i.v. Coronary vasodilating effects of both drugs were also at the same degree. Results indicate that nicorandil has cardiovascular and coronary vasodilating effects similar to those of GTN when administered intravenously.

Chronic effects of tolbutamide on myocardial tension during ischemia and reperfusion in perfused hearts isolated from insulin dependent and non insulin dependent diabetic rats.

The chronic effects of tolbutamide on myocardial contractility of the diabetic heart during ischemia and reperfusion were evaluated in perfused, isolated rat hearts. Five experimental groups were used: (1) control rats (C), (2) insulin dependent diabetic rats (IDDM, single intravenous injection of 60 mg/kg streptozotocin (STZ) in male Sprague-Dawley rats), (3) non insulin dependent diabetic rats (NIDDM; single subcutaneous injection of 90 mg/kg STZ in 5 day neonates), (4) tolbutamide-treated IDDM and (5) NIDDM (T-IDDM, T-NIDDM; giving tolbutamide 100 mg/kg/day for 6 weeks via an orogastric tube every day, respectively). At 14 weeks of age, experiments were performed using a Langendorff perfused heart preparation. After equilibration, T (myocardial developed tension), +dT/dt (contraction velocity), -dT/dt (relaxation velocity) and RT (resting tension) were measured during a 15 min period of global ischemia, followed by reperfusion for 20 min. Basal values of T increased in both T-IDDM and T-NIDDM, compared to IDDM and NIDDM, respectively. The percent recovery rate of +dT/dt in T-IDDM increased significantly during both ischemia and reperfusion, but the change in T-NIDDM was not significant. The recovery rates of -dT/dt in T-IDDM and T-NIDDM were significantly higher throughout reperfusion than in IDDM and NIDDM, respectively. On the other hand, that of T in T-IDDM and T-NIDDM were significantly higher than IDDM and NIDDM throughout ischemia and reperfusion, respectively. The RT was significantly higher in IDDM than in C and NIDDM throughout ischemia and reperfusion. The RT was significantly lower during ischemia in IDDM, but it did not differ significantly from IDDM during reperfusion. These results indicate that chronic oral administration of tolbutamide directly improved myocardial contractility throughout ischemia and reperfusion regardless of the improvement of glycemia. The improvement was also greater in IDDM than in NIDDM.

Glutathione S-transferases and chloroform toxicity in streptozotocin-induced diabetic rats.

The glutathione S-transferase activity in liver and kidney cytosol was significantly decreased in short term diabetes induced with streptozotocin, whereas no decrease in the transferase was observed in phenobarbital-treated diabetic rats. Toxicity of chloroform was potentiated in streptozotocin- or phenobarbital-treated rats. The decrease in liver cytosolic and microsomal glutathione S-transferase activity was observed in long term diabetic rats, and only microsomal transferase activity was restored by insulin treatment. There was no release of glutathione S-transferases into the serum in the diabetic rats, and the transferases were not inhibited by streptozotocin in vitro. These results showed that glutathione S-transferase activity decreased during diabetes, and this decrease may contribute to altering drug metabolism and toxicity in diabetes.

Effects of dobutamine and acetylcholine on perfused hearts isolated from streptozocin-induced diabetic rats.

In order to study the responsiveness of the diabetic heart to autonomic agents, effects of dobutamine (DOB) and acetylcholine (ACh) on perfused hearts isolated from streptozocin (streptozotocin, STZ)-induced diabetic rats and insulin-treated diabetic rats were evaluated. Male Sprague-Dawley rats, weighing 180-210 g, were divided into control (C) group, diabetes mellitus (DM) group, and diabetes mellitus treated with insulin (DMI) group. C group was injected with buffered vehicle. DM and DMI groups were injected intravenously with 60 mg/kg STZ at the first day. Three days after STZ injection, DMI group was subsequently treated with 4 U of insulin zinc suspension (lente insulin) subcutaneously every day. At 45 days after injection of STZ, experiments were performed using a Langendorff perfused heart preparation. In the evaluation of effect of ACh, heart rate and myocardial developed tension (T) were measured. In the evaluation of effect of DOB, heart was paced at 300 beats/min and T was measured isometrically. Plasma glucose values (mg/dl) were 116.0 +/- 4.9 in C, 482.3 +/- 30.3 in DM, and 204.6 +/- 34.8 in DMI group, respectively. The order of percent increases in T induced by DOB (10(-8)-3 x 10(-6) g) was C greater than DMI greater than DM. The order of percent decreases in T and heart rate by ACh (10(-7)-3 x 10(-6) g) was C greater than DMI greater than DM. These results suggest that both adrenergic receptor-mediated and cholinergic receptor-mediated cardiac responsiveness are significantly depressed in the diabetic heart.

Effects of intracoronary propranolol on coronary blood flow and regional myocardial function in dogs.

The study was conducted to evaluate the effects of intracoronary administration of dl-propranolol on coronary blood flow and regional myocardial function in anesthetized open-chest dogs. The results were compared with those obtained with d-propranolol, atenolol and lidocaine. Bolus intracoronary injections of dl-propranolol (0.02-2 mg) dose dependently produced transient increases in coronary blood flow and subsequent depression in regional segment shortening which qualitatively resembled those produced by the dextro isomer (0.02-2 mg) and lidocaine (0.2-10 mg). Atenolol (up to 2 mg) was almost devoid of these effects. Isoproterenol-induced responses were abolished by dl-propranolol and atenolol but only incompletely blocked by d-propranolol. These results demonstrate that propranolol at high doses has direct coronary vasodilating and cardiodepressant effects in situ, and indicate that the major part of these effects can be attributed to the membrane-stabilizing action rather than beta-adrenoceptor blockade.

Effects of adrenergic drugs on isolated and perfused hearts of streptozotocin-induced diabetic rats.

To examine the myocardial contractile response of the diabetic heart, effects of isoproterenol (ISO) and norepinephrine (NE) on perfused hearts isolated from streptozotocin (STZ)-induced diabetic rats and insulin-treated diabetic rats were evaluated. Male Sprague-Dawley rats, weighing 200-260 g, were divided into the control (C)-group, diabetes mellitus (DM)-group and diabetes mellitus treated with insulin (DMI)-group. The C group was injected with buffered vehicle. DM and DMI groups were injected intravenously with 60 mg/kg STZ on the first day. Three days after STZ injection, the DMI group was subsequently treated with 4 U of Lente insulin subcutaneously every day. At 45 days after injection of STZ, experiments were performed using a Langendorff perfused heart preparation. The heart was paced at 300 beats/min, and myocardial developed tension (T) was measured isometrically. Plasma glucose values (mg/dl) were 142.4 +/- 8.7 in C, 499.3 +/- 15.6 in DM and 370.6 +/- 27.6 in DMI group. The order of percent increase in T induced by ISO (3 X 10(-9) - 3 X 10(-8) g) was C = DMI much greater than DM, and that by NE (10(-7) - 10(-6) g) was C greater than DMI greater than DM. On the other hand, the percent increase in T induced by CaCl2 (1.1 X 10(-4) - 2.2 X 10(-3) g) and aminophylline (AMI, 0.31 X 10(-3) - 5.00 X 10(-3) g) was not significantly different among three groups. These results indicate that adrenergic receptor-mediated contractile response was significantly depressed in the diabetic heart.

Responses of renal, coronary and vertebral vasculatures to MC-838 and captopril in anesthetized dogs.

The regional hemodynamic effects of MC-838, a new angiotensin-converting enzyme inhibitor, and captopril at equidepressor doses were examined in the anesthetized dog by simultaneously measuring renal (RBF), coronary (CBF), vertebral (VBF) arterial and aortic blood flow (AoF). Hemodynamic responses to angiotensin I (AI), AII and noradrenaline were compared before and after the administration of each inhibitor. MC-838 (3 mg/kg i.v.) lowered gradually aortic pressure (AoP) and increased moderately AoF and RBF up to 60 min after the administration. Captopril (0.1 mg/kg i.v.) lowered AoP immediately after the administration and increased AoF and RBF more shortly than MC-838. Neither inhibitor produced a marked change in VBF or CBF. The effects of the inhibitors in the renal vascular bed was much greater than that in vertebral and coronary vascular beds, although vascular resistance in all of them was significantly reduced. Each of the drugs inhibited the pressor and renal vasoconstrictor responses to AI. These results indicate that the renal vasculature is more sensitive to both MC-838 and captopril than vertebral and coronary vasculature, but MC-838 has a slower and longer-lasting action than does captopril.

Comparison of vasodilating effects of nisoldipine and nifedipine in anesthetized open-chest dogs.

Hemodynamic effects of nisoldipine (Bay k 5552) were compared with those of nifedipine in anesthetized open-chest dogs. Both nisoldipine and nifedipine produced a fall in aortic pressure and increases in aortic, vertebral and coronary blood flows. After administration of nisoldipine, renal blood flow, heart rate and left ventricular enddiastolic pressure were not changed, but left ventricular dP/dt was increased. After administration of nifedipine, renal blood flow and left ventricular dP/dt were decreased, and left ventricular enddiastolic pressure was elevated. Heart rate was hardly changed. Durations of increases in aortic, vertebral and coronary blood flows were about 3 times longer after nisoldipine than after nifedipine. Percent decrease in coronary vascular resistance was greater and percent decrease in renal vascular resistance was smaller than that in total peripheral vascular resistance with both nisoldipine and nifedipine. Results indicate that nisoldipine and nifedipine produce marked coronary vasoldilation and the vasodilating effect of nisoldipine lasts longer than that of nifedipine.

Vasodilating effects of nicorandil and nitroglycerin in anaesthetized open-chest dogs.

Vasodilating effects of intravenous administrations of nicorandil (SG-75) and nitroglycerin were analyzed in anaesthetized open-chest dogs by measuring simultaneously, and continuously, coronary (CBF), vertebral (VBF), renal (RBF) and aortic blood flow (AoF). Nicorandil 10-300 micrograms/kg i.v. and nitroglycerin 1-30 micrograms/kg i.v. decreased aortic blood pressure and increased CBF in a dose-dependent fashion. The doses of nicorandil and nitroglycerin which reduced coronary vascular resistance to about 60% of the predrug value were 100 micrograms/kg and 10 micrograms/kg, respectively. Nicorandil 100 micrograms/kg i.v. significantly increased AoF and heart rate, significantly decreased left ventricular end-diastolic pressure and did not significantly change VBF, RBF and left ventricular dP/dt. Nitroglycerin 10 micrograms/kg i.v. significantly increased VBF and heart rate, significantly decreased left ventricular end-diastolic pressure and produced an initial increase followed by a decrease in AoF and RBF. When compared with these doses of both drugs, the ratio of percent decrease in coronary vascular resistance to that in total peripheral resistance was over 1.0 in both drugs and the value of this ratio in nicorandil was significantly larger than that in nitroglycerin. The duration of increase in CBF produced by nicorandil 10-300 micrograms/kg i.v. was dose-dependent, but was not changed by nitroglycerin 1-30 micrograms/kg i.v. The results indicate that nicorandil and nitroglycerin dilate coronary vasculature more markedly than other vascular beds and that the potency of selective coronary vasodilatation and the duration of action are more significant in nicorandil than in nitroglycerin.

Comparison of acute hemodynamic effects of MC-838, a new angiotensin-converting enzyme inhibitor, with captopril in anesthetized dogs.

Effects of a new angiotensin-converting enzyme inhibitor, N-[3-(N-cyclohexanecarbonyl-D-alanylthio)-2-methylpropanoyl] -L-proline calcium (MC-838), on the systemic and coronary circulation were evaluated in anesthetized dogs, and the effects were compared with those of captopril. Administration of MC-838 (0.1, 0.3, 1.0 and 3.0 mg/kg, i.v.) produced a gradual and dose-dependent decline in aortic pressure associated with no marked changes in coronary blood flow, heart rate and LVdP/dt. Captopril (0.01, 0.03, 0.1 and 0.3 mg/kg, i.v.) also caused a dose-related decrease in aortic pressure, but the significant hypotension appeared more rapidly than that of MC-838. Both MC-838 and captopril inhibited selectively the pressor response to angiotensin I in a dose-related manner. The doses of MC-838 and captopril to lower mean aortic pressure by 10 mmHg from the pre-drug value were 2.8 mg/kg and 0.03 mg/kg, respectively; those of these drugs to cause 50% inhibition of angiotensin I-pressor response were 1.0 mg/kg and 0.04 mg/kg, respectively. When administration of MC-838 (3.0 mg/kg) was repeated three times at a 30 min-interval, the second and third injections caused no additional hypotension, while each of the repeated injections of captopril (0.3 mg/kg) produced significant hypotension. These results indicate that MC-838 inhibits angiotension I-conversion and decreases systemic blood pressure more slowly and persistently than captopril in anesthetized dogs.