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Coronary vasoconstrictor responses to ergometrine were examined in spiral coronary arterial preparations of dogs. Either ergometrine or serotonin (5-HT) produced dose-dependent contractions of the strips. Methysergide significantly depressed the contractions induced by ergometrine or 5-Ht. Dihydroergotamine and phentolamine depressed constrictor responses to ergometrine, while phenoxybenzamine did not. The 5-HT antagonistic action of phentolamine was stronger than that of phenoxybenzamine. The results indicate that ergometrine may act on coronary arteries mainly through activation of 5-HT receptors.

Effects of nipradilol which is a new beta-adrenoceptor blocking agent endowed with nitroglycerin-like vasodilator actions, its denitrated derivative (denitro nipradilol) and propranolol on abnormalities of regional myocardial shortening produced by partial occlusion of the left circumflex coronary artery (LCX) were studied in anaesthetized open-chest dogs. In the presence of LCX stenosis, nipradilol (0.1 mg kg-1, i.v.) produced marked decreases in heart rate and LVdP/dt without a significant increase in left ventricular end-diastolic pressure (LVEDP). It improved impaired myocardial segment shortening and restored normal cardiac lactate metabolism. Denitro nipradilol (0.2 mg kg-1 i.v.) and propranolol (0.2 mg kg-1 i.v.) both caused similar haemodynamic changes to nipradilol but also produced a significant increase in LVEDP. However, improvement by these two agents of regional dysfunction in the ischaemic myocardium was comparable to those seen with nipradilol. All three agents markedly inhibited isoprenaline-induced tachycardia, but vehicle did not. Atrial pacing abolished the beneficial effect of nipradilol on myocardial shortening in the ischaemic region without affecting other haemodynamic parameters. These results indicate that nipradilol alleviates acute myocardial ischaemia produced by coronary stenosis with similar efficacy to denitro nipradilol and propranolol suggesting, that a major part of the beneficial effect of nipradilol may be attributable to its beta-adrenoceptor blocking action.

Effects of arotinolol on dog coronary arteries were investigated in vitro. In distal portions of left circumflex coronary arteries contracted with 3 X 10(-2)M KCl, norephinephrine relaxed the strips in a concentration-dependent fashion. Propranolol (10(-6)M) converted the norepinephrine-induced relaxations to contractions, and arotinolol (10(-6)-10(-5)M) inhibited the relaxations induced by norepinephrine in a concentration-dependent manner. In proximal portions of the strips after potassium-contracture, norephinephrine produced concentration-dependent contractions which were augmented by propranolol (10(-6)M) and inhibited by arotinolol (10(-6)-10(-5)M). These results suggest that arotinolol has an alpha-adrenoceptor blocking activity in addition to a beta-adrenoceptor blocking action in dog coronary arteries.

The relationship between responsiveness and high-energy phosphate metabolism was observed in isolated dog coronary arterial strips before and after equilibration, under aerobic conditions. The strips responded slowly to potassium, norepinephrine, isoproterenol and 5-hydroxytryptamine before being equilibrated but did respond quickly to these drugs after being equilibrated for 1 hour under aerobic conditions. The contents of ATP, creatine phosphate (CP) and lactate were not significantly altered before and after equilibration for 1 hr. It is proposed that, before being equilibrated under aerobic conditions, coronary arteries may be unable to utilize ATP and CP due to injury of contractile or relaxant mechanisms resulting in a weak vascular responsiveness.

The effects of nicardipine on sodium-calcium exchange activity of cardiac sarcolemma-enriched vesicles isolated from the rat heart were examined. Sodium-loaded, sarcolemma-enriched vesicles, when exposed to a medium containing 40 μM CaCl 2 , exhibited about 5 nmoles Ca 2+ /mg protein of the maximal calcium uptake; the initial rate was 21 nmoles Ca 2+ /mg protein/min. The calcium uptake was dependent on the extravesicular concentration of calcium ion. Nicardipine at concentrations of 0.1 to 10 μM depressed the rate of calcium uptake activity by 60–90%. The isolated membrane vesicles preloaded with Ca 2+ showed a calcium efflux activity, when exposed to a medium containing sodium ion. The rate of calcium efflux was 2.5 nmoles Ca 2+ /mg protein/min, when measured in a medium containing 6.5 mM NaCl. The efflux rate was facilitated with increased concentrations of sodium ion in the medium. About 75% of the preloaded calcium in the vesicles was released within 3 min of incubation. The rate of calcium efflux was stimulated in the presence of 0.1 to 10 μM nicardipine (2.5- to 4-fold increase). The present results suggest a possible action of nicardipine on the sodium-calcium exchange mechanism at cardiac sarcolemmal sites.

Effects of dihydroergotamine on the microcirculation of the rat cremaster muscle were investigated microscopically using colour photographic technique. 1. Dihydroergotamine 10(-4) g/ml constricted arterioles of the rat cremaster. 2. Dihydroergotamine 10(-4) g/ml produced a significant contraction of venules. 3. Dihydroergotamine 10(-4) g/ml markedly inhibited the contractile response of noradrenaline 10(-6) g/ml on arterioles of the rat cremaster. The results suggest that dihydroergotamine has an appreciable vasoconstrictive action, especially upon venules, and that dihydroergotamine also has an adrenergic alpha-receptor blocking action. By means of highly sensitive negative colour film we obtained a satisfactory photograph of the rat cremaster's circulation.

To evaluate the cardiac effect of an inhibitor of angiotensin-converting enzyme, the effect of intracoronary (i.c.) captopril on coronary blood flow and regional myocardial function was examined in the anesthetized open-chest dog. Blood flow of the left circumflex coronary artery (LCX), left ventricular pressure (LVP), aortic pressure (AoP) and regional myocardial segment length were measured continuously. Captopril i.v. (0.3 mg/kg) produced an immediate reduction in AoP and an increase in percent shortening of myocardial segments followed by a decrease in coronary vascular resistance and increases in heart rate and LVdP/dt. Reductions in LCX flow induced by i.c. angiotensin were attenuated and i.c. bradykinin-induced increases in LCX flow were augmented after captopril. On the contrary, i.c. infusion of captopril (0.01 mg/min) into the LCX caused no change in hemodynamic variables and myorcardial shortening although responses to angiotensin I and bradykinin were markedly modified. These results suggest that captopril may have no direct cardiac effect.

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.

Hemodynamic parameters, segment shortening in the ischemic myocardium and cardiac lactate extraction were estimated in the presence of a critical coronary stenosis, before and after administration of the selective beta 2-adrenoceptor antagonist, ICI 118,551, or the beta 1-adrenoceptor antagonist, atenolol, to anesthetized dogs. ICI 118,551 (0.2 and 0.5 mg/kg i.v.) and atenolol (0.2 mg/kg i.v.) produced significant decreases in both heart rate (by 6, 14 and 20% of the predrug value, respectively) and maxLVdP/dt (by 15, 26 and 24% of the predrug value, respectively). ICI 118,551 (0.5 mg/kg) and atenolol significantly improved the impaired shortening of the myocardial segment when compared with the change seen after saline administration. ICI 118,551 at both doses and atenolol significantly increased depressed cardiac lactate extraction while saline did not. Increasing heart rate by pacing abolished the beneficial effects of ICI 118,551 and atenolol on ischemic myocardial segment shortening and lactate metabolism. The data suggest that not only beta 1- but also beta 2-adrenoceptor blockade may contribute to the amelioration of myocardial ischemia in a model of coronary stenosis.

To evaluate the cardiac effect of an inhibitor of angiotensin-converting enzyme, the effect of intracoronary (i.c.) captopril on coronary blood flow and regional myocardial function was examined in the anesthetized open-chest dog. Blood flow of the left circumflex coronary artery (LCX), left ventricular pressure (LVP), aortic pressure (AoP) and regional myocardial segment length were measured continuously. Captopril i.v. (0.3 mg/kg) produced an immediate reduction in AoP and an increase in percent shortening of myocardial segments followed by a decrease in coronary vascular resistance and increases in heart rate and LVdP/dt. Reductions in LCX flow induced by i.c. angiotensin were attenuated and i.c. bradykinin-induced increases in LCX flow were augmented after captopril. On the contrary, i.c. infusion of captopril (0.01 mg/min) into the LCX caused no change in hemodynamic variables and myocardial shortening although responses to angiotensin I and bradykinin were markedly modified. These results suggest that captopril may have no direct cardiac effect.

The effects of propranolol and atenolol on isolated dog coronary arteries contracted with potassium were investigated in vitro. Propranolol at high concentrations (3 x 10(-5)-10(-4) M) produced relaxations of the coronary arterial strips, which were restored or prevented by exogenous calcium ions. Atenolol (10(-5)-10(-4) M) never changed the tension of the strips. The results suggest that propranolol may inhibit the coronary arteries through its calcium antagonistic action.

Under pentobarbitone anesthesia, arterial blood pressure and heart rate were recorded in rabbits. The elevation in systemic blood pressure and increased heart rate induced by electrical stimulation of the right thoracic sympathetic nerve trunk were depressed by either an intravenous injection of diltiazem (300 micrograms/kg) or by placing cotton pledgets soaked in 2 mM diltiazem solution onto the right stellate ganglion. These inhibiting effects of diltiazem were statistically significant with high sympathetic stimulation frequencies (10-20 Hz), but not when lower frequencies (1-5 Hz) were used. On the other hand, hexamethonium (10 mg/kg i.v. or 100 mM applied topically) depressed cardiovascular responses to sympathetic stimulation over a wide range of frequencies (1-20 Hz). Present results reveal a frequency-dependent inhibition of ganglionic transmission by diltiazem, and suggest that diltiazem may depress excessive sympathetic activity without affecting normal ganglionic transmission.

Effects of prostaglandins (PGs) E1, E2, E2 and F2 alpha on the vesical and urethral smooth muscles of dogs were isometrically investigated in vitro. In vesical smooth muscles, 10(-8)-10(-6) PGE1/ml produced biphasic responses in the dome preparations; relaxation at 10(-8) g/ml and contractions at 10(-7)-10(-6) g/ml. In the trigone preparations, 10(-8)-10(-6) g PGE1/ml caused dose-dependent contractions. 10(-8)-10(-6)M g PGE2/ml and 10(-7)-10(-6) g PGF2 alpha /ml induced dose-dependent contractions of the dome and the trigone preparations. In urethral smooth muscles, 10(-8)-10(-6) g PGE1/ml and 10(-8)-10(-6) g PGE2/ml produced dose-dependent relaxations, while 10(-8)-10(-6) g PGF2 alpha /ml caused dose-dependent contractions. Results indicate that PGE, particularly PGE2, is able to stimulate micturition through vesical contraction and urethral relaxation.

Afferent discharges of 64 single units were recorded from the left cardiac sympathetic nerve of anesthetized cats. Mechano-sensitive terminals of the afferent fibers were localized in the extrapulmonary part of the pulmonary artery, left atrium, left ventricle and left pericardium, as determined by direct mechanical probing of the heart after death of the animals. Conduction velocity of the fibers ranged from 2.5 to 14.6 m/s. Excitation of these Adelta-fibers with mechanically excitable endings was produced by intravenous injections of acetylcholine, 5-hydroxytryptamine, bradykinin, histamine and veratridine, and/or by topical application of these agents to the receptor region. Noxious heat to the mechanically excitable field in the wall of the pulmonary artery and the left ventricle also activated their afferent fibers. These observations provide evidence for a certain number of afferent units in the cardiac sympathetic nerve with polymodal sensitivity. These afferent fibers can provide the spinal cord with information not only on mechanical changes in cardiac events, but also changes in the chemical environment of the cardiac nerve ending, possibly produced by myocardial ischemia.

Effects of 4-aminopyridine (4-AP) and tetraethylammonium (TEA) on vasodilator actions of 2-nicotinamidoethyl nitrate (SG-75) were investigated using isolated dog coronary arteries. SG-75 10(-8)--10(-4) Gm/ml produced concentration-dependent relaxations of coronary arterial strips which were contracted with potassium 30 mM or prostaglandin (PG) F2 alpha 10(-6) Gm/ml. Both 4-AP 5 x 10(-4) Gm/ml and TEA 1.6 x 10(-3) Gm/ml produced further contractions of the strips under potassium or PGF 2 alpha contracture. The potency to constrict the strips was greater in 4-AP than in TEA. 4-AP 5 x 10(-4) Gm/ml and TEA 1.6 x 10(-3) Gm/ml did not affect the SG-75-induced relaxations of the strips under potassium-contracture, but significantly depressed them under PGF2 alpha-contracture. In the strips under a resting state, 4-AP 5 x 10(-4) Gm/ml increased tension and produced oscillations in their contractions, but TEA 1.6 x 10(-3) Gm/ml did not. Results suggest that SG-75 may display its relaxant effect on isolated dog coronary arteries in part through an increase in potassium conductance.

Calcium uptake and binding activities of microsomal fractions from bovine coronary artery and aorta were examined. The isolated microsomal fraction of the coronary artery and aorta showed 7- to 8-fold higher glucose-6-phosphatase activity and 4- to 6-fold higher NADPH-cytochrome c reductase activity as compared with the corresponding values for the homogenate fraction. Coronary artery and aorta microsomal calcium uptake activities were 118 and 159 nmoles Ca2+/mg protein/10 min in the presence of 100 microM CaCl2, respectively. These activities for bovine vascular smooth muscle microsomes are higher than those of other species investigated. The calcium uptake activities were dependent on calcium concentrations ranging from 5 to 50 microM in the assay medium. The onset of the reaction for aorta microsomal calcium uptake was faster than that for the coronary artery. The calcium uptake activity was also dependent on ATP, but it was practically independent of oxalate ions in the assay medium. Microsomal calcium binding activities of the coronary artery and aorta were maximal at 20 min of incubation under the present experimental conditions. A lower Km value of the aortic calcium binding for ATP was obtained as compared with that for the coronary artery. The present experiment explored several characteristics of the microsomal calcium-accumulating ability of vascular smooth muscle, which provides meaningful information for further study on cellular calcium movements in vascular smooth muscle.

We investigated the mechanisms responsible for indomethacin-induced contractions of coronary arteries. In isolated dog hearts perfused through the coronary circulation with blood under constant pressure, an intracoronary injection of 1 mg of indomethacin decreased coronary blood flow without significant changes in myocardial contractile force and heart rate. Indomethacin (10(-8)-10(-5) M) caused concentration-dependent contractions of isolated dog coronary arterial strips. These contractions were significantly inhibited by calcium-free solution, diltiazem, nifedipine, prostaglandin E1, arachidonic acid, and phospholipase A2, but not by phenoxybenzamine, atropine, or oleic acid. Propranolol and prostaglandin F2 alpha tended to enhance the contractions. The results indicate that indomethacin contracts dog coronary arteries through inhibition of intramural synthesis of vasodilating prostaglandins.

In the lightly anesthetized cats, acute asphyxia alone did not produce any afferent discharges in the cardiac sympathetic nerve, while prolonged low ventilation provoked spontaneous afferent discharges and acute asphyxia combined with low ventilation increased the frequency of the impulses. Intravenous injection of epinephrine, acetylcholine and veratrine did not elicit afferent activities of the cardiac sympathetic nerve and also had no effect on the discharges caused by low ventilation. Intrapericardial injection of procaine abolished the afferent discharges in the nerve exerted by prolonged low ventilation. It seems that some metabolic factors produced by low ventilation would be responsible for the initiation of impulses at the afferent nerve endings of cardiac sympathetic innervation.

In 21 open-chest dogs, changes in coronary hemodynamics and left ventricular function were evaluated after an injection of Captopril (C). C (0.01-0.3 mg/kg i.v.) immediately decreased aortic pressure (AoP) in a dose-related manner and also declined left ventricular end-diastolic pressure. No changes in left ventricular dP/dt and heart rate were observed after C. Although left circumflex coronary blood flow was slightly decreased along with a decline in AoP, coronary vascular resistance was significantly reduced by C. After C, pressor changes caused by angiotensin I were dose-dependently attenuated and those by angiotensin II were augmented, while those by norepinephrine were not altered. Percent inhibition of the response to angiotensin I and maximum reduction in AoP after C were significantly correlated. However, despite the fact that the response to angiotensin I was inhibited over 70 % by C, additional injections of C caused slight but significant decreases in AoP and coronary vascular resistance. In isolated coronary strips from dogs, C (

Isolation of mitochondrial fraction from bovine coronary artery and aorta was examined. Coronary artery and aorta were pretreated with collagenase; then the mitochondria were isolated using a differential centrifugation method. Cytochrome c oxidase activities of mitochondria isolated from coronary artery and aorta were 25-fold and 19-fold higher as compared with those of the homogenates, respectively. Mitochondrial calcium binding activity of coronary artery was about 150 nmoles Ca/mg protein at 20 min, and the calcium uptake activity was about 250 nmoles Ca/mg protein/10 min. The calcium uptake activity was depressed in the presence of several metabolic inhibitors such as sodium azide(90 % inhibition), ruthenium red(98 % inhibition) and 2,4-dinitrophenol(70 % inhibition). Sensitivity to the metabolic inhibitors and calcium accumulating activity of the bovine aortic mitochondrial fraction were similar to those of the fraction from coronary artery.