Pharmacological actions of "kyushin," a drug containing toad venom (3): Effects on experimentally induced arrhythmia.

The pharmacological effects of the toad venom-containing drug "kyushin" on aconitine- and thyroxine-induced arrhythmia in guinea pigs, on the conduction system in Langendorff preparations of rabbit hearts and on the autonomic nervous system in cats were studied. "kyushin" significantly inhibited the aconitine-induced arrhythmia after intraduodenal administration (i.d.) with 80 mg/kg, and the thyroxine-induced arrhythmia with 40 mg/kg i.d. Although "kyushin" itself did not affect the conduction system with 30 mg/ml of the maximal concentration being able to be prepared, bufalin and cinobufagin as constituents of toad venom produced inhibition with 0.3 mg/ml and 1 mg/ml, respectively. The decrease in heart rate induced by electrical stimulation to the parasympathetic nerve (vagus nerve) was potentiated by "kyushin" at 30 mg/kg i.d. The anti-arrhythmic effects of "kyushin" may be attributable to both possible inhibitory effect on the conduction system and potentiating effect on the parasympathetic nervous system.

Pharmacological actions of "kyushin," a drug containing toad venom(2): effects on urinary volume and electrolyte excretion.

A study was conducted on the pharmacological actions of the toad venom-containing drug "Kyushin" (KY-2 and KY-R) on urinary volume and electrolytes excretion, regional blood flow, renal artery blood flow and carrageenin-induced hind-paw edema. In rabbits, KY-2 and KY-R significantly increased urinary volume after intravenous administration of 8 mg/kg. In guinea pigs, KY-2 and KY-R produced a significant increase in urinary volume after intraduodenal administration (i.d.) of 80 mg/kg. In guinea pigs treated with propranolol, KY-2 at 20 and 40 mg/kg p.o. and KY-R at 40 mg/kg p.o. increased urinary volume. At 40 mg/kg i.d. both KY-2 and KY-R produced an increase in regional blood flow, as determined by the hydrogen gas clearance method, of the brain areas including the amygdaloid nucleus, but did not affect regional blood flow in liver, kidney and skeletal muscle, or renal artery blood flow. In rats, carrageenin-induced hind-paw edema was inhibited by KY-2 or KY-R at 600 mg/kg p.o.

Effects of intraduodenal administration of "kyushin," a senso (toad venom)-containing drug, on systemic hemodynamics, cardiacfunction and myocardial oxygen consumption in anesthetized dogs.

The effects of "Kyushin" (KY), a Senso (toad venom)-containing drug, on the cardiovascular system were examined by intraduodenal administration of KY in anesthetized open-chest dogs. KY (3 or 10 mg/kg) dose-dependently increased the peak positive first derivative of left ventricular pressure ((+)LVdP/dt) and mean aortic pressure, and decreased the left ventricular end-diastolic pressure (LVEDP). Myocardial oxygen consumption (MVO2) and heart rate (HR) were not significantly influenced by KY. KY produced a cardiotonic effect without any increase in MVO2, because the increase in MVO2 due to the cardiotonic effect of KY may have been cancelled by a decrease in MVO2 due to reduction of preload and the lack of increase in HR. In order to clarify the relationship between the cardiovascular effects of KY and the drug concentration in plasma, the concentration of anti-bufalin IgG reactive substance (BRS) in plasma was measured by enzyme immunoassay. The maximum BRS concentrations 20 min after administration of 3 and 10 mg/kg KY were dose-dependent. From the relationship between changes in (+)LVdP/dt and changes in BRS concentration after administration of KY, it is inferred that the effective concentration of BRS in plasma at which KY produces a cardiotonic effect in dogs is approximately 2-3 ng/ml.

Cardiovascular effect of a senso (toad venom) - containing drug in anesthetized dogs (2): Influence of propranolol.

Effects of a Senso (toad venom)-containing drug KY on systemic hemodynamics were examined, and participation of beta-adrenoceptor in its action was evaluated by using propranolol in anesthetized dogs. KY produced a positive inotropic action, and decreased total peripheral (TPR) and coronary vascular resistances (CR), while renal vascular resistance (RR) was increased. After propranolol, KY significantly increased TPR, CR, vertebral vascular resistance and RR. KY-induced positive inotropic action was partly diminished but not abolished by beta-blockade. These results indicate that the beta-adrenergic action may be involved in the vasodilating effect of KY and partly in the positive inotropic action.

Effects of "kyushin", a drug containing toad venom, on experimental congestive heart failure in rabbits.

Effects of "Kyushin" (KY-2), a drug containing toad venom, on a low-output-type heart failure model produced in rabbits by protease treatment on the left ventricular anterior wall, were examined. Heart rate, aortic blood flow (AoF), left ventricular systolic pressure (LVP) and maximal rate of rise of LVP (max dP/dt) in this model were maintained at lower levels than those in normal rabbits, while left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance (SVR) were maintained at higher levels, and the mean blood pressure (MBP) was at a normal level. KY-2 was administered intraduodenally to the animal. KY-2 improved heart failure state by increasing the AoF, LVP and max dP/dt, and by decreasing the LVEDP and SVR without a significant change in MBP. These results suggest that the beneficial effects of KY-2 on this heart failure model originate from their cardiotonic activity.

Pharmacological actions of "kyushin," a drug containing toad venom: cardiotonic and arrhythmogenic effects, and excitatory effect on respiration.

The cardiotonic and arrhythmogenic effects, and the excitatory effect on respiration of "Kyushin," a drug containing toad venom, were studied in comparison with those of digoxin. In anesthetized rabbits, the maximum rate of rise of left ventricular systolic pressure (max dP/dt) was measured as an index of cardiotonic effect, and the respiratory flow was measured as an index of respiratory function. Intraduodenal (i.d.) administration of 80 mg/kg "Kyushin" produced a cardiotonic effect and an excitatory effect on respiration, but i.d. administration of 16 mg/kg digoxin produced only a cardiotonic effect, and conversely inhibited respiration. In anesthetized open-chest guinea pigs, myocardial contractile force was measured as an index of cardiotonic effect and the arrhythmogenic effect was evaluated from the appearance of arrhythmic myocardial contraction. By i.d. administration of a 20% ethanol suspension or solution, "Kyushin" and digoxin showed a cardiotonic activity with doses higher than 40 mg/kg and 0.25 mg/kg, respectively. The arrhythmogenic doses of "Kyushin" and digoxin by i.d. administration were 2560 mg/kg and 2 mg/kg, respectively, suggesting that the safety margin of "Kyushin" is broader than that of digoxin.

Effects of a senso (toad venom) containing drug on systemic hemodynamics, cardiac function and myocardial oxygen consumption in anesthetized dogs.

Effects of a Senso (toad venom)-containing drug, KY, on cardiovascular system were examined in anesthetized open-chest dogs. KY increased aortic pressure, peak positive first derivative of left ventricular pressure, stroke work index, percent segment shortening in left ventricular myocardium and myocardial oxygen consumption, and decreased heart rate and total peripheral vascular resistance (TPR). Propranolol augmented the increase in aortic pressure with KY, inhibited the increase in aortic flow with KY and reversed KY-induced decrease in TPR to an increase. These results indicate that KY has positive inotropic and vasodilating actions possibly originating from both digitalis- and adrenaline-like action of a Senso.

Effects of Chrysanthemum indicum Linn. on coronary, vertebral, renal and aortic blood flows of the anesthetized dog.

The hemodynamic effects of the water extract of flower of Chrysanthemum indicum Linn. (CIL) and adenosine were examined in anesthetized open-chest dogs by measuring simultaneously and continuously coronary (CBF), vertebral (VBF), renal (RBF) and aortic blood flows (AoF). Intravenous administration of CIL (5-20 mg/kg) as well as adenosine (10-50 micrograms/kg) produced decreases in aortic blood pressure (AoP) and RBF, and increases in AoF, VBF, CBF and left ventricular dP/dt (LVdP/dt). Calculated coronary, vertebral and total peripheral resistances were decreased by CIL or adenosine in a dose-dependent manner. The ratio (1.69 +/- 0.27) of decrease in coronary vascular resistance to that in total peripheral resistance by CIL (10 mg/kg) was apparently smaller than that (4.03 +/- 0.48) by adenosine (10 micrograms/kg). After beta-adrenergic blockade, increases in AoF and LVdP/dt were inhibited, but decreases in AoP and coronary, vertebral and total peripheral resistances and increase in renal vascular resistance were not changed. These results indicate that CIL directly and uniformly produces coronary and systemic vasodilation with renal vasoconstriction, and that adenosine directly produces vasoconstriction in renal vasculature and vasodilation which is more potent in coronary vasculature than in systemic ones.

Effects of the water extract of Chrysanthemum indicum Linn. on coronary and systemic hemodynamics in the dog.

To clarify the pharmacological profile and the mechanism of action of the water extract of flower of Chrysanthemum indicum Linn. (CIL), a crude drug, the effects of CIL on coronary and systemic hemodynamics were examined in anesthetized open-chest dogs, and the coronary relaxing action of CIL was tested on isolated dog coronary arterial strips. Intravenous administration of CIL 5-20 mg/kg produced a decrease in aortic blood pressure and increases in coronary blood flow, left ventricular dP/dt and heart rate in a dose-dependent manner. Renal blood flow initially decreased and then increased to the values above the preinjection level. These changes by every dose of CIL returned to the preadministration level until 5 min. Dipyridamole (0.1 mg/kg i.v.) potentiated an increase in coronary blood flow of CIL and aminophylline (1.0 mg/kg i.v.) attenuated this response. Intravenous administration of adenosine 5-50 micrograms/kg produced effects similar to those of CIL. The doses of CIL and adenosine which produced a two-fold increase in coronary blood flow were 13.8 mg/kg and 29.5 micrograms/kg, respectively. In 30 mM potassium-induced contracture of dog coronary arterial strips, there was no difference in the relaxant response to CIL between large coronary arteries and medium-size coronary arteries. Adenosine tended to produce a larger relaxation in medium-size coronary arteries than in large coronary arteries. The results indicate that CIL has a coronary vasodilating action and a renal vasoconstricting action in the open-chest dog and that the pharmacological profile of CIL is in part similar to that of adenosine.

Effect of nifedipine treatment on cardiac myosin ATPase activity and responsiveness of cardiovascular system in the dog.

Effects of nifedipine treatment on cardiac myosin ATPase activity and responsiveness of cardiovascular system to catecholamine have been studied. Eight mongrel dogs weighing 7.5 to 13.5 kg were given nifedipine orally twice daily (60 mg/day) for 2 weeks. Ten minutes after the first administration of nifedipine (30 mg p.o.) the heart rate increased significantly and it lasted for, at least, 4 hours. Two-week treatment of nifedipine caused a decrease of the resting heart rate, but the maximal heart rate increase by nifedipine administration was almost the same as the one on the first day. The effects of norepinephrine on heart rate and blood pressure, responsiveness of isolated coronary arteries to some agents inducing a contraction and, Ca2+-activated and K+-activated cardiac myosin ATPase activities were not significantly different between control and nifedipine treatment groups.

Effects of 2-nicotinamidoethyl nitrate (SG-75, nicorandil) on indomethacin-induced contractions of isolated dog coronary arteries.

Effects of 2-nicotinamidoethyl nitrate (SG-75) on contractile responses of dog coronary arteries to indomethacin were investigated in vitro. Indomethacin (3 X 10(-8) and 3 X 10(-7) Gm/ml) produced contractions of isolated coronary arterial strips, which were reproduced by successive administration of the drug. SG-75 (10(-5) Gm/ml) administered 5 min prior to indomethacin, significantly depressed indomethacin-induced contractions of the strips. In coronary arterial strips under potassium-contracture, SG-75 10(-8)-10(-4) Gm/ml) produced concentration-dependent relaxations, which were not affected by prior administration of indomethacin (3 X 10(-6) Gm/ml). Tranylcypromine (10(-4) Gm/ml) did not influence the relaxant responses of the strips to SG-75 (10(-8)-10(-5) Gm/ml) but significantly depressed them to SG-75 (10(-4) Gm/ml). Results indicate that large doses of SG-75 will induce a relaxant effect on isolated dog coronary arteries through activation of intravascular biosynthesis or release of prostacyclin from vascular tissues.

In vitro evidence for dopaminergic receptors in human renal artery.

Effects of dopamine on human renal arteries were pharmacologically investigated in vitro. Norepinephrine (5 X 10(-10)-5 X 10(-5) M) produced concentration-dependent contractions of isolated renal arterial strips, which were significantly depressed by prior administration of phentolamine or phenoxybenzamine. Isoproterenol (4 X 10(-10)-4 X 10(-6) M) concentration dependently relaxed the strips under potassium contracture, but a high dose (4 X 10(-5) M) constricted them. Biphasic responses to isoproterenol were changed to concentration-dependent contractions by prior administration of propranolol, and abolished by propranolol together with phentolamine. Dopamine (5 X 10(-8)-5 X 10(-4) M) produced concentration-dependent contractions of human renal arteries, which were not significantly influenced by propranolol but which were reversed to relaxations by phentolamine. Dopamine-induced relaxations, which were obtained after administration of phentolamine, were not significantly affected by propranolol, but were significantly depressed by combined application of propranolol and haloperidol, or of propranolol and droperidol. Results suggest that isolated human renal arteries have dopaminergic receptors in their smooth muscles which show relaxations of renal arteries after alpha-adrenoceptor blockade.

A study on constrictor response of dog coronary arteries to acetylsalicylic acid.

The present study was designed to investigate the effects of acetylsalicylic acid at a high dose on dog coronary arteries. In the isolated and perfused dog hearts, an intracoronary injection of acetylsalicylic acid (10 mg) decreased coronary blood flow concomitant with diminution of myocardial contractile force, but did not change heart rate. In the isolated dog coronary arterial strips, acetylsalicylic acid (10-4 M) produced the contractions of them, which were significantly inhibited by calcium-free solution, diltiazem, nifedipine, phospholipase A2, arachidonate and prostaglandin E1. The results indicate that acetylsalicylic acid at a high dose produces coronary arterial contracture probably through inhibition of intravascular synthesis of vasodilating prostaglandins.

Effects of 2-nicotinamidoethyl nitrate (SG-75) on dog coronary artery and cat papillary muscle.

Effects of 2-nicotinamidoethyl nitrate (SG-75) on isolated dog coronary artery and cat papillary muscle were investigated. SG-75 dose-dependently relaxed the isolated coronary arterial strips contracted with potassium. Large doses of SG-75 depressed contraction of papillary muscle driven with electrical stimulation and inhibited enhancement of contraction of papillary muscle induced by calcium and isoproterenol. From these results it is suggested that SG-75 may have a weak Ca++-antagonistic action.

[Effects of Theo-Esberiven on the coronary circulation and myocardial metabolisms in dogs (author's transl)].

In isolated dog heart, Theo-Esberiven 0.1 mg, which contains 12 mg proxyphylline, 2.5 mg rutin and 5 mg Melilotus extract, and proxyphylline (12 mg) increased coronary blood flow (CBF) and was associated with increased heart rate (HR) and myocardial contractile force (MCF). The effect of Theo-Esberiven on CBF was about 1.7 times higher than that of proxyphylline. Theo-Esberiven did not significantly affect myocardial oxygen consumption (QO2) and redox potential (deltaEh), while proxyphylline aggravated myocardial metabolisms, as determined from these parameters. Esberiven 0.1 ml, which contains 2.5 mg rutin and 5 mg Melilotus extract, slightly but signficantly increased CBF and decreased QO2 and deltaEh without changing HR and MCF. In situ, intra-coronary injection of either Theo-Esberiven or proxyphylline resulted in a dose-dependent increase in left circumflex coronary flow (LCCF). The effect of Esberiven on LCCF was much less and was slight at the higher doses. Intravenous injection of Theo-Esberiven (0.1 ml/kg) increased LCCF. Besides this change, marked fall in blood pressure and tachycardia were induced by both Theo-Esberiven and proxyphylline without the change in dP/dtmax. Esberiven by the same route led to the decrease in blood pressure associated with HR and dP/dtmax. These results indicate that Theo-Esberiven may be appropriately prescribed for ischemic heart diseases.