[Show abstract][Hide abstract] ABSTRACT: 1. The antiarrhythmic properties of 5–(3-tert-butylarnino-2-hydroxy)propoxy-3,4-dihydrocarbostyril hydrochloride (OPC-1085) were compared with those of propranolol and pindolol using various kinds of preparations for experimental arrhythmia in dogs.
2. Although OPC-1085 was the most potent drug to antagonize adrenaline-induced arrhythmia in animals anaesthetized with either pentobarbitone sodium or halothane, it was scarcely effective on ouabain-induced arrhythmia in pentobarbitone sodium anaesthetized animals.
3. When these compounds were administered intravenously to conscious dogs 24 h after two-stage ligation of the anterior descending artery, ectopic ventricular beats of coronary ligation-induced arrhythmia were reduced while regular sinus beats were simultaneously increased.
4. OPC-1085 was very effective on aconitine-induced arrhythmia in dogs anaesthetized with pentobarbitone sodium. The effective dose was similar to that of propranolol but about fifteen times less than that of pindolol.
5. It is concluded that different potencies among these β-adrenoreceptor antagonists against various kinds of experimental arrhythmias cannot be simply deduced from any one of the following properties; β-adrenoreceptor antagonism, intrinsic myocardial stimulation, local anaesthetic and so-called quinidine-like effects.
No preview · Article · Jun 2007 · Clinical and Experimental Pharmacology and Physiology
[Show abstract][Hide abstract] ABSTRACT: The cardiovascular effects of OPC-13340, a newly developed 1,4-dihydropyridine calcium channel blocker, were examined in several canine preparations. In conscious normotensive and DOCA-salt hypertensive dogs, OPC-13340, at doses of 10 to 30 micrograms/kg, i.v., and 0.3 to 3 mg/kg, p.o., exerted an hypotensive action in a dose-dependent manner. The hypotensive action of OPC-13340 was longer lasting and more potent than that of nicardipine and nifedipine. In conscious, normotensive instrumented dogs, OPC-13340, at doses of 1 and 3 mg/kg, p.o., dose-dependently decreased total peripheral resistance and mean blood pressure and increased heart rate, cardiac output and left ventricular contractility. In anesthetized open-chest dogs, OPC-13340, at doses of 1 to 30 micrograms/kg, i.v., increased coronary blood flow and decreased mean blood pressure, heart rate, coronary vascular resistance, arteriovenous oxygen difference and myocardial oxygen consumption. In contrast to OPC-13340, nicardipine did not change the myocardial oxygen consumption. From these results it was concluded that OPC-13340 lowered blood pressure and improved coronary circulation in dogs and that the duration of these actions was longer lasting than that of nifedipine and nicardipine. These actions of OPC-13340 may be useful in the treatment of hypertension and angina pectoris.
[Show abstract][Hide abstract] ABSTRACT: The efficacy of orally active 3, 4-dihydro-6-[4-(3,4- dimethoxybenzoyl )-1-piperazinyl]-2(1H)- quin olinone ( OPC -8212) as a positive inotropic agent was examined using model right-sided heart failure dogs and compared with those of dobutamine and amrinone. Heart failure was produced in beagle dogs by a combination of tricuspid insufficiency and pulmonary stenosis, and then drugs were administered intravenously or orally. Intravenous OPC -8212, 1 and 3 mg/kg, amrinone, 1 and 3 mg/kg, and dobutamine, 0.01 and 0.03 mg/kg, increased the dP/dt of the right ventricular pressure for 5 to 10 min. These positive inotropic effects were accompanied by simultaneous increase in the heart rate in the cases of amrinone and dobutamine, and was accompanied by hypotension in the case of amrinone. However, OPC -8212 did not show such effects. This indicates that OPC -8212 has a relatively selective positive effect on cardiac contractility. Oral administration of OPC -8212, 10 to 100 mg/kg, and amrinone, 10 and 30 mg/kg, also showed a positive inotropic effect, appearing 1 h after administration and lasting up to the 5th h. Amrinone had about a 3 times stronger effect, but for similar positive inotropic effects, only amrinone showed positive chronotropic effect. The hypotensive effect of amrinone was also observed after oral administration, while such an effect was scarcely observed when using OPC -8212.
No preview · Article · Feb 1984 · Arzneimittel-Forschung
[Show abstract][Hide abstract] ABSTRACT: The cardiovascular effects of 3,4-dihydro-6-[4-(3,4- dimethoxybenzoyl )-1-piperazinyl]-2(1H)- qu inolinone ( OPC -8212) were investigated in isolated ventricular muscles of various mammalian species, anaesthetized dogs and conscious dogs. In the isolated ventricular muscles of the dog, cat, rabbit and guinea pig, OPC -8212 (3 X 10(-6)-3 X 10(-4) mol/l) increased the developed tension in a concentration-related manner and these positive inotropic effects of OPC -8212 were 1/140-1/120 those of dobutamine but 5-17 times and 8-25 times those of amrinone and theophylline, respectively. The positive inotropic effect of OPC -8212 was not modified by pindolol or phentolamine. In the isolated rat ventricular muscle, OPC -8212, amrinone and theophylline exerted no positive inotropic effect, although dobutamine did. In anaesthetized dogs, OPC -8212 (0.1-3 mg/kg i.v.) was nearly as active as amrinone in producing an increase in left ventricular contractile force. However, OPC -8212 was much less active than amrinone in increasing heart rate and decreasing blood pressure. In conscious dogs OPC -8212 at doses of 1 and 3 mg/kg i.v. increased peak LV dP/dt by 27% and 59%, respectively, without significant changes in heart rate and blood pressure. OPC -8212 did not affect the dog heart Na+,K+-ATPase activity. These results suggest the following: (1) OPC -8212 has a mechanism of action different from those of catecholamines and cardiac glycosides, (2) it has a useful profile in the treatment of heart failure because it caused a selective positive inotropic effect with no obvious positive chronotropic and vascular effects.
No preview · Article · Feb 1984 · Arzneimittel-Forschung
[Show abstract][Hide abstract] ABSTRACT: Pharmacological properties of procaterol (PRO) in the peripheral organs were examined in comparison with those of sulbutamol (SAL) and isoproterenol (ISO). PRO slightly enhanced twitch tension of the tibialis anterior muscle but affected little the mono- and poly-synaptic spinal reflexes and ganglionic transmission. PRO depressed spontaneous contractions of the isolated ileum, non-pregnant and pregnant uterus and also the gastrointestinal and uterine movements in vivo. PRO prolonged the time of peroral charcoal transport in the intestine. Potencies of PRO in producing these effects were between those of ISO and SAL except those on the uterus in which PRO was more potent than ISO and SAL. Pro depressed gastric and bile secretion but had no effect on pancreatic secretion. ISO, PRO and SAL reduced resistance of the common carotid, femoral and renal arteries and the relative potencies of PRO and SAL to ISO were significantly less in the renal artery than in the other arteries. In accelerating heart rate in conscious rats and dogs, PRO (p.o. or s.c.) was almost equipotent to SAL. Urine flow, GFR, RPF, free water and osmolar clearance and also excretion of electrolytes were reduced by PRO with the concomitant fall of systemic blood pressure. PRO has no effect on blood coagulation and hemolysis but inhibited carrageenin edema and an increase in permeability of blood vessels induced by acetic acid. PRO had no alpha-adrenolytic, cholinolytic and anti-histaminic effects.
No preview · Article · Jun 1979 · Folia Pharmacologica Japonica
[Show abstract][Hide abstract] ABSTRACT: Effects of procaterol (PRO) on the CNS were investigated in comparison with those of salbutamol (SAL) and isoproterenol (ISO). PRO, 15 to 50 mg/kg given subcutaneously suppressed spontaneous movement in mice, rats and rabbits and with a large dose, 1000 mg/kg, the animals became quiet and immobile. In dogs, PRO produced similar symptoms and in addition, there was nausea and vomiting. The animals recovered within 3--8 hours. ID50's in depressing spontaneous movement were 20.2 and 245 mg/kg for PRO, 51.1 and 133 mg/kg for SAL and 2.37 and 143 mg/kg for ISO, respectively, both by the subcutaneous and oral routes of administration. Methamphetamine induced increase in motility and fighting behavior was also suppressed by PRO when similar doses were given. PRO had no effect on coordinating movement, halothane anesthesia, drug and electric stimulation induced convulsions and body temperature, and there was no muscle relaxant action. However, PRO in large doses prolonged sleeping time with hexobarbital. The analgesic effect of PRO was not observed with Haffner's and Landall Selitto's methods but acetic acid induced writhing was suppressed by PRO. PRO had little effect on spontaneous EEGs either cortical or from deep structures, and EEG arousal responses. The effects of PRO on the CNS were slight and nonspecific, and similar to those of SAL and ISO.
No preview · Article · May 1979 · Folia Pharmacologica Japonica
[Show abstract][Hide abstract] ABSTRACT: The bronchodilator and cardiovascular actions of 5-(1-hydroxy 2-isopropylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrate (OPC-2009) were investigated in anesthetized dogs and compared with those of isoproterenol, salbutamol or trimetoquinol. Bronchodilator and cardiovascular effects of OPC-2009 were attributable to its beta adrenoceptor stimulant action because they were antagonized by propranolol or pindolol. OPC-2009 was almost equiactive to isoproterenol and trimetoquinol but approximately 3 times more active than salbutamol in inhibiting the histamine-induced increase in bronchial resistance. The duration of the bronchodilator action of OPC-2009 was far longer than those of trimetoquinol and salbutamol. OPC-2009 induced a moderate increase in heart rate, left ventricular contractile force, myocardial oxygen consumption and coronary sinus blood flow. These cardiac stimulant actions of OPC-2009, however, were much weaker than those of isoproterenol and trimetoquinol, and were comparable to those of salbutamol. The dose-response curves fur the cardiac actions of OPC-2009 were much less steep than those of isoproterenol. In addition, OPC-2009 was much less active in increasing left ventricular contractile force than in increasing heart rate. OPC-2009 decreased the blood pressure and the dose-response curve for OPC-2009 was roughly parallel with those for isoproterenol, trimetoquinol and salbutamol. OPC-2009 was approximately 1/15 as active as isoproterenol in decreasing the blood pressure. OPC-2009 was approximately 1/15, 1/5 and 1/70 as active as isoproterenol in increasing the femoral, superior mesenteric and renal blood flow, respectively. Calculation of selectivity ratios for these beta adrenoceptor stimulants indicates that the action of OPC-2009 is more selective on bronchial smooth muscle than on cardiac muscle, and that degree of selectivity of OPC-2009 for beta adrenoceptors in bronchial smooth muscle but not in vascular smooth muscle is greater than that of salbutamol. The results also suggest that the cardiac beta adrenoceptors may not be homogeneous, and that beta adrenoceptors in renal vasculature may be different from those in femoral and superior mesenteric vasculatures.
No preview · Article · Sep 1977 · Journal of Pharmacology and Experimental Therapeutics
[Show abstract][Hide abstract] ABSTRACT: 1. The homogeneity of beta-adrenoceptors in femoral, superior mesenteric and renal vascular beds was investigated by the use of the regional perfusion technique in dogs. 2. Isoprenaline and salbutamol produced dose-related increases in femoral and superior mesenteric blood flow. The dose-response curves for the two agonists were parallel, but salbutamol was approximately 1/15 as potent as isoprenaline on a weight basis. 3. Isoprenaline and salbutamol increased renal blood flow in a dose-related manner. However, salbutamol was approximately 1/240 as potent as isoprenaline on a weight basis, and the slope of the dose-response curve for salbutamol was less steep than that for isoprenaline. 4. The dose-response curves to isoprenaline for increase in femoral and superior mesenteric blood flow were shifted to the right by intravenous pindolol but not by intravenous or intra-arterial practolol. 5. The dose-response curves to isoprenaline for increase in renal blood flow were shifted to the right more markedly by intravenous pindolol than by intravenous or intra-arterial practolol. 6. The results indicate that beta-adrenoceptors of the renal vascular bed consist of beta1-type and beta2-type whereas the femoral and superior mesenteric vascular beds contain only beta2-adrenoceptors.
Preview · Article · May 1977 · British Journal of Pharmacology
[Show abstract][Hide abstract] ABSTRACT: 1. The antiarrhythmic properties of 5-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril hydrochloride (opc-1085) were compared with those of propranolol and pindolol using various kinds of preparations for experimental arrhythmia in dogs. 2. Although OPC-1085 was the most potent drug to antagonize adrenaline-induced arrhythmia in animals anaesthetized with either pentobarbitone sodium or halothane, it was scarcely effective on ouabain-induced arrhythmia in pentobarbitone sodium anaesthetized animals. 3. When these compounds were administered intravenously to conscious dogs 24 h after two-stage ligation of the anterior descending artery, ectopic ventricular beats of coronary ligation-induced arrhythmia were reduced while regular sinus beats were simultaneously increased. 4. OPC-1085 was very effective on aconitine-induced arrhythmia in dogs anaesthetized with pentobarbitone sodium. The effective dose was similar to that of propranolol but about fifteen times less than that of pindolol. 5. It is concluded that different potencies among these beta-adrenoreceptor antagonists against various kinds of experimental arrhythmias cannot be simply deduced from any one of the following properties; beta-adrenoreceptor antagonism, intrinsic myocardial stimulation, local anaesthetic and so-called quinidine-like effects.
No preview · Article · · Clinical and Experimental Pharmacology and Physiology