Drugs online research references
J Pharmacol Exp Ther. 1986 Jul;238(1):378-87.
Antihypertensive effects of 12 beta adrenoceptor antagonists in conscious spontaneously hypertensive rats: relationship to changes in plasma renin activity, heart rate and sympathetic nerve function.
Antonaccio MJ, High J, DeForrest JM, Sybertz E.
Twelve beta adrenoceptor antagonists were examined for their effects on mean blood pressure (MBP), heart rate (HR), plasma renin activity (PRA) and sympathetic nerve function in spontaneously hypertensive rats (SHR). The selected drugs included cardioselective agents (acebutolol, atenolol and metoprolol), agents with intrinsic sympathomimetic activity (oxprenolol, acebutolol, alprenolol and pindolol) and agents with local anesthetic activity (propranolol, oxprenolol, acebutolol, alprenolol and labetalol). All 12 beta adrenoceptor antagonists, administered once daily for 4 days (30 mg/kg p.o.), significantly decreased MBP of SHR. This reduction in MBP was dissociable from both reductions in HR as well as peripheral beta adrenoceptor blockade. In addition, the onset of MBP reduction was slower than the onset of beta adrenoceptor blockade and became greater with duration of treatment. PRA activity was significantly and markedly reduced by both bunolol and metoprolol shortly after dosing at a time when HR was significantly reduced but MBP was not. Conversely, at a time when MBP was significantly reduced by both bunolol and metoprolol, PRA and HR were found to be normal. The changes in HR and PRA were correlated with peripheral beta adrenoceptor blockade but changes in MBP were not. Bunolol, metoprolol and propranolol had no consistent inhibitory effect on pressor responses to nerve stimulation in pithed SHR, although positive chronotropic responses to norepinephrine, tyramine, dimethylphenylpiperazinium and angiotensin I and II were significantly and markedly reduced. It is concluded that beta adrenoceptor antagonists, as a class, reduce MBP of conscious SHR, provided that sufficient time is allowed for this observation to occur. Furthermore, the reduction in MBP caused by beta adrenoceptor antagonists is unrelated to acute beta adrenoceptor blockade, changes in HR, reductions in PRA or inhibition of sympathetic nerve function. Finally, cardioselectivity, intrinsic sympathomimetric activity and local anesthetic activity are not required for the antihypertensive activity of these agents.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2873238&dopt=Abstract
J Mol Cell Cardiol. 1987 Sep;19(9):841-51.
Arrhythmogenic action of alpha 1-adrenoceptor stimulation in normoxic rat ventricular myocardium: influence of nisoldipine, reduced extracellular Ca2+ and ryanodine.
Thandroyen FT, Flint NS, Worthington MG, Opie LH.
Department of Medicine, University of Cape Town, Observatory, South Africa.
This study examines the arrhythmogenic action of alpha 1 and alpha 2-adrenoceptor stimulation in the isolated perfused rat heart. The alpha 1-agonist methoxamine in the presence of the beta 1-antagonist atenolol 10(-6) M decreased the ventricular fibrillation threshold in the normoxic rat ventricular myocardium: VFT values (mA): Control 11.2 +/- 0.5; methoxamine 10(-6) M 4.9 +/- 0.9 (P less than 0.01 vs control); methoxamine 10(-5) M 3.5 +/- 0.5 (P less than 0.01 vs control). The alpha 1-antagonist prazosin 10(-8) M prevented the methoxamine-induced fall in ventricular fibrillation threshold. The alpha 2-agonist BHT 933 (azepexole) in the presence of atenolol 10(-6) M produced no alteration in the ventricular fibrillation threshold. Methoxamine 10(-6) M to 10(-5) M had a positive inotropic effect with increased left ventricular pressure development, myocardial oxygen consumption and QT-interval; however, tissue levels of cyclic AMP remained unchanged. Methoxamine 10(-6) M did not alter heart rate, coronary flow rate or deplete tissue levels of adenosine triphosphate, phosphocreatine or glycogen. The enhanced vulnerability to ventricular fibrillation induced by methoxamine could be demonstrated only at supraphysiological extracellular calcium concentrations (2.5 mM) but not at physiological calcium concentrations (1.25 mM). The arrhythmogenic and inotropic effect of methoxamine 10(-6) M was prevented by inhibition of transsarcolemmal Ca2+ ion influx by nisoldipine 10(-8) M or by inhibition of release of Ca2+ from sarcoplasmic reticulum by ryanodine 10(-9) M to 10(-8) M. Thus in isolated normoxic rat heart preparations, activity of the alpha 1-receptor appears to mediate ventricular arrhythmogenesis but only in the setting of myocardial calcium overload. The arrhythmogenic effect of alpha 1-stimulation may be due to increased transsarcolemmal calcium influx and enhanced release of calcium from the sarcoplasmic reticulum; increased myocardial oxygen consumption secondary to greater left ventricular pressure development may contribute in part.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892942&dopt=Abstract
Cardiovasc Res. 1985 Feb;19(2):69-75.
Effects of elevated extracellular potassium concentrations on the class III antiarrhythmic action of sotalol.
Cobbe SM, Manley BS.
The electrophysiological and mechanical effects of sotalol, a beta-adrenergic blocker with Class III antiarrhythmic properties, were compared with those of atenolol in rabbit right ventricular papillary muscles studied in vitro using intracellular microelectrodes. Sotalol produced a dose-dependent increase in action potential duration and effective refractory period without any effect on parameters of rapid inward current. Atenolol had no Class I or Class III effect. The actions of equipotent beta-blocking concentrations of sotalol (10(-4) mol X litre-1) and of atenolol (10(-5) mol X litre-1) in elevated extracellular potassium concentrations of 8 and 12 mmol X litre-1 were investigated. There were reductions in membrane potential, action potential amplitude and upstroke velocity in elevated potassium which were not influenced by sotalol and atenolol, apart from a small additional depression of action potential amplitude and membrane potential in 12 mmol X litre-1 potassium. Hyperkalaemia caused shortening in action potential duration but lengthening in effective refractory period (post-repolarisation refractoriness). The increase in effective refractory period over control produced by sotalol in normal potassium was preserved in elevated potassium. This effect was attributable to lengthening of action potential duration rather than alteration in the duration of post-repolarisation refractoriness. The Class III effects of sotalol are preserved even in partially depolarised fibres where rapid inward current is depressed.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3978667&dopt=Abstract
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