Aging: inotropic effects of Bay K-8644 and nifedipine on rat cardiac muscle

Ruch, Stuart; Kennedy, Richard H.; Seifen, Ernst

doi:10.1016/0014-2999(92)90436-8

Cited by 5 publications

(1 citation statement)

References 23 publications

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“…The concentration-dependent positive inotropic effects induced by isoprenaline in rat isolated left atria are similar to those found in other studies (Marquez et al 1981;Ruch et al 1992). Although radioligand binding and functional studies indicates the coexistence of β 1 -and β 2 -adrenoceptors in the hearts of various mammals (Brodde 1988;Saito et al 1989), rat left atria contain relatively more β 1 -than β 2 -adrenoceptors (Minneman et al 1979b).…”

Section: Discussionsupporting

confidence: 66%

Evidence that ranolazine behaves as a weak β 1 - and β 2 -adrenoceptor antagonist in the rat cardiovascular system

Létienne

Vié

Puech

et al. 2001

Naunyn-Schmiedeberg's Archives of Pharmacology

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The clinical anti-anginal effectiveness of ranolazine is currently being evaluated. However, the mechanism of its anti-ischaemic action is still unclear. The aim of this work was to establish whether ranolazine exerts functional beta-adrenoceptor antagonist activity in the rat cardiovascular system. Radioligand binding studies were performed in rat hearts and guinea-pig lungs for beta1- and beta2-adrenoceptor affinity, respectively. Ranolazine had micromolar affinity for both beta,- and beta2-adrenoceptors (pKi5.8 and 6.3, respectively). Developed tension was measured in isolated rat left atria (electrically driven at 4 Hz) and cumulative concentration/response curves to (+/-)isoprenaline (0.01-1,000 nM) constructed. Ranolazine (0.32-10 microM) surmountably but weakly antagonised isoprenaline-induced positive inotropic responses, with an apparent pA2 of 5.85 (5.69-6.00) and a slope of -0.74 (-0.70 to -0.77). In bivagotomised, atropinised pithed rats, ranolazine per se evoked marked bradycardia at doses above 10 mg/kg i.v. (maximum variation at 80 mg/kg -125+/-15 bpm, n=6, P<0.001) by a mechanism apparently unrelated to blockade of beta1- or beta2-adrenoceptors. Cumulative incremental doses of (+/-)isoprenaline (0.63 ng/kg to 0.16 mg/kg i.v.) administered to pithed rats induced concomitant depressor and chronotropic responses. Animals received either vehicle (saline 0.9% i.v., n=12), atenolol (0.04-2.5 mg/kg i.v., n=6 per dose), ICI 118551 (0.01-0.63 mg/kg i.v., n=6 or 7 per dose), (+/-)propranolol (0.01-0.63 mg/kg i.v., n=6 per dose) or ranolazine (2.5-80 mg/kg i.v., n=6 or 7 per dose) 10 min prior to isoprenaline. Ranolazine dose-dependently and competitively antagonised isoprenaline-induced decreases in diastolic arterial pressure (DAP, dose ratio 12.2 with 80 mg/kg ranolazine) and increases in heart rate (HR, dose ratio 20.3 with 80 mg/kg ranolazine). Collectively, these results demonstrate that ranolazine behaves as a weak beta1- and beta2-adrenoceptor antagonist in the rat cardiovascular system.

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Section: Discussionsupporting

confidence: 66%