Effect In Guinea-pig Papillary Muscles Research Articles

In vitro assessment for vascular selectivity of a new dihydropyridine derivative, NB-818

The vascular selectivity of NB-818 (isopropyl methyl 2-carbamoyloxymethyl-6-methyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylate), a newly synthesized dihydropyridine derivative, was evaluated in in vitro experiments. NB-818 and nifedipine concentration dependently caused a relaxant effect in rabbit femoral arteries precontracted with 60 mM K +, a negative inotropic effect in guinea-pig papillary muscles, and a negative chronotropic effect in guinea-pig right atria. The onset of these inhibitory effects of NB-818 was much slower than that of nifedipine when compared at concentrations producing the same inhibition. The relaxant effect of NB-818 was about 10 times more potent than that of nifedipine, while the negative inotropic effect of NB-818 was about 100 times less potent than that of nifedipine. As a result, NB-818 showed about 300 times higher vascular selectivity than nifedipine. The two drugs exhibited a similar potency for the negative chronotropic effect. In a whole-cell configuration with voltage clamp, the blocking effect of NB-818 on L-type Ca 2+ current ( I Ca) in guinea-pig ventricular cells appeared much more slowly than that of nifedipine and was hardly washed out. The potency of NB-818 to block I Ca was markedly enhanced under depolarized conditions (i.e. at a holding potential of −30 mV) compared to that under polarized conditions (i.e. at a holding potential of −70 mV). Such a voltage-dependent blocking action on I Ca was less pronounced for nifedipine. These results indicate that NB-818 is a slow-acting Ca 2+ channel antagonist with much high vascular selectivity. Its vascular selectivity may be at least in part related to the marked voltage-dependent inhibition of I Ca.

Effects of the Anemonia sulcata Toxin (ATX II) on Intracellular Sodium and Contractility in Rat and Guinea‐Pig Myocardium

The effects of the Anemonia sulcata toxin ATX II on action potentials and contractility of isolated papillary muscles and single myocytes from rat and guinea-pig hearts have been studied. ATX II prolonged the action potential in both rat and guinea-pig papillary muscle. Although it produced a positive inotropic effect in guinea-pig papillary muscle, it failed to do so in rat papillary muscle. However, in single rat and guinea-pig ventricular cells, it both prolonged the action potential and had a positive inotropic effect. We suggest that ATX II does not cause a positive inotropic effect in rat papillary muscle, because it induces Ca2+ overload. In single cells the positive inotropic effect was reduced by approximately 50% when the contractions were triggered by voltage clamp pulses of constant duration rather than by action potentials. This suggests that the inotropic effect of ATX II is in part the result of the prolongation of the action potential. The intracellular Na+ activity (a(i)Na) in single ventricular cells was measured with the Na(+)-sensitive fluorescent dye SBFI. After exposure of the cells to ATX II, a(i)Na was increased by a maximum of 1.9 +/- 0.3 and 2.2 +/- 0.3 mM in rat and guinea-pig cells, respectively. It is suggested that the positive inotropic effect of ATX II is also in part the result of the rise in a(i)Na.

Whether phenylephrine exerts inotropic effects through α‐ or β‐adrenoceptors depends upon the relative receptor populations

Phenylephrine produced concentration-related positive inotropic responses in isolated left atria and papillary muscles of guinea-pigs and rats. In rat tissues, these responses were unaffected by propranolol but antagonized by prazosin and therefore mediated via alpha 1-adrenoceptors. The alpha 1-adrenoceptor agonist methoxamine also exerted positive inotropic effects in these rat tissues. The maximum alpha-adrenoceptor-mediated effect of methoxamine (relative to the isoprenaline maximum) was greater than that of phenylephrine in left atria (in the presence of propranolol), whereas in papillary muscles phenylephrine exerted the greater maximum. In guinea-pig papillary muscles, the response to phenylephrine was unaffected by prazosin but was antagonized by propranolol and therefore caused by stimulation of beta-adrenoceptors. Methoxamine had no effect in guinea-pig papillary muscles. Guinea-pig left atria produced biphasic concentration-response curves for phenylephrine, the lower portion being antagonized by phentolamine and was therefore alpha-adrenoceptor-mediated, while the upper portion was antagonized by propranolol and therefore beta-adrenoceptor-mediated. Methoxamine exerted a small inotropic response, the maximum of which was similar to that of the first component of the phenylephrine response. Phenylephrine was a partial agonist for the cardiac beta-adrenoceptor. The density of rat ventricular alpha-adrenoceptors was 4 times greater than beta-adrenoceptor density, as measured by [3H]-prazosin and [3H]-dihydroalprenolol binding. This explains why the responses of rat papillary muscles were alpha-adrenoceptor-mediated. In contrast, the density of beta-adrenoceptor binding sites in guinea-pig ventricles was 6 times greater than the alpha-adrenoceptor density. This explains why the phenylephrine responses were beta-adrenoceptor-mediated in guinea-pig papillary muscles. In the left atria of guinea-pigs, which displayed both alpha- and beta-adrenoceptor-mediated responses, the densities of alpha- and beta-adrenoceptor binding sites were similar. Thus, phenylephrine exerts positive inotropic effects through alpha- or beta-adrenoceptors depending upon their relative densities.