Indirect and direct effects of the divalent cation ionophore A23187 on guinea pig and rat ventricular myocardium.

Abstract

SUMMARY The contractile and biochemical effects of the divalent cation ionophore A23187 were studied in isolated perfused guinea pig and rat ventricles. A23187 increased both cyclic adenosine 3':5'-monophosphate (cyclic AMP) and cyclic guanosine 3':5'-monophosphate (cyclic GMP) concentrations in guinea pig ventricles. Associated with these changes in nucleotide content were positive inotropic effects and activation of giycogen phosphorylase. Pretreatment of «nirrmln with reserpine to deplete endogenous catecholamine stores or pretreatment of hearts with propranolol failed to alter these ionophore-induced change*. In contrast, blockade of histamine (Hi) receptors with metiamide completely abolished the positive inotropic effects and activation of giycogen phosphorylase induced by A23187. In these metiamide-treated hearts, the ionophore-induced increase in cyclic AMP concentration was significantly attenuated, whereas the increase in cyclic GMP content persisted. A23187 produced a negative inotropic effect in hearts taken from rats treated with reserpine. In these rat hearts, cyclic AMP levels and giycogen phosphorylase activity were unchanged, whereas cyclic GMP concentrations were markedly increased. These results indicate that A23187 produces both indirect and direct effects on guinea pig ventricles. The indirect effects are mediated primarily by histamine, presumably released from tissue mast cells by the ionophore. Histamine in turn increases cyclic AMP levels, which leads to activation of phosphorylase and positive inotropic effects. The direct biochemical effect of A23187 is an increase in cyclic GMP concentrations. Ore Rea 44: [473][474][475][476][477][478][479][480][481][482] 1979

Positive inotropic and chronotropic effects of the calcium ionophore A23187 (calimycin) on guinea-pig atria

“…These results are consistent with the findings of Holland et al (9,10), who worked with isometrically contracting left guinea-pig atria stimulated with 2 Hz at 35 ~ and 2 mmol/ 1 [Ca2+]0. Other authors (13,15,18), who used isolated perfused ventricles or papillary muscles of guinea-pigs, observed inotropic effects of CA, similar to ours with respect to concentration range.…”

“…CA enhances the force of contraction of ventricular (13,15,18) as well as of atrial (9,10) myocardial tissue, of skeletal muscle (7) and of smooth muscle (12). Furthermore, CA modulates secretory processes, for example the release of prostaglandins (PGs) (2), catecholamines and histamine (15,19,20,23).…”

“…The cytosolic calcium thus raised can bring about direct and/or indirect positive inotropic effects (9,10,13,15,18).…”

Dissociation between the electrophysiological properties and total tissue cyclic guanosine monophosphate content of guinea pig atria.

“…Keely et al (1978) recently demonstrated that acetylcholine attenuated the positive inotropic effects of isoproterenol to a greater degree than could be accounted for by the attenuation in the generation of cyclic AMP. Finally, recent studies of A23187 performed in our laboratory suggest that cyclic GMP may antagonize the intracellular effects of cyclic AMP (Lindemann et al, 1979).…”

“…It is possible that cyclic GMP is involved in the cellular mechanisms of adrenergic-cholinergic antagonism in cardiac ventricles. Several lines of evidence accumulated over the past 2 decades indicate that activation of muscarinic cholinergic receptors antagonizes the inotropic (Levy, 1971;Watanabe and Besch, 1975;Levy, 1977), electrophysiological (Kent et al, 1973;Watanabe et aL, 1978a;Bailey et al, 1979), and metabolic (Gardner and Allen, 1976;Hess et al, 1962;Murad et aL, 1962;LaRaia and Sonnenblick, 1971;Wilkerson et al, 1976;Keeley et al, 1978;Lindemann et al, 1979;Watanabe et al, 1978b) effects of /S-adrenergic receptor stimulation. We previously suggested that this effect of acetylcholine might be mediated partially through cyclic GMP, because the choline ester antagonized the inotropic effects of isoproterenol without attenuating the amount of cyclic AMP formed in response to /?-adrenergic receptor stimulation, and these effects of acetylcholine were mimicked by dibutyryl cyclic GMP (Watanabe and Besch, 1975).…”