Crucial role of cytoskeleton reorganization in the negative inotropic effect of chromogranin A-derived peptides in eel and frog hearts

This study was performed to determine whether activation of protein kinase C is responsible for the positive inotropic effect of alpha 1-adrenoceptor stimulation in rat papillary muscle. In the presence of 1 microM propranolol, phenylephrine (10 microM) produced triphasic inotropic response that was accompanied by prolongation of action potential duration (APD) and hyperpolarization of membrane potential. Phorbol 12,13-dibutyrate (PDBu, 0.1 microM) abolished the negative inotropic effect of phenylephrine and apparently resulted in enhancement of the positive inotropic effect. PDBu also attenuated the phenylephrine-induced hyperpolarization without affecting the APD prolongation. However, such changes were not observed with 12-O-tetradecanoylphorbol-13-acetate (TPA, 0.1 microM). Neither PDBu nor TPA increased the force of contraction or prolonged APD similar to phenylephrine. The protein kinase C inhibitor 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine (H 7, 10 microM) did not suppress the changes induced by PDBu, and more importantly H 7 did not affect the inotropic and electrophysiological effects of phenylephrine. Both TPA and PDBu significantly inhibited the phenylephrine-induced phosphoinositide hydrolysis as measured by [3H]inositol monophosphate, and these inhibitory effects were eliminated in the presence of H 7. Our results provide an argument against a role of protein kinase C activation in the alpha 1-adrenoceptor-mediated inotropic and electrophysiological effects.

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Responses of contractile function to ruthenium red in rat heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.6.h1413 ◽

1988 ◽

Vol 255 (6) ◽

pp. H1413-H1420 ◽

Cited By ~ 1

Author(s):

M. P. Gupta ◽

I. R. Innes ◽

N. S. Dhalla

Keyword(s):

Rat Heart ◽

Contractile Function ◽

Negative Inotropic Effect ◽

Ruthenium Red ◽

Inotropic Effect ◽

Inotropic Effects ◽

Rat Hearts ◽

Positive Inotropic Effects ◽

High Concentrations

Isolated rat hearts exhibited a biphasic contractile response to varying concentrations of ruthenium red. A negative inotropic effect was observed with concentrations of 0.025–0.5 microM, whereas a reversal of these initial changes toward control or even exceeding the predrug values was obtained as ruthenium red concentration was increased to 2.5 or 5.0 microM. High concentrations (12.5–25.0 microM) of ruthenium red caused a sustained contracture. In contrast, isolated frog hearts exhibited only a sustained negative inotropic effect at 0.25–12.5 microM ruthenium red. In studies with rat heart, both negative and positive inotropic effects of 2.5 microM ruthenium red were blocked either by increasing the concentration of Ca2+ (from 1.25 to 5.0 mM) or by decreasing the concentration of Na+ (from 140 to 35 mM) in the perfusion medium. The contracture induced by 12.5 microM ruthenium red was markedly inhibited when Ca2+ in the medium was lowered. The positive inotropic effect and contracture due to ruthenium red were also blocked by 1 microM of verapamil and 1.5 mM of amiloride; however, these interventions did not prevent the initial negative inotropic effect of ruthenium red. These experiments suggest the role of extracellular Ca2+ in the dose- and time-dependent effects of ruthenium red on contractile function of the rat heart. Furthermore, the positive inotropic response to ruthenium red may be related to its actions on the Na+-dependent Ca2+ movements in the cardiac cell.

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