© 1993 by European Society of Cardiology
Copyright © 1993, European Society of Cardiology
Calcium dependent positive inotropic effects of low phorbol ester concentrations in isolated rat hearts
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario N6A 5C1, Canada: M Karmazyn, J V Haist.
Correspondence to Dr Karmazyn.
Objective: The aim was to examine the cardiac effects of phorbol esters over a wide concentration range and to determine if the effects are related to Ca2+ availability. Methods: Studies were carried out using isolated rat hearts exposed for 60 min either to phorbol 12-myristate 13-acetate (PMA, 10–11 to 10–6 M) or phorbol 12,13-dibutyrate (PDBu, 10–12 to 10–7 M) in the presence of either 1.25 or 2.50 mM CaCl2. Experiments were also done to assess the effect of BAY K8644, a Ca2+ agonist, on phorbol ester effects. After treatment, hearts were freeze clamped for later analysis of energy products. Results: At the lowest concentrations studied, both PMA and PDBu produced positive inotropic effects, whereas higher concentrations resulted in a loss of contractile force in hearts perfused with 1.25 mM CaCl2. Doubling the CaCl2 concentration or the presence of BAY K8644 had little effect on the negative inotropic influence of either phorbol ester but reversed the positive inotropic effect to a negative inotropic one. Neither treatment had any effect on the coronary constricting effects of phorbol esters. Increases in resting tension and reductions in high energy phosphate content were evident only with the highest phorbol ester concentrations and were unaffected either by changes in CaCl2 concentrations or the presence of BAY K8644. Conclusions: At picomolar and nanomolar concentrations phorbol esters produce positive inotropic actions which are probably mediated by enhanced Ca2+ influx. Although higher concentrations produce negative inotropic effects, these are not influenced by [Ca2+]o nor are they related to disturbances in energy metabolism except at the highest concentrations. We conclude that phorbol esters produce complex concentration dependent cardiac effects which are not mediated by a single mechanism of action.
Cardiovascular Research 1993;27:390-395
KEYWORDS phorbol esters; calcium; contractility; energy metabolism; coronary constriction; BAY K8644
This work was supported by a grant from the Medical Research Council of Canada. Dr Karmazyn is a career investigator of the Heart and Stroke Foundation of Ontario.
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