Mechanisms for cardiac depression induced by phorbol myristate acetate in working rat hearts

Abstract

The effects of the phorbol ester, phorbol myristate acetate (PMA) were examined on function and energy metabolism in the isolated working heart of the rat. At a concentration of 10−9 m. PMA produced a rapid loss in cardiac function in terms of aortic flow rate (AFR) and coronary flow rates (CFR) whereas a similar concentration of 4α‐phorbol 12,13‐didecanoate was ineffective. At a concentration of 10−10 m., the PMA‐induced depression was more gradual but nevertheless very pronounced with an almost total loss in AFR after 30 min perfusion. The reduction in CFR was more moderate than that observed with respect to AFR. The protein kinase C (PKC) inhibitor (±)‐l‐O‐hexadecyl‐2‐O‐acylglycerol significantly attenuated the loss in AFR and CFR following addition of PMA. Two inhibitors of Na+/H+ exchange, amiloride and quinacrine, totally prevented the reduction in AFR. Although the PMA‐induced depression in CFR was also attenuated by both amiloride and quinacrine, these effects were not significant, probably reflecting the less pronounced effect of PMA on this parameter. Nifedipine, a dihydropyridine calcium channel blocker reduced PMA toxicity to a similar degree as Na+/H+ exchange inhibition whereas the calcium channel agonist Bay K 8644 was without effect. Tissue content of energy metabolites including high energy phosphates, total adenine nucleotides or lactate were not significantly affected by PMA perfusion. We conclude that PKC activation is necessary for phorbol ester‐induced cardiac dysfunction. The consequence of PKC stimulation includes (1) Na+/H+ exchange activation and a subsequent elevation in intracellular calcium [Ca2+]i via Na+/Ca2+ exchange and (2) PKC‐dependent phosphorylation of the calcium channel, both of which would produce toxicity by elevation of [Ca2+]i. Pharmacological manipulation of any of these steps prevents PMA toxicity by virtue of a reduction in the accumulation of [Ca2+]i. PMA effects or their prevention are unrelated to any changes in energy metabolism.

Mepacrine‐induced inhibition of the inward current mediated by 5‐HT3 receptors in rat nodose ganglion neurones

“…At this concentration-range, mepacrine inhibited acetylcholine bindings to muscarinic (O'Donnell & Howlett, 1991) and nicotinic receptors (Grunhagen & Changeux, 1976;Cox et al, 1985), decreased voltage-gated Ca2+ currents (Mironov & Lux, 1992;Sargent et al, 1992) and a fast transient outward K+ current (Kehl, 1991), depressed Na+/Ca2" and Na+/H' exchange (Shepherd et al, 1991;Karmazyn et at., 1990) and had a cardioprotective effect against ischaemia (Chiariello et al, 1987;Sargent et al, 1992). All these mepacrine effects were independent of phospholipase A2 activity, although the effective mepacrine concentration for the inhibition of phospholipase A2 is also in this range (Billah et al, 1981).…”

“…Several studies have shown that mepacrine interacts with voltage-gated ion channels such as the fast transient outward K+ channels in rat melanotrophs (Kehl, 1991) and the high-threshold Ca2+ channel in rat hippocampal cells (Mironov & Lux, 1992). Mepacrine has also been reported to inhibit Na+/H' exchange (Karmazyn et al, 1990), Na+/Ca2+ exchange (Shepherd et al, 1991) and to protect animals from myocardial ischaemia (Chariello et al, 1987;Sargent et al, 1992). In the present study, mepacrine was found to inhibit the inward current mediated by receptors in rat nodose ganglion neurones and to increase the rate of current decay.…”

Effects of ?1-adrenergic stimulation on normal and hypertrophied mouse hearts. Relation to caveolin-3 expression

“…To assess effect of PKC activation on PIE following a 1 -ADR stimulation we used phorbol 12-myristate 13-acetate (PMA) [13]. In isolated work performing Ntg mouse heart, the PKC-activator produced a dose-dependent suppression of cardiac contractility and relaxation (Fig.…”

Potential role and mechanisms of subcellular remodeling in cardiac dysfunction due to ischemic heart disease

“…The effects of H 2 O 2 are shown to be mediated through the activation of protein kinase C, mitogen-activated protein kinase and/or stress-activated protein kinase [193][194][195], and translocation of protein kinase C has been shown to occur in the ischemic heart [196,197]. Because the activation of protein kinase C by phorbol ester has been observed to produce cardiodepression [198], it is believed that cardiac dysfunction in the I/R heart is elicited through the activation of protein kinase C. Nonetheless, isolated cardiomyocytes exposed to oxyradical generating systems were observed to undergo changes in the electrophysiological behavior similar to those seen in IHD [60]. It should also be noted that various oxyradical generating systems are considered to depress the cardiac SR Ca 2þ -uptake by depressing Ca 2þ -stimulated ATPase activities [199][200][201].…”