ARACHIDONIC-ACID ENHANCES CONTRACTION AND INTRACELLULAR CA2+ TRANSIENTS IN INDIVIDUAL RAT VENTRICULAR MYOCYTES

Modulation of intracellular free Ca2+ concentration ([Ca2+](i)) by ino tropic stimuli alters contractility in cardiac muscle. Arachidonic aci d (AA), a precursor for eicosanoid formation, is released in response to receptor activation and myocardial ischemia and has been demonstrat ed to alter K+ and Ca2+ channel activity. We investigated the effects of AA on contractility by simultaneously measuring [Ca2+](i) and short ening in single field-stimulated rat ventricular myocytes. [Ca2+](i) t ransients were measured using fura 2, and myocyte shortening was asses sed using video edge detection. AA stimulated a doubling in the amplit ude of the [Ca2+](i) transient and a twofold increase in myocyte short ening. In addition, AA stimulated a 30% in crease in the time to 50% d iastolic [Ca2+](i) and a 35% increase in the time to 50% relengthening . These effects of AA were mediated by AA itself (56 +/- 5%) and by cy clooxygenase metabolites. Pretreatment with the protein kinase C inhib itors staurosporine and chelerythrine nearly abolished (>90% inhibitio n) these AA-induced effects. Inhibition of voltage-gated K+ channels w ith 4-aminopyridine mimicked the effects of AA. Addition of AA to the 4-aminopyridine-treated myocyte had no additional effect on parameters of contractile function. These data indicate that AA alters the ampli tude and duration of Ca2+ transients and myocyte shortening via protei n kinase C-dependent inhibition of voltage-gated K+ channels. Release of AA by phospholipases in response to receptor activation by endogeno us mediators or pathological stimuli may be involved in mediating inot ropic responses in cardiac muscle.