MECHANISM OF NEGATIVE LUSITROPIC EFFECT OF ALPHA(1)-ADRENOCEPTOR STIMULATION IN CAT PAPILLARY-MUSCLES

Experiments were performed in cat papillary muscles to explore the mec hanisms by which alpha(1)-adrenoceptor stimulation affects myocardial relaxation. Phenylephrine (PE; 10 mu M) + atenolol (1 mu M; n = 8 expe riments) produced a negative lusitropic effect, i.e., a prolongation o f half-relaxation time (t(1/2); time to 50% relaxation) by 30 +/- 10% (P < 0.05) and a proportionally smaller increase in maximal velocity o f relaxation (-T) than in maximal velocity of contraction (+T), which significantly increased the ratio +T/-T. A similar increase in contrac tility, produced by increasing calcium, failed to significantly change t(1/2) and +T/-T. PE-induced negative lusitropic effect was significa ntly inhibited by two protein kinase C (PKC) inhibitors, staurosporine (0.1 mu M) and chelerythrine (10 mu M). PE also increased intracellul ar pH by 0.18 +/- 0.05 pH units (P < 0.05, n = 4), as measured by the fluorescent dye 2'-7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Int racellular alkalosis and the negative lusitropic effect of PE were pre vented by the Na+/H+ exchanger inhibitor ethylisopropylamiloride (10 m u M). No significant changes in calcium myofilament sensitivity and ma ximal tension were detected in trabeculae treated with PE either befor e or after chemical skinning. These results indicate that a Na+/H+ exc hanger-induced intracellular alkalosis, possibly mediated by PKC activ ation, may fully account for the negative lusitropism of alpha(1)-adre noceptor stimulation.