Mechanism of negative lusitropic effect of α₁-adrenoceptor stimulation in cat papillary muscles

Experiments were performed in cat papillary muscles to explore the mechanisms by which α₁-adrenoceptor stimulation affects myocardial relaxation. Phenylephrine (PE; 10 μM) + atenolol (1 μM; n = 8 experiments) produced a negative lusitropic effect, i.e., a prolongation of half- relaxation time (t(1/2); time to 50% relaxation) by 30 ± 10% (P < 0.05) and a proportionally smaller increase in maximal velocity of relaxation (-Ṫ) than in maximal velocity of contraction (+Ṫ), which significantly increased the ratio +Ṫ/-Ṫ. A similar increase in contractility, produced by increasing calcium, failed to significantly change t(1/2) and +Ṫ/-Ṫ. PE- induced negative lusitropic effect was significantly inhibited by two protein kinase C (PKC) inhibitors, staurosporine (0.1 μM) and chelerythrine (10 μM). PE also increased intracellular 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. Intracellular alkalosis and the negative lusitropic effect of PE were prevented by the Na⁺/H⁺ exchanger inhibitor ethylisopropylamiloride (10 μM). No significant changes in calcium myofilament sensitivity and maximal tension were detected in trabeculae treated with PE either before or after chemical skinning. These results indicate that a Na⁺/H⁺ exchanger-induced intracellular alkalosis, possibly mediated by PKC activation, may fully account for the negative lusitropism of α₁-adrenoceptor stimulation.