Abstract

Derivatives of amiloride that exhibit greater specificity for inhibition of either Na+/H+ or Na+/Ca(+)+ exchange were evaluated for their ability to influence phenylephrine (PE)-induced contractions of the rabbit aorta. Most, but not all, derivatives with alkyl substituents at the 5-amino position (which exhibit greater potency for Na+/H+ exchange inhibition) caused a dose-dependent contraction at concentrations above 10 microM. At higher concentrations and longer incubation times this contraction reached 70 to 80% of the maximal PE response. Contractions induced by 5-amino-substituted amiloride derivatives were dependent upon extracellular Ca(+)+ and were inhibited by either extracellular acidification or intracellular alkalinization. This suggests that they resulted from an influence of intracellular acidification on Ca(+)+ transport. Contractile responses to PE (1 microM) were reduced by most but not all 5-amino-substituted derivatives in conjunction with tension development. Dimethylamiloride, however, failed to cause a contraction at doses up to 100 microM but was the most potent inhibitor of PE-induced contractions among the 5-amino derivatives. Dose-response curves for PE were shifted both to the right and downward by increasing concentrations of amiloride, which indicates both competitive and noncompetitive types of inhibition. Guanidino-substituted derivatives such as benzobenzamil were the most potent antagonists, producing noncompetitive inhibition in excess of 90% at a concentration of 10 microM. The differing patterns of inhibition as well as the presence or absence of intrinsic contractile activity indicate that amiloride derivatives have the potential for multiple pathways of action that modify arterial contractility.