Negative inotropic effect induced by diethylamiloride (DEA) in rabbit myocardium

Abstract

The effects of the Na+/H+ exchange blocking drug diethylamiloride (DEA) on mechanical function have been studied in the rabbit isolated, arterially perfused interventricular septum. At concentrations of 10(-6)-10(-5) M, DEA induced a significant, dose-dependent, negative inotropic effect (a 54% decrease from control values at the highest concentration), which was slow to develop. After a 45 min washout, recovery was almost complete (95 +/- 3.4%). At concentrations greater than 5 x 10(-5) M, DEA induced a rapid and marked decrease in developed tension, associated with a progressive decrease in excitability and incomplete recovery. Resting tension was not significantly modified at any of the concentrations tested. At greater than 10(-6) M DEA enhanced significantly the transient negative inotropic effect of the brief intracellular acidosis induced by removal of NH4Cl perfusion, both by decreasing the minimal value of developed tension and by increasing the time required to produce this effect. These effects suggest that the dose-dependent DEA negative inotropic effect could be mediated by a progressive intracellular acidosis produced by inhibition of the Na+/H+ exchange system.

Amiloride Derivatives as Blockers of Na+/Ca2+ Exchange: Effects on Mechanical and Electrical Function of Guinea‐Pig Myocardium

“…Block of Na+/H+ exchange deprives the heart cell of its main transport mechanism to expel1 protons (Roos & Boron 1981). Thus the negative inotropic effect observed in our experiments could be mediated by a progressive intracellular acidosis due to impairment of the Na+/H+ exchange (Perez et al 1990) and, therefore, one explanation of the differences in contractile responses to BB as compared to DCB and CBDB could be the possible differences in the ratio of inhibitory action on Na+/H+ and Nat/Ca2+ exchange.…”

Mechanisms of cardiodepression by an Na+–H+exchange inhibitor methyl-N-isobutyl amiloride (MIA) on the heart: lack of beneficial effects in ischemia–reperfusion injuryThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.

“…Although MIA was found to decrease the intracellular pH in cardiomyocytes, the pH values in the presence of HCO 3 -buffer were only slightly but not significantly greater than those in the absence of HCO 3 -buffer. Nonetheless, Perez et al (1990) have shown the occurrence of a progressive intracellular acidosis owing to the effect of NHE exchange inhibitor, diethylamiloride, on the heart. Since an increase in intracellular H + accumulation has been observed to cause the release of Ca 2+ from SR and reduce Ca 2+ uptake by SR (Orchard and Kentish 1990), these indirect effects of MIA can be seen to raise [Ca 2+ ] i and produce initial positive inotropic action of this agent.…”