On the mechanism of the positive inotropic action of the alpha adrenoceptor agonist, phenylephrine, in isolated rat left atria

Alpha adrenoceptor agonists have been reported to increase contractile force and to stimulate Na⁺/H⁺ exchange in the heart. We studied the influence of hexamethylamiloride (HMA), a selective inhibitor of Na⁺/H⁺ exchange, on the positive inotropic action of phenylephrine in isolated, paced rat leff atria (3 μM propranolol). HMA (10 μM) blocked the ouabain-induced contracture, an event dependent on Na⁺ uptake via the Na⁺/H⁺ exchanger. The same concentration of HMA prevented 50% of the positive inotropic effect of phenylephrine (10 μM), but had no effect on base-line developed force. HMA reduced the maximal effect (234 ± 19 vs. 117 ± 20% increase of base-line), but not the EC₅₀ (4.4 ± 1.0 vs. 3.6 ± 2 μM) of phenylephrine. Phenylephrine (100 μM) caused both a leftward and upward shift of the Ca⁺⁺ concentration-effect curve, but only a leftward shift, in the additional presence of HMA (3 μM). It is known that lithium, but not choline, will exchange for H⁺ via the Na⁺/H⁺ exchanger: phenylephrine's (100 μM) positive inotropic effect in choline-substituted solutions averaged 37% of that in lithium-substituted solutions. The positive inotropic effect of phenylephrine was amplified by ouabain (200 μM). These results are consistent with the hypothesis that alpha adrenoceptor agonists produce their positive inotropic effects, in part, via stimulation of Na⁺/H⁺ exchange. Such stimulation could cause an intracellular alkalinization and (in the presence of ouabain), elevated intracellular Na⁺.