FUNCTIONAL COUPLING OF NA+ H+ AND NA+/CA2+ EXCHANGERS IN THE ALPHA(1)-ADRENOCEPTOR-MEDIATED ACTIVATION OF HEPATIC-METABOLISM/

The purpose of this study was to characterize the role of ions other t han Ca2+ in hepatic responses to alpha1-adrenergic stimulation. We rep ort that the alpha1-adrenoreceptor activation of hepatic functions is accompanied by extracellular acidification and an increase in intracel lular pH. These effects are dependent on extracellular Na+ concentrati on and are inhibited by the Na+/H+ antiporter blocker 5-(N-ethyl-N-iso propyl) amiloride under conditions that preclude antagonistic effects on agonist binding. Thus, the activation of plasma membrane Na+/H+ exc hange is an essential feature of the hepatic alpha-adrenoreceptor-coup led signaling pathway. The following observations indicate that the su stained hepatic alpha1-adrenergic actions rely on a functional couplin g between the plasma membrane Na+/H+ and Na+/Ca2+ exchangers, resultin g in the stimulation of Ca2+ influx. 1) Inhibition of the Na+/K+-ATPas e does not prevent the alpha1-adrenergic effects. However, alpha1-adre noreceptor stimulation fails to induce intracellular alkalinization an d to acidify the extracellular medium in the absence of extracellular Ca2+. 2) A non-receptor-induced increase in intracellular Na+ concentr ation, caused by the ionophore monensin, stimulates Ca2+ influx and in creases vascular resistance. 3) Inhibition of Na+/Ca2+ exchange preven ts, in a concentration-dependent manner, most of the alpha1-agonist-in duced responses. 4) The actions of Ca2+-mobilizing vasoactive peptide receptors or alpha2-adrenoreceptors, which produce neither sustained e xtracellular acidification nor release of Ca2+, are insensitive to Na/H+ exchange blockers.