Functional coupling of Na+/H+ and Na+/Ca2+ exchangers in the alpha 1-adrenoreceptor-mediated activation of hepatic metabolism.
The purpose of this study was to characterize the role of ions other than Ca2+ in hepatic responses to alpha 1-adrenergic stimulation. We report that the alpha 1-adrenoreceptor activation of hepatic functions is accompanied by extracellular acidification and an increase in intracellular pH. These effects are dependent on extracellular Na+ concentration and are inhibited by the Na+/H+ antiporter blocker 5-(N-ethyl-N-isopropyl) amiloride under conditions that preclude antagonistic effects on agonist binding. Thus, the activation of plasma membrane Na+/H+ exchange is an essential feature of the hepatic alpha-adrenoreceptor-coupled signaling pathway. The following observations indicate that the sustained hepatic alpha 1-adrenergic actions rely on a functional coupling between the plasma membrane Na+/H+ and Na+/Ca2+ exchangers, resulting in the stimulation of Ca2+ influx. 1) Inhibition of the Na+/K(+)-ATPase does not prevent the alpha 1-adrenergic effects. However, alpha 1-adrenoreceptor stimulation fails to induce intracellular alkalinization and to acidify the extracellular medium in the absence of extracellular Ca2+. 2) A non-receptor-induced increase in intracellular Na+ concentration, caused by the ionophore monensin, stimulates Ca2+ influx and increases vascular resistance. 3) Inhibition of Na+/Ca2+ exchange prevents, in a concentration-dependent manner, most of the alpha 1-agonist-induced responses. 4) The actions of Ca(2+)-mobilizing vasoactive peptide receptors or alpha 2-adrenoreceptors, which produce neither sustained extracellular acidification nor release of Ca2+, are insensitive to Na+/H+ exchange blockers.
Urcelay
E
E
Endocrine Physiology Unit, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.
Butta
N
N
Ciprés
G
G
Martín-Requero
A
A
Ayuso
M S
MS
Parrilla
R
R
D000584:Amiloride / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D008099:Liver / Q000378:metabolism*; D008564:Membrane Potentials; D008985:Monensin / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism* / Q000502:physiology*; D012964:Sodium / Q000494:pharmacology; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism*; D014667:Vasopressins / Q000494:pharmacology
D002352:Carrier Proteins; D011942:Receptors, Adrenergic, alpha; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; C013407:benzamil; D014667:Vasopressins; D010042:Ouabain; D000584:Amiloride; D008985:Monensin; D012964:Sodium; D002118:Calcium; C039614:ethylisopropylamiloride