SIGNALS MEDIATING STIMULATION OF CARDIOMYOCYTE GLUCOSE-TRANSPORT BY THE ALPHA-ADRENERGIC AGONIST PHENYLEPHRINE

Phenylephrine, a potent stimulator of cardiomyocyte glucose transport (GT), caused a rapid rise in cytosolic Ca2+ by 30%. Agents inducing a similar Ca2+ response did not stimulate (angiotensin II, vasopressin) or inhibited GT by 20% (elevated extracellular Ca2+). Stimulation of G T by phorbol myristate acetate was additive to both phases of phenylep hrine's effect (4 min, 60 min). Phenylephrine had no influence on the adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP) levels. Agents raising cAMP (isoproterenol) or c GMP (e.g., nitroprusside) did not stimulate GT. Wortmannin (inhibitor of 1-phosphatidylinositol 3-kinase) suppressed the action of insulin o n GT but not that of phenylephrine. In contrast, the Na+/H+ exchange i nhibitor amiloride (which blocks phenylephrine-induced cytosolic alkal inization or even lowers cellular pH) depressed the effect of phenylep hrine by 50%, whereas insulin-stimulated GT was little affected. Howev er, raising extracellular pH up to 8.4 failed to increase GT. Lowering pH to 6.8 decreased phenylephrine's effect by 40%, whereas insulin-de pendent GT was not significantly altered. Clorgyline, tranylcypromine (monoamine oxidase inhibitors), and added catalase suppressed the slow phase of phenylephrine's action, whereas amiloride also affected the fast phase. We conclude that 1) stimulation of cardiomyocyte GT by phe nylephrine does not involve cAMP, cGMP, or 1-phosphatidylinositol 3-ki nase; 2) protein kinase C activation cannot explain the full extent of stimulation; 3) Ca2+ release or cytosolic alkalinization may be requi red but is not sufficient to trigger phenylephrine's action; and 4) th e slow phase of stimulation is mediated by the monoamine oxidase-depen dent degradation of phenylephrine and by the resulting H2O2 formation.