ALPHA(1)-ADRENERGIC ACTIVATION OF MYOCARDIAL NA-K-2CL COTRANSPORT INVOLVING MITOGEN-ACTIVATED PROTEIN-KINASE

The translocation mechanisms involved in the alpha(1)-adrenoceptor-sti mulated efflux of the potassium analog Rb-86(+) were studied in isolat ed rat hearts. Phenylephrine tin the presence of a p-blocker) increase d the efflux of Rb-86(+) and K-42(+), and the Na-K-2Cl (or K-Cl) cotra nsport inhibitor bumetanide reduced the response by 42 +/- 11%. Furose mide inhibited the response with a lower potency than that of bumetani de. The bumetanide-insensitive efflux was largely sensitive to the Kchannel inhibitor 4-aminopyridine. Inhibitors of the Na+/H+ exchanger or the Na+-K+ pump had no effect on the increased Rb-86(+) efflux. The activation of the Na-K-2Cl cotransporter was dependent on the extrace llular signal-regulated kinase (ERK) subgroup of the mitogen-activated protein (MAP) kinase family. Phenylephrine stimulation increased ERK activity 3.4-fold. PD98059, an inhibitor of the ERK cascade, reduced b oth the increased Rb-86(+) efflux and ERK activity. Specific inhibitor s of protein kinase C and Ca2+/calmodulin-dependent kinase II had no e ffect. In conclusion, al-adrenoceptor stimulation increases Rb-86(+) e fflux from the rat heart via K+ channels and a Na-K-2Cl cotransporter. Activation of the Na-K-2Cl cotransporter is apparently dependent on t he MAP kinase pathway.