MECHANISM OF ERGONOVINE-INDUCED CONTRACTION IN THE MESENTERIC-ARTERY FROM DEOXYCORTICOSTERONE ACETATE SALT HYPERTENSIVE RAT

Contractile responsiveness of the rat mesenteric artery to the ergot a lkaloid ergonovine is enhanced in deoxycorticosterone acetate (DOCA) h ypertension. This study determines if this abnormality is mediated thr ough serotonergic or alpha adrenergic receptors and investigates the c ellular mechanism of the contraction. Mesenteric arteries were dissect ed from DOCA hypertensive and normotensive rats for use in isolated ti ssue experiments. Contractions to 5-hydroxytryptamine, phenylephrine, norepinephrine, dopamine and histamine were of a similar maximum in th e hypertensive and sham artery with phenylephrine, dopamine and seroto nin more potent in hypertension. Ergonovine contracted hypertensive ar teries (maximum = 245 +/- 27 mg) but only minimally in sham arteries ( maximum = 83 +/- 19 mg). Endothelium removal did not enhance contracti on to ergonovine. The alpha-1 antagonist prazosin (10(-6) M) and the s erotonergic antagonist 1-naphthylpiperazine (10(-6) M) shifted the erg onovine concentration response of the hypertensive artery rightward. T he alpha-2 receptor antagonist idazoxan (10(-6) M) and dopamine antago nist haloperidol did not affect contraction to ergonovine. Contraction to ergonovine was not altered by indomethacin or 2-nitro-4-carboxyphe nyl-N,N-diphenylcarbamate and was minimally affected by genistein, ind icating that ergonovine does not activate pathways which involve cyclo oxygenase, phospholipase C or tyrosine kinases, respectively. The prot ein kinase C inhibitor chelerythrine (10(-5) M), nifedipine (10(-6) M) and calcium-free medium blocked ergonovine-induced contraction. These studies support that 1) DOCA hypertension induces a dramatic change i n arterial responsiveness to ergonovine; 2) a portion of this response is dependent on stimulation of alpha-1 adrenergic and serotonergic re ceptors; and 3) arterial contraction to ergonovine is dependent on enh anced protein kinase C activation which is dependent on extracellular calcium.