Peripheral neurogenic mechanisms in deoxycorticosterone acetate--salt hypertension in the rat

The finding of elevated circulating catecholamine levels in experimental and human hypertension suggests an active sympathoadrenal participation in the pathogenesis of hypertension. In deoxycorticosterone acetate (DOCA)-salt hypertensive rats and in spontaneously hypertensive rats (SHR) the sympathoadrenal reactivity was found to be potentiated in response to various stimuli suggesting alterations in baroreflex functions or in local modulatory mechanisms. Several studies have suggested an attenuation of the alpha 2-presynaptic or local inhibitory mechanism and a potentiation of the beta 2-facilitatory presynaptic mechanism in the peripheral sympathetic system, thus possibly explaining the potentiated sympathoadrenal reactivity in those hypertensive animals. At postsynaptic adrenergic sites, beta-adrenoceptor numbers were reported to be decreased, whereas alpha 1-adrenoceptor numbers were unchanged in the cardiovascular system of DOCA hypertensive rats, thus favoring a dominance of alpha 1-postsynaptic responses in those animals. In support of this concept, the production of inositol monophosphate, used as an index of inositol triphosphate production, was found to be markedly enhanced following norepinephrine-induced alpha 1-stimulation in atria and ventricles as well as in mesenteric and femoral arteries of DOCA-salt hypertensive rats thus suggesting an increased reactivity of the second messenger system linked to alpha 1-adrenoceptors. Since similar abnormalities were also observed in SHR and in human hypertension, it thus appears that an imbalance between alpha- and beta-postsynaptic receptors may exist in various forms of hypertension. These studies therefore suggest the existence of multiple abnormalities in pre- and post-synaptic adrenergic mechanisms in experimental and human hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)     

Superoxide anion-induced formation of inositol phosphates involves tyrosine kinase activation in smooth muscle cells from rat mesenteric artery.

Our previous studies have demonstrated an enhanced production of inositol phosphates (IPs) induced by superoxide in smooth muscle cells (SMCs). The mechanisms for this effect, however, remained largely unknown. In the present study, it was found that superoxide increased IP production in SMCs from rat mesenteric arteries in a time-dependent manner. The effect of superoxide on IP formation was significantly inhibited by the antioxidants n-acetylcysteine or alpha-lipoic acid. Genistein and tyrphostin A25, two tyrosine kinase inhibitors, also inhibited the superoxide-induced IP formation. The application of monoclonal antibody against phospholipase Cgamma (PLCgamma) significantly inhibited the superoxide-induced IP formation. Finally, the expression level of PLCgamma proteins was increased 6 hrs after exposing SMCs to superoxide. The present findings demonstrate that superoxide activates the tyrosine kinase pathway and suggest that the tyrosine kinase-mediated IP formation may represent a novel mechanism underlying the signalling role of superoxide in rat mesenteric artery SMCs.