Augmented phosphoinositide metabolism in aortas from genetically hypertensive rats.
Recent studies suggest that serotonergic receptor activation is coupled to phospholipase C-mediated phosphoinositide hydrolysis, which results in the release of intracellular second messengers. The purpose of this study was to determine whether altered phosphoinositide metabolism is the basis for augmented vascular responsiveness to serotonin in genetic hypertension. Thoracic aortic segments isolated from stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto normotensive rats (WKY) were labeled with myo-[3H]inositol and stimulated with serotonin in the presence of LiCl. Accumulation of [3H]inositol phosphates was then quantitated by column chromatography. Basal inositol phosphate accumulation and basal incorporation of myo-[3H]inositol into aortic cell membranes from SHRSP was not significantly different from WKY values. At 2.6 x 10(-7) to 2.6 x 10(-4) M serotonin, phosphoinositide metabolism was significantly augmented in aortae from SHRSP compared with WKY. Depolarization (100 mM KCl) did not increase phosphoinositide hydrolysis above basal levels in SHRSP or WKY. 2-Nitro-4-carboxyphenyl-N,N-diphenyl carbamate (NCDC), an inhibitor of phospholipase C, prevented the serotonin-induced phosphoinositide metabolism. NCDC also partially inhibited phasic contractions (responses in calcium-free solution) to serotonin in aortas from SHRSP and WKY. In conclusion, abnormal phosphoinositide metabolism may be one mechanism responsible for the characteristic increase in vascular reactivity to serotonin in hypertension.
Turla
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MB
Department of Physiology, University of Michigan Medical School, Ann Arbor 48109-0622.
Webb
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RC
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D002219:Carbamates / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D048448:Phenylcarbamates; D010716:Phosphatidylinositols / Q000378:metabolism*; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D012701:Serotonin / Q000494:pharmacology; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors; D014661:Vasoconstriction
D002219:Carbamates; D007295:Inositol Phosphates; D048448:Phenylcarbamates; D010716:Phosphatidylinositols; D011480:Protease Inhibitors; C025508:2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate; D012701:Serotonin; D010738:Type C Phospholipases