Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bovine coronary arteries relax in response to bradykinin, methacholine, sodium nitroprusside, isoproterenol, and arachidonic acid in a concentration-dependent manner. The relaxations to methacholine, bradykinin, and arachidonic acid are lost when endothelium is removed. Indomethacin, a cyclooxygenase inhibitor, attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC50 (control versus indomethacin) to each (1 x 10(-7) versus 3 x 10(-7) mo1/L, 3 x 10(-10) versus 2 x 10(-9) mo1/L, and 3 x 10(-7) versus 2 x 10(-6) mo1/L, respectively). Nitro-L-arginine, a nitric oxide synthase inhibitor, also attenuated the relaxations to methacholine, bradykinin, and arachidonic acid and shifted the EC50 (control versus nitro-L-arginine) to each (1 x 10(-7) versus 3 x 10(-7) mo1/L, 3 x 10(-10) versus > 10(-9) mo1/L, and 3 x 10(-7) versus > 10(-6) mo1/L, respectively). The combination of indomethacin and nitro-L-arginine blunted the relaxations to these agents and also shifted the EC50 values (control versus indomethacin plus nitro-L-arginine) to each (1 x 10(-7) versus 5 x 10(-7) mo1/L, 3 x 10(-10) versus > 10(-9) mo1/L, and 3 x 10(-7) versus > 10(-6) mo1/L, respectively). Methacholine, bradykinin, and arachidonic acid stimulated the release of prostaglandin I2, measured as 6-keto-PGF1 alpha. Indomethacin, but not nitro-L-arginine, inhibited arachidonic acid-induced release of 6-keto-PGF1 alpha. Vascular cGMP content was unchanged by arachidonic acid but was significantly elevated by bradykinin. Relaxations to prostaglandin I2 and sodium nitroprusside, but not 8,9-epoxyeicosatrienoic acid or isoproterenol, were inhibited by nitro-L-arginine. We conclude that the endothelium-dependent relaxations to methacholine, bradykinin, and arachidonic acid are partly due to prostaglandin I2 release. The remainder of the responses to these agents is due to the release of other relaxing factor or factors. Since bradykinin increased cGMP and nitro-L-arginine partially inhibited its relaxant effects, nitric oxide also appears to participate in the bradykinin-induced effect. Since the combination of indomethacin and nitro-L-arginine failed to completely block the relaxations to methacholine, bradykinin, and arachidonic acid, another endothelial factor must contribute to their vascular effects. Surprisingly, nitro-L-arginine attenuated the relaxations to arachidonic acid; however, L-arginine failed to reverse the effects of nitro-L-arginine on arachidonic acid-induced relaxations. In addition, arachidonic acid failed to increase cGMP. Nitro-L-arginine also reduced the responses to prostaglandin I2 and sodium nitroprusside. These data indicate that these arginine analogues may have effects other than competitive inhibition of nitric oxide synthase.
Hypertension 1996 Jul
PMID:Mediators of arachidonic acid-induced relaxation of bovine coronary artery. 867 67

Endothelium-derived hyperpolarizing factor (EDHF) mediates NO/prostacyclin-independent relaxation in the coronary circulation. Because hemodynamic stimuli modulate endothelial gene expression and because coronary arteries are subjected to pronounced variations in vessel distension, we determined the effects of cyclic stretch on the expression and activity of the coronary EDHF synthase/cytochrome P450 (CYP) 2C8/9. In cultured porcine coronary and human umbilical vein endothelial cells, acute application of cyclic stretch (6%, 1 Hz, 10 minutes) elicited the generation of 8,9-epoxyeicosatrienoic acid (EET), 11,12-EET, and 14,15-EET. Prolonged stretch (4 to 36 hours) increased the expression of CYP 2C mRNA and protein 5- to 10-fold and was accompanied by a 4- to 8-fold increase in EET generation. A corresponding increase in CYP 2C mRNA and protein was also observed in pressurized segments of porcine coronary artery perfused under pulsatile conditions (8%, 1 Hz) for 6 hours. Although in cultured endothelial cells, cyclic stretch elicited the rapid activation of tyrosine kinases as well as Akt and the p38 mitogen-activated protein kinase, the mechanism by which cyclic stretch induces the expression of CYP 2C could not be elucidated, because inhibitors of these pathways induced CYP 2C expression in cells maintained under static conditions. These results have identified coronary EDHF synthase/CYP 2C as a novel mechanosensitive gene product in native and cultured endothelial cells. Because this enzyme generates both EETs and superoxide anions, this finding has wide-reaching implications for vascular homeostasis in conditions of manifest endothelial dysfunction.
Hypertension 2001 Dec 01
PMID:Cyclic stretch enhances the expression and activity of coronary endothelium-derived hyperpolarizing factor synthase. 1175 30