title: Mechanisms underlying altered extracellular nucleotide-induced contractions in mesenteric arteries from rats in later-stage type 2 diabetes: effect of ANG II type 1 receptor antagonism.
abstract: Little is known about the vascular contractile responsiveness to, and signaling pathways for, extracellular nucleotides in the chronic stage of type 2 diabetes or whether the ANG II type 1 receptor blocker losartan might alter such responses. We hypothesized that nucleotide-induced arterial contractions are augmented in diabetic Goto-Kakizaki (GK) rats and that treatment with losartan would normalize the contractions. Here, we investigated the vasoconstrictor effects of ATP/UTP in superior mesenteric arteries isolated from GK rats (37-42 wk old) that had or had not received 2 wk of losartan (25 mg·kg(-1)·day(-1)). In arteries from GK rats (vs. those from Wistar rats), 1) ATP- and UTP-induced contractions, which were blocked by the nonselective P2 antagonist suramin, were enhanced, and these enhancements were suppressed by endothelial denudation, by cyclooxygenase (COX) inhibitors, or by a cytosolic phospholipase A(2) (cPLA(2)) inhibitor; 2) both nucleotides induced increased release of PGE(2) and PGF(2α); 3) nucleotide-stimulated cPLA(2) phosphorylations were increased; 4) COX-1 and COX-2 expressions were increased; and 5) neither P2Y2 nor P2Y6 receptor expression differed, but P2Y4 receptor expression was decreased. Mesenteric arteries from GK rats treated with losartan exhibited (vs. untreated GK) 1) reduced nucleotide-induced contractions, 2) suppressed UTP-induced release of PGE(2) and PGF(2α), 3) suppressed UTP-stimulated cPLA(2) phosphorylation, 4) normalized expressions of COX-2 and P2Y4 receptors, and 5) reduced superoxide generation. Our data suggest that the diabetes-related enhancement of ATP-mediated vasoconstriction was due to P2Y receptor-mediated activation of the cPLA(2)/COX pathway and, moreover, that losartan normalizes such contractions by a suppressing action within this pathway.
authors.affiliation: Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Ishida
authors.forename: Takayuki
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Kumiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Katsuo
authors.initials: K
authors.lastname: Kamata
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Kobayashi
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D017538:Mesenteric Artery, Superior / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D058919:Purinergic P2 Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D014544:Uridine Triphosphate / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058473:Receptors, Purinergic P2Y2; C104749:purinoceptor P2Y4; C099845:purinoceptor P2Y6; D013481:Superoxides; D000255:Adenosine Triphosphate; D015237:Dinoprost; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496513:Ptgs1 protein, rat; C489691:Ptgs2 protein, rat; D054513:Group IV Phospholipases A2; D019808:Losartan; D015232:Dinoprostone; D014544:Uridine Triphosphate