NDLI: Dissociation of hyperglycemia from altered vascular contraction and relaxation mechanisms in caveolin-1 null mice.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Pojoga, Luminita H. Yao, Tham M. Opsasnick, Lauren A. Garza, Amanda E. Reslan, Ossama M. Adler, Gail K. Williams, Gordon H. Khalil, Raouf A.
Description	Author Affiliation: Pojoga LH ( Cardiovascular Endocrine Section, Endocrinology, Diabetes and Hypertension Division (L.H.P., T.M.Y., A.E.G., G.K.A., G.H.W.), and Division of Vascular and Endovascular Surgery (L.A.O., O.M.R., R.A.K.), Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts.)
Abstract	Hyperglycemia and endothelial dysfunction are associated with hypertension, but the specific causality and genetic underpinning are unclear. Caveolin-1 (cav-1) is a plasmalemmal anchoring protein and modulator of vascular function and glucose homeostasis. Cav-1 gene variants are associated with reduced insulin sensitivity in hypertensive individuals, and cav-1(-/-) mice show endothelial dysfunction, hyperglycemia, and increased blood pressure (BP). On the other hand, insulin-sensitizing therapy with metformin may inadequately control hyperglycemia while affecting the vascular outcome in certain patients with diabetes. To test whether the pressor and vascular changes in cav-1 deficiency states are related to hyperglycemia and to assess the vascular mechanisms of metformin under these conditions, wild-type (WT) and cav-1(-/-) mice were treated with either placebo or metformin (400 mg/kg daily for 21 days). BP and fasting blood glucose were in cav-1(-/-) > WT and did not change with metformin. Phenylephrine (Phe)- and KCl-induced aortic contraction was in cav-1(-/-) < WT; endothelium removal, the nitric-oxide synthase (NOS) blocker L-NAME (N(ω)-nitro-L-arginine methyl ester), or soluble guanylate cyclase (sGC) inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) enhanced Phe contraction, and metformin blunted this effect. Acetylcholine-induced relaxation was in cav-1(-/-) > WT, abolished by endothelium removal, L-NAME or ODQ, and reduced with metformin. Nitric oxide donor sodium nitroprusside was more potent in inducing relaxation in cav-1(-/-) than in WT, and metformin reversed this effect. Aortic eNOS, AMPK, and sGC were in cav-1(-/-) > WT, and metformin decreased total and phosphorylated eNOS and AMPK in cav-1(-/-). Thus, metformin inhibits both vascular contraction and NO-cGMP-dependent relaxation but does not affect BP or blood glucose in cav-1(-/-) mice, suggesting dissociation of hyperglycemia from altered vascular function in cav-1-deficiency states.
File Format	HTM / HTML
ISSN	00223565
e-ISSN	15210103
DOI	10.1124/jpet.113.209189
Journal	Journal of Pharmacology and Experimental Therapeutics
Issue Number	2
Volume Number	348
Language	English
Publisher	American Society for Pharmacology and Experimental Therapeutics
Publisher Date	2014-02-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Enzyme Inhibitors Phosphorylation Discipline Pharmacology Vasodilation Antagonists & Inhibitors Blood Hypoglycemic Agents Hyperglycemia Caveolin 1 Muscle, Smooth, Vascular Etiology Aorta Genetics Amp-activated Protein Kinases Hypertension Prevention & Control Vasoconstriction Drug Therapy Nitric Oxide Synthase Type Iii Pharmacology Metabolism Drug Effects Therapeutic Use Physiopathology Mice, Knockout Chemistry Animals Guanylate Cyclase Discipline Therapeutics Protein Processing, Post-translational Mice Metformin Endothelium, Vascular
Content Type	Text
Resource Type	Article
Subject	Molecular Medicine Pharmacology

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Dissociation of Hyperglycemia from Altered Vascular Contraction and Relaxation Mechanisms in Caveolin-1 Null Mice

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