Effect of vasopressin antagonism on structure and mechanics of small arteries and vascular expression of endothelin-1 in deoxycorticosterone acetate salt hypertensive rats.
The structural and mechanical properties of small arteries are altered in rat models of hypertension. The precise role of humoral factors in these changes has not been determined. In deoxycorticosterone acetate (DOCA) salt hypertension, endothelin-1 (ET-1) peptide content and gene expression are enhanced in mesenteric resistance arteries. These vessels also present augmented vasoconstrictor responsiveness to vasopressin versus control uninephrectomized rats. To determine whether an interaction exists between vasopressin and ET-1 in the pathogenesis of small-artery structural alterations in DOCA-salt rats, we examined the effect of chronic V1 vasopressin receptor antagonism (OPC-21268, 30 mg/kg BID) on the structure and mechanical properties of mesenteric resistance arteries using a pressure myograph and the effect on preproendothelin-1 (preproET-1) gene expression, determined by Northern blot analysis of preproET-1 mRNA. Tail-cuff systolic pressures were elevated in DOCA-salt (200+/-11 mm Hg) versus uninephrectomized rats (109+/-4 mm Hg) and decreased slightly but significantly by OPC-21268 to 187+/-7 mm Hg (P<0.01). Treatment with DOCA-salt increased vascular media-lumen ratios and media cross-sectional areas and reduced both stress and incremental elastic modulus for a given pressure. However, there was no change in distensibility or incremental elastic modulus versus media stress. OPC-21268 partially attenuated the vascular growth in DOCA-salt rats. PreproET-1 mRNA was increased 2-fold in mesenteric arteries of DOCA-salt rats versus uninephrectomized rats, an effect abrogated by OPC-21268. Thus, DOCA-salt hypertension is associated with altered morphology of the small-arterial wall, without altering stiffness of the arterial wall components. OPC-21268 regressed in part these changes, suggesting the involvement of vasopressin. The concomitant attenuation of enhanced ET-1 expression by OPC-21268 suggests that ET-1 may be involved in mediating in part the vascular effects of vasopressin in DOCA-salt hypertensive rats.
Intengan
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Medical Research Council Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
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Schiffrin
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D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001696:Biomechanical Phenomena; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone / Q000633:toxicity; D004195:Disease Models, Animal; D004548:Elasticity / Q000187:drug effects; D019332:Endothelin-1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D009392:Nephrectomy; D010880:Piperidines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology*; D012333:RNA, Messenger / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D014664:Vasodilation / Q000187:drug effects
D065092:Antidiuretic Hormone Receptor Antagonists; D019332:Endothelin-1; D010880:Piperidines; D015363:Quinolones; D012333:RNA, Messenger; C068644:OPC 21268; D003900:Desoxycorticosterone; D012083:Renin