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5-HT2B-receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats.

Abstract
We previously demonstrated a change in the receptors mediating 5-hydroxytryptamine (5-HT)-induced contraction in arteries of deoxycorticosterone acetate (DOCA)-salt-hypertensive rats. Specifically, contraction to 5-HT is mediated primarily by 5-HT2A receptors in arteries from normotensive sham rats and by both 5-HT2A and 5-HT2B receptors in arteries from hypertensive rats. We hypothesized that the 5-HT2B receptor may play a role in maintaining the high blood pressure of DOCA-salt-hypertensive rats, and herein we provide data connecting in vitro and in vivo findings. The endothelium-denuded isolated superior mesenteric artery of DOCA-salt rats displayed a marked increase in maximum contraction to the newly available 5-HT2B-receptor agonist BW-723C86 compared with that of arteries from sham rats, confirming that the 5-HT2B receptor plays a greater role in 5-HT-induced contraction in arteries from DOCA-salt rats. In chronically instrumented rats, the 5-HT2B-receptor antagonist LY-272015 (0.3, 1.0, and 3.0 mg/kg iv at 30-min intervals) was given cumulatively 1 time/wk during 4 wk of continued DOCA-salt treatment. LY-272015 did not reduce blood pressure of the sham-treated rats at any time or dose. However, LY-272015 (1.0 and 3. 0 mg/kg) significantly reduced mean blood pressure in a subgroup of week 3 (-20 mmHg) and week 4 DOCA-salt (-40 mmHg) rats that had extremely high blood pressure (mean arterial blood pressure approximately 200 mmHg). Blockade of 5-HT2B receptors by in vivo administration of LY-272015 (3.0 mg/kg) was verified by observing reduced 5-HT-induced contraction in rat stomach fundus, the tissue from which the 5-HT2B receptor was originally cloned. These data support the novel hypothesis that 5-HT2B-receptor expression is induced during the development of DOCA-salt hypertension and contributes to the maintenance of severe blood pressure elevations.
AuthorsS W Watts, G D Fink
JournalThe American journal of physiology (Am J Physiol) Vol. 276 Issue 3 Pt 2 Pg. H944-52 (Mar 1999) ISSN: 0002-9513 [Print] UNITED STATES
PMID10070078 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine
  • Antihypertensive Agents
  • Indoles
  • LY 272015
  • Organic Chemicals
  • Serotonin Antagonists
  • Serotonin Receptor Agonists
  • Thiophenes
  • Serotonin
  • Desoxycorticosterone
  • Sodium Chloride
Topics
  • Animals
  • Antihypertensive Agents (pharmacology)
  • Blood Pressure (drug effects)
  • Desoxycorticosterone
  • Gastric Fundus (drug effects)
  • Gastrointestinal Motility (drug effects)
  • Hypertension (chemically induced, physiopathology)
  • Indoles (pharmacology)
  • Male
  • Mesenteric Arteries (drug effects, physiology)
  • Organic Chemicals
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin (pharmacology)
  • Serotonin Antagonists (pharmacology)
  • Serotonin Receptor Agonists (pharmacology)
  • Sodium Chloride
  • Thiophenes (pharmacology)
  • Time Factors
  • Vasoconstriction (physiology)

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