Serotonin-induced contraction in mesenteric resistance arteries: signaling and changes in deoxycorticosterone acetate-salt hypertension.
Large arteries from hypertensive subjects are hyperresponsiveness to 5-hydroxytryptamine (5-HT). We tested the hypothesis that small arteries (225 micro ID) have a profile similar to conduit arteries, including signal transduction mechanisms and the 5-HT receptor subtype(s) mediating arterial contraction in normal and high blood pressure. Aorta and mesenteric arteries from Sprague-Dawley (232+/-6 micro ID), sham (229+/-7 micro ID; systolic blood pressure, 120+/-2 mm Hg), or deoxycorticosterone acetate (DOCA)-salt rats (255+/-11 micro ID, 192+/-8 mm Hg) were mounted in a wire-based myograph. In resistance arteries from Sprague-Dawley rats, the 5-HT2A receptor mediated contraction; agonists of the 5-HT1B, 5-HT1D, 5-HT1F, and 5-HT2B receptor were inactive. The tyrosine kinase inhibitor genistein (5 micromol/L, 4.8-fold rightward shift), PD 098,059 (10 micromol/L, 3.2-fold shift), phospholipase C inhibitor NCDC (100 micromol/L), and nifedipine (50 nmol/L) reduced maximum 5-HT-induced contraction in small arteries (4.5% and 53% control, respectively). As in aorta, 5-HT had a decrease in threshold (100-fold lower), increase in potency (11.6-fold leftward shift), and increase in efficacy (140% sham response) in small arteries from DOCA-salt rats compared with sham. Unlike in aorta, 5-HT-induced contraction in DOCA-salt small arteries was shifted competitively by the 5-HT2A receptor antagonist ketanserin (-log K(B) [mol/L] for both sham and DOCA-salt, 9.25+/-0.1), and contraction to the 5-HT2B agonist BW723C86 was not observed. Thus, the 5-HT2A receptor remains the contractile receptor in hypertension in small arteries. Although similarities were observed for large and small arteries, differences under the condition of DOCA-salt hypertension exist that may determine serotonergic compounds effective in lowering blood pressure.
Watts
Stephanie W
SW
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824-1317, USA. wattss@msu.edu
D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D003900:Desoxycorticosterone; D004305:Dose-Response Relationship, Drug; D005464:Fluorobenzenes / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction; D018170:Sumatriptan / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects*
C092430:1-(5-(2-thenyloxy)-1H-indol-3-yl)propan-2-amine; D002227:Carbazoles; D005464:Fluorobenzenes; D007211:Indoles; C109453:LY 344864; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013876:Thiophenes; D012701:Serotonin; D003900:Desoxycorticosterone; D018170:Sumatriptan; D007650:Ketanserin