5-Hydroxytryptamine(2B) receptor function is enhanced in the N(omega)-nitro-L-arginine hypertensive rat.
Arterial hyperresponsiveness to serotonin (5-hydroxytryptamine, 5-HT) is observed in experimental models and human forms of hypertension. Presently, we test the hypothesis that the 5-HT(2B) receptor is up-regulated and necessary for maintaining elevated blood pressure in a rat made hypertensive by the nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine (LNNA; 0.5 g/l). After 2 weeks of treatment, thoracic aorta were removed from LNNA hypertensive (systolic blood pressure = 189 +/- 5 mm Hg) and sham normotensive rats (121 +/- 1 mm Hg), denuded, and mounted into isolated tissue baths for measurement of isometric contraction. In sham tissues, 5-HT-induced contraction was mediated by the 5-HT(2A) receptor as evidence by a parallel rightward shift in response to 5-HT by the 5-HT(2A/2C) receptor antagonist ketanserin (10 nM) and lack of shift by the 5-HT(2B) receptor antagonist 6-methyl-1,2,3,4-tetrahydro-1-[3,4-dimethoxyphenyl)methyl]-9H-pyrido[3,4-b]indole hydrochloride (LY272015) (10 nM). In contrast, LY272015 produced a 4-fold rightward shift to 5-HT in aorta from LNNA hypertensive rats, and blockade by ketanserin did not occur at low concentrations of 5-HT. Maximal contraction to the 5-HT(2B) receptor agonist 1-[5-(2-thienylmethoxy)-1H-3-indolyl]propan-2-amine hydrochloride was significantly greater in LNNA hypertensive rats (percentage of phenylephrine contraction in sham = 7 +/- 4, and in LNNA = 61 +/- 7%). 5-HT(2B) receptor protein was present in aortic homogenates from sham and LNNA rats, but the density of 5-HT(2B) receptor protein in LNNA homogenates was 300% that in sham. Importantly, the 5-HT(2B) receptor antagonist LY272015 reduced blood pressure of the LNNA hypertensive but not the sham normotensive rats. Thus, these data suggest that the up-regulated 5-HT(2B) receptor in the LNNA hypertensive rats is physiologically activated to maintain elevated blood pressure.
Russell
Amber
A
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA.
Banes
Amy
A
Berlin
Hilary
H
Fink
Gregory D
GD
Watts
Stephanie W
SW
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D019335:Nitroarginine / Q000494:pharmacology*; D009930:Organic Chemicals; D051381:Rats; D017207:Rats, Sprague-Dawley; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D000959:Antihypertensive Agents; C118304:LY 272015; D009930:Organic Chemicals; D044403:Receptor, Serotonin, 5-HT2B; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D019335:Nitroarginine; D012701:Serotonin; D007650:Ketanserin