The 5-hydroxytryptamine2B receptor and 5-HT receptor signal transduction in mesenteric arteries from deoxycorticosterone acetate-salt hypertensive rats.
One of the most profound increases in vascular responsiveness in hypertension has been observed for serotonin (5-hydroxytryptamine, 5-HT). This study investigates the hypothesis that the increase in vascular responsiveness to 5-HT is the result of altered 5-HT receptor signal transduction. Mesenteric arteries were dissected from deoxycorticosterone- (DOCA) salt hypertensive and sham-normotensive rats for use in isolated tissue experiments. Agonist contractile potencies indicated that a 5-HT2 receptor mediates contraction to 5-HT in both sham and DOCA-salt arteries. In arteries from sham rats, ketanserin (5-HT2A/5-HT2C selective), LY53857 (5-HT2 selective) and spiperone (5-HT2A/5-HT2C selective) shifted contraction to 5-HT (pKB = 8.58, 8.35 and 9.52, respectively) indicating that a 5-HT2A receptor mediates contraction in arteries from normotensive rats. By contrast, ketanserin and spiperone did not shift contraction to 5-HT in DOCA-salt mesenteric arteries (pKB > 6.52, > 7.52, respectively). LY53857 did shift the response to 5-HT in DOCA-salt mesenteric arteries (pKB = 7.85). Thus, contraction in arteries from DOCA-salt rats is predominantly mediated by 5-HT2B receptors. Unlike the 5-HT receptor in the sham mesenteric artery and aorta (5-HT2A receptor), the 5-HT receptor in DOCA-salt mesenteric arteries and stomach fundus (5-HT2B receptor) were relatively insensitive to phenoxybenzamine (10-300 nM). These data suggest that the 5-HT2B receptor is insensitive to phenoxybenzamine, is increased in number or, alternatively, has increased G protein coupling. DOCA-salt mesenteric arteries were more sensitive to contraction by the direct G protein stimulator AIF4- (-log EC50 [M]: DOCA-salt = 2.82 +/- 0.04; sham = 2.55 +/- 0.03, P < .05). PCR analyses indicated an increase in mRNA for the 5-HT2B receptor in mesenteric arteries of DOCA-salt hypertensive arteries, supporting an increase in receptor number. Taken together these studies demonstrate significant changes in 5-HT receptor signal transduction in DOCA-salt hypertension, both at the level of the receptor and G protein and may provide one reason why ketanserin has proved to be a relatively ineffective antihypertensive agent in some forms of hypertension.
Watts
S W
SW
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, USA.
Baez
M
M
Webb
R C
RC
D000818:Animals; D001483:Base Sequence; D003900:Desoxycorticosterone; D019204:GTP-Binding Proteins / Q000502:physiology; D006973:Hypertension / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology; D008969:Molecular Sequence Data; D010643:Phenoxybenzamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D015398:Signal Transduction; D012965:Sodium Chloride; D014661:Vasoconstriction / Q000187:drug effects
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D010643:Phenoxybenzamine; D003900:Desoxycorticosterone; D012965:Sodium Chloride; D019204:GTP-Binding Proteins