The 5-hydroxytryptamine_2B 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-hydroxy-tryptamine, 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-HT_2A/5-HT_2C selective), LY53857 (5-HT₂ selective) and spiperone (5-HT_2A/5-HT_2C selective) shifted contraction to 5-HT (pK_B = 8.58, 8.35 and 9.52, respectively) indicating that a 5-HT_2A 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 (pK_B > 6.52, >7.52, respectively). LY53857 did shift the response to 5-HT in DOCA-salt mesenteric arteries (pK_B = 7.85). Thus, contraction in arteries from DOCA-salt rats is predominantly mediated by 5-HT_2B receptors. Unlike the 5-HT receptor in the sham mesenteric artery and aorta (5-HT_2A receptor), the 5-HT receptor in DOCA-salt mesenteric arteries and stomach fundus (5-HT_2B receptor) were relatively insensitive to phenoxybenzamine (10-300 nM). These data suggest that the 5-HT_2B 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-HT_2B 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.