rs-17053 and Hypertension

To determine which subtype of alpha1-adrenergic receptors plays a role in the regulation of blood pressure, with alpha1A-adrenergic receptor-mediated vasoconstriction in perfused hindlimb as a control, we compared the inhibitory effects of various alpha1-adrenergic receptor selective antagonists on the vasopressure responses to phenylephrine between the mean arterial pressure and hindlimb perfusion pressure in anesthetized rats. In Normotensive Wistar rats, the results showed that the inhibitory effects (dose ratios of ED50, Dr) of alpha1-adrenoceptor selective antagonist (prazosin, Dr 13.5+/-3.6 vs.15.1+/-4.3, n = 11), alpha1A-adrenoceptor selective antagonist (5-methyl-urapidil, Dr 2.4+/-0.9 vs. 3.7+/-2.3, n = 12; RS-17053, Dr 3.2+/-1.6 vs. 4.4+/-3.3, n =12) and alpha1D-adrenoceptor selective antagonist (BMY7378, Dr 1.9+/-0.9 vs. 2.2+/-0.8, n=8) on phenylephrine- induced increases of perfusion pressure in the autoperfused femoral beds were the same as that in the mean arterial blood pressure in normotensive Wistar rats. The inhibitory effects of antagonists (RS-17053, Dr 3.4+/-0.6 vs. 4.3+/-0.9, n = 5; BMY7378, Dr 1.7+/-0.5 vs. 1.7+/-0.5, n = 8) in spontaneous hypertensive rats were similar with the Wistar rats. These results suggest that the mean arterial pressure induced by phenylephrine was mainly mediated by alpha1A-adrenergic receptor in both the anesthetized Wistar rats and spontaneous hypertensive rats.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Blood Pressure; Hypertension; Indoles; Male; Phenylephrine; Piperazines; Rats; Rats, Inbred SHR; Rats, Wistar; Receptors, Adrenergic, alpha-1

Alterations in alpha1-adrenoceptor subtypes in aortas from 12-month-old spontaneously hypertensive rats (SHR) were studied in functional studies and RNase protection assays. The norepinephrine-induced contraction, including maximum response and pD2 values, was not significantly different between the SHR and age-matched Kyoto Wistar (WKY) rats. The pA2 values of the alpha1D-adrenoceptor subtype-selective antagonist BMY7378 (8-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-8-azaspiro(4.5)dec ane-7,9-dionedihydrochloride) were increased from 8.10 +/- 0.12 in WKY rats to 8.45 +/- 0.13 in SHR (P < 0.05). The pA2 values of the alpha1A-adrenoceptor subtype-selective antagonist RS-17053 (N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alpha-dim ethyl-1H-indole-3-ethanamine hydrochloride) were reduced from 8.52 +/- 0.20 in WKY rats to 7.82 +/- 0.18 in SHR (P < 0.05), whereas the pA2 values of the alpha1A/alpha1D-adrenoceptor subtype-selective antagonist WB4101 (2-(2,6-dimethoxphenoxyethyl)-aminomethyl-1,4 benzodioxane) were not significantly different between WKY rats and SHR (9.05 +/- 0.22 versus 9.27 +/- 0.15, P > 0.05). Preincubation of preparations in 50 microM chloroethylclonidine for 30 min irreversibly inhibited the norepinephrine-induced response more profoundly in aortas from SHR than in aortas from WKY rats. The results of RNase protection assays showed that mRNAs for alpha1A- and alpha1B-adrenoceptor subtypes were decreased and that mRNA for the alpha1D-adrenoceptor subtype was increased in aortas from SHR compared with WKY rats. The results suggested that the alpha1A-adrenoceptor subtype was decreased and the alpha1D-adrenoceptor subtype was increased in aortas of 12-month-old SHR.

Topics: Adrenergic alpha-Antagonists; Animals; Aorta; Clonidine; Dioxanes; Hypertension; Indoles; Male; Muscle Contraction; Norepinephrine; Piperazines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, Adrenergic, alpha-1; Ribonucleases