Hitoshi Take (1), Katsushi Shibata (1), Takeo Awaji (1), Akira Hirasawa
(1), Ichiro Ikegaki (2), Toshio Asano (2), Tatsuyuki Takada (1) and Gozoh
Tsujimoto (1,*)
(1) Department of Molecular, Cell Pharmacology, National Children's Medical
Research Center, 3-35-31 Taishido, Setagaya-ku, Tokyo 154-8509, Japan
(2) First Laboratory for Pharmacological Research, Institute for Life Science
Research, Asahi Chemical Industry, 632-1 Mifuku, Ohito-cho, Tagata-gun,
Shizuoka 410-2321, Japan
(*) To whom correspondence should be addressed.
Abstract: Newly developed alpha1-adrenoceptor antagonists including
naftopidil are free from the "prazosin-like" side effect of orthostatic
hypotension and associated symptoms. We investigated the mechanism for the
differential effects of naftopidil and prazosin on the development of postural
hypotension, with special attention on their selectivity for the alpha1-adrenoceptor
subtype. We observed that head-up tilt caused a similar extent of drop in
mean arterial pressure in control, naftopidil (1 mg/kg)- or prazosin (10
microg/kg)-treated rats; however, the tilt-induced postural hypotension
was recovered within 2 min in the naftopidil-treated group, but not in the
prazosin-treated group. Comparing an inhibitory effect on noradrenaline-induced
contraction in the rat aorta and portal vein, we found that naftopidil was
sixfold less potent in the portal vein, while prazosin showed similar potency
in both tissues. Reverse transcription-polymerase chain reaction analysis
showed that the expression of alpha1d-adrenoceptor mRNA predominated in
the aorta, while that of alpha1b-adrenoceptor mRNA predominated in the portal
vein. Using cloned rat alpha1-adrenoceptor subtypes, we found that naftopidil
was selective for the alpha1d-subtype with approximately ninefold higher
affinity than at the other subtypes. These results show that the pharmacological
character of naftopidil, combined with the differential expression of the
alpha1-adrenoceptor subtype in the artery and the vein, may partly explain
the differential effect of naftopidil and prazosin on head-up tilt-induced
hemodynamic responses.
Keywords: alpha1-Adrenoceptor, Naftopidil, Prazosin, Postural hypotension,
Reverse transcription-polymerase chain reaction