H. Take et al., VASCULAR ALPHA(1)-ADRENOCEPTOR SUBTYPE SELECTIVITY AND ALPHA(1)-BLOCKER-INDUCED ORTHOSTATIC HYPOTENSION, Japanese Journal of Pharmacology, 77(1), 1998, pp. 61-70
Newly developed alpha(1)-adrenoceptor antagonists including naftopidil
are free from the ''prazosin-like'' side effect of orthostatic hypote
nsion and associated symptoms. We investigated the mechanism for the d
ifferential effects of naftopidil and prazosin on the development of p
ostural hypotension, with special attention on their selectivity for t
he alpha(1)-adrenoceptor subtype. We observed that head-up tilt caused
a similar extent of drop in mean arterial pressure in control, naftop
idil (1 mg/kg)- or prazosin (10 mu g/kg)-treated rats; however, the ti
lt-induced postural hypotension was recovered within 2 min in the naft
opidil-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 poten
t in the portal vein, while prazosin showed similar potency in both ti
ssues. Reverse transcription-polymerase chain reaction analysis showed
that the expression of alpha(1d)-adrenoceptor mRNA predominated in th
e aorta, while that of alpha(1d)-adrenoceptor mRNA predominated in the
portal vein. Using cloned rat alpha(1)-adrenoceptor subtypes, we foun
d that naftopidil was selective for the alpha(1d)-subtype with approxi
mately ninefold higher affinity than at the other subtypes. These resu
lts show that the pharmacological character of naftopidil, combined wi
th the differential expression of the alpha(1)-adrenoceptor subtype in
the artery and the vein, may partly explain the differential effect o
f naftopidil and prazosin on head-up tilt-induced hemodynamic response
s.