A propanolamine derivative with vanillylamide base,
KMUP 880602, was first investigated under in vivo and in vitro conditions. IV
KMUP 880602 (0.1, 0.5, 1.0, and 2.0 mg/kg) produced dose-dependent hypotensive and
bradycardia responses in
pentobarbital-anesthetized Wistar rats.
KMUP 880602 also markedly inhibited both the
tachycardia effects induced by (-)
isoproterenol and arterial pressor responses induced by
phenylephrine. In isolated guinea pig tissues,
KMUP 880602 competitively antagonized (-)
isoproterenol-induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses. The apparent pA2 values
KMUP 880602 were 7.24 +/- 0.08 (right atria), 7.42 +/- 0.07 (left atria), and 6.24 +/- 0.06 (trachea).
KMUP 880602 also produced a competitive antagonism of
norepinephrine-induced contraction in the isolated rat aorta with pA2 values of 7.64 +/- 0.18. In the radioligand-binding assay, [3H]
CGP-12177 binding to rat ventricle and lung tissues and [3H]
prazosin binding to brain membranes were inhibited by
KMUP 880602 with pKi values of 7.27, 6.08, and 8.25, respectively. In isolated rat thoracic aorta, the
vasorelaxant effects of
KMUP 880602 on
phenylephrine-induced contractions were attenuated by pretreatment with
tetraethylammonium (10-3 M) and
charybdotoxin (10-7 M) but not by
glibenclamide,
4-aminopyridine, and
apamin. In conclusion,
KMUP 880602 is an alpha/beta-
adrenoceptor blocker, with selective beta1-adrenoceptor blocking and vascular smooth muscle relaxation activities. Particularly, the
vasorelaxant effect of
KMUP 880602 is partially mediated by the opening of
charybdotoxin-sensitive K+ channel.