| Abstract: | A vanillylamide‐based propanolamine derivative, KMUP 880708, was first investigated both in vivo and in vitro. KMUP 880708 (0.1, 0.5, 1.0, and 2.0 mg kg–1, iv) produced dose‐dependent hypotensive and bradycardia responses in pentobarbital‐anesthetized Wistar rats. KMUP 880708 (0.1, 0.5, and 1.0 mg kg–1, iv) also markedly inhibited both the tachycardia effects induced by (–)isoproterenol and arterial pressor responses induced by phenylephrine. KMUP 880708 competitively antagonized (–)isoproterenol‐induced positive inotropic and chronotropic effects of the atria and tracheal relaxation responses on isolated guinea pig tissues. The apparent pA2 values for KMUP 880708 was 7.82 ± 0.06 in the right atria, 7.51 ± 0.13 in the left atria, and 6.31 ± 0.07 in the trachea, respectively, indicating that KMUP 880708 was selective β1‐adrenoceptor blocker. In thoracic aorta experiments, KMUP 880708 also produced a competitive antagonism of norepinephrine‐induced contraction with pA2 value of 7.92 ± 0.52, indicating that KMUP 880708 was α‐adrenoceptor antagonist. In isolated rat thoracic aorta, KMUP 880708 more potently relaxed the contractions induced by phenylephrine (10–5 M) than those by high K+ (75 mM). KMUP 880708‐induced relaxation was significantly reduced by endothelium removal and by exposure to L‐NG‐nitro arginine methyl ester (L‐NAME, 1 and 3 × 10–4 M), indomethacin (3 × 10–5 M), methylene blue (10–5 M) and 1H‐[1,2,4]oxadiazolol[4,3,‐a]quinoxalin‐1‐one (ODQ, 10–6 M). The vasorelaxant effect of KMUP 880708 on phenylephrine‐induced contraction was attenuated by the pretreatment with tetraethylammonium (TEA), glibenclamide, charybdotoxin, and apamin, but not by 4‐aminopyridine (4‐AP). In addition, KMUP 880708 inhibited phenylephrine‐induced biphasic contraction and affected the fast‐twitch phase more significantly than the slow tonic phase. In the radioligand‐binding assay, the Ki values of [3H]CGP‐12177 binding to rat ventricle and lung membranes were 15.14 and 524.81 nM, respectively, and the value of [3H]prazosin binding to rat brain membrane was 3.89 nM. The ranking order of inhibition for [3H]CGP‐12177 binding on β‐adrenoceptor was propranolol > labetalol > KMUP 880708 > atenolol, and that for [3H]prazosin binding to α‐adrenoceptor was KMUP 880708 > labetalol. In conclusion, KMUP 880708 was found to be a new generation α/β‐adrenoceptor blocker with selective β1‐adrenoceptor blocking and vascular smooth muscle relaxation activities. Furthermore, the vasodilator effect of KMUP 880708 is attributed to the release of NO or NO‐related substance from vascular endothelium. While the endothelium‐independent mechanism involved in the relaxation of KMUP 880708 is probably linked to K+ channel activation in these vessels. Drug Dev. Res. 55:104–117, 2002. © 2002 Wiley‐Liss, Inc. |
