| 11284450 |
Tanaka Y, Mitani A, Igarashi T, Someya S, Otsuka K, Imai T, Yamaki F, Tanaka H, Saitoh M, Nakazawa T, Noguchi K, Hashimoto K, Shigenobu K: HNS-32, a novel azulene-1-carboxamidine derivative, inhibits nifedipine-sensitive and -insensitive contraction of the isolated rabbit aorta. Naunyn Schmiedebergs Arch Pharmacol. 2001 Mar;363(3):344-52.
The vasorelaxant profile of a novel azulene-1-carboxamidine derivative, HNS-32 [N1,N1-dimethyl-N2-(2-pyridylmethyl)-5-isopropyl-3,8-dimethyl-azulene-1-ca rboxamidine, CAS 186086-10-2], was investigated in the isolated rabbit aorta precontracted with high KCl, noradrenaline (NA) or phorbol 12, 13-dibutyrate (PDBu) and compared with those of nifedipine and nitroglycerin. In preparations without endothelium, HNS-32 elicited concentration-dependent, full inhibition of contractions elicited by high KCI (80 mM), NA (3x10 (-6) M) or PDBu (10 (-6) M). In contrast, nifedipine inhibited only the contraction elicited by membrane depolarization with high KCl. Nitroglycerin also attenuated high-KCl-, NA- and PDBu-elicited contractions effectively, although full suppression was obtained only for NA-elicited contraction. Whilst the relaxant effect of HNS-32 was not affected by the presence of endothelium, the relaxant response to acetylcholine was endothelium dependent. Addition of excess Ca2+ restored both the HNS-32-reduced tension in muscle precontracted with high KCI and the nifedipine-mediated tension decrease. Relaxation elicited by HNS-32 was not affected by the adenylate cyclase inhibitor, 9-(tetrahydro-2'-furyl) adenine (SQ 22,536, 10 (-4) M), the soluble guanylate cyclase inhibitor, 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one (ODQ, 10 (-5) M) or a cocktail of K+ channel blockers (glybenclamide 10 (-6) M, tetraethylammonium 2x10 (-3) M, apamin 10 (-7) M, 4-aminopyridine 10 (-4) M and Ba2+ 10 (-5) M). These findings indicate that HNS-32 inhibits both L-type Ca2+ channel-dependent and -independent vascular contraction. Blockade of Ca2+ entry through L-type Ca2+ channels may be involved in the inhibitory effect of HNS-32 on the contraction due to membrane depolarization with high KCl. On the other hand, HNS-32 seems to inhibit Ca2+ channel-independent contraction via mechanism (s) other than elevation of cyclic nucleotides (cAMP and cGMP) and opening of K+ channels. |
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