HNS-32, a novel azulene-1-carboxamidine derivative, inhibits nifedipine-sensitive and -insensitive contraction of the isolated rabbit aorta

The vasorelaxant profile of a novel azulene-1-carboxamidine derivative, HNS -32 [N-1,N-1-dimethyl-N-2-(2-pyridylmethyl)-5-isopropyl-3,8-dimethyl-azulen e-1-carboxammidine, CAS 186086-10-2], was investigated in the isolated rabb it 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-dependen t, full inhibition of contractions elicited by high KCl (80 mM), NA (3x10(- 6) M) or PDBu (10(-6) M). In contrast, nifedipine inhibited only the contra ction elicited by membrane depolarization with high KCl. Nitroglycerin also attenuated high-KCl-, NA- and PDBu-elicited contractions effectively, alth ough full suppression was obtained only for NA-elicited contraction. Whilst the relaxant effect of HNS-32 was not affected by the presence of endothel ium, the relaxant response to acetylcholine was endothelium dependent. Addi tion of excess Ca2+ restored both the HNS-32-reduced tension in muscle prec ontracted with high KCl and the nifedipine-mediated tension decrease. Relax ation elicited by HNS-32 was not affected by the adenylate cyclase inhibito r, 9-(tetrahydro-2'-furyl)adenine (SQ 22,536, 10(-4) M), the soluble guanyl ate 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, te traethylammonium 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 Ca 2+ channel-dependent and -independent vascular contraction, Blockade of Ca2 + entry through L-type Ca2+ channels may be involved in the inhibitory effe ct of HNS-32 oil the contraction due to membrane depolarization with high K Cl. On the other hand, HNS-32 seems to inhibit Ca2+ channel-independent con traction via mechanism(s) other than elevation of cyclic nucleotides (cAMP and cGMP) and opening of K+ channels.