CHARACTERIZATION OF FUROXANS AS A NEW CLASS OF TOLERANCE-RESISTANT NITROVASODILATORS

The vasodilator effects of C99-4609 (4-hydroxymethyl-furoxan-3-carboxa mide, CAS 1609), C92-4678(4-phenyl-furoxan-3-carboxylic acid pyridyl-3 -yl-methyl)-amide), C92-4679 (3-phenyl-furoxan-4-carboxylic acid (pyri dyl-3-yl-methyl)-amide) and C93-4759 (3-hydroxymethyl-furoxan-4-carbox amide) were studied in the isolated rabbit femoral artery and jugular vein. All furoxans were potent vasodilators in the femoral artery (EC( 50) 0.1-50 mu M), while they were less potent in the jugular vein by a t least one order of magnitude. Apart from C92-4679, the vasodilatory potency of the furoxans correlated well with their nitric oxide (NO)-r eleasing capacity which was estimated both by stimulation of purified soluble guanylyl cyclase activity and electron spin resonance spectros copy with a trapping agent for NO. The hypothesis that furoxans stimul ate soluble guanylyl cyclase in the smooth muscle by spontaneously rel easing NO was supported by the marked attenuation of their vasodilator effect in the presence of oxyhaemoglobin (10 mu M) or following treat ment with methylene blue (30 mu M). In contrast to earlier findings, N O release from these furoxans was not thiol-dependent, as demonstrated for C92-4609, the relaxant effect of which in the femoral artery was not altered in the presence of N-acetyl-L-cysteine (1 mM). Moreover th e K-Ca(+) channel inhibitor, tetrabutylammonium (3 mM), but not the K- ATP(+) channel inhibitor, glibenclamide (3 mu M), significantly attenu ated the dilator response to C92-4679 in the femoral artery. Pretreatm ent of these segments with the cytochrome P450 inhibitor, SKF525(a) (3 0 mu M), also reduced the C92-4679-induced relaxation in this vascular bed. The vasorelaxant activity of C92-4679 thus appears to be based b oth on the spontaneous release of NO, which is accelerated due to biot ransformation within the vessel wall, and a direct interaction with K- Ca(+) channels in the smooth muscle. In the rabbit jugular vein, the d ilator response to C92-4609 was not affected following exposure to gly ceryl trinitrate (1 mM) for 1 hour or pretreatment with the same conce ntration of C92-4609 or its isomer, C93-4759. This lack of tolerance d evelopment together with their pharmacological potency may render the new generation of furoxans useful drugs in the treatment of coronary h eart disease.