Characterization of furoxans as a new class of tolerance-resistant nitrovasodilators

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Abstract
The vasodilator effects of C92-4609 (4-hydroxymethyl-furoxan-3-carboxamide, CAS 1609), C92-4678(4-phenyl-furoxan-3-carboxylic acid (pyridyl-3-yl-methyl)-amide), C92-4679 (3-phenyl-furoxan4-carboxylic acid (pyridyl-3-yl-methyl)-amide) and C93-4759 (3-hydroxymethyl-furoxan-4-carboxamide) were studied in the isolated rabbit femoral artery and jugular vein. All furoxans were potent vasodilators in the femoral artery (EC50 0.1–50 μM), while they were less potent in the jugular vein by at least one order of magnitude. Apart from C92-4679, the vasodilatory potency of the furoxans correlated well with their nitric oxide (NO)-releasing capacity which was estimated both by stimulation of purified soluble guanylyl cyclase activity and electron spin resonance spectroscopy with a trapping agent for NO. The hypothesis that furoxans stimulate soluble guanylyl cyclase in the smooth muscle by spontaneously releasing NO was supported by the marked attenuation of their vasodilator effect in the presence of oxyhaemoglobin (10 μM) or following treatment with methylene blue (30 μM). In contrast to earlier findings, NO 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 the K infCa sup+ channel inhibitor, tetrabutylammonium (3 mM), but not the K infATP sup+ channel inhibitor, glibenclamide (3 μM), significantly attenuated the dilator response to C92-4679 in the femoral artery. Pretreatment of these segments with the cytochrome P450 inhibitor, SKF525a (30 μM), also reduced the C92-4679-induced relaxation in this vascular bed. The vasorelaxant activity of C92-4679 thus appears to be based both on the spontaneous release of NO2 which is accelerated due to biotransformation within the vessel wall, and a direct interaction with K+Ca channels in the smooth muscle. In the rabbit jugular vein, the dilator response to C92-4609 was not affected following exposure to glyceryl trinitrate (1 mM) for 1 hour or pretreatment with the same concentration of C92-4609 or its isomer, C93-4759. This lack of tolerance development together with their pharmacological potency may render the new generation of furoxans useful drugs in the treatment of coronary heart disease.

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