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

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-furoxan-4-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 microM), 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 microM) or following treatment with methylene blue (30 microM). 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 KCa+ channel inhibitor, tetrabutylammonium (3 mM), but not the KATP+ channel inhibitor, glibenclamide (3 microM), significantly attenuated the dilator response to C92-4679 in the femoral artery. Pretreatment of these segments with the cytochrome P450 inhibitor, SKF525a (30 microM), also reduced the C92-4679-induced relaxation in this vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential regulation of endothelial cell adhesion molecule expression by nitric oxide donors and antioxidants

“…The furoxan CAS 1609 release NO relatively slowly compared to the other NO donors such as SNP [34,35]. The NO donor, GSNO, most effectively inhibited VCAM-1 expression.…”

“…Endothelial expression of ICAM-1, E-selectin, and VCAM-1 was inhibited by three structurally different NO donors, suggesting that NO is the probable inhibitory mediator. The furoxan CAS 1609 release NO relatively slowly compared to the other NO donors such as SNP [34,35]. The NO donor, GSNO, most effectively inhibited VCAM-1 expression.…”

NO donors: Focus on furoxan derivatives

“…When the segments are preincubated with proadifen, an inhibitor of cytochrome P450, there is a significant rightward shift of the concentration-response curve. This could suggest the involvement of this enzyme in the bioactivation of the product [12]. By contrast, this enzyme does not seem to be involved in the NO release of other furoxancarbonamides, such as CAS-1609 ( Fig.…”

“…It remained a potent vasodilator when administered orally to conscious dog for a period of five days. The lack of tolerance appears to be an important property of vasodilatory furoxan derivatives [12,14,15]. Unfortunately, CAS 1609 has mutagenic activity, and this precluded any further clinical study.…”

Nitric oxide modulators: An emerging class of medicinal agents

“…The most probable mechanism of NO release by them is via nucleophilic attack of thiolates[4748]. However, new furoxan derivatives have been reported to release NO spontaneously independent of thiols and without requiring enzymatic metabolism[49]. The most promising furoxan derivative has been CAS 1609 (fig.…”