Gtn

Fig. 1. Mechanisms of action of GTN. GTN is metabolized to NO which stimulates the synthesis of cGMP. In turn, cGMP reduces cytoplasmic Ca2+ by inhibiting inflow and stimulating mitochondrial uptake, causing relaxation of smooth muscle cells. PDE1A1 = Phosphodiesterase 1A1; GTP = guanosine triphosphate; cGMP = cyclic guanosine monophosphate; ATII = angiotensin II; K+ = potassium currents [7].

vascular beds [6]. Subsequent work also showed that NO produced in the endothelium could diffuse into nearby smooth muscle, where the NO stimulated the synthesis of soluble guanylate cyclase that, in turn, increased the synthesis of cyclic guanosine monophosphate from guanosine triphosphate. It is the guanosine monophosphate that finally leads to smooth muscle relaxation by reducing cytoplasmic calcium. This is accomplished by inhibiting inflow of calcium into the cell and stimulating the uptake of calcium by the mitochondria (fig. 1) [7].

Although the mechanism of action of endogenous NO is now well understood and accepted, the same cannot be said for the biotransformation of NTG and other similar therapeutic drugs into pharmacologically active agents. Since both NTG and nitroprusside (NTP) have vasodilator activity similar to that of NO, it is reasonable to believe that in some way, each contributes NO, or an NO intermediary, to the vasodilation process, but the mechanism(s) by which this takes place is not clear. Initially it was believed that these nitrate donors reacted with cysteine to form unstable intermediate S-nitrosothiols that in turn activated guanylate cyclase [8]. This has not been completely ac-

Fig. 2. Coronary arteriolar responses to 10 ^M nitroglycerin (GTN). Large symbols represent means for groups with control diameters <100 ^m (open circles) and >100 ^m (filled circles) ± SEM. GTN dilated large vessels from 183 ± 12 to 218 ± 15 ^m but had no effect on small vessels (58.5 ± 5 to 58.9 ± 5 ^m). * Different from control value, p < 0.05 [13].

Fig. 2. Coronary arteriolar responses to 10 ^M nitroglycerin (GTN). Large symbols represent means for groups with control diameters <100 ^m (open circles) and >100 ^m (filled circles) ± SEM. GTN dilated large vessels from 183 ± 12 to 218 ± 15 ^m but had no effect on small vessels (58.5 ± 5 to 58.9 ± 5 ^m). * Different from control value, p < 0.05 [13].

cepted [9] and alternative possibilities have been proposed [10]. The release of NO from the non-organic NTP appears to be less complex and related only to a single electron transfer [9]. These differences in the biotransformation of NTG and NTP help explain some of the other differences in the behavior of these two drugs and from endogenous NO.

Endothelial function may be disturbed either locally or systemically by a variety of clinical conditions such as hypertension, diabetes mellitus or coronary atherosclerosis. This dysfunction of the endothelium reduces the amount and the influence of endogenous NO on vascular tone. But the therapeutically administered nitrate donors bypass endothelium and stimulate smooth muscle relaxation more directly. Although the vasorelaxation induced by both endogenous NO and the nitrate donors are similar, the mechanisms for the release of the active principle from the donor molecules induce some differences in behavior. For example, NO is a potent vasodilator of resistance microvessels of all sizes. But NTG, while successfully dilating microvessels >100 ^m in diameter, does not dilate vessels <100 ^m (fig. 2). This has been attributed to a suspected relative deficiency of available sulfhydryl groups in the small vessels and their resulting inability to process NTG to an active form - possibly that of nitrosothiols [11-13]. In contrast to NTG, the release of an active principle from NTP is simpler, permitting it to be active in the small microvessels.

Another difference between endothelium-derived NO and therapeutical-ly administered NTG is the development of NTG tolerance. There is no tolerance to NO alone. Initially, tolerance to NTG was attributed to reduced availability of local thiols for the biotransformation of NTG. Since then, many other explanations have been proposed [7, 14]. Of these, two seem more promising than the others. NTG tolerance is associated with increased levels of angioten-sin II and some investigators have described the relief of tolerance with both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The other plausible explanation for NTG tolerance involves the link with oxi-dative stress [15]. NO as well as NTG react readily with superoxide radicals to form peroxynitrite - a mystery molecule with both beneficial and harmful effects [15-17]. This binding of therapeutically useful nitrates may explain the reduced endothelial function induced by oxidative stress and the reduced vasodilator effects of continued NTG use. Whether or not antioxidants are useful in the relief of NTG tolerance remains controversial.

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