Isolated segments of porcine vena cordis magna exhibited a reproducible contractile activity upon application of prostaglandin F2α (PGF2α) or KCl, that was independent of the presence of intact endothelium. Substance P (3 nm) elicited strictly endothelium‐dependent relaxations amounting to 46.1 ± 1.4% (n = 206) of contractions induced by 10 μm PGF2α.

S‐nitroso‐N‐acetyl‐d,l‐penicillamine (SNAP), a compound that spontaneously liberates nitric oxide, concentration‐dependently relaxed PGF2α‐precontracted (50 μm) venous segments. Tolerance induction (incubation with 100 μm SNAP for 30 min) within the same segments resulted in a 3 fold attenuation of this effect, which was not further reduced after additional preincubation with glyceryl trinitrate (GTN). Removal of endothelium or the presence of Nω‐nitro‐l‐arginine methylester (l‐NAME) significantly improved the potency of SNAP before and after tolerance induction.

Concentration‐dependent relaxations induced by GTN in non‐tolerant veins were similar in the presence and absence of endothelium but much more reduced in tolerant endothelium‐denuded (75 fold) compared to intact (20 fold) segments. In contrast, the presence of l‐NAME significantly improved GTN‐activity solely in non‐tolerant veins, which, therefore, also resulted in a more pronounced attenuation of activity due to tolerance induction (100 fold). Preincubation of intact veins with SNAP also reduced GTN‐activity but to a lesser extent (10 fold).

The more delayed but much longer, and compared to GTN somewhat weaker, acting new nitrovasodilator N‐(3‐nitrato‐pivaloyl)‐1‐cysteineethylester (SPM 3672) was more potent in denuded than intact non‐tolerant venous segments. Induction of tolerance by GTN resulted in a 2 fold‐attenuation of potency. This effect was increased to 15 fold in denuded veins but solely due to enhanced potency of SPM 3672 caused by removal of endothelium.

These data demonstrate that intact endothelium of porcine vena cordis magna attenuates the relaxant potency of nitrovasodilators but also probably participates in vascular bioactivation of GTN. We suggest that the reduced potency of nitrovasodilators is due to endogenous production of nitric oxide, which may affect the soluble guanylate cyclase/cyclic GMP‐system or inhibit nitrate bioactivation pathways.

1993-12-01·European Journal of Pharmacology3区 · 医学

Influence of endothelium and nitrovasodilators on free thiols and disulfides in porcine coronary smooth muscle

3区 · 医学

Article

作者: Georg Kojda ; Eike Noack ; Wilfried Meyer

It is hypothesised that the well known development of tolerance to the vasodilating action of organic nitrates is contributed by intracellular depletion of free thiols occurring during repeated treatment with these drugs. Therefore, ring segments of porcine coronary arteries with and without endothelium were treated for 30 min with either vehicle or 100 microM of isosorbide-5-mononitrate, glyceryl trinitrate, S-nitroso-N-acetyl-D,L-penicillamine or N-(3-nitratopivaloyl)-1-cysteine-ethylester (SPM 3672), and the content of histochemically stained free thiols (-SH) and disulfides (S-S-) was measured densitometrically in single smooth muscle cells. In the presence of endothelium the content of -SH in smooth muscle cells of controls (n = 8) gave an extinction of 0.127 +/- 0.013 in the intima and 0.120 +/- 0.010 in the media. The corresponding values for S-S- were 0.684 +/- 0.084 and 0.535 +/- 0.120 (n = 8). Removal of endothelium reduced S-S- to 82.1 +/- 70% and increased -SH to 126.7 +/- 6.7%. Treatment with all nitrates reduced -SH in intact artery segments to a similar degree, ranging between 54.0 +/- 4.4 and 68.7 +/- 4.7% (n = 8-10). In contrast, S-S- content was less affected and reached values between 70.6 +/- 2.8 and 91.6 +/- 6.0% (n = 8-9). As evaluated by tension studies, tolerance developed for glycerol trinitrate and isosorbide-5-mononitrate but not for S-nitroso-N-acetyl-D,L-penicillamine. Induction of tolerance with glycerol trinitrate (0.1 mM) produced a significantly more pronounced attenuation in activity of isosorbide-5-mononitrate than tolerance induction with isosorbide-5-mononitrate (1 mM). In contrast, the potency of SPM 3672 was not reduced in glycerol trinitrate-tolerant arteries. We conclude that, in porcine coronary arteries, an intact endothelium modifies intracellular thiols and disulfides. In addition, nitrate tolerance is associated with, but probably not caused by, thiol depletion.

1993-07-01·Journal of Cardiovascular Pharmacology4区 · 医学

Nitric Oxide Liberating, Soluble Guanylate Cyclase Stimulating and Vasorelaxing Properties of the New Nitrate-Compound SPM 3672

4区 · 医学

Article

作者: Noack, Eike ; Kojda, Georg

Development of tolerance as a consequence of organic nitrate therapy such as that which occurs with glyceryl trinitrate (GTN) appears to be associated with a depletion of free thiols in vascular smooth muscle. In this study, we investigated N-[3-nitratopivaloyl]-L-cysteineethylester (SPM 3672), a new compound containing a nitrate and a thiol moiety, in direct comparison with GTN. Liberation of nitric oxide (NO) from GTN and SPM 3672 measured in vitro was rather low and was markedly potentiated by addition of cysteine only in the case of GTN. Pronounced activation of a partially purified human soluble guanylate cyclase (sGC) by GTN was observed only after addition of cysteine, whereas a comparative activation by SPM 3672 occurred with and without addition of this thiol. In contrast, SPM 4946 (N(-)[3-hydroxypivaloyl]-L-cysteineethylester), a derivative of SPM 3672 lacking the nitrate-ester moiety, did not activate sGC. Activation of sGC by GTN and SPM 3672 was nearly abolished by oxyhemoglobin. Incubation of isolated porcine coronary artery rings with GTN or SPM 3672 resulted in a similar increase in vascular cyclic GMP levels. In rat aorta, GTN was a more potent vasorelaxant than SPM 3672 and produced a greater degree of tolerance. Vasorelaxation induced by GTN occurred with rapid onset and was brief, whereas SPM 3672 produced long-lasting relaxation with a more delayed onset. This kinetic pattern was confirmed in porcine coronary arteries, in which both nitrates exhibited marked relaxation, with GTN being slightly more potent than SPM 3672.(ABSTRACT TRUNCATED AT 250 WORDS)

100 项与 SPM-4946 相关的药物交易

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