Nitrovasodilator‐induced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium

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Abstract
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.