Impaired vasodilator response to organic nitrates in isolated basilar arteries

Abstract

1. The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache. 2. Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and endothelium-dependent vasodilation was investigated for comparison purpose. 3. The vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.33+/-0.1, n=8), ISMN (1.61+/-0.07, n=7) and PETN (>10 microM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52+/-0.06, n=12), ISMN (3.66+/-0.08, n=10) and PETN (6.3+/-0.13, n=8) observed in coronary arteries. 4. In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in -logM) was almost similar in basilar (7.76+/-0.05, n=7) and coronary arteries (7.59+/-0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed. 5. Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.84+/-0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO-synthase inhibitor N(omega)-nitro-L-arginine (4.59+/-0.05, n=9, P<0.03). 6. These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO.

Figure 1

Original registration showing vascular responses of isolated perfused porcine basilar artery segments. Spontaneous vasoconstriction (myogenic tone) developed within 60 min of perfusion. Further vasoconstriction could be achieved by 10 μM prostaglandin F₂α (PGF₂α), while addition of 10 μM noradrenaline induced maximal vasodilation. This vasodilation was completely reversible, since the myogenic tone fully recovered after washout of noradrenaline (see washout arrow). Substance P (3 nM) induced an endothelium-dependent relaxation, which reversed the vascular constriction induced by exogenous vasoconstrictors. Please note that the interruptions of the ordinate indicate different time scales.

Figure 2

Nitrovasodilator induced relaxation of isolated porcine basilar artery segments. The vasodilator activity of S-nitroso-N-acetyl-D,L-penicillamine (SNAP), glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN) was assessed in the presence (intact) and absence (denuded) of intact endothelium. Each concentration-response curve is plotted by taking the respective mean values of 6 – 9 individual experiments (s.e.mean indicated by bars, ^*P<0.05 compared to intact endothelium, halfmaximal effective concentrations, see Table 1).

Figure 3

Nitrovasodilator induced relaxation of isolated porcine coronary artery segments. The vasodilator activity of S-nitroso-N-acetyl-D,L-penicillamine (SNAP), glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN) was assessed in the presence (intact) and absence (denuded) of intact endothelium. Each concentration-response curve is plotted by taking the respective mean values of 6 – 12 individual experiments (s.e.mean indicated by bars, ^*P<0.05 compared to intact endothelium, halfmaximal effective concentration, see Table 1).

Figure 4

Low potency of organic nitrates in basilar versus coronary artery segments as indicated by the fold increase in the IC₅₀-values. Given are the ratios of the halfmaximal effective concentration of the spontaneous NO-donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and the organic nitrates glyceryl trinitrate (GTN) and isosorbide-5-nitrate (ISMN) in cardinal numbers (halfmaximal effective concentration, see Table 1).