Studies on Vascular Smooth Muscle Tolerance to Different cGMP-Mediated Vasodilators and Cross-Tolerance to Glyceryl Trinitrate

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Abstract
In the present study the possible existence of cross-tolerance between GTN, atrial natriuretic peptide and the endothelium-dependent vasodilators acetycholine and calcium ionophore A23187 was investigated. Pretreatment of bovine mesenteric arteries (BMA) with GTN (0.44 mM) for 2 hrs caused a significant (P<0.001) right-shift of the concentration-effect curve for GTN as compared to controls (pD2=6.96.+-.0.208 and 4.57 .+-. 0.148 in controls and GTN treated vessels, respectively), thus indicating the development of tolerance. Cross-tolerance between GTN and the endothelium-dependent vasodilators acetycholine and calcium ionophore A23187 was found as judged from cumulative concentration-effect curves. The cGMP response evoked by 1 .mu.M GTN was markedly blunted in the GTN-pretreated vessels (P=0.0056). Similarly the cGMP elevation induced by 10 .mu.M acetylcholine and 0.1 .mu.M calcium ionophore A23187 was significantly reduced in GTN-pretreated muscle specimens (P=0.0475 and P=0.0103, respectively). No cross-tolerance between GTN and atrial natriuretic peptide (ANP) could be established from tension studies. Furthermore, the CGMP response induced by atrial natriuretic peptide was not significantly different in GTN-tolerent vessels as compared to in controls (P=0.2097). BMA specimens were also incubated with acetycholine and ANP (2 hrs and 6 hrs, respectively) and the vessels were thereafter tested for their responsiveness to acetylcholine, ANP and GTN. Preincubation with acetylcholine (10 .mu.M) for 2 hrs did not affect the relaxant response to a subsequent challenge with acetylcholine or GTN. Preincubation of BMA with ANP (0.1 .mu.M) for 6 hrs was also without effect on the responsiveness to ANP or GTN. The ANP-evoked cGMP increase was however somewhat reduced in ANP-incubated BMA. These results suggests the existence of a certain degree of cross-tolerance between GTN and endothelium-dependent vasodilators, while GTN-pretreatment has no effect on relaxations induced by ANP in BMA.

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