Studies on vascular smooth muscle tolerance to different cGMP-mediated vasodilators and cross-tolerance to glyceryl trinitrate.
In the present study the possible existence of cross-tolerance between GTN, atrial natriuretic peptide and the endothelium-dependent vasodilators acetylcholine and calcium ionophore A23187 was investigated. Pretreatment of bovine mesenteric arteries (BMA) with GTN (0.44 mM) for 2 hrs caused a significant (P less than 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 acetylcholine and calcium ionophore A23187 was found as judged from cumulative concentration-effect curves. The cGMP response evoked by 1 microM GTN was markedly blunted in the GTN-pretreated vessels (P = 0.0056). Similarly the cGMP elevation induced by 10 microM acetylcholine and 0.1 microM calcium ionophore A 23187 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-tolerant vessels as compared to in controls (P = 0.2097). BMA specimens were also incubated with acetylcholine 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 microM) for 2 hrs did not affect the relaxant response to a subsequent challenge with acetylcholine or GTN. Preincubation of BMA with ANP (0.1 microM) for 6 hrs was also without effect on the responsiveness to ANP or GTN.(ABSTRACT TRUNCATED AT 250 WORDS)
Ljusegren
M E
ME
Department of Pharmacology, Linköping University, Sweden.
Ahlner
J
J
Axelsson
K L
KL
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002417:Cattle; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D004361:Drug Tolerance; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D005996:Nitroglycerin / Q000494:pharmacology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; D000001:Calcimycin; D005996:Nitroglycerin; D006152:Cyclic GMP; D000109:Acetylcholine