Development of tolerance towards glyceryl trinitrate in vitro. Low concentration induced tolerance and changes in cyclic guanosine-3',5'-monophosphate metabolism.
Bovine mesenteric arteries were exposed to glyceryl trinitrate (GTN) in vitro for 2 and 8 h in a low concentration (0.1 nmol/l), that equals the plasma concentrations reached by using GTN-discs in patients with angina pectoris. After reexposure to GTN a significantly reduced relaxant response was observed. In the concentration range 1 pmol/l to 10 nmol/l a 10-fold right shift of the concentration-effect curve was noted as compared to control vessels not previously exposed to GTN. The reduced relaxant response was accompanied by a significantly impaired ability to form cyclic guanosine-3',5'-monophosphate (cGMP). The results are interpreted as a development of tolerance towards GTN at the level of the vascular smooth muscle cell. A concentration of GTN (0.1 mmol/l) previously used to induce tolerance in vitro, produced a much more pronounced shift to the right of the concentration-response curve, especially in the concentration range 10 nmol/l to 0.1 mmol/l. This might indicate that tolerance to GTN can be induced by 2 different mechanisms, which in turn might be interpreted as the existence of 2 mechanisms of action by GTN in inducing vascular smooth muscle relaxation.
Ahlner
J
J
Department of Clinical Pharmacology, University Hospital, Linköping, Sweden.
Andersson
R G
RG
Axelsson
K L
KL
Ekstam Ljusegren
M
M
D000818:Animals; D002417:Cattle; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D004361:Drug Tolerance; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D014303:Trinitrotoluene / Q000494:pharmacology*
D014303:Trinitrotoluene; D000242:Cyclic AMP; D006152:Cyclic GMP