The involvement of the endothelium in the action of drugs which relax the rat aortic strip.

Abstract

Acetylcholine (ACh), histamine (HIST), vasoactive intestinal polypeptide (VIP), adenosine triphosphate (ATP), adenosine diphosphate (ADP) and A23187 were all found to induce dose-dependent relaxations of the rat aortic strip which were dependent on the presence of the endothelium. These endothelial-dependent relaxations were not inhibited by the cyclooxygenase inhibitor indomethacin (INDO) but were inhibited by the dual cyclooxygenase/lipoxygenase inhibitor eicosatetraynoic acid (ETYA). Other lipooxygenase inhibitors which were also inhibitory to the endothelium dependent relaxations were BW755C and nordihydroguaiaretic acid (NDGA) Arachidonic acid (AA) caused both contractile and relaxant effects depending on the bath concentration. The contractile effect was inhibited by INDO. The relaxant effect of AA was not inhibited by INDO but was inhibited by ETYA, and was also dependent on the endothelium. Other unsaturated fatty acids - eicosapentaenoic acid, homogammalinolenic acid, docasahexaenoic acid and alpha-linolenic acid - also induced endothelial-dependent relaxations on the rat aortic strip. Lysophosphatidylcholine induced dose-dependent relaxations which were not inhibited by INDO but were inhibited by ETYA. This effect was also dependent on the endothelium. Platelet-activating factor (PAF) induced a single non-sustained relaxation. Phospholipase A2 (PLA2) did not induce relaxation but phospholipase C (PLC) elicited a single relaxation which was dependent on the endothelium. Addition of ACh or further PLC to a pre-contracted strip following a PLC induced relaxation failed to induce any decrease in tension. Several antioxidants including a-tocopherol, cysteine and hydroquinone inhibited endothelium dependent relaxations but free-radical scavengers such as superoxide dismutase (SOD) and catalase were without effect. The guanylate cyclase inhibitor methylene blue inhibited endothelial dependent relaxations. However cyclic 3',5' guanosine monophosphate (cGMP) and dibutryrl cGMP failed to elicit relaxation when added to the bathing medium of a pre-contracted aortic strip. Cyclic 3',5' adenosine monophosphate (cAMP) and dibutryrl cAMP were also without effect. In diabetic rats, the sensitivity of the aorta to noradrenaline (NA) is significantly increased but the relaxant effect of ACh, although lower in diabetic rats does not differ significantly from control. In the mesenteric vascular bed ACh, HIST, ATP and papaverine (PAP) induced dose-dependent decreases in perfusion pressure. The response to ACh was inhibited slightly by INDO. Dual cyclooxygenase/lipoxygenase inhibitors could not be used as they resulted in a loss of ability of the preparation to contract to phenylephrine. Pumping air through the preparation which is thought to result in removal of the endothelium much reduced the vasodepressor effects of ACh and ATP but not those to HIST and PAP.

Date of Award	1984
Original language	English
Awarding Institution	University of Bath