Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.

Bradykinin elicits relaxation of isolated transverse rings of canine coronary, celiac, superior mesenteric, renal, splenic, pulmonary, gastric, and femoral arteries. After endothelial cells of the vessel wall are removed by rubbing of the intimal surface, canine arteries fail to relax upon addition of bradykinin. The endothelium-dependentrelaxation ofcanine arteries remains intact after treatment with cyclooxygenase inhibitors (indomethacin and flurbiprofen), and this argues against mediation by prostaglandins. When they are stimulated with bradykinin, endothelial cells of canine arteries appear to release a substance mediating vascular smooth muscle relaxation. In contrast, preparations of arteries of cats (superior-mesenteric) and rabbits (superior mesenteric and celiac) may be rubbed on the intimal surface without a consistent loss of sensitivity to the relaxing effects of bradykinin. In addition, relaxation of the cat and rabbit arteries is completely blocked by cyclooxygenase inhibitors. Preliminarystudies indicate that bradykinin relaxes human arteries in an endothelium.dependent manner and that this effect is not mediated byprostaglandins. We have previously reported that arteries of all species tested require the presence ofendothelial cells for relaxation in response to acetylcholine and we have also demonstrated, using the rabbit aorta, that this effect is mediated by the release of an uncharacterized substance from these cells that relaxes vascular smooth muscle. We conclude that bradykinin relaxes canine and human arteries via a similar mechanism but that it relaxes cat and rabbit arteries by stimulating release of prostaglandins from as yet undefined cell types.One of the chief physiological properties of bradykinin (BKN) is its ability to produce a fall in blood pressure when injected intravenously in minute amounts. With the purification and characterization of the molecule (1, 2) it became apparent that on a molar basis the nonapeptide was one of the most potent vasodilator substances known. However, its vasodilator activity is not consistently reflected in studies performed on isolated blood vessels. Depending on the species and anatomical origin of the blood vessel, application of BKN may elicit relaxation, contraction, or no response at all (3-5).It has been argued that at least part of the vasodilator response to BKN is an indirect effect mediated by release ofprostaglandins (PGs) (6), and support is given by the observed effects of the peptide on vascular PG synthesis (7). We have recently reported that other potent vasodilator agents relax vascular smooth muscle in an indirect manner by stimulating the release of a relaxing substance from endothelial cells. This endothelium-derived relaxing factor (EDRF) is not a PG (8-11). Acetylcholine (AcCho) and substance P (SP) act exclusively by this mechanism in producing relaxation of isolated arteries (8-10), and ATP and ADP exert their relaxing effects predominantly by stimulating endothelial cells and, to a lesser degree, by a direct act...

No abstract

No abstract