Mechanical stretch reveals different components of endothelial‐mediated vascular tone in rat aortic strips

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Abstract
Since the role of mechanical stretches in vascular tone regulation is poorly understood, we studied how stretch can influence endothelial tone. Isometric contractions of isolated rat aortic helical strips were recorded. The resting tension was set at 0.7 g, 1.2 g or 2.5 g. Endothelium‐preserved strips were precontracted with either phenylephrine or prostaglandin F2α (PGF2α). In control conditions, acetylcholine (ACh) dose‐dependently relaxed phenylephrine‐precontracted strips independently of resting tension. At 0.7 g resting tension, nitric oxide synthase (NOS) inhibitors did not reduce ACh‐induced relaxation, while either a guanylyl cyclase inhibitor or a NO trapping agent prevented it. At 1.2 g and 2.5 g resting tensions, NOS inhibitors shifted the ACh dose‐response curve to the right. After preincubation with indomethacin (5 μM) or ibuprofen (10 and 100 μM), at 0.7 g and 1.2 g resting tensions, ACh induced an endothelium‐dependent, dose‐dependent contraction. ACh (10−6 M) increased the contraction up to two times greater the phenylephrine‐induced one. Lipoxygenase inhibitors prevented it. At high stretch, the ACh vasorelaxant effect was marginally influenced by cyclooxygenase (COX) inhibition. Similar results were obtained when aortic strips were precontracted with PGF2α. Our data indicate that when resting tension is low, ACh mobilizes a stored NO pool that, synergistically with COX‐derived metabolites, can relax precontracted strips. COX inhibition up‐regulates the lipoxygenase metabolic pathway, accounting for the ACh contractile effect. At an intermediate resting tension, NO production is present, but COX inhibition reveals a lipoxygenase‐dependent, ACh‐induced contraction. At high resting tension, NO synthesis predominates and COX metabolites influence ACh‐induced relaxation marginally. British Journal of Pharmacology (2000) 131, 1355–1362; doi:10.1038/sj.bjp.0703707