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Reduced endothelium‐dependent relaxation at enhanced NO release in hearts of hypercholesterolaemic rabbits
Author(s) -
Woditsch Isabelle,
Schrör Karsten
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb14848.x
Subject(s) - bradykinin , medicine , endocrinology , prostacyclin , endothelium , nitric oxide , nitroarginine , vasodilation , perfusion , chemistry , nitric oxide synthase , receptor
1 Langendorff hearts, perfused at constant volume, were prepared from rabbits fed a cholesterol‐enriched diet for 4 months. Coronary perfusion pressure and nitric oxide (NO) release (oxyhaemoglobin technique) into the coronary effluent were measured continuously. Prostacyclin (PGI 2 ) in the effluents was determined by radioimmunoassay (6‐oxo‐PGF 1α ). 2 Basal NO release was not different between control and hypercholesterolaemic rabbits. However, the coronary vasculature of hypercholesterolaemic rabbits showed a considerably (> 50%) reduced endothelium‐dependent relaxation in response to short‐term (3 min) infusion of bradykinin (50 n m ) and substance P (50 n m ) ( P <0.05, n = 8–9). Under these conditions, NO release into the vessel lumen was increased, by 26%, in hypercholesterolaemic hearts ( P <0.05, n = 8–9). N G ‐nitro‐ l ‐arginine ( l ‐NOARG, 30 μ m ) significantly attenuated both bradykinin‐induced NO formation and vessel relaxation in control hearts but only NO release in hypercholesterolaemia. l ‐Arginine (200 μ m ) restored the response to that before l ‐NOARG but did not improve the reduced endothelium‐dependent relaxation in cholesterol‐fed rabbits. 3 Superoxide dismutase (10 u ml −1 ) significantly improved vessel relaxation without changing the hypercholesterolaemia‐related coronary dysfunction. Vasodilatation in response to exogenous NO donors (linsidomine) was diminished in hypercholesterolaemia as compared to controls. 4 Basal PGI 2 release was unchanged in hypercholesterolaemic hearts. There was a tendency in these hearts for greater PGI 2 formation after stimulation by substance P and bradykinin ( P ≥ 0.05). The coronary relaxation to iloprost was unchanged. 5 The data demonstrate impaired endothelium‐dependent relaxation of coronary arterial resistance vessels in hypercholesterolaemia. This diminished vascular response was not due to reduced NO generation but probably a reduced action of released NO, either by accelerated degradation and/or disturbed signal transduction pathways to vascular smooth muscle cells. There was no significant change in PGI 2 related pathways of vasomotor control in hypercholesterolaemia.