Reduced endothelium‐dependent relaxation at enhanced NO release in hearts of hypercholesterolaemic rabbits

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Abstract
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 (PGI2) in the effluents was determined by radioimmunoassay (6‐oxo‐PGF1α). 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 nm) and substance P (50 nm) (Pn = 8–9). Under these conditions, NO release into the vessel lumen was increased, by 26%, in hypercholesterolaemic hearts (Pn = 8–9). NG‐nitro‐l‐arginine (l‐NOARG, 30 μm) significantly attenuated both bradykinin‐induced NO formation and vessel relaxation in control hearts but only NO release in hypercholesterolaemia. l‐Arginine (200 μm) restored the response to that before l‐NOARG but did not improve the reduced endothelium‐dependent relaxation in cholesterol‐fed rabbits. 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. Basal PGI2 release was unchanged in hypercholesterolaemic hearts. There was a tendency in these hearts for greater PGI2 formation after stimulation by substance P and bradykinin (P ≥ 0.05). The coronary relaxation to iloprost was unchanged. 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 PGI2 related pathways of vasomotor control in hypercholesterolaemia.