1. Endothelial cells release endothelium-derived hyperpolarizing factor (EDHF), as well as nitric oxide (NO). It has recently been suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) improve NO-mediated endothelial function, partially independently of their cholesterol-lowering effects. It is, however, unclear whether statins improve EDHF-mediated responses. 2. Eight-month-old stroke-prone spontaneously hypertensive rats (SHRSP) were treated with fluvastatin (10 mg/kg per day) for 1 month. Age-matched, normotensive Wistar Kyoto (WKY) rats served as controls. Both EDHF- and NO-mediated relaxations were impaired in SHRSP compared with WKY rats. 3. Fluvastatin treatment did not affect blood pressure and serum total cholesterol. The acetylcholine (ACh)-induced, EDHF-mediated hyperpolarization in mesenteric arteries did not significantly differ between fluvastatin-treated SHRSP and untreated SHRSP and the responses in both groups were significantly smaller compared with those of WKY rats. Endothelium-derived hyperpolarizing factor-mediated relaxations, as assessed by the relaxation to ACh in mesenteric arteries contracted with noradrenaline in the presence of NG-nitro-L- arginine and indomethacin, were virtually absent and similar in both SHRSP groups. In contrast, NO-mediated relaxation, as assessed by the relaxation in response to ACh in rings contracted witli 77 mmol/L KCl, was improved in fluvastatin-treated SHRSP compared with untreated SHRSP (maximum relaxation in control and fluvastatin groups 42.0 ± 5.2 and 61.2 ± 3.8%, respectively; P < 0.05). 4. Hyperpolarization and relaxation in response to levcromakalim, an ATP-sensitive K+ channel opener, were similar between the two SHRSP groups. 5. These findings suggest that fluvasfatin improves NO-mediated relaxation, but not EDHF-mediated hyperpolarization and relaxation, in SHRSP. Thus, the beneficial effects of the statin on endothelial function may be mainly ascribed to an improvement in the NO pathway, but not EDHF.
|ジャーナル||Clinical and Experimental Pharmacology and Physiology|
|出版ステータス||出版済み - 5 2004|
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