Fasudil evokes vasodilatation of rat mesenteric vascular bed via Ca2+ channels and Rho/ROCK pathway

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Abstract

As a Rho kinase (ROCK) inhibitor, fasudil has been used in clinical trials of several cardiovascular diseases. This study was to investigate the vasorelaxant effect of fasudil on resistance arterial rings including mesenteric, renal, ventral tail and basilar artery. We also examined the potential mechanisms of its vasodilatory action using mesenteric artery rings.

A DMT multiwire myograph system was used to test the tension of isolated small arteries. K+ channel blockers, NO-cGMP pathway blockers and Ca2+-free physiological salt solution (PSS) were employed to verify the underlying mechanisms.

Fasudil (10−7–10−4 M) relaxed four types of small artery rings pre-contracted by 60 mmol/l KCl (pEC50: 6.01±0.09, 5.47±0.03, 5.54±0.04, and 5.72±0.10 for mesenteric, renal, ventral tail and basilar artery rings, respectively). Pre-incubation with fasudil (1, 3, or 10 μmol/l) attenuated KCl (10–60 mmol/l) and angiotensin II (Ang II; 1 μmol/l)-induced vasoconstriction in mesenteric artery rings. Fasudil at the concentration of 10−6 mol/l showed different relaxant potency in endothelium intact (pEC50:6.01±0.09) or denued (5.75±0.06) mesenteric artery. The influx and release of Ca2+ were inhibited by fasudil. In addition, fasudil could block the increased phosphorylation level of myosin light chain (MLC) and myosin-binding subunit of myosin phosphatase (MYPT1) induced by Ang II. However, pretreatment with various K+ channel blockers did not affect the relaxant effects of fasudil remarkably.

The present results demonstrate that fasudil has a vasorelaxant effect on isolated rat resistance arteries, including mesenteric, renal, ventral tail and basilar artery, and may exert its action through the endothelium, Ca2+ channels, and the Rho/ROCK pathway.

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