Inhibition of Rho-Kinase by Hydroxyfasudil Prevents Vasopressin-Induced Myocardial Ischemia in Donryu Rats by Attenuating Coronary Vasoconstriction

BACKGROUND: Inhibition of rho-kinase has been shown to attenuate vasopressin (AVP)-induced myocardial ischemia measured as S-wave depression in Donryu rats. This has been attributed to a direct inhibitory effect on AVP-induced coronary vasoconstriction. However, since AVP also increased mean arterial blood pressure (MAP) which was attenuated by the rho-kinase inhibitors used, the prevention of myocardial ischemia could have been due to effects on afterload. RESULTS: The purpose of this study was to determine if rho-kinase inhibition prevents S-wave depression independent of the effects on blood pressure. In anesthetized Donryu rats (200-340 g), infusion of AVP (0.1 IU/kg) resulted in a sustained increase in MAP (DeltaMAP=46+/-7 mm Hg) and a transient S-wave depression (-90+/-20 microV). Infusion of phenylephrine titrated to achieve a comparable pressor response (DeltaMAP=52+/-2 mm Hg) resulted in a significantly smaller S-wave depression (-30+/-20 microV). Pretreatment with the rho-kinase inhibitor, hydroxyfasudil (3 mg/kg), decreased MAP by -28+/-2 mm Hg and significantly attenuated AVP-induced S-wave depression (-10+/-10 microV) compared to AVP. When rats were pretreated with phenylephrine titrated to maintain MAP, hydroxyfasudil still significantly attenuated AVP-induced S-wave depression (-14+/-12 microV). Hydralazine (1 mg/kg), which lowered MAP by -36+/-5 mm Hg, had no significant effect on AVP-induced S-wave depression (-105+/-32 microV). CONCLUSION: These data indicate that inhibition of rho-kinase with hydroxyfasudil attenuates AVP-induced myocardial ischemia independent of changes in MAP and are consistent with an inhibitory effect on coronary vasoconstriction.