ha-1100 and Myocardial-Ischemia

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.. 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).. 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.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Arginine Vasopressin; Blood Pressure; Electrocardiography; Intracellular Signaling Peptides and Proteins; Male; Myocardial Ischemia; Protein Serine-Threonine Kinases; Rats; rho-Associated Kinases; Vasoconstriction; Vasodilator Agents

1. The effects of Rho-kinase inhibitor, fasudil, and of a more specific Rho-kinase inhibitor, hydroxyfasudil, on pacing-induced myocardial ischaemia were determined in anaesthetized open-chest dogs. 2. The dogs were subjected to left anterior descending coronary artery (LAD) stenosis producing a sufficient ischaemia as measured by ST-segment depression on electrocardiograms only when the hearts were paced 60 beats min(-1) above the baseline. After a recovery (nonpacing) period, drugs or saline were infused intravenously over 30 min. The animals were again subjected to 5 min of pacing 25 min after the initiation of the treatment. 3. Hydroxyfasudil (0.1 and 0.3 mg kg(-1)) and fasudil (0.3 mg kg(-1)) suppressed the ST-segment depression. Hydroxyfasudil and fasudil also increased the regional blood flow of the LAD perfused endomyocardium region in the canine model of effort angina. 4. To determine the flow profile for hydroxyfasudil in dogs, blood flow in three vascular beds was measured. Hydroxyfasudil (0.3 mg kg(-1) for 30 min) significantly increased coronary blood flow and vertebral blood flow, without significantly changing the femoral blood flow. 5. Hydroxyfasudil had no inotropic or chronotropic effect on the isolated hearts of guinea-pigs. Hydroxyfasudil (2 mg kg(-1) for 20 min) did not affect the PR or QTc interval in anaesthetized dogs. 6. Inhibition of Rho-kinase appears to protect myocardium subjected to pacing-induced ischaemia through the increase in the regional myocardial blood flow. Hydroxyfasudil may be categorized as a novel type of anti-anginal drug, without any inotropic or chronotropic effects.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Anesthesia; Angina Pectoris; Animals; Cardiac Pacing, Artificial; Coronary Circulation; Coronary Stenosis; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Enzyme Inhibitors; Female; Guinea Pigs; Heart Atria; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Male; Myocardial Ischemia; Physical Exertion; Protein Serine-Threonine Kinases; Regional Blood Flow; rho-Associated Kinases; Vasodilator Agents