pituitrin and fasudil

The aim of this study was to develop a new model of vasopressin-induced chronic myocardial damage based on sustained ST-segment depression in electrocardiogram (ECG) with progression of myocardial fibrosis in rats. Furthermore, using this model, we examined the prophylactic potential of fasudil, a Rho-kinase inhibitor, against myocardial damage induced by vasopressin. In 10-week old male Donryu rats, intravenous administration of arginine vasopressin (0.5 iu/kg) induced significant ST-segment depression. Two days and one week after the administration of vasopressin, ST-segment depression was -0.19 +/- 0.02 and -0.14 +/- 0.02 mV, respectively. Fasudil (10 and 30 mg/kg, p.o.) significantly attenuated the ST-segment depression induced by vasopressin. One week after the administration of vasopressin, the percent area of myocardial fibrosis in control animals (0.42 +/- 0.11%, p < 0.01) was significantly greater than that in normal animals (0.05 +/- 0.01%). Fasudil (10 and 30 mg/kg) significantly prevented the development of the fibrosis. We present a new model of chronic myocardial damage based on sustained ST-segment depression with progression of myocardial fibrosis in rats, and suggest that this model may be useful to investigate the treatment of chronic angina. Inhibition of Rho-kinase is efficacious in preventing the ECG change and development of fibrosis induced by vasopressin in this model.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Cardiomyopathies; Chronic Disease; Disease Models, Animal; Disease Progression; Electrocardiography; Enzyme Inhibitors; Fibrosis; Intracellular Signaling Peptides and Proteins; Kinetics; Male; Protein Serine-Threonine Kinases; Rats; rho-Associated Kinases; Vasopressins

We studied the antiischemic properties of fasudil, a Rho-kinase inhibitor, in conscious rabbits with coronary vasospasm induced by vasopressin and endothelin. Pretreatment with fasudil (0.3 and 3 mg/kg) attenuated the maximum elevation of the T-wave elicited by endothelin. Pretreatment with fasudil inhibited the T-wave elevation elicited by vasopressin. Fasudil and hydroxy fasudil, an active metabolite of fasudil, relaxed the endothelin-, U-46619-, 5-hydroxytryptamine- or histamine-induced contraction in swine coronary arterial strips. Fasudil and hydroxy fasudil significantly prevented the reduction in coronary flow by vasopressin in the Langendorff perfused rat heart. Fasudil was effective in protecting the heart against vasopressin and endothelin-induced myocardial ischemic change in conscious rabbits, and this beneficial effect can be attributed to its action of ameliorating the severe contraction of arteries. The inhibition of Rho-kinase may have implications for the development of novel therapeutic strategies for vasospastic angina in patients.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Angina Pectoris; Animals; Coronary Vasospasm; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Endothelins; Histamine; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Male; Protein Serine-Threonine Kinases; Rabbits; Rats; Rats, Wistar; rho-Associated Kinases; Swine; Time Factors; Vasodilation; Vasodilator Agents; Vasopressins