Combined simvastatin-manidipine protect against ischemia-reperfusion injury in isolated hearts from normocholesterolemic rats.
This study investigated whether oral simvastatin and manidipine interact in protecting the perfused rat heart from ischemia-reperfusion damage. Simvastatin (0.3 to 3 mg/kg) and manidipine (1 to 10 mg/kg) were given orally singly or together to normocholesterolemic rats once a day for seven consecutive days. At the end of treatment, systolic blood pressure and heart rate were measured in conscious rats, and the lipid profile and other biochemical markers, such as thromboxane B(2), nitrite/nitrates and 6-keto-prostaglandin F(1alpha) (6-keto-PGF(1alpha)) were determined in the plasma. Hearts were then isolated, perfused with Krebs-Henseleit, and subjected to low flow ischemia-reperfusion injury. Post-ischemic recovery of left ventricular function was measured as left ventricular developed pressure and left ventricular end-diastolic pressure. Creatine kinase, lactate dehydrogenase, tumor necrosis factor-alpha and 6-keto-PGF(1alpha) were measured in the heart effluents. In conscious animals, simvastatin alone increased plasma 6-keto-PGF(1alpha) release while manidipine alone reduced systolic blood pressure with a slight sympathetic reflex increase in heart rate, and increased plasma nitrite/nitrates. The combined treatment produced the same effects, but significantly more marked, and accompanied by a significant reduction of thromboxane B(2). Combined treatment was also significantly more effective than the single drugs in protecting the hearts from ischemia-reperfusion injury, with inhibition of creatine kinase, lactate dehydrogenase and tumor necrosis factor-alpha, and enhancement of 6-keto-PGF(1alpha) during reperfusion. These data show that simvastatin and manidipine interact positively in protecting the rat heart from ischemia-reperfusion injury, possibly through increased prostaglandin and nitric oxide formation by the vascular endothelial cells.
Rossoni
Giuseppe
G
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Italy. giuseppe.rossoni@unimi.it <giuseppe.rossoni@unimi.it>
Manfredi
Barbara
B
Civelli
Maurizio
M
Berti
Ferruccio
F
Razzetti
Roberta
R
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D002784:Cholesterol / Q000097:blood / Q000502:physiology*; D003402:Creatine Kinase / Q000378:metabolism; D004095:Dihydropyridines / Q000627:therapeutic use*; D011464:Epoprostenol / Q000097:blood / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D066298:In Vitro Techniques; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008055:Lipids / Q000097:blood; D008297:Male; D009578:Nitrobenzenes; D010879:Piperazines; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy*; D019821:Simvastatin / Q000627:therapeutic use*; D013929:Thromboxane B2 / Q000097:blood; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001786:Blood Glucose; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D009578:Nitrobenzenes; D010879:Piperazines; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D013929:Thromboxane B2; C054218:manidipine; D002784:Cholesterol; D019821:Simvastatin; D011464:Epoprostenol; D007770:L-Lactate Dehydrogenase; D003402:Creatine Kinase