ABSTRACT
Title
Zucher Diabetic Fatty rats with metabolic syndrome are protected from acute myocardial infarction by three weeks treatment with telmisartan
Authors
L. Sodano1, B. Rinaldi1, C. Di Filippo1, A. Capuano1, M. Donniacuo1, F. Ferraraccio2, F.Rossi1, M.D’Amico1.
1Dept. of Experimental Medicine, Section of Pharmacology “L. Donatelli”, Excellence Centre for Cardiovascular Disease.
2Dept. of Clinical, Public and Preventive Medicine, 2nd University of Naples, Italy.
1Dept. of Experimental Medicine, Section of Pharmacology “L. Donatelli”, Excellence Centre for Cardiovascular Disease.
2Dept. of Clinical, Public and Preventive Medicine, 2nd University of Naples, Italy.
Abstract
Patients with the metabolic syndrome are atconsiderable risk for developing atherosclerosis-related diseases,including a 2- to 4-fold increased risk of stroke and a 3- to4-fold increased risk of myocardial infarction compared withthose without the metabolic syndrome (Lakka et al., 2002). Currently, many classes of drugs can act positively on metabolic syndrome such as statins (Tan et al., 2002), glitazones (Hanefeld et al., 2007) and drugs used to lower blood pressure such as the angiotensin receptor blockers (Nakayama et al., 2008). Among these, telmisartan, an angiotensin AT1 receptor antagonist and a gamma peroxisome proliferator-activated receptor (PPAR-γ) partial agonist, gained interest because of its property to improve the glycemic and lipidic components of the metabolic syndrome (Derosa et al., 2007), effects that seem to depend on its dual-functional property, a partial PPAR-γ agonist and an AT1 blocking (Nakayama et al., 2008; Negro et al., 2006; Yamagishi et al., 2007).No study, however, has documented whether the above mentioned metabolic improvements, induced by telmisartan, would relate to reductions of negative consequences that the syndrome has on the cardiovascular system, such as the worsening of the myocardial infarction.
For this purpose, in this study we investigated the cardio-protective potential of telmisartan, a selective angiotensin type 1 receptor antagonist and gamma peroxisome proliferator-activated receptor (PPAR-γ) partial agonist, against the myocardial infarction induced in Zucker Diabetic Fatty (ZDF) rats treated for three weeks with telmisartan at doses of 2, 7 and 12 mg/kg/day. At the end of this period a 25 min occlusion and 2h reperfusion (I/R) of the heart left descending coronary artery (LADCA) was applied.
I/R caused myocardial tissue injury with a value of ~53% IS/AR (infarct size as fraction of the area at risk), and a ~28% IS/LV (infarct size as fraction of the left ventricle) in ZDF rats treated with vehicle for three weeks.
A three weeks treatment with telmisartan at the doses of 7 mg/kg/day and 12 mg/kg/day produced attenuations of myocardial damage. Particularly, 12 mg/kg/day telmisartan gave IS/AR of ~28% (p<0.01 vs vehicle) while 7 mg/kg/day telmisartan afforded lower cardio-protection with an IS/AR of 46% (p<0.05 vs vehicle). Telmisartan reduced the plasma levels of the specific marker of myocardial damage, the troponin I, and caused a dose-dependent increase of the levels of the adipokine adiponectin within the plasma and cardiac tissue of the infarcted ZDF rats. These levels were minimally increased (p<0.05 vs vehicle) by telmisartan 7 mg/kg/day and reached the maximum values with the telmisartan highest dose 12 mg/kg/day (p<0.01 vs vehicle). In contrast, telmisartan treatment decreased the markers of inflammation such as the transcription factor NF-κB, the toll-like receptors (TLR2 and TLR4) and the cytokine TNF-alpha (TNF-α) within the infarcted tissue. Nitrosative stress was maximal in vehicle infarcted heart as evidenced by the expression of iNOS within the tissue, and minimally present after telmisartan treatment.
Telmisartan, therefore, an angiotensin II receptor antagonist and a partial agonist of PPAR-γ receptor, increased the plasma and cardiac adiponectin and decreased the markers of inflammation, providing a significant cardio-protection against ischemia/reperfusion in ZDF rats.
For this purpose, in this study we investigated the cardio-protective potential of telmisartan, a selective angiotensin type 1 receptor antagonist and gamma peroxisome proliferator-activated receptor (PPAR-γ) partial agonist, against the myocardial infarction induced in Zucker Diabetic Fatty (ZDF) rats treated for three weeks with telmisartan at doses of 2, 7 and 12 mg/kg/day. At the end of this period a 25 min occlusion and 2h reperfusion (I/R) of the heart left descending coronary artery (LADCA) was applied.
I/R caused myocardial tissue injury with a value of ~53% IS/AR (infarct size as fraction of the area at risk), and a ~28% IS/LV (infarct size as fraction of the left ventricle) in ZDF rats treated with vehicle for three weeks.
A three weeks treatment with telmisartan at the doses of 7 mg/kg/day and 12 mg/kg/day produced attenuations of myocardial damage. Particularly, 12 mg/kg/day telmisartan gave IS/AR of ~28% (p<0.01 vs vehicle) while 7 mg/kg/day telmisartan afforded lower cardio-protection with an IS/AR of 46% (p<0.05 vs vehicle). Telmisartan reduced the plasma levels of the specific marker of myocardial damage, the troponin I, and caused a dose-dependent increase of the levels of the adipokine adiponectin within the plasma and cardiac tissue of the infarcted ZDF rats. These levels were minimally increased (p<0.05 vs vehicle) by telmisartan 7 mg/kg/day and reached the maximum values with the telmisartan highest dose 12 mg/kg/day (p<0.01 vs vehicle). In contrast, telmisartan treatment decreased the markers of inflammation such as the transcription factor NF-κB, the toll-like receptors (TLR2 and TLR4) and the cytokine TNF-alpha (TNF-α) within the infarcted tissue. Nitrosative stress was maximal in vehicle infarcted heart as evidenced by the expression of iNOS within the tissue, and minimally present after telmisartan treatment.
Telmisartan, therefore, an angiotensin II receptor antagonist and a partial agonist of PPAR-γ receptor, increased the plasma and cardiac adiponectin and decreased the markers of inflammation, providing a significant cardio-protection against ischemia/reperfusion in ZDF rats.