title: Telmisartan, a dual ARB/partial PPAR-γ agonist, protects myocardium from ischaemic reperfusion injury in experimental diabetes.
abstract: OBJECTIVE
  Apart from its angiotensin receptor blocker (ARB) activity, telmisartan is also a partial agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ). Therefore, we assessed whether telmisartan treatment attenuates myocardial ischaemia/reperfusion (I/R) injury in diabetic rats through PPAR-γ pathway.
  
  
  METHODS
  Diabetic rats were randomized to receive vehicle (sham and I/R), telmisartan (10 mg/kg/day, orally), PPAR-γ antagonist GW9662 (1 mg/kg/day, intraperitoneally) or both for 14 days. On 15th day, excluding sham group, left anterior descending coronary artery occlusion was performed for 45 min followed by 1 h of reperfusion. Haemodynamic, biochemical, histopathological, ultrastructural, immunohistochemical (Bax and Bcl-2 protein), TUNEL positivity, infarct size and western blot studies were performed.
  
  
  RESULTS
  Telmisartan treatment significantly improved cardiac function by normalizing mean arterial pressure, left ventricular pressure (±LVdP/dt(max) , a marker of myocardial contraction and relaxation), by decreasing left ventricular end-diastolic pressure (a marker of preload, 3.7 ± 0.41 vs. 7.3 ± 0.89, p < 0.001) and percent infarct area (37.52 ± 5.83 vs. 46.27 ± 3.20, p < 0.01) as compared to diabetic I/R group. Interestingly, GW9662 worsens the I/R injury (percent infarct area, 54.38 ± 6.48 vs. 46.27 ± 3.20, p < 0.01), whereas telmisartan with GW9662 (percent infarct area, 41.16 ± 8.23 vs. 46.27 ± 3.20, p < 0.05) showed lesser significant results as compared to telmisartan alone. Additionally, telmisartan significantly ameliorates activities of endogenous antioxidants, creatine kinase-MB isoenzyme, lactate dehydrogenase and prevented the increase of tumour necrosis factor-alpha and malondialdehyde in myocardium. Furthermore, telmisartan also decreased Bax expression (4.45 ± 1.24% vs. 10.25 ± 0.96%, p < 0.01), number of TUNEL-positive cells (6.2 ± 0.98% vs. 13.0 ± 1.6, p < 0.01), inflammation, myonecrosis and increased Bcl-2 expression (5.45 ± 0.15% vs. 1.24 ± 0.3%, p < 0.01). On the other hand, GW9662 treatment alone increased the Bax expression, TUNEL positivity and decreased Bcl-2 expression. Telmisartan protective effects were partially attenuated by a co-administration with GW9662. Western blot analysis showed that telmisartan treatment enhanced PPAR-γ expression, whereas GW9662 decreased it in myocardium.
  
  
  CONCLUSIONS
  In addition to the class effect of ARBs, telmisartan has a beneficial effect in I/R injury in diabetic rats in part because of activation of PPAR-γ.
authors.affiliation: Cardiovascular Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: S N
authors.initials: SN
authors.lastname: Goyal
authors.forename: S
authors.initials: S
authors.lastname: Bharti
authors.forename: J
authors.initials: J
authors.lastname: Bhatia
authors.forename: T C
authors.initials: TC
authors.lastname: Nag
authors.forename: R
authors.initials: R
authors.lastname: Ray
authors.forename: D S
authors.initials: DS
authors.lastname: Arya
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium; D047495:PPAR gamma / Q000819:agonists*; D051381:Rats; D000077333:Telmisartan
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D047495:PPAR gamma; D000077333:Telmisartan