Korean Circ J.  2017 Mar;47(2):182-192. 10.4070/kcj.2015.0295.

AT1 Receptor Modulator Attenuates the Hypercholesterolemia-Induced Impairment of the Myocardial Ischemic Post-Conditioning Benefits

Affiliations
  • 1Department of Cardiology, Henan University Huaihe Hospital, Henan, China. drliyanming86@hotmail.com

Abstract

BACKGROUND AND OBJECTIVES
Ischemic post-conditioning (PostC) has been demonstrated as a novel strategy to harness nature's protection against myocardial ischemia-reperfusion (I/R). Hypercholesterolemia (HC) has been reported to block the effect of PostC on the heart. Angiotensin II type-1 (AT1) modulators have shown benefits in myocardial ischemia. The present study investigates the effect of a novel inhibitor of AT1, azilsartan in PostC of the heart of normocholesterolemic (NC) and HC rats.
MATERIALS AND METHODS
HC was induced by the administration of high-fat diet to the animals for eight weeks. Isolated Langendorff's perfused NC and HC rat hearts were exposed to global ischemia for 30 min and reperfusion for 120 min. I/R-injury had been assessed by cardiac hemodynamic parameters, myocardial infarct size, release of tumor necrosis factor-alpha troponin I, lactate dehydrogenase, creatine kinase, nitrite in coronary effluent, thiobarbituric acid reactive species, a reduced form of glutathione, superoxide anion, and left ventricle collagen content in normal and HC rat hearts.
RESULTS
Azilsartan post-treatment and six episodes of PostC (10 sec each) afforded cardioprotection against I/R-injury in normal rat hearts. PostC protection against I/R-injury was abolished in HC rat hearts. Azilsartan prevented the HC-mediated impairment of the beneficial effects of PostC in I/R-induced myocardial injury, which was inhibited by L-N⁵-(1-Iminoethyl)ornithinehydrochloride, a potent inhibitor of endothelial nitric oxide synthase (eNOS).
CONCLUSION
Azilsartan treatment has attenuated the HC-induced impairment of beneficial effects of PostC in I/R-injury of rat hearts, by specifically modulating eNOS. Azilsartan may be explored further in I/R-myocardial injury, both in NC and HC conditions, with or without PostC.

Keyword

AT1 receptor blocker; Ischemia-reperfusion injury; Azilsartan; myocardial infarction

MeSH Terms

Angiotensin II
Animals
Collagen
Creatine Kinase
Diet, High-Fat
Glutathione
Heart
Heart Ventricles
Hemodynamics
Hypercholesterolemia
Ischemia
Ischemic Postconditioning*
L-Lactate Dehydrogenase
Myocardial Infarction
Myocardial Ischemia
Nitric Oxide Synthase Type III
Rats
Reperfusion
Reperfusion Injury
Superoxides
Troponin I
Tumor Necrosis Factor-alpha
Angiotensin II
Collagen
Creatine Kinase
Glutathione
L-Lactate Dehydrogenase
Nitric Oxide Synthase Type III
Superoxides
Troponin I
Tumor Necrosis Factor-alpha

Figure

  • Fig. 1 Diagrammatic representation of experimental protocol. NC: normocholesteroleic, I/R: ischemia-reperfusion, I: ischemia, R: reperfusion, L-NIO: L-N5-(1-Iminobutyl)ornithine hydrochloride, HCI: hydrochloric acid, HC: hypercholeterolemic, S: stablization, P: perfusion, K-H: Krebs Henseleit.

  • Fig. 2 Effect of azilsartan perfusion on the hemodynamic parameters of an isolated heart in ischemia-reperfusion injury and ischemic-post conditioning of normal and hypercholesterolemic rats. Results are expressed as mean±standard deviation. ap<0.05 vs. sham control group; bp<0.05 vs. I/R-NC group; cp<0.05 vs. sham control-HC group; dp<0.05 vs. I/R-HC group; ep<0.05 vs. AZ+PostC-I/R-HC group. BMP: beats per minute, NC: normocholesterolemic, I/R: ischemia-reperfusion, PostC: post-conditioning, AZ: azilsartan, HC: hypercholesterolemic, L-NIO: selective eNOS inhibitor, LVEDP: left ventricular end-diastolic pressure, LVPP: left ventricular protection period.

  • Fig. 3 Effect of azilsartan perfusion on (A) LDH, (B) K-MB and (C) TNF-α in ischemia-reperfusion injury and ischemic-post conditioning of normal and hypercholesterolemic rats. Results are expressed as mean±standard deviation. ap<0.05 vs. sham control-NC group. bp<0.05 vs. I/R-NC group. cp<0.05 vs. sham control-HC group. dp<0.05 vs. I/R-HC group. ep<0.05 vs. AZ+PostC-I/R-HC group. LDH: lactate dehydrogenase, CK-MB: creatine kinase, TNF-α: tumor necrosis factor-alpha, NC: normocholesterolemic, I/R: ischemia-reperfusion, NC: normocholesterolemic, PostC: post-conditioning, HC: hypercholesterolemic, AZ: azilsartan, L-NIO: selective eNOS inhibitor.

  • Fig. 4 Effect of azilsartan perfusion on (A) nitrite levels and (B) TnI in ischemia-reperfusion injury and ischemic-post conditioning of normal and hypercholesterolemic rats. Results are expressed as mean±standard deviation. ap<0.05 vs. sham control-NC group. bp<0.05 vs. I/R-NC group. cp<0.05 vs. sham control–HC group. dp<0.05 vs. I/R-HC group. ep<0.05 vs. AZ+PostC-I/R–HC group. TnI: troponin-I, NC: normocholesterolemic, HC: hypercholesterolemic, AZ: azilsartan, I/R: ischemia-reperfusion, PostC: post-conditioning, L-NIO: selective eNOS inhibitor.

  • Fig. 5 Effect of azilsartan perfusion on (A) percent infarct size and (B) left ventricle collagen content in ischemia-reperfusion injury and ischemic-post conditioning of normal and hypercholesterolemic rats. Results are expressed as mean±standard deviation. ap<0.05 vs. sham control-NC group. bp<0.05 vs. I/R-NC group. cp<0.05 vs. sham control-HC group. dp<0.05 vs. I/R-HC group. ep<0.05 vs. AZ+PostC-I/R-HC group. NC: normocholesterolemic, HC: hypercholesterolemic, AZ: azilsartan, I/R: ischemia-reperfusion, PostC: post-conditioning, L-NIO: selective eNOS inhibitor.

  • Fig. 6 Effect of azilsartan perfusion on (A) TBARS, (B) SA and (C) GSH in ischemia-reperfusion injury and ischemic-post conditioning of normal and hypercholesterolemic rats. Results are expressed as mean±standard deviation. ap<0.05 vs. sham control–NC group. bp<0.05 vs. I/R–NC group. cp<0.05 vs. sham control–HC group. dp<0.05 vs. I/R–HC group. ep<0.05 vs. AZ+PostC-I/R–HC group. TBARS: thiobarbituric acid reactive substances, SA: superoxide anion, GSH: reduced form of the glutathione, NC: normocholesterolemic, HC: hypercholesterolemic, AZ: azilsartan, I/R: ischemia-reperfusion, PostC: post-conditioning, L-NIO: selective eNOS inhibitor.


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