Intermittent Losartan Administration Triggers Cardiac Post-Conditioning in Isolated Rat Hearts: Role of BK2 ReceptorsReport as inadecuate




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Introduction

The angiotensin Ang and bradykinin BK tissue-system plays a pivotal role in post-conditioning, but the efficacy of angiotensin type 1 receptor AT1R blockers ARBs in post-ischemic strategies is still under investigation. We evaluated functional and morphological outcomes, together with activation of cytosolic RISK pathway kinases, in rat hearts subjected to losartan LOS or irbesartan IRB post-ischemic administration.

Methods

Isolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Post-conditioning was obtained by intermittent 10 s-each or continuous drug infusion during the first 3 min of reperfusion. Left ventricular end-diastolic pressure LVEDP, left ventricular developed pressure dLVP, coronary flow CF, and left ventricular infarct mass IM were measured together with the activation status of RISK kinases Akt, p42-44 MAPK and GSK3β.

Results

When compared to hearts subjected to ischemia-reperfusion iI-R alone, continuous IRB or LOS administration did not significantly reduce total infarct mass cIRB or cLOS vs. iI-R, p = 0.2. Similarly, intermittent IRB iIRB was not able to enhance cardioprotection. Conversely, intermittent LOS administration iLOS significantly ameliorated cardiac recovery iLOS vs iI-R, p<0.01. Differences between iLOS and iIRB persisted under continuous blockade of AT2R iLOS+cPD vs. iIRB+cPD, p<0.05. Interestingly, iLOS cardioprotection was lost when BK2R was simultaneously blocked iLOS+cHOE vs. iI-R, p = 0.6, whereas concurrent administration of iBK and iIRB replicated iLOS effects iIRB+iBK vs. iLOS, p = 0.7. At the molecular level, iIRB treatment did not significantly activate RISK kinases, whereas both iLOS and iBK treatments were associated with activation of the Akt-GSK3β branch of the RISK pathways p<0.05 vs. iI-R, for both.

Conclusions

Our results suggest that intermittent losartan is effective in mediating post-conditioning cardioprotection, whereas irbesartan is not. The infarct mass reduction by intermittent losartan seem mainly related on its specific ability to modulate BK2R, and only modestly associated on AT1R blocking properties.



Author: Luca Sgarra, Valentina Leo, Francesco Addabbo, Dominga Iacobazzi, Maria Rosaria Carratù, Monica Montagnani , Maria Assunta Poten

Source: http://plos.srce.hr/



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