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Pulsatile antagonism on bradykinin 2-receptor (BK2R) by icatibant triggers the most effective kinin-dependent post-conditioning on rat hearts.

Abstract：

OBJECTIVE:Pharmacological post-conditioning (PC) by intermittent but not continuous administration of exogenous bradykinin (BK) reduces ischemia/reperfusion (I/R) injury via the Reperfusion Injury Salvage Kinase (RISK) pathway activation. We evaluated whether intermittent administration with icatibant (HOE140), a BK2R antagonist, may represent an effective PC strategy, with the advantage of limiting the potential risks of supra-physiologic BK activity. MATERIALS AND METHODS:Hearts from male Sprague-Dawley (SD) rats on a Langendorff system were exposed to I/R injury (30/120 min). BK (100 nM) and HOE140 (1 µM) were administered post-ischemically during the first 3 min of reperfusion, under continuous or intermittent infusion (10 s/each). Hearts were randomly assigned to 5 groups: 1) I/R alone (n=5); 2) continuous HOE140 (cHOE n=6); 3) intermittent HOE140 (iHOE n=6); 4) continuous BK (cBK n=6); 5) intermittent BK (iBK n=6). End-diastolic left ventricular pressure (LVEDP), developed left ventricular pressure (dLVP) and coronary flow (CF) were monitored throughout reperfusion. Left ventricular infarct mass (IM) was quantified together with the phosphorylated levels of Akt and GSK3β (RISK pathway kinases) at the end of reperfusion. RESULTS:IM was not significantly changed in cBK or cHOE groups (vs. I/R). Conversely, both iBK and iHOE groups showed a significant limitation in IM (vs. I/R, p<0.05, p<0.01, respectively). Akt and GSK3β phosphorylation levels were higher in iBK and iHOE groups (vs. I/R, p<0.05). When compared to I/R group, both LVEDP values (p<0.05, first 60-min reperfusion), as well as dLVP values (p<0.01) were improved only in iHOE group. CF values did not vary among all groups. CONCLUSIONS:In isolated rat hearts, intermittent modulation of the endogenous kallikrein-kinin system by a selective BK2R antagonist mediates PC cardioprotection via RISK signaling.

journal_name

Eur Rev Med Pharmacol Sci

journal_title

European review for medical and pharmacological sciences

authors

Sgarra L,Coco C,Montagnani M,Potenza MA

doi

10.26355/eurrev_201905_17953

subject

Has Abstract

pub_date

2019-05-01 00:00:00

pages

4439-4447

issue

eissn

1128-3602

issn

2284-0729

journal_volume

pub_type

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Pulsatile antagonism on bradykinin 2-receptor (BK2R) by icatibant triggers the most effective kinin-dependent post-conditioning on rat hearts.