Effects of a protocol of ischemic postconditioning and/or captopril in hearts of normotensive and hypertensive rats (original) (raw)
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Circulation, 2000
Background-Ischemic preconditioning (PC) represents a state-of-the-art technique for myocardial preservation. Although certain intracellular mediators have been shown to play a role in PC, the exact nature of the trigger for PC is not known. Our previous study demonstrated that intracellular bradykinin released from the heart during ischemia/reperfusion plays a role in myocardial preservation. This study was undertaken to further examine the mechanism of bradykinin-mediated PC. Methods and Results-Since the bradykinin B 2 receptor is likely to provide cardioprotection by blocking angiotensin II formation, we determined the effects of an angiotensin II type 1 (AT 1) receptor blocker, losartan, and a bradykinin B 2 receptor blocker, HOE 140, on myocardial protection. Isolated rat hearts were perfused initially by the Langendorff mode with Krebs-Henseleit buffer (KHB) for 15 minutes in the absence (control) or presence of losartan (4.5 mol/L) and/or HOE 140 (10 mol/L). After conversion to the working mode for 10 minutes (baseline), randomly assigned control and experimental hearts were subjected to 30 minutes of normothermic global ischemia followed by 2 hours of reperfusion. Myocardial function, infarct size, cardiomyocyte apoptosis, and amount of bradykinin/angiotensin released from the hearts were measured at baseline and during reperfusion while in the working mode. Significant postischemic ventricular recovery was demonstrated by improved developed pressure and aortic flow and reduced myocardial infarct size and apoptotic cell death with losartan, whereas the reverse was true for HOE 140. The functional recovery and infarct size-lowering ability of losartan were partially blocked and the antiapoptotic function of losartan was completely blocked by HOE 140. Conclusions-The results document that losartan reduced whereas HOE 140 increased myocardial ischemia/reperfusion injury by blocking AT 1 and bradykinin B 2 receptors, respectively, suggesting a role of the bradykinin B 2 receptor in PC. Losartan provided cardioprotection through both bradykinin-dependent and bradykinin-independent mechanisms.
Circulation, 1994
Background Attenuation of myocardial stunning by several angiotensin-converting enzyme (ACE) inhibitors has been demonstrated. However, the signal cascade mediating such protective effect has not been analyzed in detail so far. Methods and Results In a first protocol, we addressed the role of bradykinin and analyzed the effect of the ACE inhibitor ramiprilat without and with added bradykinin B2 receptor antagonist HOE 140 on regional myocardial blood flow (colored microspheres) and function (sonomicrometry). Thirtytwo enflurane/N2O-anesthetized open-chest dogs were subjected to 15 minutes of occlusion of the left circumflex coronary artery (LCx) and 4 hours of subsequent reperfusion. Eight dogs served as placebo controls (group 1), and 8 dogs received ramiprilat (20 ,ug/kg IV) before LCx occlusion (group 2). Eight dogs received a continuous intracoronary infusion of HOE 140 [0.5 ng/(mL. min) IC] during ischemia and reperfusion (group 3), and in 8 dogs HOE 140 was infused continuously during ischemia and reperfusion, starting 45 minutes before the administration of ramiprilat (group 4). Mean aortic pressure was kept constant with an intra-aortic balloon, and heart rate did not change throughout the experimental protocols. Under control conditions and during myocardial ischemia, posterior transmural blood flow (BF) and systolic wall thickening (WT) were not different in the four groups of dogs. However, at 4 hours of reperfusion, WT was still depressed in groups 1 (-10±20% of control [mean±SD]), 3 (-18±12% of control), and 4 (-12±21% of control), whereas WT in group 2 had recovered to 55 ±20% of control (P<.05 versus group 1). BF at 4 hours of reperfusion was not T nhe attenuation of myocardial stunning by several angiotensin-converting enzyme (ACE) inhibitors has been demonstrated in a number of experimental studies in vitro'-5 and in ViVO.6-8 The mechanism underlying the cardioprotective action of ACE inhibitors, however, is not fully clear.9 One mechanism might be the prevention of bradykinin degradation during myocardial ischemia/reperfusion, since ACE is responsible not only for the conversion of angiotensin
Angiotensin-Converting Enzyme Inhibition After Experimental Myocardial Infarct
Hypertension, 2008
We sought to define the contribution of each of the 2 kinin receptors (bradykinin 1 receptor [B 1 R] and bradykinin 2 receptor [B 2 R]) to the cardioprotection of angiotensin-converting enzyme (ACE) inhibition after acute myocardial infarct. Wild-type mice and gene knockout mice missing either B 1 R or B 2 R were submitted to coronary ligation with or without concurrent ACE inhibition and had evaluation of left ventricular systolic capacity by assessment of fractional shortening (FS). Baseline FS was similar in all of the animals and remained unchanged in sham-operated ones. At 3 weeks after myocardial infarct, in the wild-type group there was a 27% reduction of FS (PϽ0.5) without ACE inhibition and 8% with ACE inhibition; in the B 1 R Ϫ/Ϫ groups the FS was reduced by 24% and was no different (at 28%) with ACE inhibition; in the B 2 R Ϫ/Ϫ groups, however, the FS was decreased by 39% and with ACE inhibition was decreased further by 52%. Analysis of bradykinin receptor gene expression in hearts showed that when one receptor was missing, the other became significantly upregulated; but the B 1 R remained highly overexpressed in the B 2 R Ϫ/Ϫ mice throughout, whereas the overexpressed B 2 R became significantly suppressed in the B 1 R Ϫ/Ϫ mice in a manner quantitatively and directionally similar to that of wild-type mice. We conclude that both bradykinin receptors contribute to the cardioprotective bradykinin-mediated effect of ACE inhibition, not only the B 2 R as believed previously; but, whereas with potentiated bradykinin in the absence of B 1 R, the upregulation of B 2 R is simply insufficient to provide full cardioprotection, in the absence of B 2 R, the upregulated B 1 R actually seems to inflict further tissue damage.
Myocardial Ischemia and Reperfusion, 1998
The aim was to determine whether enalaprilat (0.08 mg/kg/min) or losartan (0.01 mg/kg/min) administration before ischemia can improve postischemic systolic and diastolic dysfunction ('stunned myocardium') and attenuate the 'hyperfunction' phase at the beginning of reperfusion. An isolated isovolumic rabbit heart preparation was subjected to 15 min of ischemia followed by 30 min of reperfusion without (group 1) or with pretreatment with enalaprilat (group 2) or losartan (group 3). Left ventricular developed pressure and end-diastolic pressure (diastolic stiffness) were measured and the time constant of isovolumic relaxation (T, Tau) and the ratio between +dP/dt and -dP/dt were calculated. In comparison to the stunned group (group 1) both enalaprilat (group 2) and losartan (group 3) exerted a significant protective effect on postischemic recovery of contractile state and diastolic stiffness. Only enalaprilat attenuated the 'hypercontractile' phase. However, both enalaprilat and losartan failed to improve myocardial relaxation. In summary, these data strongly suggest a direct deleterious action of the local renin-angiotensin system on ischemic myocardium and diminution of myocardial stunning with its successful blockade. Although, we can not exclude the possibility that bradykinin has some cardioprotective effect, these data suggest that angiotensin exacerbates myocardial injury. (Mol Cell Biochem 186: 117-121, 1998)
Cardiovascular Research, 1997
Objectives: Substantial release of bradykinin has been demonstrated to occur during short periods of myocardial ischaemia in various species. The aim of the present study was to investigate the protective effect of bradykinin in ischaemia and whether bradykinin could be involved in ischaemic preconditioning in the rat heart. Methods: Isolated, buffer-perfused hearts were subjected to 30 min of global ischaemia, followed by 30 min of reperfusion. Postischaemic functional recovery was recorded in the following groups: (1) control; (2) treatment with 0.1 WM bradykinin for 10 min before ischaemia (BK); (3) bradykinin treatment combined with pretreatment with the specific bradykinin B2-receptor antagonist, HOE 140; (4) ischaemic preconditioning by 5 min ischaemia + 5 min reperfusion prior to sustained ischaemia (1P); and (5) ischaemic preconditioning combined with HOE 140 administration. Results:Postischaemic myocardial function was significantly improved in both BK and 1P groups (developed pressure 66.9 + 6.8 and 67.6 + 7.1 mmHg, respectively, vs. 43.1 t 5.9 mmHg in controls, P < 0.05). Pretreatment with 1 WM HOE 140 completely abolished the effect of bradykinin, while protection achieved by 1P was unaltered by this drug. None of the protective interventions was associated with any significant improvement in myocardial adenosine triphosphate, creatine phosphate, glycogen, lactate or glucose tissue levels, detected either at the end of ischaemia or after 30 min of reperftrsion. Conclusions: Bradykinin, acting via B2-receptors, can protect against postischaemic contractile dysfunction to a similar extent as 1P. An involvement of B2-receptors in the ischaemic preconditioning phenomenon could, however, not be demonstrated.
Bradykinin mediates cardiac preconditioning at a distance
American Journal of Physiology-heart and Circulatory Physiology - AMER J PHYSIOL-HEART CIRC PHY, 2000
Preconditioning the heart by brief coronary (CAO) or mesenteric artery occlusion (MAO) can protect against damage during subsequent prolonged CAO and reperfusion. The role of bradykinin (BK) in remote cardiac preconditioning by MAO is investigated by antagonizing the BK B(2) receptor [Hoechst 140 (HOE-140)] or simulating local BK release by mesenteric intra-arterial infusion. Anesthetized male Wistar rats (n = 6-8) were treated with HOE-140 or saline before starting the preconditioning protocol, CAO, MAO, or non-preconditioned control. Infarct size related to risk area [ratio of infarct area to area at risk (IA/AR)] was determined after 3 h of reperfusion following a 60-min CAO. IA/AR was 62 +/- 5% in controls and not affected by HOE-140 (58 +/- 6%). CAO as well as MAO significantly protected the heart (IA/AR, 37 +/- 3 and 35 +/- 5%), which was prevented by HOE-140 (IA/AR, 71 +/- 6 and 65 +/- 7%, respectively). Brief intramesenteric BK infusion mimicked MAO (IA/AR, 26 +/- 3%). Pretr...