Comparison of the effects of ACE inhibition with those of Angiotensin II receptor antagonism on systolic and diastolic myocardial stunning in isolated rabbit heart (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.
Angiotensin and bradykinin peptides in rats with myocardial infarction
Journal of Cardiac Failure, 1997
Background: Angiotensin II (Ang II) stimulates cardiac hypertrophy and fibrosis, whereas bradykinin [BK-(1-9)] has cardioprotective actions and reduces infarct size following myocardial infarction. Methods and ResuRs: We investigated whether myocardial infarction and cardiac failure are associated with changes in circulating and tissue levels of angiotensin and bradykinin peptides. Myocardial infarction was produced in rats by coronary artery ligation and confirmed by electrocardiogram. Ang H, Ang I, BK-(I-9), and its metabolite BK-(1-7) were measured 1, 2, 3, 7, and 28 days after myocardial infarction. In comparison with sham operated rats, myocardial infarction reduced blood pressure and body weight, and produced cardiac hypertrophy and cardiac failure. Myocardial infarction increased plasma renin and ACE activity, reduced plasma angiotensinogen, and increased Ang II levels in plasma, aorta, kidney, and lung. Ang [I levels in whole cardiac ventricles were similar in infarct and sham operated rats, but were positively correlated with heart weight/body weight ratio in infarct rats 3, 7, and 28 days after infarction. In a separate study of cardiac regions, Ang II levels were similar in infarct mad sham operated rats, except at 7 days post surgery when fight ventficular Ang II levels were higher in infarct rats. In infarct rats, Ang II levels were higher in the right ventricle and in the infarct than in the non-infarcted left ventricle at 7 days, but these differences were not apparent at 28 days after infarction. BK-(I-9) levels were increased in the heart and lung on days 2 and 3 post infarction, but not in the aorta or kidney. A decrease in BK-(1-7)/BK-(1-9) ratio suggested reduced metabolism of BK-(1-9) to BK-(1-7) in infarcted hearts. Conclusions: The transient activation of the circulating renin angiotensin system, and increased Ang Ii levels in the aorta, kidney, and lung may contribute to the systemic responses to myocardial infarction and cardiac failure. The correlations between cardiac Ang II levels and heart weight/body weight ratio noted for whole cardiac ventricles support a role for local Ang II levels in the process of myocardial remodeling post infarction. The increased cardiac BK-(1-9) levels in the acute phase of myocardial infarction were consistent with a role for this peptide in cardioprotection and limitation of infarct size.
Annals of the New York Academy of Sciences, 1999
This review focuses on the importance of bradykinin in myocardial preservation during ischemic arrest. Bradykinin is released from the heart spontaneously in response to ischemic stress, which may be viewed as a survival signal of the heart against ischemia. Bradykinin appears to function as a signaling molecule by controlling the release of other intracellular modulators, such as prostacyclins and nitric oxide, which also exert beneficial effects on the ischemic myocardium.
Brazilian Journal of Medical and Biological Research, 2000
It has been shown that angiotensin-(1-7) (Ang-(1-7)) infusion potentiates the bradykinin (BK)-induced hypotensive response in conscious rats. The present study was conducted to identify Ang-(1-7)-BK interactions in the isolated rat heart perfused according to the Langendorff technique. Hearts were excised and perfused through the aortic stump under a constant flow with Krebs-Ringer solution and the changes in perfusion pressure and heart contractile force were recorded. Bolus injections of BK (2.5, 5, 10 and 20 ng) produced a dosedependent hypotensive effect. Ang-(1-7) added to the perfusion solution (2 ng/ml) did not change the perfusion pressure or the contractile force but doubled the hypotensive effect of the lower doses of BK. The BK-potentiating Ang-(1-7) activity was blocked by pretreatment with indomethacin (5 mg/kg, ip) or L-NAME (30 mg/kg, ip). The Ang-(1-7) antagonist A-779 (50 ng/ml in Krebs-Ringer) completely blocked the effect of Ang-(1-7) on BK-induced vasodilation. These data suggest that the potentiation of the BK-induced vasodilation by Ang-(1-7) can be attributed to the release of nitric oxide and vasodilator prostaglandins through an Ang-(1-7) receptor-mediated mechanism.
Angiotensins and the Heart: Is Angiotensin-(1-7) Cardioprotective?
Hypertension, 2015
L eft ventricular hypertrophy is the most common cardiac complication of hypertension. Although the initial adaptations associated with cardiac hypertrophy are compensatory, ultimately abnormal ventricular function including diastolic dysfunction (impaired relaxation) and often heart failure may develop. 1 Activation of the renin-angiotensin system and its main effector peptide angiotensin II (Ang II), acting on the Ang II type 1 receptor, has been considered an important part of the cascade leading to left ventricular hypertrophy and cardiac fibrosis. 1,2 Recent work, however, examining the effects of Ang II infusion using cardiomyocyte and vascular smooth muscle-specific Ang II type 1 receptor knockouts suggests that the hypertension-induced increase in afterload, rather than direct Ang II-Ang II type 1 receptor signaling in the heart, is the key factor that promotes hypertrophic responses. 2 The renin-angiotensin system peptide Ang-(1-7), which is generated from Ang II by the action of carboxypeptidases, such as ACE2, 3 exhibits actions that are mainly opposite to those of Ang II, including vasodilatory and antifibrotic effects. In this issue, Machado de Almeida et al 5 report a series of interesting observations that suggest that in an Ang-(1-7) transgenic line, TGR(A1-7)3292, there is cardioprotection from deoxycorticosterone acetate (DOCA)-salt induced hypertension which is independent of blood pressure. The latter conclusion is not unexpected considering the strong evidence against an antihypertensive effect of Ang-(1-7): (1) acute infusions of supraphysiologic concentrations of this peptide do not lower blood pressure in mice, (2) a 4-week continuous infusion of Ang-(1-7) did not decrease blood pressure in DOCA-treated Sprague-Dawley (SD) rats, 6 (3) acutely Ang-(1-7) does not attenuate the hypertensive effect of infused Ang II, and a blocker of the Mas receptor also does not worsen the blood pressure response to infused Ang II, 3 and (4) the antihypertensive effects of an Ang II antagonist are not altered by the concomitant administration of the Ang-(1-7) receptor blocker. 7 Notwithstanding these observations, the rat transgenic TGR(A1-7)3292 used displayed an attenuated hypertensive response to DOCA, and appropriate experiments were performed to show that the observed cardioprotective effects were not found in control animals with hydralazineinduced attenuated blood pressure levels. 5 Previous studies have shown cardioprotective effects of Ang-(1-7). The question then arises: how does Ang-(1-7) act directly on cardiomyocytes to reduce hypertrophic responses?
Journal of the American College of Cardiology, 1998
The clinical use of adrlamynin (ADR) is limited by its cardlofox. ICily In which free radicals and lipid peroxldaflon m~y be involved, Melatonln (MEL) has gained Increasing interest aa a strong antloxldsnt. Accordingly, the protective effects of MEL ~galnst ADR cardiomyopathy was evaluated. Method: Male Sprague.Dawley r~t~ were divided Into 4 gro~,=p~ as follows: ADR (ADR treated, cumulative dose 15 mg/kg bw, Ip, for 2 weeks), MEL (MEL treated, cumulative dose 84 mglkg bw, Ip), MEL + ADR (MEL + ADR treated), and CeNT (control), After 3 weeks of post treatment observation. their cardiac perferman0e w{la assessed, and th(~lr lloarts worn used to study myocardial lipid pcroxtd~tion by measuring thiobarblturtc acid reactive ~ubstance (TBARS) along wttl~ ultrastructuro, Results: MEL rovemea the ADR induced cl~nnflo~ in myocardial ultrastructure aa well as parameters shown below, CeNT ADR MEL MEL + AOR
Possible mechanism of cardioprotective effect of angiotensin preconditioning in isolated rat heart
European Journal of Pharmacology, 2000
The present study is designed to investigate the mechanism of the cardioprotective effect of ischaemic preconditioning. Isolated perfused rat heart was subjected to global ischaemia for 30 min followed by reperfusion for 120 min. Coronary effluent was analysed for LDH and CK release to assess the degree of cardiac injury. Myocardial infarct size was estimated macroscopically using TTC staining. Four episodes of ischaemic preconditioning markedly reduced LDH and CK release in the coronary effluent and decreased myocardial infarct Ž . size. Administration of prazosin ␣ adrenoceptor antagonist before global ischaemia 1 reduced the extent of ischaemia-reperfusion induced myocardial injury. The cardioprotec-Ž tive effect of ischaemic preconditioning was abolished by prazosin and colchicine micro-. tubule disaggregator . On the basis of these results, it may be concluded that the cardioprotective effects of ischaemic preconditioning may be mediated through stimulation of ␣ 1 adrenoceptors and translocation of PKC.