Low-pressure reperfusion alters mitochondrial permeability transition

Abstract

We hypothesized that low-pressure reperfusion may limit myocardial necrosis and attenuate postischemic contractile dysfunction by inhibiting mitochondrial permeability transition pore (mPTP) opening. Male Wistar rat hearts (n = 36) were perfused according to the Langendorff technique, exposed to 40 min of ischemia, and assigned to one of the following groups: 1) reperfusion with normal pressure (NP = 100 cmH(2)O) or 2) reperfusion with low pressure (LP = 70 cmH(2)O). Creatine kinase release and tetraphenyltetrazolium chloride staining were used to evaluate infarct size. Modifications of cardiac function were assessed by changes in coronary flow, heart rate (HR), left ventricular developed pressure (LVDP), the first derivate of the pressure curve (dP/dt), and the rate-pressure product (RPP = LVDP x HR). Mitochondria were isolated from the reperfused myocardium, and the Ca(2+)-induced mPTP opening was measured using a potentiometric approach. Lipid peroxidation was assessed by measuring malondialdehyde production. Infarct size was significantly reduced in the LP group, averaging 17 +/- 3 vs. 33 +/- 3% of the left ventricular weight in NP hearts. At the end of reperfusion, functional recovery was significantly improved in LP hearts, with RPP averaging 10,392 +/- 876 vs. 3,969 +/- 534 mmHg/min in NP hearts (P < 0.001). The Ca(2+) load required to induce mPTP opening averaged 232 +/- 10 and 128 +/- 16 microM in LP and NP hearts, respectively (P < 0.001). Myocardial malondialdehyde was significantly lower in LP than in NP hearts (P < 0.05). These results suggest that the protection afforded by low-pressure reperfusion involves an inhibition of the opening of the mPTP, possibly via reduction of reactive oxygen species production.

Myocardial ischemia-reperfusion injury: a neglected therapeutic target

“…In contrast to unimpeded reperfusion, IPost is intermittent reperfusion of the acute ischemic myocardium, which has been reported to prevent myocardial reperfusion injury and reduce MI size by 40%-50% (61). It must be appreciated that IPost represents a form of modified reperfusion that was demonstrated in the 1980s to be beneficial in the form of gradual reperfusion (62)(63)(64)(65). Staat et al (66) first applied IPost to the clinical setting of PPCI: immediately after direct stenting, coronary blood reflow was allowed for 60 seconds, following which the angioplasty balloon was inflated upstream of the stent for 60 seconds to occlude coronary blood flow, and this cycle was repeated 4 times in total ( Table 1).…”

Postconditioning: from experimental proof to clinical concept

“…This observation has since been confirmed in several experimental preparations and with different animal species (rats, rabbits and mice), showing that, when applied at the time of reperfusion, postconditioning significantly reduced infarct size with results comparable to preconditioning (Bopassa et al, 2006;Bopassa et al, 2005;Kin et al, 2005;Kin et al, 2004;Tsang et al, 2004).…”

“…Postconditioning also significantly reduced the lipid peroxidation in the myocardial area at risk compared with the control group. All those results showed that postconditioning significantly reduced the reperfusion injury phenomenon.This observation has since been confirmed in several experimental preparations and with different animal species (rats, rabbits and mice), showing that, when applied at the time of reperfusion, postconditioning significantly reduced infarct size with results comparable to preconditioning (Bopassa et al, 2006;Bopassa et al, 2005; Kin et al, 2005; Kin et al, 2004;Tsang et al, 2004).At first glance, the underlying mechanisms of cardioprotection seem to be complex and varied. The mechanisms involve activation of the prosurvival kinases phosphoinositide 3-kinase (PI3K)-Akt and endothelial nitric oxide synthase (eNOS) of the reperfusion injury salvage kinase (RISK) pathway (Tsang et al, 2004), interaction with the mPTP (Hausenloy et al, 2002;Bopassa et al, 2005), and activation of the endogenous receptors of adenosine (Kin et al, 2005).…”

“…The mechanisms involve activation of the prosurvival kinases phosphoinositide 3-kinase (PI3K)-Akt and endothelial nitric oxide synthase (eNOS) of the reperfusion injury salvage kinase (RISK) pathway (Tsang et al, 2004), interaction with the mPTP (Hausenloy et al, 2002;Bopassa et al, 2005), and activation of the endogenous receptors of adenosine (Kin et al, 2005). These underlying cellular mechanisms of postconditioning were identified using animal models of ischemia-reperfusion that are now leading progress towards direct clinical applications.…”

Oxygen Concentration during Reperfusion in Mitral Valve Surgery

“…The concept of reperfusion injury remains controversial with several proposed mechanisms, but it is mainly oxygen-derived free radicals and calcium overload that play an important role in the development of left ventricular dysfunction, stunning, reperfusion arrhythmias, vascular damage, and endothelial dysfunction [15]. Various strategy used to reduce ischemic-reperfusion injury include lowering blood pressure during reperfusion, reducing blood flow during reperfusion, but one of the most vigorously researched methods is controlling arterial oxygen tension in order to reduce reperfusion injury [16][17][18]. Maintaining normoxic cardiopulmonary bypass in children with cyanotic congenital heart disease resulted in dramatically reduced levels of conjugated diens, which represents the lipid peroxidation levels of the heart, compared with patients that maintained on hyperoxic cardiopulmonary bypass [19].…”