Increased Tolerance of the Chronically Hypoxic Immature Heart to Ischemia

Baker, John E.; Curry, Brian; Olinger, Gordon N.; Gross, Garrett J.

doi:10.1161/01.cir.95.5.1278

Cited by 68 publications

(73 citation statements)

References 19 publications

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“…Cardiac output was similar in all groups, except for group 9, where cardiac output was lower than that of group 8. The heart rate in group 1 was lower than in groups 3,7,8,10, and 11. LV external heart work in groups 1, 2, 5, and 6 and RV external heart work in the other groups were not different from each other ( Table 4).…”

Section: Resultsmentioning

confidence: 69%

“…A prior study (3) in immature rabbit hearts demonstrated postischemic recoveries of hypoxic RVs and LVs that were similarly improved over those of the respective normoxic controls. In contrast, in the present study using adult rat hearts, chronic hypoxia improved postischemic RV but not LV func- Values are means Ϯ SE; n, no.…”

Section: Discussionmentioning

confidence: 70%

“…The beneficial effects of chronic hypoxic preconditioning on left and right ventricular (RV) developed pressure were abolished by the K ATP channel antagonist glibenclamide. The K ATP channel agonist bimakalim enhanced postischemic left ventricular (LV) function in normoxic hearts similar to that of hypoxic hearts (3). As in ischemic preconditioning, these results suggested a role for the K ATP channel in hypoxic preconditioning.…”

mentioning

confidence: 81%

“…Baker et al (3,4) reported that the increased tolerance to ischemia in isolated crystalloid-perfused immature rabbit hearts exposed to chronic hypoxia is associated with an activation of the K ATP channels. The beneficial effects of chronic hypoxic preconditioning on left and right ventricular (RV) developed pressure were abolished by the K ATP channel antagonist glibenclamide.…”

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confidence: 99%

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Responses of chronically hypoxic rat hearts to ischemia: K_ATP channel blockade does not abolish increased RV tolerance to ischemia

Forkel¹,

Chen²,

Wandinger³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia. Am J Physiol Heart Circ Physiol 286: H545-H551, 2004. First published October 9, 2003 10.1152/ajpheart.00022.2003.-Chronic hypoxia may precondition the myocardium and protect from ischemia-reperfusion damage. We therefore examined the recovery of left and right ventricular function after ischemia and reperfusion (15 min each) in isolated blood-perfused working hearts from normoxic (Norm) and hypoxic (Hypo; 14 days, 10.5% O2) adult rats. In addition, the mRNA expression of hypoxia-inducible factor (HIF)-1␣ and the protein expression of endothelial nitric oxide synthase (eNOS) were measured. Postischemic left ventricular function recovered to 66 Ϯ 6% and 67 Ϯ 5% of baseline in Norm and Hypo, respectively. In contrast, postischemic right ventricular function was 93 Ϯ 2% of baseline in Hypo vs. 67 Ϯ 3% in Norm (P Ͻ 0.05). Improved postischemic right ventricular function in Hypo (93 Ϯ 2% and 96 Ϯ 2% of baseline) was observed with 95% O 2 or 21% O2 in the perfusate, and it was not attenuated by glibenclamide (5 and 10 mol/l) (86 Ϯ 4% and 106 Ϯ 6% recovery). HIF-1␣ mRNA and eNOS protein expression were increased in both left and right hypoxic ventricles. In conclusion, postischemic right, but not left, ventricular function was improved by preceding chronic hypoxia. ATP-sensitive K ϩ channels are not responsible for the increased right ventricular tolerance to ischemia after chronic hypoxia in adult rat hearts. chronic hypoxia; glibenclamide; hypoxia-inducible factor-1␣; endothelial nitric oxide synthase ISCHEMIC PRECONDITIONING protects myocardium against subsequent ischemia-reperfusion injury (19). Protection is evident by limitation of infarct size (19,22), better recovery of myocardial contractile function in some models (8), preservation of high-energy phosphate levels (13), and attenuation of arrhythmias (23). ATP-sensitive K ϩ (K ATP ) channels are crucially involved in the protection of ischemic preconditioning (10).Chronic hypoxic preconditioning also increases the tolerance of the myocardium to ischemia. In an isolated adult rat heart model, chronic hypoxia improved postischemic systolic function and protected against prolonged periods of ischemia (27). Although similarities of the phenomena of hypoxic and ischemic preconditioning have been found in protecting the myocardium, the additive cardioprotective effects of hypoxic and ischemic preconditioning suggest different mechanisms of protection (27). Baker et al. (3,4) reported that the increased tolerance to ischemia in isolated crystalloid-perfused immature rabbit hearts exposed to chronic hypoxia is associated with an activation of the K ATP channels. The beneficial effects of chronic hypoxic preconditioning on left and right ventricular (RV) developed pressure were abolished by the K ATP channel antagonist glibenclamide. The K ATP channel agonist bimakalim enhanced postischemic left ventricular (LV) function in normoxic heart...

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Section: Resultsmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 81%

mentioning

confidence: 99%

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Responses of chronically hypoxic rat hearts to ischemia: K_ATP channel blockade does not abolish increased RV tolerance to ischemia

Forkel¹,

Chen²,

Wandinger³

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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“…Experimental studies in the newborn heart suggest a lower tolerance of the LV to ischemia, as LV recovery of function following ischemia is far worse than that seen in the RV (3). Whether these findings are a result of ventricle-specific differences in postnatal myocardial metabolic maturation is currently unknown.…”

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confidence: 99%

Ventricle-Specific Metabolic Differences in the Newborn Piglet Myocardium In Vivo and During Arrested Global Ischemia

2008

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Ventricular dysfunction is reported greater in the left (LV) versus right ventricle (RV) in infants following surgically induced ischemia. Ventricle-specific differences in baseline metabolism may alter response to ischemia thus affecting postischemic functional recovery. This study identifies ventricle-specific metabolic differences in the newborn (piglet) heart at baseline (working) and during ischemia (arrested). Baseline LV citrate synthase (CS) and hydroxyacyl-CoA dehydrogenase (HAD) activities were 15% and 18% lower (p Ͻ 0.02), whereas creatine kinase (CK) and phosphofructokinase (PFK) activities were 40% and 23% higher (p Ͻ 0.04) than the RV. Baseline LV glycogen reserves were also 55% higher (p ϭ 0.004). By 15 min of ischemia, LV ATP was 20% lower (p Ͻ 0.05), lactate was 51% higher (p ϭ 0.001), and hydrogen ions (H ϩ ) were 43% higher (p ϭ 0.03) compared with the RV. These differences persisted for the entire ischemic period (p Ͻ 0.02). After 45 min of ischemia, the LV used 58% less (p Ͻ 0.05) glycogen than the RV. These findings demonstrate that the enhanced glycolytic capacity of the newborn LV was accompanied by greater anaerobic end-product accumulation and lower energy levels during ischemia. This profile may offer one explanation for greater LV-dysfunction relative to the RV in children following ischemia. C linical studies continue to report persistent postoperative dysfunction in the left ventricle (LV) of children even after successful repair of pathology affecting the right ventricle (RV) (1,2). Experimental studies in the newborn heart suggest a lower tolerance of the LV to ischemia, as LV recovery of function following ischemia is far worse than that seen in the RV (3). Whether these findings are a result of ventricle-specific differences in postnatal myocardial metabolic maturation is currently unknown.During postnatal cardiac maturation, the LV undergoes rapid "physiologic" hypertrophy relative to the RV in response to postnatal changes in systemic and pulmonary circulation (4). Morphologic studies using newborn animals have reported a lower capillary density in the LV relative to the RV as noted by greater LV myocyte-to-capillary ratios and intercapillary distances (5). Lower tissue perfusion capacity in the face of increased postnatal ventricular workloads and rapid ventricular growth in the newborn LV may result in underperfusion. Whether this has detrimental effects on metabolic capacity and response to ischemia is unknown.During postnatal cardiac maturation, there is a shift in energy substrate reliance where the use of fatty acids dramatically increases and that of glucose decreases (6 -9). Central to this transition is an early decrease in the activity of key enzymes involved in the glycolytic pathway and an increase in the enzymes responsible for fatty acid and oxidative metabolism (8,9). Interestingly, studies have shown that adult hearts adapt to chronic increases in ventricular workloads by shifting energy substrate reliance away from fatty acid and oxidative pathways b...

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Myocardial Preconditioning in the Experimental Model: A New Strategy to Improve Myocardial Protection

Rosenkranz¹,

Feng²,

Li³

2003

Myocardial Protection

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Increased Tolerance of the Chronically Hypoxic Immature Heart to Ischemia

Abstract: Increased tolerance to ischemia exhibited by chronically hypoxic rabbit hearts is associated with increased activation of the KATP channel. This increased KATP activity may be the result of increased intracellular concentrations of lactate.

Cited by 68 publications

References 19 publications

Responses of chronically hypoxic rat hearts to ischemia: K_ATP channel blockade does not abolish increased RV tolerance to ischemia

Responses of chronically hypoxic rat hearts to ischemia: K_ATP channel blockade does not abolish increased RV tolerance to ischemia

Ventricle-Specific Metabolic Differences in the Newborn Piglet Myocardium In Vivo and During Arrested Global Ischemia

Myocardial Preconditioning in the Experimental Model: A New Strategy to Improve Myocardial Protection

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