Tolerance of the developing heart to ischemia: impact of hypoxemia from birth

Baker, Edward J.; Boerboom, Lawrence E.; Olinger, Gordon N.; Baker, John E.

doi:10.1152/ajpheart.1995.268.3.h1165

Cited by 45 publications

(53 citation statements)

References 16 publications

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“…Indeed, the effect of chronic hypoxia on ischemic tolerance has been shown to be age dependent in the LV. In a Langendorff model, LVs of immature rabbit hearts (hypoxic from birth) were more tolerant to ischemia than LVs of adult rabbits subjected to chronic hypoxia (2). Differences concerning postischemic LV functional recovery between our and earlier investigations (3) could thus be explained by different responses of immature and adult LVs to chronic hypoxia.…”

Section: Discussioncontrasting

confidence: 69%

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: Discussioncontrasting

confidence: 69%

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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“…The improved recovery of cardiac contractile function in the hypoxic group confirms our previous observations (23), as well as those of others (4,41), indicating that the already high ischemic tolerance of the immature heart can be further increased by chronic hypoxia. Despite a certain recent progress in understanding this protective phenomenon, its detailed mechanism is still far from clear (15).…”

Section: Discussionsupporting

confidence: 90%

ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats

Rakusan¹,

Chvojkova²,

Oliviéro³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Rakusan K, Chvojkova Z, Oliviero P, Ostadalova I, Kolar F, Chassagne C, Samuel JL, Ostadal B. ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats. Am J Physiol Heart Circ Physiol 292: H1237-H1244, 2007. First published December 1, 2006; doi:10.1152/ajpheart.00965.2006.-Chronic hypoxia has been shown to stimulate myocardial microvascular growth and improve cardiac ischemic tolerance in young and adult rats. The aim of this study was to determine whether the ANG II type 1 receptor (AT1) pathway was involved in these processes. Newborn Wistar rats, exposed to chronic intermittent hypoxia (8 h/day) for 10 days, were simultaneously treated with AT1 receptor blocker irbesartan and compared with untreated animals. The major finding is that chronic hypoxia increased the capillary supply of myocardial tissue, which was even more pronounced in hypertrophied right ventricle, whereas increased arteriolar supply was found only in the left ventricle. This angiogenic response was completely prevented by irbesartan. Moreover, chronic hypoxia improved the postischemic recovery of cardiac contractile function during reperfusion, and this protective effect was also completely abolished by irbesartan. Chronic hypoxia increased the myocardial density of AT1 but not of ANG II type 2 receptor subtypes, whereas the effect of irbesartan was not significant. The expression of caveolin-1␣ markedly increased in response to chronic hypoxia, and irbesartan prevented this effect. Neither hypoxia nor irbesartan treatment altered the expression of nitric oxide synthase 3, heat shock protein 90, and VEGF. It is concluded that the AT1 receptor pathway plays an important role in coronary angiogenesis and improved cardiac ischemic tolerance induced in neonatal rats by chronic hypoxia.angiotensin II receptors; ischemia-reperfusion; caveolin-1 ADAPTATION TO CHRONIC HYPOXIA increases cardiac tolerance to all major deleterious consequences of acute oxygen deprivation in both adult and immature heart. In addition to the protective effect, chronic hypoxia may also induce other adaptive responses, including hypoxic pulmonary hypertension and right ventricular (RV) hypertrophy (22). This is a beneficial adaptation, allowing the RV to cope with an increased afterload and to maintain cardiac output. Although many potential factors have been proposed to play a role in the mechanisms of cardiac adaptation to chronic hypoxia, the available data are not sufficiently conclusive. Moreover, a substantial amount of information concerning the adaptive response was obtained from the adult myocardium, whereas much less is known about this process in the immature heart. However, clinical relevance of the developmental approach is obvious: chronic hypoxia is the main pathophysiological feature of hypoxemic congenital heart disease. Understanding the mechanisms by which these malformations modify the myocardium and how they impact on the adaptive mechanisms during ischemia may provide ins...

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“…The hearts were perfused at 39°C in the Langendorff mode 11 at a perfusion pressure equivalent to 45 mm Hg. 12 The heart and perfusion fluids were immersed in nongassed physiological saline solution within temperature-controlled chambers to maintain the myocardium at 39°C, which is normothermic for rabbit. …”

Section: Perfusion Studiesmentioning

confidence: 99%

Chronic Hypoxia Increases Endothelial Nitric Oxide Synthase Generation of Nitric Oxide by Increasing Heat Shock Protein 90 Association and Serine Phosphorylation

Shi

Baker

Zhang

et al. 2002

Circulation Research

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Abstract-Chronic hypoxia increases endothelial nitric oxide synthase (eNOS) production of nitric oxide (·NO) and cardioprotection in neonatal rabbit hearts. However, the mechanism by which this occurs remains unclear. Recent studies suggest that heat shock protein 90 (hsp90) alters eNOS function. In the present study, we examined the role of hsp90 in eNOS-dependent cardioprotection in neonatal rabbit hearts. Chronic hypoxia increased recovery of postischemic left ventricular developed pressure (LVDP). Geldanamycin (GA), which inhibits hsp90 and increases oxidative stress, decreased functional recovery in normoxic and hypoxic hearts. To determine if a loss in ·NO, afforded by GA, decreased recovery, GA-treated hearts were perfused with S-nitrosoglutathione (GSNO) as a source of ·NO. GSNO increased recovery of postischemic LVDP in GA-treated normoxic and hypoxic hearts to baseline levels. Although chronic hypoxia decreased phosphorylated eNOS (S1177) levels by Ϸ4-to 5-fold and total Akt and phosphorylated Akt by 4-and 5-fold, it also increased hsp90 association with eNOS by more than 3-fold. Using hydroethidine (HEt), a fluorescent probe for superoxide, we found that hypoxic hearts contained less ethidine (Et) staining than normoxic hearts. Normoxic hearts generated 3 times more superoxide by an N -nitro-L-arginine methyl ester (L-NAME)-inhibitable mechanism than hypoxic hearts. Taken together, these data indicate that the association of hsp90 with eNOS is important for increasing ·NO production and limiting eNOS-dependent superoxide anion generation. Such changes in eNOS function appear to play a critical role in protecting the myocardium against ischemic injury. (Circ Res. 2002;91:300-306.) Key Words: chronic hypoxia Ⅲ endothelial NOS Ⅲ heat shock protein 90 Ⅲ superoxide anion Ⅲ nitric oxide N itric oxide plays an important role in protecting the heart against ischemic injury. S-nitrosoglutathione (GSNO), a nitric oxide (·NO) donor, improves functional recovery after ischemia, which is associated with increased cGMP. 1 Chronic hypoxia from birth in a neonatal rabbit model increases recovery of postischemic left ventricular developed pressure (LVDP) compared with recovery in normoxic hearts. 2 It is important to note that nitric oxide synthase (NOS) inhibitors, N -nitro-Larginine methyl ester (L-NAME) and N G -methyl-L-arginine (L-NMA), decrease functional recovery of postischemic LVDP in hypoxic hearts after ischemia but do not decrease recovery in normoxic hearts. 2,3 These findings suggest that chronic hypoxia may alter the function of endothelial nitric oxide synthase (eNOS), the most abundant NOS isozyme in the rabbit heart, to increase cardioprotection. 2 An increase in the association of heat shock protein 90 (hsp90) with eNOS increases production and activity of ·NO in response to growth factor stimulation. 4 Disruption of this protein-protein interaction decreases ·NO and blocks vasodilation in response to agonists. 4 -7 Geldanamycin (GA), which inhibits conformational changes in hsp90 8 and increases ox...

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Tolerance of the developing heart to ischemia: impact of hypoxemia from birth

Cited by 45 publications

References 16 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

ANG II type 1 receptor antagonist irbesartan inhibits coronary angiogenesis stimulated by chronic intermittent hypoxia in neonatal rats

Chronic Hypoxia Increases Endothelial Nitric Oxide Synthase Generation of Nitric Oxide by Increasing Heat Shock Protein 90 Association and Serine Phosphorylation

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