Effect of Ischemic Preconditioning of the Myocardium on cAMP

Abstract

Reduction of cAMP has been implicated in the protection of ischemic preconditioning (IP), but until now, this possibility has not been directly addressed. In this study, we found that in the in vivo rabbit heart 10 to 30 minutes of sustained regional ischemia was accompanied by a nearly twofold rise in cAMP levels. This increase in cAMP was attenuated when sustained ischemia was preceded by IP induced with a single cycle of transient ischemia and reperfusion (TI/R) and prevented when ischemia was preceded by three cycles of TI/R. The mechanism of cAMP reduction by IP does not involve activation of protein kinase C (PKC), since the PKC inhibitor polymyxin B (24 mg/kg) did not raise cAMP levels during sustained ischemia in IP hearts. Furthermore, this effect is also not mediated by reduced responsiveness of the beta-adrenergic effector pathway, since both nonischemic hearts and hearts subjected to three cycles of TI/R exhibited similar increases in cAMP in response to 5 micrograms/kg isoproterenol. However, propranolol (0.75 mg/kg) abolished the rise in cAMP levels observed during sustained ischemia in control hearts but did not reduce cAMP levels further in IP hearts. These data indicate that the ischemia-induced rise in cAMP levels in control hearts was mediated by activation of the beta-adrenergic receptor. Taken together with data demonstrating that beta-adrenergic responsiveness was not affected by IP, these data support the conclusion that the lack of elevation in cAMP levels observed during sustained ischemia in IP hearts is mediated by an attenuation of norepinephrine release. To examine whether the protection of IP against necrosis was mediated by the lack of elevation in cAmp levels, we determined whether the infarct size-limiting effect of IP could be blocked by NKH477, an activator of adenylyl cyclase. Four groups or rabbits were subjected to 30 minutes of in vivo regional ischemia and 90 minutes of reperfusion. Control hearts (n = 10) had 53.6 +/- 5.5% infarction of the area at risk. IP with three cycles of transient ischemia limited infarct size to 3.2 +/- 1.3% (N = 13, p < .0001). NKH477 (45 micrograms/kg) increased average cAMP levels in IP hearts during sustained ischemia to levels similar to those in untreated control hearts. However, NKH477 did not block IP (50.2 +/- 7.7% of the area at risk was infarcted in the control +NKH477 group [n = 10] versus 10.0 +/- 5.9% in the IP + NKH477 group [n = 7], P < .05). Therefore, we conclude that although IP lowers cAMP levels during sustained ischemia, this effect is not necessary for its protection against necrosis, since raising cAMP does not block this protection of IP.

Myocardial autophagic energy stress responses—macroautophagy, mitophagy, and glycophagy

“…Glucose liberated from glycogen degradation exits lysosomes via the lysosomal membrane glucose carrier (55). The glycogen hydrolyzing activity of acid ␣-glucosidase is enhanced by Ca 2ϩ , which in the setting of increased cytosolic Ca 2ϩ in the ischemic myocardium, in concert with cAMP-mediated augmented lysosomal Ca 2ϩ uptake, may prime lysosomes for accelerated glycogen degradation (41,79). There is strong evidence from glycogen storage diseases that autophagic/lysosomal glycogen breakdown is important for maintaining normal cardiac glycogen levels and does not simply constitute a redundant alternative breakdown route for glycogen (68).…”

Protein Kinase A as Another Mediator of Ischemic Preconditioning Independent of Protein Kinase C

“…However, more studies might be expected to clarify these issues. On the other hand, IP leads to decreased cAMP accumulation during sustained ischemia, 22 but it is controversial whether this explains the cardioprotection afforded by preischemic activation of PKA. 5,22 Enhancement of cAMP accumulation during sustained ischemia fails to block cardioprotection by IP.…”

“…On the other hand, IP leads to decreased cAMP accumulation during sustained ischemia, 22 but it is controversial whether this explains the cardioprotection afforded by preischemic activation of PKA. 5,22 Enhancement of cAMP accumulation during sustained ischemia fails to block cardioprotection by IP. 22 Moreover, overexpression of ␤-adrenergic receptor kinase-1, which causes functional uncoupling of ␤-adrenoceptors, impairs ischemia-reperfusion injury, and this impairment is reversed by co-overexpression of ␤-adrenergic receptor kinase-1 inhibitor.…”

“…5,22 Enhancement of cAMP accumulation during sustained ischemia fails to block cardioprotection by IP. 22 Moreover, overexpression of ␤-adrenergic receptor kinase-1, which causes functional uncoupling of ␤-adrenoceptors, impairs ischemia-reperfusion injury, and this impairment is reversed by co-overexpression of ␤-adrenergic receptor kinase-1 inhibitor. 23 …”

Ischemic Preconditioning and the β-Adrenergic Signal Transduction Pathway

“…Involvement of the ␤-adrenergic signal transduction pathway in preconditioning has recently been suggested: we 4 and others 5,6 have shown that preconditioning attenuates cAMP generation during sustained ischemia in rat and rabbit myocardium. Sandhu et al 5 proposed reduced stimulation of the ␤-adrenergic receptor secondary to reduced release of norepinephrine 7 rather than desensitization as an explanation.…”