Consecutive Isoproterenol and Adenosine Treatment Confers Marked Protection against Reperfusion Injury in Adult but Not in Immature Heart: A Role for Glycogen

Abstract

Consecutive treatment of adult rat heart with isoproterenol and adenosine (Iso/Aden), known to consecutively activate PKA/PKC signaling, is cardioprotective against ischemia and reperfusion (I/R). Whether this is cardioprotective in an immature heart is unknown. Langendorff–perfused hearts from adult and immature (60 and 14 days old) male Wistar rats were exposed to 30 min ischemia and 120 min reperfusion, with or without prior perfusion with 5 nM Iso for 3 min followed by 30 μM Aden for 5 min. Changes in hemodynamics (developed pressure and coronary flow) and cardiac injury (Lactate Dehydrogenase (LDH) release and infarct size) were measured. Additional hearts were used to measure glycogen content. Iso induced a similar inotropic response in both age groups. Treatment with Iso/Aden resulted in a significant reduction in time to the onset of ischemic contracture in both age groups whilst time to peak contracture was significantly shorter only in immature hearts. Upon reperfusion, the intervention reduced cardiac injury and functional impairment in adults with no protection of immature heart. Immature hearts have significantly less glycogen content compared to adult. This work shows that Iso/Aden perfusion confers protection in an adult heart but not in an immature heart. It is likely that metabolic differences including glycogen content contribute to this difference.

Comparison of the effects of adenosine, isoproterenol and their combinations on pulmonary transit time in rats using contrast echocardiography

“…Ade and Iso, in addition to routine clinical use, also used to mimic the potent cardioprotection of temperature preconditioning by consecutive activation of protein kinases A and protein kinases C [10,11]. Moreover, Iso and Ade, alone or simultaneously, protected isolated rat hearts but the consecutive treatment gave the highest protection [13].…”

“…Even so, our study had several limitations that should be considered. First of all, doses of Ade and Iso used in this study were selected according to our previous studies, without reference to those in vitro studies (sequentially with 5 nM Iso and 30 μM Ade) [10,11]. Further systematic exploration is required.…”

“…Adenosine (Ade) and isoproterenol (Iso) are two different kinds of cardiopulmonary medication. Studies have shown that consecutive treatment of isolated heart with a high dose of Iso and Ade (Iso/Ade treatment) confers strong protection against ischaemia/reperfusion injury during heart surgery [10,11].…”

Cardioprotection of Immature Heart by Simultaneous Activation of PKA and EPAC : A Role for the Mitochondrial Permeability Transition Pore

“…Stimulation of either PKA or EPAC alone does not produce the same effect as with both; an intermediate response is seen. Our previous work [7,23] demonstrated that β-adrenoreceptor stimulation was in part responsible for a cardioprotective effect following a short period of activation. However, it is known that sustained activity at this receptor family does produce deleterious consequences for the heart at both the subcellular and whole organ level, including mitochondrial dysfunction, hypertrophy, heart failure, and death [24][25][26].…”

A Review of Humoral Factors in Remote Preconditioning of the Heart

“…Norepinephrine as a humoral factor in RIP was first proposed by Dickson et al 18 Indeed, norepinephrine titers in the blood increase after RIP. 88 It should be noted that the stimulation of b-adrenergic receptors in the period preceding ischemia can promote an increase in cardiac tolerance to I/R, 89,90 so norepinephrine cannot be discounted as both a neurogenic and a humoral factor in RIP.…”