Cardioprotection in Pigs by Exogenous Norepinephrine but not by Cerebral Ischemia–Induced Release of Endogenous Norepinephrine

Abstract

Background and Purpose-Endogenous norepinephrine release induced by cerebral ischemia may lead to small areas of necrosis in normal hearts. Conversely, norepinephrine may be one of the mediators that limit myocardial infarct size by ischemic preconditioning. Because brief ischemia in kidneys or skeletal muscle limits infarct size produced by coronary artery occlusion, we investigated whether cardiac norepinephrine release during transient cerebral ischemia also elicits remote myocardial preconditioning. Methods-Forty-one crossbred pigs of either sex were assigned to 1 of 7 experimental groups, of which in 6 groups myocardial infarct size was determined after a 60-minute coronary occlusion and 120 minutes of reperfusion. One group served as control (no pretreatment), while the other groups were pretreated with either cerebral ischemia or an intracoronary infusion of norepinephrine. Results-In 10 anesthetized control pigs, infarct size was 84Ϯ3% (meanϮSEM) of the area at risk after a 60-minute coronary occlusion and 120 minutes of reperfusion. Intracoronary infusion of 0.03 nmol/kg · min Ϫ1 norepinephrine for 10 minutes before coronary occlusion did not affect infarct size (80Ϯ3%; nϭ6), whereas infusion of 0.12 nmol/kg · min Ϫ1 limited infarct size (65Ϯ2%; nϭ7; PϽ0.05). Neither 10-minute (nϭ5) nor 30-minute (nϭ6) cerebral ischemia produced by elevation of intracranial pressure before coronary occlusion affected infarct size (83Ϯ4% and 82Ϯ3%, respectively). Myocardial interstitial norepinephrine levels tripled during cerebral ischemia and during low-dose norepinephrine but increased 10-fold during high-dose norepinephrine. Norepinephrine levels increased progressively up to 500-fold in the area at risk during the 60-minute coronary occlusion, independent of the pretreatment, while norepinephrine levels remained unchanged in adjacent nonischemic myocardium and arterial plasma. Conclusions-Cerebral ischemia preceding a coronary occlusion did not modify infarct size, which is likely related to the modest increase in myocardial norepinephrine levels during cerebral ischemia. The infarct size limitation by high-dose exogenous norepinephrine is not associated with blunting of the ischemia-induced increase in myocardial interstitial norepinephrine levels. (Stroke. 2001;32:767-774.)

Preservation of ischemia and isoflurane-induced preconditioning after brain death in rabbit hearts

“…Sebbag et al (21) could not protect the dog heart by intracoronary administration of the ␣ 1 -adrenoreceptor agonist methoxamine. In contrast, our results are in close agreement with those of de Zeeuw et al (8) who reported that transient intracerebral hypertension cannot precondition the pig heart despite a major myocardial norepinephrine release, as demonstrated by microdialysis. Also, Kirsch et al (15) recently showed that BD does not trigger preconditioning in the rabbit.…”

“…This is, however, unlikely because myocardial damage possibly induced by catecholamine rarely exceed small foci of necrosis. Finally, it is possible that, although plasma levels of norepinephrine and epinephrine were dramatically increased in our preparation, their concentration within the myocardium remained beyond a given threshold necessary to trigger preconditioning, as suggested by de Zeeuw et al (8).…”

Evidence that NOS2 acts as a trigger and mediator of late preconditioning induced by acute systemic hypoxia

“…Therefore, one could expect that an adequate degree and duration of SH may induce protective effect in multiple organs, which may be more advantageous than ischemic preconditioning where the remote protection has not been consistently demonstrated. For example, a brief ischemia in kidneys or skeletal muscle could reduce myocardial infarct size caused by a subsequent coronary occlusion, a transient cerebral ischemia failed to produce the similar cardioprotection (7).…”

A Preliminary Study on the Cardioprotection of Acupuncture Pretreatment in Rats with Ischemia and Reperfusion: Involvement of Cardiac β-Adrenoceptors

“…It is well documented that ischemic preconditioning protects the cardiac cells from injury induced by subsequent ischemia and reperfusion. Pretreatment with norepinephrine [4], a neurotransmitter of sympathetic endings in the heart, was shown to effectively mimic the protective effect of ischemic preconditioning on the heart subjected to ischemia and reperfusion. The protective effect induced by this pretreatment was associated with the induction of cardiac tolerance or adaptation to the subsequent overstimulation of β-adrenoceptors in cardiomyocytes [5] during the ischemia and reperfusion so as to attenuate the consequent cardiac impairment [6].…”