Myocardial ischemia is associated with a pronounced increase of MIF catecholamines, which is at least in part mediated by a reversed neuronal reuptake mechanism. The increase of MIF epinephrine implies a (probably neuronal) cardiac source, whereas the preserved catecholamine response to tyramine in postischemic necrotic myocardium indicates functional integrity of sympathetic nerve terminals.

Experimental findings suggest a pronounced concentration gradient of norepinephrine (NE) between the intravascular and interstitial compartments of the heart, compatible with an active neuronal reuptake (U1) and/or an endothelial barrier. Using the microdialysis technique in eight anesthetized pigs, we investigated this NE gradient, both under baseline conditions and during increments in either systemic or myocardial interstitial fluid (MIF) NE concentration. At steady state, baseline MIF NE (0.9 +/- 0.1 nmol/l) was higher than arterial NE (0.3 +/- 0.1 nmol/l) but was not different from coronary venous NE (1.5 +/- 0.3 nmol/l). Local U1 inhibition raised MIF NE concentration to 6.5 +/- 0.9 nmol/l. During intravenous NE infusions (0.6 and 1.8 nmol. kg(-1). min(-1)), the fractional removal of NE by the myocardium was 79 +/- 4% to 69 +/- 3%, depending on the infusion rate. Despite this extensive removal, the quotient of changes in MIF and arterial concentration (DeltaMIF/DeltaA ratio) for NE were only 0.10 +/- 0.02 for the lower infusion rate and 0.11 +/- 0.01 for the higher infusion rate, whereas U1 blockade caused the DeltaMIF/DeltaA ratio to rise to 0.21 +/- 0.03 and 0.36 +/- 0.05, respectively. From the differences in DeltaMIF/DeltaA ratios with and without U1 inhibition, we calculated that 67 +/- 5% of MIF NE is removed by U1. Intracoronary infusion of tyramine (154 nmol. kg(-1). min(-1)) caused a 15-fold increase in MIF NE concentration. This pronounced increase was paralleled by a comparable increase of NE in the coronary vein. We conclude that U1 and extraneuronal uptake, and not an endothelial barrier, are the principal mechanisms underlying the concentration gradient of NE between the interstitial and intravascular compartments in the porcine heart.

Plasma and myocardial interstitial fluid angiotensin levels are of the same order of magnitude. Plasma Ang II does not contribute to the interstitial fluid level of Ang II, most likely because of its rapid metabolism in the vascular wall. Binding to AT1 receptors protects Ang II against metabolism.

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.)

1 Ca 2+ sensitizers enhance systolic function, but may impair relaxation in vitro; these e ects may di er in stunned and normal myocardium. We therefore studied the e ect of EMD 57033 on systolic and diastolic function of normal and stunned porcine myocardium in vivo. 2 Myocardial stunning by 15 min coronary occlusion and 30 min reperfusion abolished systolic shortening (SS) (baseline 13+1%) and decreased end-systolic elastance (E es ) from 67+7 to 47+5 mmHg mm 71 (both P50.05). Maximum rate of fall of myocardial elastance (dE/dt min ) decreased from 7850+100 to 7320+30 mmHg mm 71 s 71 , while the time constant t e of the decay of elastance increased from 58+3 to 68+6 ms (both P50.05). End-diastolic elastance (E ed ) was unchanged although the zero pressure intercept (L 0,ed ) had increased. 3 In the stunned region, EMD 57033 (0.2 mg kg 71 min 71 for 60 min, i.v., n=7) increased SS to 19+2%, E es to 287+40 mmHg mm 71 , dE/dt min to 73630+640 mmHg mm 71 s 71 and decreased t e to 50+3 ms, while E ed remained unchanged. In the normal region, EMD 57033 increased SS from 14+2 to 18+3%, E es from 59+4 to 263+23 mmHg mm 71 , dE/dt min from 7480+70 to 72280+700 mmHg mm 71 s 71 and decreased t e from 91+12 to 61+3 ms (all P50.05), while E ed remained unchanged. These responses were minimally a ected by adrenoceptor blockade (n=7). Vehicle (n=7) had no e ect on either region. 4 EMD 57033 increased cardiac output (up to 27+8%) and LVdP/dt max (86+19%). Mean aortic pressure decreased (19+7%) due to systemic vasodilation that was not amenable to blockade of adrenoceptors or NO synthesis. 5 In conclusion, EMD 57033 restored systolic and diastolic function of stunned myocardium, and produced similar improvements in systolic and diastolic function in normal myocardium. British Journal of Pharmacology (2000)