5 research outputs found
Exogenous angiotensin II does not facilitate norepinephrine release in the heart
Studies on the effect of angiotensin II on norepinephrine release from
sympathetic nerve terminals through stimulation of presynaptic angiotensin
II type 1 receptors are equivocal. Furthermore, evidence that angiotensin
II activates the cardiac sympathetic nervous system in vivo is scarce or
indirect. In the intact porcine heart, we investigated whether angiotensin
II increases norepinephrine concentrations in the myocardial interstitial
fluid (NE(MIF)) under basal conditions and during sympathetic activation
and whether it enhances exocytotic and nonexocytotic ischemia-induced
norepinephrine release. In 27 anesthetized pigs, NE(MIF) was measured in
the left ventricular myocardium using the microdialysis technique. Local
infusion of angiotensin II into the left anterior descending coronary
artery (LAD) at consecutive rates of 0.05, 0.5, and 5 ng/kg per minute did
not affect NE(MIF), LAD flow, left ventricular dP/dt(max), and arterial
pressure despite large increments in coronary arterial and venous
angiotensin II concentrations. In the presence of neuronal reuptake
inhibition and alpha-adrenergic receptor blockade, left stellate ganglion
stimulation increased NE(MIF) from 2.7+/-0.3 to 7.3+/-1.2 before, and from
2.3+/-0.4 to 6.9+/-1.3 nmol/L during, infusion of 0.5 ng/kg per minute
angiotensin II. Sixty minutes of 70% LAD flow reduction caused a
progressive increase in NE(MIF) from 0.9+/-0.1 to 16+/-6 nmol/L, which was
not enhanced by concomitant infusion of 0.5 ng/kg per minute angiotensin
II. In conclusion, we did not observe any facilitation of cardiac
norepinephrine release by angiotensin II under basal conditions and during
either physiological (ganglion stimulation) or pathophysiological (acute
ischemia) sympathetic activation. Hence, angiotensin II is not a local
mediator of cardiac sympathetic activity in the in vivo porcine heart
Cardioprotection in pigs by exogenous norepinephrine but not by cerebral ischemia-induced release of endogenous norepinephrine
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 12
Epinephrine in the heart: uptake and release, but no facilitation of norepinephrine release
BACKGROUND: Several studies have suggested that epinephrine augments the
release of norepinephrine from sympathetic nerve terminals through
stimulation of presynaptic receptors, but evidence pertaining to this
mechanism in the heart is scarce and conflicting. Using the microdialysis
technique in the porcine heart, we investigated whether epinephrine, taken
up by and released from cardiac sympathetic nerves, can increase
norepinephrine concentrations in myocardial interstitial fluid (NE(MIF))
under basal conditions and during sympathetic activation. METHODS AND
RESULTS: During intracoronary epinephrine infusion of 10, 50, and 100
ng/kg per minute under basal conditions, large increments in interstitial
(from 0.31+/-0.05 up to 140+/-30 nmol/L) and coronary venous (from
0.16+/-0.08 up to 228+/-39 nmol/L) epinephrine concentrations were found,
but NE(MIF) did not change. Left stellate ganglion stimulation increased
NE(MIF) from 3.4+/-0.5 to 8.2+/-1.5 nmol/L, but again, this increase was
not enhanced by concomitant intracoronary epinephrine infusion.
Intracoronary infusion of tyramine resulted in a negligible increase in
epinephrine concentration in myocardial interstitial fluid (EPI(MIF)),
whereas 30 minutes after infusion of epinephrine an increase of 9.5 nmol/L
in EPI(MIF) was observed, indicating that epinephrine is taken up by and
released from cardiac sympathetic neurons. Although 68% to 78% of infused
epinephrine was extracted over the heart, the ratio of interstitial to
arterial epinephrine concentrations was only approximately 20%, increasing
to 29% with neuronal reuptake inhibition. CONCLUSIONS: Our findings
demonstrate epinephrine release from cardiac sympathetic neurons, but they
do not provide evidence that epinephrine augments cardiac sympathoneural
norepinephrine release under basal conditions or during sympathetic
activation
Catecholamine handling in the porcine heart: a microdialysis approach
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
Time Course and Mechanism of Myocardial Catecholamine Release During Transient Ischemia In Vivo
BACKGROUND: Elevated concentrations of norepinephrine (NE) have been
observed in ischemic myocardium. We investigated the magnitude and
mechanism of catecholamine release in the myocardial interstitial fluid
(MIF) during ischemia and reperfusion in vivo through the use of
microdialysis. METHODS AND RESULTS: In 9 anesthetized pigs, interstitial
catecholamine concentrations were measured in the perfusion areas of the
left anterior descending coronary artery (LAD) and the left circumflex
coronary artery. After stabilization, the LAD was occluded for 60 minutes
and reperfused for 150 minutes. During the final 30 minutes, tyramine (154
nmol. kg(-1). min(-1)) was infused into the LAD. During LAD occlusion, MIF
NE concentrations in the ischemic region increased progressively from 1.
0+/-0.1 to 524+/-125 nmol/L. MIF concentrations of dopamine and
epinephrine rose from 0.4+/-0.1 to 43.9+/-9.5 nmol/L and from <0.2
(detection limit) to 4.7+/-0.7 nmol/L, respectively. Local uptake-1
blockade attenuated release of all 3 catecholamines by >50%. During
reperfusion, MIF catecholamine concentrations returned to baseline within
120 minutes. At that time, the tyramine-induced NE release was similar to
that seen in nonischemic control animals despite massive infarction.
Arterial and MIF catecholamine concentrations in the left circumflex
coronary artery region remained unchanged. CONCLUSIONS: 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