Functional differences between junctional and extrajunctional adrenergic receptor activation in mammalian ventricle

Increased cardiac sympathetic activation worsens dispersion of repolarization and is proarrhythmic. The functional differences between intrinsic nerve stimulation and adrenergic receptor activation remain incompletely understood. This study was undertaken to determine the functional differences between efferent cardiac sympathetic nerve stimulation and direct adrenergic receptor activation in porcine ventricles. Female Yorkshire pigs ( n = 13) underwent surgical exposure of the heart and stellate ganglia. A 56-electrode sock was placed over the ventricles to record epicardial electrograms. Animals underwent bilateral sympathetic stimulation (BSS) ( n = 8) or norepinephrine (NE) administration ( n = 5). Activation recovery intervals (ARIs) were measured at each electrode before and during BSS or NE. The degree of ARI shortening during BSS or NE administration was used as a measure of functional nerve or adrenergic receptor density. During BSS, ARI shortening was nonuniform across the epicardium (F value 9.62, P = 0.003), with ARI shortening greatest in the mid-basal lateral right ventricle and least in the midposterior left ventricle (LV) (mean normalized values: 0.9 ± 0.08 vs. 0.56 ± 0.08; P = 0.03). NE administration resulted in greater ARI shortening in the LV apex than basal segments [0.91 ± 0.04 vs. 0.63 ± 0.05 (averaged basal segments); P = 0.003]. Dispersion of ARIs increased in 50% and 60% of the subjects undergoing BSS and NE, respectively, but decreased in the others. There is nonuniform response to cardiac sympathetic activation of both porcine ventricles, which is not fully explained by adrenergic receptor density. Different pools of adrenergic receptors may mediate the cardiac electrophysiological effects of efferent sympathetic nerve activity and circulating catecholamines.

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Sympathetic Nerve Stimulation, Not Circulating Norepinephrine, Modulates T-Peak to T-End Interval by Increasing Global Dispersion of Repolarization

Circulation Arrhythmia and Electrophysiology ◽

10.1161/circep.114.002195 ◽

2015 ◽

Vol 8 (1) ◽

pp. 174-185 ◽

Cited By ~ 50

Author(s):

Daigo Yagishita ◽

Ray W. Chui ◽

Kentaro Yamakawa ◽

Pradeep S. Rajendran ◽

Olujimi A. Ajijola ◽

...

Keyword(s):

Nerve Stimulation ◽

Sympathetic Nerve ◽

Sympathetic Nerve Stimulation ◽

Dispersion Of Repolarization

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Sympathetic nerve stimulation induces local endothelial Ca2+ signals to oppose vasoconstriction of mouse mesenteric arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00773.2011 ◽

2012 ◽

Vol 302 (3) ◽

pp. H594-H602 ◽

Cited By ~ 58

Author(s):

Lydia W. M. Nausch ◽

Adrian D. Bonev ◽

Thomas J. Heppner ◽

Yvonne Tallini ◽

Michael I. Kotlikoff ◽

...

Keyword(s):

Smooth Muscle ◽

Nerve Stimulation ◽

Sympathetic Nerve ◽

Adrenergic Receptor ◽

Ryanodine Receptors ◽

Electrical Field Stimulation ◽

Sympathetic Nerves ◽

Mesenteric Arteries ◽

Sympathetic Nerve Stimulation ◽

Voltage Dependent

It is generally accepted that the endothelium regulates vascular tone independent of the activity of the sympathetic nervous system. Here, we tested the hypothesis that the activation of sympathetic nerves engages the endothelium to oppose vasoconstriction. Local inositol 1,4,5-trisphosphate (IP3)-mediated Ca2+ signals (“pulsars”) in or near endothelial projections to vascular smooth muscle (VSM) were measured in an en face mouse mesenteric artery preparation. Electrical field stimulation of sympathetic nerves induced an increase in endothelial cell (EC) Ca2+ pulsars, recruiting new pulsar sites without affecting activity at existing sites. This increase in Ca2+ pulsars was blocked by bath application of the α-adrenergic receptor antagonist prazosin or by TTX but was unaffected by directly picospritzing the α-adrenergic receptor agonist phenylephrine onto the vascular endothelium, indicating that nerve-derived norepinephrine acted through α-adrenergic receptors on smooth muscle cells. Moreover, EC Ca2+ signaling was not blocked by inhibitors of purinergic receptors, ryanodine receptors, or voltage-dependent Ca2+ channels, suggesting a role for IP3, rather than Ca2+, in VSM-to-endothelium communication. Block of intermediate-conductance Ca2+-sensitive K+ channels, which have been shown to colocalize with IP3 receptors in endothelial projections to VSM, enhanced nerve-evoked constriction. Collectively, our results support the concept of a transcellular negative feedback module whereby sympathetic nerve stimulation elevates EC Ca2+ signals to oppose vasoconstriction.

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Failure of Beta-Adrenergic Receptor Blockade to Prevent Arrhythmias Induced by Sympathetic Nerve Stimulation

Science ◽

10.1126/science.185.4145.70 ◽

1974 ◽

Vol 185 (4145) ◽

pp. 70-72 ◽

Cited By ~ 15

Author(s):

R. A. Gillis ◽

D. L. Pearle ◽

T. Hoekman

Keyword(s):

Nerve Stimulation ◽

Sympathetic Nerve ◽

Adrenergic Receptor ◽

Receptor Blockade ◽

Beta Adrenergic Receptor ◽

Sympathetic Nerve Stimulation ◽

Beta Adrenergic ◽

Adrenergic Receptor Blockade

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Mode of neural control mediating rat tail vasodilation during heating

Journal of Applied Physiology ◽

10.1152/jappl.1985.59.5.1533 ◽

1985 ◽

Vol 59 (5) ◽

pp. 1533-1538 ◽

Cited By ~ 82

Author(s):

D. S. O'Leary ◽

J. M. Johnson ◽

W. F. Taylor

Keyword(s):

Nerve Stimulation ◽

Sympathetic Nerve ◽

Adrenergic Receptor ◽

Neural Control ◽

Receptor Blockade ◽

Nerve Activity ◽

Sympathetic Nerve Stimulation ◽

Alpha Adrenergic Receptor ◽

Rat Tail ◽

Tail Blood

The purpose of this investigation was to delineate the mode of efferent neural control mediating rat tail vasodilation during body heating. Tail blood flow (venous occlusion plethysmography), tail skin temperature over the ventral vascular bundle, and arterial pressure were measured in Sprague-Dawley rats anesthetized with pentobarbital sodium (45 mg/kg). Three protocols were followed: anesthesia of the lumbar sympathetic chain, bilateral lumbar sympathectomy, and sympathetic nerve stimulation during varying degrees of alpha-adrenergic receptor blockade. Mean tail blood flow and tail vascular conductance (TVC) during body heating were 40.3 +/- 8.7 ml X 100 ml-1 X min-1 and 39.2 +/- 9.2 ml X 100 ml-1 X min-1 X 100 mmHg-1, respectively. Interruption of sympathetic nerve activity by sympathetic nerve anesthetization or sympathectomy during heat stress caused a nonsignificant increase in TVC to 112.7 +/- 1.8 and 121.12 +/- 6.3%, respectively, of the values achieved with body heating. Sympathectomy performed in normothermic animals that had recovered from prior heating caused an increase in TVC to 128.4 +/- 14.0% of the levels achieved during the previous heating period. In addition, sympathetic nerve stimulation after complete alpha-adrenergic receptor blockade failed to produce a vasodilation [control TVC = 10.2 +/- 3.9 vs. TVC during nerve stimulation = 10.4 +/- 3.9 (P greater than 0.05)]. It is concluded that the increase in TVC during body heating occurs solely via a reduction in vasoconstrictor nerve activity.

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Postjunctional α2-adrenoceptors are not present in proximal arterioles of rat intestine

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.274.1.h202 ◽

1998 ◽

Vol 274 (1) ◽

pp. H202-H208 ◽

Cited By ~ 4

Author(s):

Geoffrey P. Nase ◽

Matthew A. Boegehold

Keyword(s):

Shear Stress ◽

Nerve Stimulation ◽

Sympathetic Nerve ◽

Receptor Activation ◽

Sympathetic Nerve Stimulation ◽

No Release ◽

Before And After ◽

Sympathetic Nerve Activation ◽

Intestinal Submucosa ◽

Resting Tone

The purpose of this study was to evaluate two potential stimuli for nitric oxide (NO) release in rat intestinal arterioles during sympathetic nerve activation. To determine whether these vessels contain endothelial α2-adrenoceptors linked to thel-arginine-NO pathway, intravital microscopy was used to study the response of first-order arterioles (1As, 20–40 μm ID) to direct application of 1) the selective α2-agonist BHT-933 and 2) norepinephrine (NE) or sympathetic nerve stimulation before and after α1- or α2-receptor blockade. The effect of sympathetic nerve stimulation on 1A wall shear rate (WSR) was also determined to evaluate the possibility of hemodynamic shear stress as a stimulus for NO release. BHT-933 had no effect on 1A diameter, whereas NE produced dose-dependent constrictions of 5 ± 3 to 15 ± 3 μm, which were usually abolished by the α1-antagonist prazosin but unaffected by the α2-antagonist idazoxan. Sympathetic nerve stimulation at 3, 8, and 16 Hz induced constrictions of 4 ± 1, 8 ± 2, and 17 ± 4 μm, respectively, and these constrictions were also usually abolished by prazosin but unaffected by idazoxan. Resting WSR averaged 1,997 ± 163 s−1 and decreased to 1,587 ± 209, 1,087 ± 195, and 537 ± 99 s−1 during 3-, 8-, and 16-Hz nerve stimulation. These results suggest that α2-adrenoceptor-dependent pathways do not influence either resting tone or sympathetic constriction of proximal arterioles in the intestinal submucosa and that luminal shear stress in these vessels significantly decreases with sympathetic constriction. It therefore appears unlikely that either α2-receptor activation or changes in hemodynamic shear serve as stimuli for arteriolar NO release during periods of increased sympathetic nerve activity.

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Sympathetic activation induces asynchronous contraction in awake dogs with regional denervation

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1988.255.2.h358 ◽

1988 ◽

Vol 255 (2) ◽

pp. H358-H365 ◽

Cited By ~ 2

Author(s):

D. R. Knight ◽

Y. T. Shen ◽

J. X. Thomas ◽

W. C. Randall ◽

S. F. Vatner

Keyword(s):

Adrenergic Receptor ◽

Posterior Wall ◽

Receptor Activation ◽

Anterior Wall ◽

Left Ventricular ◽

Conscious Dogs ◽

Wall Thickening ◽

Neural Activation ◽

Sympathetic Activation ◽

Intact Group

To determine effects of regional left ventricular (LV) denervation on regional contractile responses to sympathetic activation, dogs with posterior LV wall denervation (posterior wall-denervated group) and dogs with innervated posterior LV walls (intact group) were studied during excitement, exercise, bilateral sympathetic nerve stimulation, and norepinephrine infusion. In intact conscious dogs, all modes of sympathetic activation increased the magnitude and decreased the time of onset of systolic wall thickening (WT) similarly in the anterior and posterior wall. In the denervated group, excitement failed to increase posterior WT during systole but instead elicited asynchronous contraction, i.e., postsystolic WT, as well as delayed onset of contraction. Asynchronous contraction was not observed with excitement after beta-adrenergic receptor blockade. Asynchronous contraction of the posterior wall was also observed during the initial phase of exercise in conscious dogs and during bilateral stellate stimulation in anesthetized dogs in the posterior wall-denervated group. In comparison to neural activation, adrenergic receptor activation with norepinephrine (0.2 microgram/kg-1.min-1 iv) induced a supersensitive increase in systolic WT in the denervated posterior wall (36 +/- 5%) compared with the anterior wall (17 +/- 2%) and a delay in the end of contraction in the anterior region. Thus asynchronous contraction can be elicited in dogs with regional LV denervation as a result of an early and enhanced contraction in the innervated region during neural sympathetic activation. The reverse was observed with systemic administration of norepinephrine because of catecholamine supersensitivity in the denervated posterior wall.

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