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Background: Altered nitric oxide synthase (NOS) has been implicated in the pathophysiology of heart failure (HF). Recent evidence links hypothyroidism to the pathology of HF. However, the precise mechanisms are incompletely understood. The alterations and functional effects of cardiac NOS in hypothyroidism are unknown. We tested the hypothesis that hypothyroidism increases cardiomyocyte inducible NOS (iNOS) expression, which plays an important role in hypothyroidism-induced depression of cardiomyocyte contractile properties, [Ca(2+)]i transient ([Ca(2+)]iT), and β-adrenergic hyporesponsiveness., Methods and Results: We simultaneously evaluated LV functional performance and compared myocyte three NOS, β-adrenergic receptors (AR) and SERCA2a expressions and assessed cardiomyocyte contractile and [Ca(2+)]iT responses to β-AR stimulation with and without pretreatment of iNOS inhibitor (1400 W, 10(-5)mol/L) in 26 controls and 26 rats with hypothyroidism induced by methimazole (~30 mg/kg/day for 8 weeks in the drinking water). Compared with controls, in hypothyroidism, total serum T3 and T4 were significantly reduced followed by significantly decreased LV contractility (EES) with increased LV time constant of relaxation. These LV abnormalities were accompanied by concomitant significant decreases in myocyte contraction (dL/dtmax), relaxation (dR/dtmax), and [Ca(2+)]iT. In hypothyroidism, isoproterenol (10(-8)M) produced significantly smaller increases in dL/dtmax, dR/dtmax and [Ca(2+)]iT. These changes were associated with decreased β1-AR and SERCA2a, but significantly increased iNOS. Moreover, only in hypothyroidism, pretreatment with iNOS inhibitor significantly improved basal and isoproterenol-stimulated myocyte contraction, relaxation and [Ca(2+)]iT., Conclusions: Hypothyroidism produces intrinsic defects of LV myocyte force-generating capacity and relaxation with β-AR desensitization. Up-regulation of cardiomyocyte iNOS may promote progressive cardiac dysfunction in hypothyroidism., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Botulinum neurotoxin-A (BoNTA) is used to treat several disorders, including Raynaud phenomenon. Recent investigations cite toxin-induced increases in blood flow, but no mechanism for BoNTA's actions is proposed. This study hypothesized that local application of BoNTA causes arteriolar vasodilation through sympathetic blockade and results in increased blood flow., Methods: Microvascular effects of BoNTA were assessed using a rat cremaster preparation. Cremaster microvascular diameters were measured in the muscle before and after treatment with the muscle paralytic agent gallamine triethiodide. Preparations were then treated with one of the following: BoNTA (4, 6, or 10 units), BoNTA dilution vehicle, or denatured BoNTA. Arteriolar diameters were measured repeatedly over the observation period. Additional preparations were treated with either tetrodotoxin or prazosin and rauwolscine before BoNTA to confirm that the observed vasodilatory responses were the result of sympathetic neural inhibition., Results: The BoNTA application resulted in a significant dose-dependent vasodilation (13% to 15%) of observed cremaster arterioles. Control treatments did not cause vasodilation. Both tetrodotoxin and prazosin/rauwolscine treatments elicited similar vasodilatory effects, with no additional vasodilation elicited by BoNTA. Addition of sodium nitroprusside following BoNTA elicited further vasodilation. In addition, systemic arterial pressure was unaffected by the local administration of BoNTA., Conclusions: Local application of BoNTA results in arteriolar dilation that yields an approximate 69% increase in blood flow, without changing systemic arterial pressure. A BoNTA-mediated vasodilation through sympathetic blockade is a likely mechanism to explain the increase in blood flow reported after treatment with the toxin., Clinical Relevance: The ability of BoNTA to inhibit sympathetic nervous input reduces vasoconstriction, which is the most likely mechanism for improvement seen in Raynaud phenomenon patients following BoNTA injection., (Copyright © 2012 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

Purpose: The chemical denervation that results from botulinum neurotoxin A (BoNT-A) causes a temporary, reversible paresis that can result in easier surgical manipulation of the muscle-tendon unit in the context of tendon rupture and repair. The purpose of the study was to determine whether BoNT-A injections can be used to temporarily and reversibly modulate active and passive skeletal muscle properties., Methods: Male CD1 mice weighing 40-50 g were divided into a 1-week postinjection group (n = 13: n = 5 saline and n = 8 BoNT-A) and a 2-week postinjection group (n = 17: n = 7 saline and n = 10 BoNT-A). The animals had in vivo muscle force testing and in vivo biomechanical evaluation., Results: There was a substantial decline in the maximal single twitch amplitude (p < .05) and tetanic amplitude (p < .05) at one week and at 2 weeks after BoNT-A injection, when compared to saline-injected controls. BoNT-A injection significantly reduced the peak passive properties of the muscle-tendon unit as a function of displacement at one week (p < .05). Specifically, the stiffness of the BoNT-A injected muscle-tendon unit was 0.417 N/mm compared to the control saline injected group, which was 0.634 N/mm, a 35% reduction in stiffness (p < .05)., Conclusions: Presurgical treatment with BoNT-A might improve the surgical manipulation of the muscle-tendon unit, thus improving surgical outcomes. The results implicate neural tone as a substantial contributor to the passive repair tension of the muscle-tendon unit. The modulation of neural tone through temporary, reversible paresis is a novel approach that might improve intraoperative and postoperative passive muscle properties, allowing for progressive rehabilitation while protecting the surgical repair site., (Copyright © 2011 American Society for Surgery of the Hand. Published by Elsevier Inc. All rights reserved.)

The blunting of arterial pressure increases to a variety of pressor agents or the lowering of arterial pressure in some models of hypertension following intracerebroventricular administration of an angiotensin II (AII) antagonist, has been interpreted as prima facie evidence for the involvement of the central AII system in these situations. Central administration of vasopressin or carbachol (a cholinergic agonist) produces pressor effects which have been reported to be due to an increase in the activity of the sympathetic nervous system. We now report that central administration of AII antagonists [either (Sar-1, Ile-8) AII or (Sar-1, Ala-8) AII] in rats prevents the majority (greater than 70%) of the pressor effects of intraventricular vasopressin or carbachol. These results can be interpreted in two ways. The first is that all of these pressor agents use a central angiotensinergic mechanism(s) to increase sympathetic nervous system activity. An alternative hypothesis is that centrally administered AII antagonists non-specifically inhibit sympathetic nervous system function.

Multiple behavioral and neurochemical abnormalities are found in the genetically obese mouse, obob , including hyperphagia, elevated hypothalamic norepinephrine (NE) levels, and increases alpha-1 receptor density. The obese mutant also responds abnormally to neuropharmacological agents. In the current study the alpha-2 receptor blockers yohimbine and rauwolscine were administered to food-restricted (6-hour food access) obob and lean mice. Yohimbine and rauwolscine significantly reduced the 3- and 6-hour food intake of both obob and lean mice. The obob mice were, however, more sensitive to this anorectic effect than lean mice. Effective anorectic doses of yohimbine did not affect water intake in water-deprived lean mice, suggesting a specific effect of the drug upon food intake. Low doses (50 and 100 micrograms) of the alpha-2 agonist clonidine increased the 1-hour food intake of obob mice, but did not affect the food intake of lean mice. No differences were found between obob and lean mice in the number of alpha-receptors in the hypothalamus. The results suggest that modification of NE release by manipulation of alpha-2 receptor can alter food intake, and that the obob mutant is particularly sensitive to this effect.

The antinociceptive, cardiovascular, and autonomic nervous system actions of [D-Ala2]-methionine enkephalinamide (DALA) were assessed in conscious and pentobarbital-anesthetized rats. Intravenous administration of DALA inhibited the tail-flick reflex evoked by noxious radiant heat in both conscious and pentobarbital-anesthetized rats. In general, the magnitude of the inhibition was not significantly affected by the presence of pentobarbital-anesthesia. DALA also induced hypotension and bradycardia in these rats, but these responses were significantly attenuated by pentobarbital-anesthesia. Arterial blood flows were initially decreased and vascular resistances increased in mesenteric, renal, and hindquarter beds following DALA administration, but these parameters rapidly returned to baseline levels except in the hindquarter bed where flows increased significantly above baseline levels. All of the changes in blood flows were significantly greater in conscious compared to pentobarbital-anesthetized rats. In intact pentobarbital-anesthetized rats, DALA induced inhibition of renal sympathetic nerve activity. However, DALA induced a pressor response with a brief increase in renal sympathetic nerve activity in rats with bilateral vagotomy. Similarly, in the conscious rat with ganglionic blockade, DALA induces a brief pressor response. These outcomes indicate that the brief hypotension observed in the intact rat following administration of DALA is probably the net outcome of a large vagally-induced decrease in sympathetic tone and a small increase in sympathetic tone of either neurogenic or peripheral origin. These outcomes are discussed in terms of cardiovascular-somatosensory interactions.