SUMMARY Arterial baroreceptors provide a neural sensory input that reflexly regulates the autonomic drive of the circulation. Our goal was to test the hypothesis that a member of the acid sensing ion channel (ASIC) subfamily of the DEG/ENaC superfamily is an important determinant of the arterial baroreceptor reflex. We found that aortic baroreceptor neurons in the nodose ganglia and their terminals express ASIC2. Conscious ASIC2 null mice developed hypertension, had exaggerated sympathetic and depressed parasympathetic control of the circulation, and a decreased gain of the baroreflex, all indicative of an impaired baroreceptor reflex. Multiple measures of baroreceptor activity each suggests that mechanosensitivity is diminished in ASIC2- null mice. The results define ASIC2 as an important determinant of autonomic circulatory control and of baroreceptor sensitivity. The genetic disruption of ASIC2 recapitulates the pathological dysautonomia seen in heart failure and hypertension and defines a molecular defect that may be relevant to its development.

The methods used to assess cardiac parasympathetic (cardiovagal) activity and its effects on the heart in both humans and animal models are reviewed. Heart rate (HR)-based methods include measurements of the HR response to blockade of muscarinic cholinergic receptors (parasympathetic tone), beat-to-beat HR variability (HRV) (parasympathetic modulation), rate of post-exercise HR recovery (parasympathetic reactivation), and reflex-mediated changes in HR evoked by activation or inhibition of sensory (afferent) nerves. Sources of excitatory afferent input that increase cardiovagal activity and decrease HR include baroreceptors, chemoreceptors, trigeminal receptors, and subsets of cardiopulmonary receptors with vagal afferents. Sources of inhibitory afferent input include pulmonary stretch receptors with vagal afferents and subsets of visceral and somatic receptors with spinal afferents. The different methods used to assess cardiovagal control of the heart engage different mechanisms, and therefore provide unique and complementary insights into underlying physiology and pathophysiology. In addition, techniques for direct recording of cardiovagal nerve activity in animals; the use of decerebrate and in vitro preparations that avoid confounding effects of anesthesia; cardiovagal control of cardiac conduction, contractility, and refractoriness; and noncholinergic mechanisms are described. Advantages and limitations of the various methods are addressed, and future directions are proposed.

Abstract-Calcitonin gene-related peptide (CGRP) is a powerful vasodilator that interacts with the autonomic nervous system. A subunit of the CGRP receptor complex, receptor activity-modifying protein 1 (RAMP1), is required for trafficking of the receptor to the cell surface and high-affinity binding to CGRP. We hypothesized that upregulation of RAMP1 would favorably enhance autonomic regulation and attenuate hypertension. Blood pressure, heart rate, and locomotor activity were measured by radiotelemetry in transgenic mice with ubiquitous expression of human RAMP1 (hRAMP1) and littermate controls. Compared with control mice, hRAMP1 mice exhibited similar mean arterial pressure, a lower mean heart rate, increased heart rate variability, reduced blood pressure variability, and increased baroreflex sensitivity (2.83Ϯ0.20 versus 1.49Ϯ0.10 ms/mm Hg in controls; PϽ0.05). In control mice, infusion of angiotensin II (Ang-II) increased mean arterial pressure from 118Ϯ2 mm Hg to 153Ϯ4 and 174Ϯ6 mm Hg after 7 and 14 days of infusion, respectively (PϽ0.05). In contrast, Ang-II hypertension was markedly attenuated in hRAMP1 mice with corresponding values of mean arterial pressure of 111Ϯ2, 119Ϯ2, and 132Ϯ3 mm Hg. Ang-II induced decreases in baroreflex sensitivity and heart rate variability, and increases in blood pressure variability observed in control mice were also abrogated or reversed in hRAMP1 mice (PϽ0.05). Moreover, during the Ang-II infusion, the pressor response to the CGRP receptor antagonist CGRP 8-37 was significantly greater (PϽ0.05) in hRAMP1 mice (ϩ30Ϯ2 mm Hg) than in control mice (ϩ19Ϯ2 mm Hg), confirming a significantly greater antihypertensive action of endogenous CGRP in hRAMP1 mice. We conclude that RAMP1 overexpression attenuates Ang-II-induced hypertension and induces a protective change in cardiovascular autonomic regulation. (Hypertension. 2010;55:627-635.)Key Words: calcitonin gene-related peptide Ⅲ parasympathetic nerve activity Ⅲ heart rate variability Ⅲ baroreflex sensitivity Ⅲ blood pressure Ⅲ transgenic mice C alcitonin gene-related peptide (CGRP) is expressed predominantly in the nervous system and contributes to a variety of physiological and pathological processes, including neurogenic inflammation, inhibition of cell proliferation and oxidative stress, and cardiovascular regulation. 1,2 CGRP is one of the most powerful vasodilators known, and sensory nerves containing CGRP provide extensive innervation of blood vessels. 1,2 Furthermore, CGRP and/or CGRP receptor expression are increased in several models of hypertension, including that induced by infusion of the vasoconstrictor peptide angiotensin II (Ang-II). [3][4][5][6] Although pharmacological blockade of CGRP receptors does not influence mean arterial pressure (MAP) of normotensive subjects, receptor blockade increases the severity of hypertension in several experimental models. 6 -8 These findings suggest that endogenous CGRP operates through a negative-feedback mechanism to oppose the development of hypertension.Although it is reason...

Background: Vascular dysfunction and hypertension caused by RGS2 deficiency occur by poorly understood mechanisms. Results: Endothelial RGS2 deficiency impaired endothelium-derived hyperpolarizing factor-mediated relaxation of resistance arteries by a pertussis toxin-sensitive mechanism, without increasing blood pressure significantly. Conclusion: Endothelial dysfunction, a common feature of hypertension, can be caused by RGS2 deficiency. Significance: RGS2 deficiency in several cell types may be required to increase blood pressure.

Chronic musculoskeletal pain (CMP) conditions, like fibromyalgia, are associated with widespread pain and alterations in autonomic function. Regular physical activity prevents development of CMP and can reduce autonomic dysfunction. We tested if there were alterations in autonomic function in sedentary mice with CMP, and if exercise reduced the autonomic dysfunction and pain induced by CMP. CMP was induced by two intramuscular injections of pH 5 in combination with a single fatiguing exercise task. A running wheel was placed into cages so that the mouse had free access for either 5 days or 8 weeks (exercise groups) and these animals were compared to sedentary mice without running wheels. Autonomic function and nociceptive withdrawal thresholds of the paw and muscle were assessed before and after induction of CMP in exercised and sedentary mice. In sedentary mice, we show decreased baroreflex sensitivity, increased blood pressure variability, decreased heart rate variability and decreased withdrawal thresholds of the paw and muscle 24h after induction of CMP. There were no sex differences after induction of the CMP in any outcome measure. We further show that both 5 days and 8 weeks of physical activity prevent the development of autonomic dysfunction and decreases in withdrawal threshold induced by CMP. Thus, this study uniquely shows development of autonomic dysfunction in animals with chronic muscle hyperalgesia that can be prevented with as little as 5 days of physical activity, and suggest that physical activity may prevent the development of pain and autonomic dysfunction in people with CMP.

Muscular dystrophies are a group of heterogeneous genetic disorders that cause progressive muscle weakness and wasting, dilated cardiomyopathy and early mortality. There are different types of muscular dystrophies with varying etiologies but they all have a common hallmark of myofiber degeneration, atrophy and decreased mobility. Mutation in sarcoglycan-delta (Sgcd), a subunit of dystrophin glycoprotein complex, causes Limb Girdle Muscular Dystrophy 2F (LGMD2F). Previously we have reported that Sgcd deficient (Sgcd−/−) mice exhibit angiotensin II (Ang II) induced autonomic and skeletal muscle dysfunction at a young age which contributes to onset of dilated cardiomyopathy and mortality at older ages. Two counter-regulatory renin angiotensin system (RAS) pathways have been identified – deleterious actions of angiotensin II (Ang II) acting on type 1 receptor (AT1R) versus protective actions of Ang-(1-7) acting on Mas receptors. We propose that the balance between the Ang II/AT1R and Ang-(1-7)/Mas axes is disturbed in Sgcd−/− mice. Control C57BL/6 and Sgcd−/− mice were treated with Ang-(1-7) included in hydroxypropyl β-cyclodextrin (drinking water) for 8–9 weeks beginning at 3 weeks of age. Ang-(1-7) treatment restored Ang II/AT1R vs. Ang-(1-7)/Mas balance, decreased oxidative stress and fibrosis in skeletal muscle, increased locomotor activity, and prevented autonomic dysfunction without lowering blood pressure in Sgcd−/− mice. Our results suggest that correcting the early autonomic dysregulation by administering Ang(1-7) or enhancing its endogenous production may provide a novel therapeutic approach in muscular dystrophy.

Thepresentstudyinvestigatedtheeffectofacutehypothermiaonbaroreflexcontrolofheartrate(HR) and renal sympathetic nerve activity (RSNA) by generating baroreflex logistic function curves, using bolus doses of phenylephrine and sodium nitroprusside, in anaesthetized male Wistar rats at a core temperature (T b ) of 37• C, during acute severe hypothermia at T b = 25 • C and on rewarming to 37• C. Comparisons were made between rats without (euthermic, n = 6) and with (acclimated, n = 7) prior exposure to lower ambient temperatures and shorter photoperiod, simulating adaptation to winter conditions. In both groups of rats, acute hypothermia to T b = 25• C shifted the baroreflex-RSNA curve slightly leftwards and downwards with decreases in the setpoint pressure and maximal gain, whereas it markedly impaired the baroreflex-HR curve characterized by decreases in response range by ∼90% (P < 0.001), minimum response by ∼10% (P < 0.05) and maximum gain by ∼95% (P < 0.001), from that at T b = 37• C. All parameters were restored to precooling levels on rewarming. Electrical stimulation of cardiac vagal efferents induced a voltage-related bradycardia, the magnitude of whichwaspartiallyreducedduringacutehypothermia,andtherewasasignificantprolongation of the electrocardiogram intervals indicating a delay in cardiac conduction. Mild suppression of baroreflex control of RSNA could contribute to hypothermic hypotension and may primarily reflect an effect of T b on central drive. The marked attenuation of the baroreflex control of HR during hypothermia was likely to be due to an impairment of both the central and peripheral components of the reflex arc. Baroreflex control of RSNA and HR was similar between both groups of rats, which implied that the control was non-adaptive on chronic cold exposure.

Acute hypothermia has a major impact on cardiovascular control and renal function, but the extent to which these can be correlated with and influenced by changes in the altered pattern of sympathetic outflow to the kidneys is unclear. Moreover, it is unknown whether these responses to acute hypothermia are altered by chronic cold exposure and this study aimed to examine these factors. Renal function and renal sympathetic nerve activity (RSNA) were measured in male Wistar rats, euthermic (control) or acclimatized (exposed to progressively lower environmental temperature and photoperiod over 8 weeks), anaesthetized with chloralose/urethane. Reduction of core temperature (T c ) to 25• C caused ∼40% reduction in heart rate (HR), ∼10% fall in mean arterial blood pressure (MABP), and decreased glomerular filtration rate (GFR) by ∼50% and ∼5% in euthermic and acclimatized rats, respectively. At 25• C, urine flow increased some two-fold and absolute and fractional sodium excretions by 4-to 6-fold in the euthermic rats and to a lesser extent in the cold acclimatized rats, while basal levels of fluid excretion were higher in the acclimatized rats. A loss of pulsatility in the RSNA signal with cooling was seen in both groups. One of the factors contributing to modest hypotension during acute hypothermia is a reduction in RSNA. There was a progressive fall in the proportion of RSNA power at HR frequency with cooling of 20% in euthermic and 80% in acclimatized rats. All variables were restored to basal levels on rewarming in both groups of rats. We conclude that natriuresis and diuresis in euthermic rats during hypothermia is a consequence of a reduction in nephron reabsorption, reduced urine osmolality and possibly altered patterning of RSNA. In acclimatized rats, the response was modified by altered renal haemodynamics and/or hormonal influences induced by chronic cold exposure to minimize the hypothermic stress on renal function.