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Interleukin-6 (IL-6) signaling via the soluble IL-6 receptor (sIL-6r) has been shown to increase primary afferent responsiveness to noxious stimuli. This finding prompted us to test the hypothesis that IL-6 and sIL-6r would increase the exercise pressor reflex in decerebrate rats with freely perfused femoral arteries. We also tested the hypothesis that soluble glycoprotein 130 (sgp130), an inhibitor of IL-6/sIL-6r signaling, would decrease the exaggerated exercise pressor reflex that is found in decerebrate rats with ligated femoral arteries. In rats with freely perfused femoral arteries, co-injection of 50 ng of IL-6 and sIL-6r into the arterial supply of the hindlimb significantly increased the peak pressor response to static (control: 14±3, IL-6/sIL-6r: 17±2 mmHg, p=0.03) and intermittent isometric (control: 10±2, IL-6/sIL-6r: 15±4 mmHg, p=0.03) hindlimb muscle contraction. In rats with ligated femoral arteries injection of 50 ng of sgp130 into the arterial supply of the hindlimb reduced the peak pressor response to static (control: 24±2, sgp130: 16±3 mmHg, p=0.01) and intermittent isometric (control: 16±2, sgp130: 13±2 mmHg, p=0.04) hindlimb muscle contraction whereas there was no effect of sgp130 on the exercise pressor reflex in rats with freely perfused femoral arteries. We conclude that co-injection of exogenous IL-6 and sIL-6r increased the exercise pressor reflex in rats with freely perfused femoral arteries. More importantly, we also conclude that IL-6 and sIL-6r play an endogenous role in evoking the exercise pressor reflex in rats with ligated femoral arteries but not in rats with freely perfused femoral arteries. [ABSTRACT FROM AUTHOR]

Static muscle contraction activates the exercise pressor reflex, which in turn increases sympathetic nerve activity (SNA) and blood pressure (BP). Bradykinin (BK) is considered as a muscle metabolite responsible for modulation of the sympathetic and cardiovascular responses to muscle contraction. Prior studies have suggested that kinin B2 receptor mediates the effects of BK on the reflex SNA and BP responses during stimulation of skeletal muscle afferents. In patients with peripheral artery disease and a rat model with femoral artery ligation, amplified SNA and BP responses to static exercise were observed. This dysfunction of the exercise pressor reflex has previously been shown to be mediated, in part, by muscle mechanoreflex overactivity. Thus, in this report, we determined whether kinin B2 receptor contributes to the augmented mechanoreflex activity inrats with 24 h of femoral artery occlusion. First, Western blot analysis was used to examine protein expression of B2 receptors in dorsal root ganglion tissues of control limbs and ligated limbs. Our data show that B2 receptor displays significant overexpression in ligated limbs as compared with control limbs (optical density: 0.94± 0.02 in control and 1.87 ± 0.08 after ligation, P < 0.05 vs. control; n = 6 in each group). Second, mechanoreflex was evoked by muscle stretch and the reflex renal SNA (RSNA) and mean arterial pressure (MAP) responses to muscle stretch were examined after HOE-140, a B2 receptors blocker, was injected into the arterial blood supply of the hindlimb muscles. The results demonstrate that the stretch-evoked reflex responses were attenuated by administration of HOE-140 in control rats and ligated rats; however, the attenuating effects of HOE-140 were significantly greater in ligated rats, i.e., after 5 μg/kg of HOE-140 RSNA and MAP responses evoked by 0.5 kg of muscle tension were attenuated by 43% and 25% in control vs. 54% and 34% in ligation (P < 0.05 vs. control group; n = 11 in each group). In contrast, there was no significant difference in B1 receptor expression in both experimental groups, and arterial injection of R-715, a B1 receptors blocker, had no significant effects on RSNA and MAP responses evoked by muscle stretch. Accordingly, results obtained from this study support our hypothesis that heightened kinin B2 receptor expression in the sensory nerves contributes to the exaggerated muscle mechanoreflex in rats with femoral artery occlusion. [ABSTRACT FROM AUTHOR]

Femoral artery occlusion augments the sympathetic nerve and pressor responses to muscle contraction and muscle metabolites injected into the arterial blood supply of the hindlimb muscles in rats. The underlying mechanism by which these reflex responses are enhanced after muscle vascular insufficiency is unclear. Purinergic P2X3 receptor has been reported to contribute to the metabolic component of the exercise pressor reflex. Thus the purpose of this study was to examine if chronic femoral occlusion would alter the expression of P2X3 in dorsal root ganglion (DRG) neurons of rats. Also, P2X3-mediated sympathetic responsiveness was examined after femoral occlusion. In addition, the role played by nerve growth factor (NGF) in regulating the expression and response of P2X3 was examined. Western blot analysis showed that 24 h of femoral ligation increased the levels of P2X3 (optical density: 0.93 ± 0.07 in control and 1.37 ± 0.10 after occlusion; P < 0.05 vs. control). The fluorescence immunohistochemistry further demonstrated that the occlusion elevated P2X3 expression in DRG neurons (percentage of P2X3-positive cells: 33 ± 3% in control and 51 ± 3% in occlusion; P < 0.05 vs. control). Furthermore, the results showed that responses of renal sympathetic nerve activity and blood pressure to stimulation of P2X were greater in occluded rats than responses in control rats by injection of α,β-methylene ATP into the arterial blood supply of the hindlimb muscle. Finally, infusion of NGF in the hindlimb muscles of healthy rats increased P2X3 (optical density: 0.98 ± 0.12 in control and 1.37 ± 0.16 with NGF; P < 0.05 vs. control). The pressor response to injection of α,β-methylene ATP was increased in the rats with NGF infusion. Likewise, blocking NGF attenuated exaggeration of the reflex response induced by α,β-methylene ATP in occluded rats. The findings of this study suggest that the levels of P2X3 in primary afferent neurons are upregulated as the blood supply to the hindlimb is deficient under ischemic conditions, leading to augmentation of the muscle reflex. NGF is closely related to increases in P2X3 receptor expression and response. [ABSTRACT FROM AUTHOR]

Acid-sensing ion channels (ASICs) in sensory nerves are responsive to increases in the levels of protons in the extracellular medium. Prior studies suggest that the muscle metabolite, lactic acid, plays a role in reflex sympathetic and cardiovascular responses via stimulation of thin muscle afferent nerves. Also, femoral artery occlusion augments the reflex sympathetic nerve response in rats. ASIC3 is a main subtype to appear in sensory nerves in mediating the response induced by increases in protons in the interstitial space of contracting muscles. Thus, in this article, we hypothesized that femoral occlusion increases the expression of ASIC3 in primary afferent neurons innervating muscles, and this contributes to the exaggerated reflex sympathetic responses. Femoral occlusion/vascular insufficiency of the hindlimb muscles was induced by the femoral artery ligation in rats. First, Western blot analysis shows that 24-72 h of femoral artery ligation significantly increased the expression of ASIC3 protein in dorsal root ganglion (optical density, 1.0 ± 0.07 in control vs. 1.65 ± 0.1 after 24 h of occlusion, P < 0.05; n = 6 in each group). There were no significant differences for increases in ASIC3 24 and 72 h postocclusion. Second, experiments using fluorescent immunohistochemistry and retrograde-labeling technique show that a greater percentage of ASIC3 staining neurons are localized in muscle-innervating dorsal root ganglion neurons after the arterial occlusion (78 ± 3% in 24 h post occlusion vs. 59 ± 5% in control, P < 0.05; n = 6 in each group). Third, the reflex responses in renal sympathetic nerve and arterial blood pressure induced by the stimulation of ASIC were examined after an injection of lactic acid into the arterial blood supply of hindlimb muscles of control rats and ligated rats. The results demonstrate that the sympathetic and pressor responses to lactic acid were significantly augmented after femoral occlusion compared with those in the control group. The data of this study suggest that enhanced ASIC3 expression in muscle afferent nerves contributes to the exaggerated reflex sympathetic and pressor responses to lactic acid as seen in arterial occlusion. [ABSTRACT FROM AUTHOR]

Previous animal and human studies have suggested that a muscle reflex engaged during contraction leads to heightened levels of sympathetic activity in congestive heart failure (CHF). The present experiment was designed to test the role for bradykinin, which is produced within contracting skeletal muscle and contributes to the muscle reflex through its action on kinin B2 receptors located on the endings of thin fiber muscle afferents. CHF was induced in rats by myocardial infarction (MI) after coronary artery ligation. Echocardiography was performed to determine fractional shortening (FS), an index of the left ventricular function. In the decerebrate rats, we examined renal sympathetic nerve activity (RSNA) during 1 mm intermittent (1 to 4 s stimulation to relaxation) contraction of left triceps surae muscles. RSNA responded synchronously as tension was developed, and the response was significantly (P < 0.05) greater in MI rats -1+39 ± 9% s-1 (integrated RSNA over time); n = 16] with 20 ± 2% of FS than that in control healthy rats (+19 ± 2% s-1 n = 16) with 49 ± 2% of FS. Tension development did not differ significantly between the two groups of rats. Thirty minutes after intra-arterial injection into the hindlimb circulation of the kinin B2 receptor antagonist, HOE-140 (2 rig/kg), the RSNA response to contraction was significantly reduced in the MI rats (+26 ± 7% s-1) but not in the control rats (+17 ± 2% s'). These data suggest that bradykinin within contracting muscle is part of the exaggerated muscle reflex seen in CHF. [ABSTRACT FROM AUTHOR]

Xing J, Lu J, Li J. Contribution of nerve growth factor to augmented TRPV1 responses of muscle sensoiy neurons by femoral artery occlusion. Am J Physiol Heart Circ Physiol 296: H1380-H1387, 2009. First published March 13, 2009; doi: 10.1 152/ajpheart.00063.2009.-In rats, hindlimb muscle ischemia induced by femoral artery occlusion augments the sympathetic nervous response to stimulation of transient receptor potential vanilloid type 1 (TRPV 1) by injection of capsaicin into the arterial blood supply of the hindlimb muscles. The enhanced sympathetic response is due to alterations in TRPV 1 receptor expression and its responsiveness in sensory neurons. The underlying mechanism by which TRPV 1 receptor responses are increased after muscle vascular insufficiency/ischemia is unclear. In this report we tested the hypothesis that muscle ischemia elevates nerve growth factOr (NGF) levels in primary afferent neurons, thereby increasing TRPV1 responsiveness. Muscle vascular insufficiency induced by the femoral artery ligation significantly increased NGF in the dorsal root ganglion (DRO) compared with sham controls. Furthermore, when NGF was infused in the hindlimb muscles of healthy rats (72 h using an osmotic minipump), the magnitude of the DRG neuron response to capsaicin was augmented (5.4 ± 0.54 nA with NGF infusion vs. 3.0 ± 0.17 nA in control; P < 0.05). With the addition of NGF in the culture dish containing the DRG neurons, the magnitude of the DRG neuron response to capsaicin was greater (6.4 ± 0.27 nA; P < 0.05 vs. control) than that seen in control (2.9 ± 0.16 nA). Note that this NGF effect was seen in isolectin B4-negative DRO neurons, a group of thin fiber nerves that contain neuropeptides and depend on NGF for survival. These data suggest that NGF affects a selective subpopulation of the afferent neurons in mediating augmented TRPV 1 responses after femoral artery occlusion. [ABSTRACT FROM AUTHOR]

Muscle metabolic by-products stimulate thin fiber muscle afferent nerves and evoke reflex increases in blood pressure and sympathetic nerve activity. Previous studies reported that chemically sensitive transient receptor potential vanilloid type 1 (TRPV1) channels present on sensory muscle afferent neurons have an important impact on sympathetically mediated cardiovascular responses. The reflex-mediated reduction in blood flow to skeletal muscle leads to limited exercise capacity in patients with peripheral arterial occlusive disease. Thus, in this study, we tested the hypothesis that the expression of enhanced TRPV1 receptor and its responsiveness in primary afferent neurons innervating muscles initiate exaggerated reflex sympathetic responses after vascular insufficiency to the muscle. Muscle vascular insufficiency was induced by the femoral artery ligation in rats for 24 h. Our data show that 1) the ligation surgery leads to the upregulation of TRPV1 expression in the dorsal root ganglion; 2) the magnitude of the dorsal root ganglion neuron TRPV1 response induced by capsaicin is greater in vascular insufficiency (4.0 ± 0.31 nA, P < 0.05 vs. sham-operated control) than that in sham-operated control (2.9 ± 0.23 nA); and 3) renal sympathetic nerve activity and mean arterial pres- sure responses to capsaicin (0.5 µg/kg body wt) are also enhanced by vascular insufficiency (54 ± 11%, 9 ± 2 mmHg in sham-operated controls vs. 98 ± 13%, 33 ± 5 mmHg after vascular insufficiency, P < 0.05). In conclusion, sympathetic nerve responses to the activation of metabolite-sensitive TRPV1 receptors are augmented in rats with the femoral artery occlusion compared with sham-operated control animals, due to alterations in the expression of TRPV1 receptor and its responsiveness in sensory neurons. [ABSTRACT FROM AUTHOR]

Congestive heart failure (CHF) induces abnormal regulation of peripheral blood flow during exercise. Previous studies have suggested that a reflex from contracting muscle is disordered in this disease. However, there has been very little investigation of the muscle reflex regulating sympathetic outflows in CHF. Myocardial infarction (Ml) was induced by the coronary artery ligation in rats. Echocardiography was performed to determine fractional shortening (FS), an index of the left ventricular function. We examined renal and lumbar sympathetic nerve activities (RSNA and LSNA, respectively) during 1-min repetitive (1- to 4-s stimulation to relaxation) contraction or stretch of the triceps surae muscles. During these interventions, the RSNA and LSNA responded synchronously as tension was developed. The RSNA and LSNA responses to contraction were significantly greater in MI rats (n = 13) with FS <30% than in control animals (n = 13) with FS >40% (RSNA: +49 ± 7 vs. + 19 ± 4 a.u., P < 0.01; LSNA: +28 ± 7 vs. +8 ± 2 a.u., P < 0.01) at the same tension development. Stretch also increased the RSNA and LSNA to a larger degree in MI (n = 13) than in control animals (n = 13) (RSNA: +36 ± 6 vs. +19 ± 3 au., P < 0.05; LSNA: +24 ± 3 vs. +9 ± 2 au., P < 0.01). The data demonstrate that CHF exaggerates sympathetic nerve responses to muscle contraction as well as stretch. We suggest that muscle afferent-mediated sympathetic outflows contribute to the abnormal regulation of peripheral blood flow seen during exercise in CHF. [ABSTRACT FROM AUTHOR]

The present study was undertaken to test the hypothesis that activation of the muscle reflex elicits less sympathetic activation in skeletal muscle than in internal organs. In decerebrate rats, we examined renal and lumbar (mainly innervating hindlimb blood vessels) sympathetic nerve activities (RSNA and LSNA, respectively) during 1 min of 1) repetitive (1- to 4-s stimulation-to-relaxation) contraction of the triceps surae muscle, 2) repetitive tendon stretch, and 3) repetitive contraction with hindlimb circulatory occlusion. During these interventions, RSNA and LSNA responded synchronously as tension developed. The increase was greater in RSNA than in LSNA [+51 ± 14 vs, +24 ± 5% (P < 0.05) with contraction. +46 ± 8 vs. +17 ± 4% (P < 0.05) with stretch, +76 ± 20 vs. 39 ± 7% (P < 0.05) with contraction during occlusion] during all three interventions: repetitive contraction (n = 10, +508 ± 48 g tension from baseline), tendon stretch (n = 12, +454 ± 34 g), and contraction during occlusion (n = 9, +473 ± 33 g). Additionally, hindlimb circulatory occlusion significantly enhanced RSNA and LSNA responses to contraction. These data demonstrate that RSNA responses to muscle contraction and stretch are greater than LSNA responses. We suggest that activation of the muscle afferents induces the differential sympathetic outflow that is directed toward the kidney as opposed to the limbs. This differential outflow contributes to the distribution of cardiac output observed during exercise. We further suggest that as exercise proceeds, muscle metabolites produced in contracting muscle sensitize muscle afferents and enhance sympathetic drive to limbs and renal beds. [ABSTRACT FROM AUTHOR]

During exercise, sympathetic nerve responses are accentuated in heart failure (HF), and this enhances norepinephrine (NE) release and evokes vasoconstriction. Two key pathophysiological responses could contribute to the greater NE release: 1) increased sympathetic nerve discharge and 2) increased NE in the neurovascular junction for a given level of sympathetic discharge. In this report, we focus on the second of these two general issues and test the following hypotheses: 1) in HF for a given level of sympathetic nerve stimulation, NE concentration in the interstitium (an index of neurovascular NE) would be greater, and 2) the greater interstitial NE concentration would be linked to reduced NE uptake. Studies were performed in rats 8-10 wk after induction of myocardial infarction (MI). Interstitial NE samples were collected from microdialysis probes inserted into the hindlimb muscle. Dialysate concentration of NE was determined by the HPLC method. First, interstitial NE concentration increased during electrical stimulation of the lumbar sympathetic nerves in eight control rats. An increase in interstitial NE concentration was significantly greater in 10 rats with severe MI. Additionally, an NE uptake-1 inhibitor (desipramine, 1 µM) was injected into the arterial blood supply of the muscle in six control and eight MI rats. Desipramine increased interstitial NE concentration by 24% in control and by only 3% (P < 0.05 vs. control) in MI rats. In conclusion, given levels of electrical stimulation of the lumbar sympathetic nerve lead to higher interstitial NE concentration in HF. This effect is due, in part, to reduced NE uptake-1 in HF. [ABSTRACT FROM AUTHOR]

A previous report from this laboratory demonstrated that the ATP-sensitive P2X receptor-mediated muscle pressor reflex was augmented in rats with heart failure (HF). The purpose of this study was to better understand the underlying mechanisms for this greater response in HF rats. We examined 1) responsiveness of the P2X receptor to α,β-methylene ATP (α,β-me-ATP), a P2X receptor agonist, in control and HF rats induced by myocardial infarction (MI); 2) the relationship between P2X-induced blood pressure response and left ventricular (LV) function; and 3) the expression of P2X receptors in the dorsal root ganglion (DRG) of control rats and rats with HF. Eight to 14 wk after coronary artery ligation, the severity of the MI was determined by echocardiography. In the first group of the experiment, α,β-me-ATP (0.0625, 0.125, 0.25, and 0.5 mM) was injected into the arterial blood supply of the hindlimb muscles to evoke a pressor response in 17 decerebrated rats (6 controls, 6 small MIs with infarcts of the LV between 10 and 35%, and 5 large MIs with infarcts >35%). The P2X agonist increased blood pressure, and the effect was significantly accentuated in large MI rats compared with small MI rats and control rats. A significant correlation was observed between α,β-me-ATP-evoked pressor response and the LV fractional shortening, an index of LV function. In the second group of the experiment, immunocytochemistry was used to examine the immunoreactivity of P2X receptor in the DRO neurons of small diameter fibers in six healthy control rats, five small MI, and five large Ml rats. The percentage of P2X immunostaining-positive neurons in the DRO was markedly greater in large MI rats (52% vs. 29% in controls and 34% in small MIs, P < 0.05). In conclusion, our findings demonstrate that 1) muscle afferent-mediated pressor response of P2X activation was exaggerated in MI animals, and the responsiveness was related to the degree of LV dysfunction; and 2) augmented reflex response was associated with upregulated P2X receptors in the DRG neurons of thin fiber afferent nerves following MI. The data suggest that P2X-mediated responsiveness in the processing of muscle afferent signals may have important implications for understanding cardiovascular responses to exercise in HF. [ABSTRACT FROM AUTHOR]

In congestive heart failure (CHF), exaggerated sympathetic activation is observed during exercise, which elicits excess peripheral vasoconstriction. The mechanisms causing this abnormality are not fully understood. Central command is a central neural process that induces parallel activation of motor and cardiovascular systems. This study was undertaken to determine whether central command serves as a mechanism that contributes to the exaggerated sympathetic response to exercise in CHF. In decerebrated rats, renal and lumbar sympathetic nerve responses (RSNA and LSNA, respectively) to 30s of fictive locomotion were examined. The fictive locomotion was induced by electrical stimulation of the mesencephalic locomotor region (MLR). The study was performed in control animals (fractional shortening > 40%) and animals with myocardial infarctions (MI; fractional shortening < 30%). With low stimulation of the MLR (current intensity = 20 µA), the sympathetic responses were not significantly different in the control (RSNA: +18 ± 4%; LSNA: +3 ± 2%) and Ml rats (RSNA: +16 ± 5%; LSNA: +8 ± 3%). With intense stimulation of the MLR (50 µA), the responses were significantly greater in MI rats (RSNA: +127 ± 15%; LSNA: +57 ± 10%) than in the control rats (RSNA: +62 ± 5%; LSNA: +21 ± 6%). In this study, the data demonstrate that RSNA and LSNA responses to intense stimulation of the MLR are exaggerated in MI rats. We suggest that intense activation of central command may play a role in evoking exaggerated sympathetic activation and inducing excessive peripheral vasoconstriction during exercise in CHF. [ABSTRACT FROM AUTHOR]

Static muscle contraction increases ATP release into the muscle interstitial space. Elevated ATP in muscle stimulates thin fiber muscle afferents and increases blood pressure via engagement of purinergic P2X receptors. In addition, ATP activates P2X receptors and enhances cardiovascular responses induced by stimulation of muscle mechanoreceptors. In this study, we examined whether elevated muscle temperature would attenuate and whether reduced temperature would potentiate P2X effects on reflex muscle responses. α,β-Methylene ATP (α,β-MeATP) was injected into the arterial blood supply of hindlimb muscle to stimulate P2X receptors, and muscle stretch was induced to activate mechanically sensitive muscle afferents as α,β-MeATP was injected in 10 anesthetized cats. Femoral arterial injection of α,β-MeATP (l.0 mM) increased mean arterial pressure (MAP) by 35 ± 5 (35°C), 26 ± 3 (37°C), and 19 ± 3 mmHg (39°C; P < 0.05 vs. 35°C), respectively. Muscle stretch (2 kg) elevated MAP. The MAP response was significantly enhanced 34% and 36% when α,β-MeATP (0.2 mM) was arterially infused 5 min before muscle stretch at 35° and 37°C, respectively. However, as muscle temperature reached 39°C, the stretch-evoked response was augmented only 6% by α,β-MeATP injection, and the response was significantly attenuated compared with the response with muscle temperature of 35° and 37°C. In addition, we also examined effects of muscle temperature on α,β-MeATP enhancement of the cardiovascular responses to static muscle contraction while the muscles were freely perfused and the circulation to the muscles was occluded. Because muscle temperature was 37°C, arterial injections of α,β-MeATP significantly augmented contraction-evoked MAP response by 49% (freely perfused) and 53% (ischemic condition), respectively. It is noted that this effect was significantly attenuated at a muscle temperature of 39°C. These data indicate that the effect of P2X receptor on reflex muscle response is sensitive to alternations of muscle temperature and that elevated temperature attenuates the response. [ABSTRACT FROM AUTHOR]

Static contraction of skeletal muscle evokes increases in blood pressure and heart rate. Previous studies suggested that the dorsal horn of the spinal cord is the first synaptic site responsible for those cardiovascular responses. In this study, we examined the role of ATP-sensitive P2X receptors in the cardiovascular responses to contraction by microdialyzing the P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS) into the L7 level of the dorsal horn of nine anesthetized cats. Contraction was elicited by electrical stimulation of the L7 and SI ventral roots. Blockade of P2X receptor attenuated the contraction induced-pressor response [change in mean arterial pressure (ΔMAP): 16 ± 4 mmHg after 10 mM PPADS vs. 42 ± 8 mmHg in control; P < 0.05]. In addition, the pressor response to muscle stretch was also blunted by PPADS (ΔMAP: 27 ± 5 mmHg after PPADS vs. 49 ± 8 mmHg in control; P < 0.05). Finally, activation of P2X receptor by microdialyzing 0.5 mM α,β-methylene into the dorsal horn significantly augmented the pressor response to contraction. This effect was antagonized by prior PPADS dialysis. These data demonstrate that blockade of P2X receptors in the dorsal horn attenuates the pressor response to activation of muscle afferents and that stimulation of P2X receptors enhances the reflex response, indicating that P2X receptors play a role in mediating the muscle pressor reflex at the first synaptic site of this reflex. [ABSTRACT FROM AUTHOR]

It has been suggested that nitric oxide (NO) is a key modulator of both baroreceptor and exercise pressor reflex afferent signals processed within the nucleus tractus solitarius (NTS). However, studies investigating the independent effects of NO within the NTS on the function of each reflex have produced inconsistent results. To address these concerns, the effects of microdialyzing 10 mM L-arginine, an NO precursor, and 20 mM MG-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, into the NTS on baroreceptor and exercise pressor reflex function were examined in 17 anesthetized cats. Arterial baroreflex regulation of heart rate was quantified using vasoactive drugs to induce acute changes in mean arterial pressure (MAP). To activate the exercise pressor reflex, static hindlimb contractions were induced by electrical stimulation of spinal ventral roots. To isolate the exercise pressor reflex, contractions were repeated after barodenervation. The gain coefficient of the arterial cardiac baroreflex was significantly different from control (-0.24 ± 0.04 beats·min-1·mmHg-1)after the dialysis of L-argrnine (-0.18 ± 0.02 beats·min-1·mmHg-1) and iNAME (-0.29 ± 0.02 beats·min-1·mmHg-1. In barodenervated animals, the peak MAP response to activation of the exercise pressor reflex (change in MAP from baseline, 39 ± 7 mmHg) was significantly attenuated by the dialysis of L-arginine (change in MAP from baseline, 29 ± 6 mmHg). The results demonstrate that NO within the NTS can independently modulate both the arterial cardiac baroreflex and the exercise pressor reflex. Collectively, these findings provide a neuroanatomical and chemical basis for the regulation of baroreflex and exercise pressor reflex function within the central nervous system. [ABSTRACT FROM AUTHOR]

It has been suggested that the midbrain periaqueductal gray (PAG) is a neural integrating site for the interaction between the muscle pressor reflex and the arterial baroreceptor reflex. The underlying mechanisms are poorly understood. The purpose of this study was to examine the roles of GABA and nitric oxide (NO) in modulating the PAG integration of both reflexes. To activate muscle afferents, static contraction of the triceps surae muscle was evoked by electrical stimulation of the L7 and S1 ventral roots of 18 anesthetized cats. In the first group of experiments (n = 6), the pressor response to muscle contraction was attenuated by bilateral microinjection of muscimol (a GABA receptor agonist) into the lateral PAG [change in mean arterial pressure (ΔMAP) = 24 ± 5 vs. 46 ± 8 mmHg in control]. Conversely, the pressor response was significantly augmented by 0.1 mM bicuculline, a GABAA receptor antagonist (ΔMAP = 65 ± 10 mmHg). In addition, the effect of GABAA receptor blockade on the reflex response was significantly blunted after sinoaortic denervation and vagotomy (n = 4). In the second group of experiments (n = 8), the pressor response to contraction was significantly attenuated by microinjection of L-arginine into the lateral PAG (ΔMAP = 26 ± 4 mmHg after L-arginine injection vs. 45 ± 7 mmHg in control). The effect of NO attenuation was antagonized by bicuculline and was reduced after denervation. These data demonstrate that GABA and NO within the PAG modulate the pressor response to muscle contraction and that NO attenuation of the muscle pressor reflex is mediated via arterial baroreflex-engaged GABA increase. The results suggest that the PAG plays an important role in modulating cardiovascular responses when muscle afferents are activated. [ABSTRACT FROM AUTHOR]

We have previously reported that both skeletal muscle receptor and arterial baroreceptor afferent inputs activate neurons in the dorsolateral (DL) and lateral regions of the midbrain periaqueductal gray (PAG). In this study, we determined whether the excitatory amino acid glutamate (Glu) is released to mediate the increased activity in these regions. Static contraction of the triceps surae muscle for 4 min was evoked by electrical stimulation of the L7 and S1 ventral roots in cats. Activation of arterial baroreceptor was induced by intravenous injection of phenylephrine. The endogenous release of Glu from the PAG was recovered with the use of a microdialysis probe. Glu concentration was measured by the HPLC method. Muscle contraction increased mean arterial pressure (MAP) from 98 ± 10 to 149 ± 12 mmHg (P < 0.05) and increased Glu release in the DL and lateral regions of the middle PAG from 0.39 ± 0.10 to 0.73 ± 0.12 µM (87%, P < 0.05) in intact cats. After sinoaortic denervation and vagotomy were performed, contraction increased MAP from 95 ± 12 to 158 ± 15 mmHg, and Glu from 0.34 ± 0.08 to 0.54 ± 0.10 µM (59%, P < 0.05). The increases in arterial pressure and Glu were abolished by muscle paralysis. Phenylephrine increased MAP from 100 ± 13 to 162 ± 22 mmHg and increased Glu from 0.36 ± 0.10 to 0.59 ± 0.18 µM (64%, P < 0.05) in intact animals. Denervation abolished this Glu increase. Summation of the changes in Glu evoked by muscle receptor and arterial baroreceptor afferent inputs was greater than the increase in Glu produced when both reflexes were activated simultaneously in intact state (123% vs. 87%). These data demonstrate that activation of skeletal muscle receptors evokes release of Glu in the DL and lateral regions of the middle PAG, and convergence of afferent inputs from muscle receptors and arterial baroreceptors in these regions inhibits the... [ABSTRACT FROM AUTHOR]

We examined whether ATP stimulation of P2X purinoceptors would raise blood pressure in decerebrate cats. Femoral arterial injection of the P2X receptor agonist α,β-methylene ATP into the blood supply of the triceps surae muscle induced a dose-dependent increase in arterial blood pressure. The maximal increase in mean arterial pressure (MAP) evoked by 0.1, 0.2, and 0.5 mM α,β-methylene ATP (0.5 ml/min injection rate) was 6.2 ± 2.5, 22.5 ± 4.4, and 35.2 ± 3.9 mmHg, respectively. The P2X receptor antagonist pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (2 mM ia) attenuated the increase in MAP elicited by intra-arterial α,β-methylene ATP (0.5 mM), whereas the P2Y receptor antagonist reactive blue 2 (2 mM ia) did not affect the MAP response to α,βmethylene ATP. In a second group of experiments, we tested the hypothesis that ATP acting through P2X receptors would sensitize muscle afferents and, thereby, augment the blood pressure response to muscle stretch. Two kilograms of muscle stretch evoked a 26.5 ± 4.3 mmHg increase in MAP. This MAP response was enhanced when 2 mM ATP or 0.1 mM α,β-methylene ATP (0.5 ml/min) was arterially infused 10 min before muscle stretch. Furthermore, this effect of ATP on the pressor response to stretch was attenuated by 2 mM pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (P < 0.05) but not by the P1 purinoceptor antagonist 8-(p-sulfophenyl)-theophylline (2 mM). These data indicate that activation of ATP-sensitive P2X receptors evokes a skeletal muscle afferent-mediated pressor response and that ATP at relatively low doses enhances the muscle pressor response to stretch via engagement of P2X receptors. [ABSTRACT FROM AUTHOR]

Investigates the role of nitric oxide (NO) in modulating neuronal activity in superficial dorsal horn of spinal cord during exercise pressor reflux. Changes in muscle tension and mean arterial pressure (MAP; Distribution of c-Fos label in superficial dorsal horn of spinal cord; Effects of muscle contraction.

Presents a study which examined Fos-like immunoreactivity in the regions of the periaqueductal gray during static muscle contraction. Methods; Results; Discussion.

Examines Fos-like immunoreactivity (FLI) in the medulla induced by electrical stimulation of L7 and S1 ventral roots of the spinal cord. Presence of significant FLI in the nucleus of solitary tract and in the regions of ventrolateral medulla in barointact animals; Activation of cardiovascular regions in the medulla by input from different activity.