Gadolinium attenuates exercise pressor reflex in cats

The exercise pressor reflex, which arises from the contraction-induced stimulation of group III and IV muscle afferents, is widely believed to be evoked by metabolic stimuli signaling a mismatch between blood/oxygen demand and supply in the working muscles. Nevertheless, mechanical stimuli may also play a role in evoking the exercise pressor reflex. To determine this role, we examined the effect of gadolinium, which blocks mechanosensitive channels, on the exercise pressor reflex in both decerebrate and alpha-chloralose-anesthetized cats. We found that gadolinium (10 mM; 1 ml) injected into the femoral artery significantly attenuated the reflex pressor responses to static contraction of the triceps surae muscles and to stretch of the calcaneal (Achilles) tendon. In contrast, gadolinium had no effect on the reflex pressor response to femoral arterial injection of capsaicin (5 microg). In addition, gadolinium significantly attenuated the responses of group III muscle afferents, many of which are mechanically sensitive, to both static contraction and to tendon stretch. Gadolinium, however, had no effect on the responses of group IV muscle afferents, many of which are metabolically sensitive, to either static contraction or to capsaicin injection. We conclude that mechanical stimuli arising in contracting skeletal muscles contribute to the elicitation of the exercise pressor reflex.     

Estrogen attenuates the exercise pressor reflex in female cats.

In humans, the pressor and muscle sympathetic nerve responses to static exercise are less in women than in men. The difference has been attributed to the effect of estrogen on the exercise pressor reflex. Estrogen receptors are abundant in areas of the dorsal horn receiving input from group III and IV muscle afferents, which comprise the sensory limb of the exercise pressor reflex arc. These findings prompted us to investigate the effect of estrogen on the spinal pathway of the exercise pressor reflex arc. Previously, we found that the threshold concentration of 17beta-estradiol needed to attenuate the exercise pressor reflex in male decerebrate cats was 10 microg/ml (Schmitt PM and Kaufman MP. J Appl Physiol 94: 1431-1436, 2003). The threshold concentration for female cats, however, is not known. Consequently, we applied 17beta-estradiol to a well covering the L6-S1 spinal cord in decerebrate female cats. The exercise pressor reflex was evoked by electrical stimulation of the L7 or S1 ventral root, a maneuver that caused the hindlimb muscles to contract statically. We found that the pressor response to contraction averaged 38 +/- 7 mmHg before the application of 17beta-estradiol (0.01 microg/ml) to the spinal cord, whereas it averaged only 23 +/- 4 mmHg 30 min after application (P < 0.05). Recovery of the pressor response to contraction was not obtained for 2 h after application of 17beta-estradiol. Application of 17beta-estradiol in a dose of 0.001 microg/ml had no effect on the exercise pressor reflex (n = 5). We conclude that the concentration of 17beta-estradiol required to attenuate the exercise pressor reflex is 1,000 times more dilute in female cats than that needed to attenuate this reflex in male cats.     

alpha,beta-Methylene ATP elicits a reflex pressor response arising from muscle in decerebrate cats.

In part, the exercise pressor reflex is believed to be evoked by chemical stimuli signaling that blood supply to exercising muscles is not adequate to meet its metabolic demands. There is evidence that either ATP or adenosine may function as one of these chemical stimuli. For example, muscle interstitial concentrations of both substances have been found to increase during exercise. This finding led us to test the hypothesis that popliteal arterial injection of alpha,beta-methylene ATP (5, 20, and 50 microg/kg), which stimulates P2X receptors, and 2-chloroadenosine (25 microg/kg), which stimulates P1 receptors, evokes reflex pressor responses in decerebrate, unanesthetized cats. We found that popliteal arterial injection of the two highest doses of alpha,beta-methylene ATP evoked pressor responses, whereas popliteal arterial injection of 2-chloroadenosine did not. In addition, the pressor responses evoked by alpha,beta-methylene ATP were blocked either by section of the sciatic nerve or by prior popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (10 mg/kg), a selective P2-receptor antagonist. We conclude that the stimulation of P2 receptors, which are accessible through the vascular supply of skeletal muscle, evokes reflex pressor responses. In addition, our findings are consistent with the hypothesis that the stimulation of P2 receptors comprises part of the metabolic error signal evoking the exercise pressor reflex.     

Exercise pressor reflex in decerebrate and anesthetized rats

I investigated whether muscular contraction evokes cardiorespiratory increases (exercise pressor reflex) in alpha-chloralose- and chloral hydrate-anesthetized and precollicular, midcollicular, and postcollicular decerebrated rats. Mean arterial pressure (MAP), heart rate (HR), and minute ventilation (Ve) were recorded before and during 1-min sciatic nerve stimulation, which induced static contraction of the triceps surae muscles, and during 1-min stretch of the calcaneal tendon, which selectively stimulated mechanosensitive receptors in the muscles. Anesthetized rats showed various patterns of MAP response to both stimuli, i.e., biphasic, depressor, pressor, and no response. Sciatic nerve stimulation to muscle in precollicular decerebrated rats always evoked spontaneous running, so the exercise pressor reflex was not determined from these preparations. None of the postcollicular decerebrated rats showed a MAP response or spontaneous running. Midcollicular decerebrated rats consistently showed biphasic blood pressure response to both stimulations. The increases in MAP, HR, and Ve were related to the tension developed. The static contractions in midcollicular decerebrated rats (381 +/- 65 g developed tension) significantly increased MAP, HR, and Ve from 103 +/- 12 to 119 +/- 24 mmHg, from 386 +/- 30 to 406 +/- 83 beats/min, and from 122 +/- 7 to 133 +/- 25 ml/min, respectively. After paralysis, sciatic nerve stimulation had no effect on MAP, HR, or Ve. These results indicate that the midcollicular decerebrated rat can be a model for the study of the exercise pressor reflex.     

Comparison of the exercise pressor reflex between forelimb and hindlimb muscles in cats

In thirteen cats anesthetized with alpha-chloralose, we compared the cardiovascular and ventilatory responses to both static contraction and tendon stretch of a hindlimb muscle group, the triceps surae, with those to contraction and stretch of a forelimb muscle group, the triceps brachii. Static contraction and stretch of both muscle groups increased mean arterial pressure and heart rate, and the responses were directly proportional to the developed tension. The cardiovascular increases, however, were significantly greater (P < 0.05) when the triceps brachii muscles were contracted or stretched than when the triceps surae muscles were contracted or stretched, even when the tension developed by either maneuver was corrected for muscle weight. Likewise, the ventilatory increases were greater when the triceps brachii muscles were stretched than when the triceps surae muscles were stretched. Contraction of either muscle group did not increase ventilation. Our results suggest that in the anesthetized cat the cardiovascular responses to both static contraction and tendon stretch are greater when arising from forelimb muscles than from hindlimb muscles.     

High concentrations of 17beta -estradiol attenuate the exercise pressor reflex in male cats.

Previously, intravenous injection of 17beta-estradiol in decerebrate male cats was found to attenuate central command but not the exercise pressor reflex. This latter finding was surprising because the dorsal horn, the spinal site receiving synaptic input from thin-fiber muscle afferents, is known to contain estrogen receptors. We were prompted, therefore, to reexamine this issue. Instead of injecting 17beta-estradiol intravenously, we applied it topically to the L(7) and S(1) spinal cord of male decerebrate cats. We found that topical application (150-200 micro l) of 17beta-estradiol in concentrations of 0.01, 0.1, and 1 micro g/ml had no effect on the exercise pressor reflex, whereas a concentration of 10 micro g/ml attenuated the reflex. We conclude that, in male cats, estrogen can only attenuate the exercise pressor reflex in concentrations that exceed the physiological level.     

Central neural stimulation of respiration in unanesthetized decerebrate cats.

A previously reported central neural respiratory control process was restudied in unanesthetized decerebrate cats during spontaneous breathing, and during conditions of constant chemical stimulation where phrenic nerve activity was used to quantitate respiratory output. Respiration was increased by carotid sinus nerve stimulation. The pattern of respiration was examined at the cessation of such stimulation. In spontaneously breathing animals, active hyperventilation (HV) was followed by hyperpnea for up to 30 s and never by apnea. Passive HV was always followed by apnea. In animals with controlled chemical conditions, the transient at the end of stimulation consisted of two components, the first an immediate decrease in respiratory output and the second a slow decrease with a period of over 5 m. It is suggested that a facilitatory feedback process, probably located in the reticular activating system, maintains respiratory output for some time after cessation of a stimulus. This study duplicates the results of previous studies and shows that no area of the brain above the pons is required for the mechanism's operation.     

Estrogen's attenuating effect on the exercise pressor reflex is more opioid dependent in gonadally intact than in ovariectomized female cats.

Using gonadally intact female cats, we showed previously that estrogen, applied topically to the spinal cord, attenuated the exercise pressor reflex. Although the mechanism by which estrogen exerted its attenuating effect is unknown, this steroid hormone has been shown to influence spinal opioid pathways, which in turn have been implicated in the regulation of the exercise pressor reflex. These findings prompted us to test the hypothesis that opioids mediate the attenuating effect of estrogen on the exercise pressor reflex in both gonadally intact female and ovariectomized cats. We therefore applied 200 microl of 17beta-estradiol (0.01 microg/ml) with and without the addition of 1,000 microg naloxone, a mu- and delta-opioid antagonist, to a spinal well covering the L6-S1 spinal cord in decerebrated female cats that were either gonadally intact or ovariectomized. The exercise pressor reflex was evoked by electrical stimulation of the L7 or S1 ventral root, a maneuver that caused the hindlimb muscles to contract statically. We found that, in gonadally intact cats, the attenuating effect of estrogen was more pronounced than that in ovariectomized cats. We also found that, in gonadally intact female cats, naloxone partly reversed the attenuation of the pressor response to static contraction caused by spinal estrogen application. For example, in intact cats, the pressor response to contraction before estrogen application averaged 39 +/- 4 mmHg (n = 10), whereas the pressor response 60 min afterward averaged only 18 +/- 4 mmHg (P < 0.05). In contrast, the pressor response to contraction before estrogen and naloxone application averaged 33 +/- 5 mmHg (n = 11), whereas afterward it averaged 27 +/- 6 mmHg (P < 0.05). In ovariectomized cats, naloxone was less effective in reversing the attenuating effect of estrogen on the exercise pressor reflex.     

Cholinergic stimulation of the pons depresses respiration in decerebrate cats

The injection of carbachol into the pontine tegmentum of decerebrate cats evokes a postural motor atonia that has many of the characteristics of the atonia of natural rapid-eye-movement (REM) sleep (Morales et al. J. Neurophysiol. 57: 1118-1129, 1987). We have used the carbachol-injected decerebrate cat to study the changes in respiratory neuronal activity that accompany the atonia. The activities of representative respiratory motor nerves--phrenic, intercostal, and hypoglossal--and that of a motor branch of C4 were recorded in decerebrate, vagotomized, paralyzed, and artificially ventilated cats. After the microinjection of carbachol, there was a profound suppression of activity in all the nerves and a decrease in respiratory rate. This was a consistent stereotyped response in which the magnitude of the suppression of respiratory-related activity was phrenic (to approximately 65% of control) less than inspiratory intercostal (approximately 50%) less than hypoglossal (approximately 10%) less than expiratory intercostal (approximately 5%). The decrease in respiratory rate (to approximately 70% of control) was caused by a prolongation of both inspiratory and expiratory durations. Complete reversal of the carbachol effect was elicited by the microinjection of atropine into the same site as the carbachol injection. This allowed us to produce a second episode of atonia by the injection of carbachol into the contralateral pons. Thus we have demonstrated the existence of neural pathways originating in the cholinoceptive cells of the pons that have the potential to powerfully and differentially depress various respiratory motoneuronal pools and to reduce the respiratory rate. These pathways are likely to be activated along with the atonia of REM sleep.     

Exercise pressor reflex in humans with end-stage renal disease

Previous work has suggested that end-stage renal disease (ESRD) patients may have an exaggerated sympathetic nervous system (SNS) response during exercise. We hypothesized that ESRD patients have an exaggerated blood pressure (BP) response during moderate static handgrip exercise (SHG 30%) and that the exaggerated BP response is mediated by SNS overactivation, characterized by augmented mechanoreceptor activation and blunted metaboreceptor control, as has been described in other chronic diseases. We measured hemodynamics and muscle sympathetic nerve activity (MSNA) in 13 ESRD and 16 controls during: 1) passive hand movement (PHM; mechanoreceptor isolation); 2) low-level rhythmic handgrip exercise (RHG 20%; central command and mechanoreceptor activation); 3) SHG 30%, followed by posthandgrip circulatory arrest (PHGCA; metaboreceptor activation); and 4) cold pressor test (CPT; nonexercise stimulus). ESRD patients had exaggerated increases in systolic BP during SHG 30%; however, the absolute and relative increase in MSNA was not augmented, excluding SNS overactivation as the cause of the exaggerated BP response. Increase in MSNA was not exaggerated during RHG 20% and PHM, demonstrating that mechanoreceptor activation is not heightened in ESRD. During PHGCA, MSNA remained elevated in controls but decreased rapidly to baseline levels in ESRD, indicative of markedly blunted metaboreceptor control of MSNA. MSNA response to CPT was virtually identical in ESRD and controls, excluding a generalized sympathetic hyporeactivity in ESRD. In conclusion, ESRD patients have an exaggerated increase in SBP during SHG 30% that is not mediated by overactivation of the SNS directed to muscle. SBP responses were also exaggerated during mechanoreceptor activation and metaboreceptor activation, but without concomitant augmentation in MSNA responses. Metaboreceptor control of MSNA was blunted in ESRD, but the overall ability to mount a SNS response was not impaired. Other mechanisms besides SNS overactivation, such as impaired vasodilatation, should be explored to explain the exaggerated exercise pressor reflex in ESRD.     

Gastric pH changes following intramedullary electrical stimulation in anesthetized and decerebrate cats

In anesthetized and decerebrate cats, a pH-sensitive glass electrode inserted into the gastric antral region through a fistula recorded immediate pH changes. In the anesthetized cats (pentobarbital sodium, 35-40 mg/kg, i.p.), electrical stimulation within the medulla oblongata with a coaxial electrode (train of pulses at 300-500 Hz for 10-30 sec; individual pulse width 0.1-0.5 msec and amplitude not exceeding 0.5 mA) induced an increase in gastric acid secretion equivalent to a delta pH of 1.26 +/- 0.1 units. In the decerebrate (following induction with ether), the same type of stimulation elicited a more intense gastric acid secretion equivalent to a delta pH of 5.18 +/- 0.09 units which is significantly different (P less than 0.001) from that recorded in the anesthetized cats. Reversible blockage of the vagus nerves eliminated these responses during the block. Our results indicate that electrical stimulation in the posterior region of the medulla oblongata evokes an immediate and significant increase in gastric acid secretion, which is mediated through the vagus nerve, and is most evident in decerebrate unanesthetized cats.     

Both central command and exercise pressor reflex reset carotid sinus baroreflex

In decerebrate unanesthetized cats, we determined whether either "central command," the exercise pressor reflex, or the muscle mechanoreceptor reflex reset the carotid baroreflex. Both carotid sinuses were vascularly isolated, and the carotid baroreceptors were stimulated with pulsatile pressure. Carotid baroreflex function curves were determined for aortic pressure, heart rate, and renal vascular conductance. Central command was evoked by electrical stimulation of the mesencephalic locomotor region (MLR) in cats that were paralyzed. The exercise pressor reflex was evoked by statically contracting the triceps surae muscles in cats that were not paralyzed. Likewise, the muscle mechanoreceptor reflex was evoked by stretching the calcaneal tendon in cats that were not paralyzed. We found that each of the three maneuvers shifted upward the linear relationship between carotid sinus pressure and aortic pressure and heart rate. Each of the maneuvers, however, had no effect on the slope of these baroreflex function curves. Our findings show that central command arising from the MLR as well as the exercise pressor reflex are capable of resetting the carotid baroreflex.     

室旁核在剌激猫肾神经传入纤维引起的血压效应中的应用

The purpose of this study is to investigate the role of paraventricular nucleus of the hypothalamus (PVN) and alpha 1 adrenergic receptor of PVN in the pressor responses to stimulation of renal afferent nerve in alpha 1-chloralose-anesthetized cats with carotid sinoaortic denervation and vagotomy. The pressor response to stimulation of renal afferent nerve consisted of a primary and a second components. The primary component response was completely blocked while the second component was not blocked by autonomic blocking agents (hexomethonium and atropine). Bilateral lesions of PVN greatly attenuated the pressor response before and after autonomic blockade. Intracerebroventricular and PVN injection alpha 1, adrenergic antagonist (prazosin) significantly decreased in the pressor response to stimulation of renal afferent nerve. These results indicate that paraventricular nucleus of the hypothalamus and alpha 1 adrenergic receptors in central nervous system, especially in PVN, play an important role in the pressor responses to stimulation of renal afferent nerve.     

Classification of coupling patterns among spontaneous rhythms and ventilation in the sympathetic discharge of decerebrate cats

 The spontaneous low- and high-frequency rhythms in the sympathetic discharge of decerebrate artificially ventilated cats are affected by external ventilation. Two graphical methods (i.e. the space-time separation plot and the frequency tracking locus) are used to classify the non-linear interactions. The observed behaviours in the sympathetic discharge consist of phase-locked periodic dynamics (at various frequency ratios with ventilation), quasiperiodic and aperiodic patterns. They depend on the experimental condition. In control condition the sympathetic discharge appears more frequently locked to each ventilatory cycle (1 : 1 dynamics). However, some cases of quasiperiodic dynamics are found. A sympathetic activation stimulus, such as inferior vena cava occlusion, is able to synchronise slow rhythms in the sympathetic discharge to a subharmonic of ventilation. During a sympathetic inhibition stimulus, such as aortic constriction, 1 : 1 dynamics is detected but the amplitude of the sympathetic responses can be modulated by unlocked slow rhythms. Moreover, some cases of aperiodic dynamics are observed. Vagotomy reduces the 1 : 1 coupling between sympathetic outflow and ventilation. Vagotomy plus spinalisation disrupts periodic dynamics in the sympathetic discharge so that irregular and complex patterns are found. Received: 19 July 1995/Accepted in revised form: 20 May 1996