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.     

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.     

Estrogen attenuates the cardiovascular and ventilatory responses to central command in cats.

Static exercise is well known to increase heart rate, arterial blood pressure, and ventilation. These increases appear to be less in women than in men, a difference that has been attributed to an effect of estrogen on neuronal function. In decerebrate male cats, we examined the effect of estrogen (17beta-estradiol; 0.001, 0.01, 0.1, and 1.0 microg/kg iv) on the cardiovascular and ventilatory responses to central command and the exercise pressor reflex, the two neural mechanisms responsible for evoking the autonomic and ventilatory responses to exercise. We found that 17beta-estradiol, in each of the three doses tested, attenuated the pressor, cardioaccelerator, and phrenic nerve responses to electrical stimulation of the mesencephalic locomotor region (i.e., central command). In contrast, none of the doses of 17beta-estradiol had any effect on the pressor, cardioaccelerator, and ventilatory responses to static contraction or stretch of the triceps surae muscles. We conclude that, in decerebrate male cats, estrogen injected intravenously attenuates cardiovascular and ventilatory responses to central command but has no effect on responses to the exercise pressor reflex.     

PPADS does not block contraction-induced prostaglandin E2 synthesis in cat skeletal muscle

Pyridoxal-phosphate-6-azophenyl-2'-4-disulfonate (PPADS), a purinergic 2 (P2) receptor antagonist, has been shown to attenuate the exercise pressor reflex in cats. In vitro, however, PPADS has been shown to block the production of prostaglandins, some of which play a role in evoking the exercise pressor reflex. Thus the possibility exists that PPADS blocks the exercise pressor reflex through a reduction in prostaglandin synthesis rather than through the blockade of P2 receptors. Using microdialysis, we collected interstitial fluid from skeletal muscle to determine prostaglandin E2 (PGE2) concentrations during the intermittent contraction of the triceps surae muscle before and after a popliteal arterial injection of PPADS (10 mg/kg). We found that the PGE2 concentration increased in response to the intermittent contraction before and after the injection of PPADS (both, P < 0.05). PPADS reduced the pressor response to exercise (P < 0.05) but had no effect on the magnitude of PGE2 production during contraction (P = 0.48). These experiments demonstrate that PPADS does not block the exercise pressor reflex through a reduction in PGE2 synthesis. We suggest that PGE2 and P2 receptors play independent roles in stimulating the exercise pressor reflex.     

Exercise pressor reflex function in female rats fluctuates with the estrous cycle

In women, sympathoexcitation during static handgrip exercise is reduced during the follicular phase of the ovarian cycle compared with the menstrual phase. Previous animal studies have demonstrated that estrogen modulates the exercise pressor reflex, a sympathoexcitatory mechanism originating in contracting skeletal muscle. The present study was conducted in female rats to determine whether skeletal muscle contraction-evoked reflex sympathoexcitation fluctuates with the estrous cycle. The estrous cycle was judged by vaginal smear. Plasma concentrations of estrogen were significantly (P < 0.05) higher in rats during the proestrus phase of the estrus cycle than those during the diestrus phase. In decerebrate rats, either electrically induced 30-s continuous static contraction of the hindlimb muscle or 30-s passive stretch of Achilles tendon (a maneuver that selectively stimulates mechanically sensitive muscle afferents) evoked less renal sympathoexcitatory and pressor responses in the proestrus animals than in the diestrus animals. Renal sympathoexcitatory response to 1-min intermittent (1- to 4-s stimulation to relaxation) bouts of static contraction was also significantly less in the proestrus rats than that in the diestrus rats. In ovariectomized female rats, 17β-estradiol applied into a well covering the dorsal surface of the lumbar spinal cord significantly reduced skeletal muscle contraction-evoked responses. These observations demonstrate that the exercise pressor reflex function and its mechanical component fluctuate with the estrous cycle in rats. Estrogen may cause these fluctuations through its attenuating effects on the spinal component of the reflex arc.     

Acid-sensing ion and epithelial sodium channels do not contribute to the mechanoreceptor component of the exercise pressor reflex

Amiloride, injected into the popliteal artery, has been reported to attenuate the reflex pressor response to static contraction of the triceps surae muscles. Both mechanical and metabolic stimuli arising in contracting skeletal muscle are believed to evoke this effect, which has been named the exercise pressor reflex. Amiloride blocks both acid-sensing ion channels, as well as epithelial sodium channels. Nevertheless, amiloride is thought to block the metabolic stimulus to the reflex, because this agent has been shown to attenuate the reflex pressor response to injection of lactic acid into the arterial supply of skeletal muscle. The possibility exists, however, that amiloride may also block mechanical stimuli evoking the exercise pressor reflex. The mechanical component of the reflex can be assessed by measuring renal sympathetic nerve activity during the first 2-5 s of contraction. During this period of time, the sudden tension developed by contraction onset briskly discharges mechanoreceptors, whereas it has little effect on the discharge of metaboreceptors. We, therefore, examined the effect of amiloride (0.5 microg/kg) injected into the popliteal artery on the renal sympathetic and pressor responses to static contraction of the triceps surae muscles in decerebrated cats. We found that amiloride significantly attenuated the pressor and renal sympathetic responses to contraction; for the latter variable, the attenuation started 10 s after the onset of contraction. Our findings lead us to conclude that acid-sensing ion channels and epithelial sodium channels play little, if any, role in evoking the mechanical component of the exercise pressor reflex.     

Role played by purinergic receptors on muscle afferents in evoking the exercise pressor reflex.

The exercise pressor reflex is believed to be evoked, in part, by multiple metabolic stimuli that are generated when blood supply to exercising muscles is inadequate to meet metabolic demand. Recently, ATP, which is a P2 receptor agonist, has been suggested to be one of the metabolic stimuli evoking this reflex. We therefore tested the hypothesis that blockade of P2 receptors within contracting skeletal muscle attenuated the exercise pressor reflex in decerebrate cats. We found that popliteal arterial injection of pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS; 10 mg/kg), a P2 receptor antagonist, attenuated the pressor response to static contraction of the triceps surae muscles. Specifically, the pressor response to contraction before PPADS averaged 36 +/- 3 mmHg, whereas afterward it averaged 14 +/- 3 mmHg (P < 0.001; n = 19). In addition, PPADS attenuated the pressor response to postcontraction circulatory occlusion (P < 0.01; n = 11). In contrast, popliteal arterial injection of CGS-15943 (250 micro g/kg), a P1 receptor antagonist, had no effect on the pressor response to static contraction of the triceps surae muscles. In addition, popliteal arterial injection of PPADS but not CGS-15943 attenuated the pressor response to stretch of the calcaneal (Achilles) tendon. We conclude that P2 receptors on the endings of thin fiber muscle afferents play a role in evoking both the metabolic and mechanoreceptor components of the exercise pressor reflex.     

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.     

Independent modification of baroreceptor and exercise pressor reflex function by nitric oxide in nucleus tractus solitarius

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 N(G)-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-arginine (-0.18 +/- 0.02 beats.min(-1).mmHg(-1)) and L-NAME (-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.     

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.     

Thin-fiber mechanoreceptors reflexly increase renal sympathetic nerve activity during static contraction

The renal vasoconstriction induced by the sympathetic outflow during exercise serves to direct blood flow from the kidney toward the exercising muscles. The renal circulation seems to be particularly important in this regard, because it receives a substantial part of the cardiac output, which in resting humans has been estimated to be 20%. The role of group III mechanoreceptors in causing the reflex renal sympathetic response to static contraction remains an open question. To shed some light on this question, we recorded the renal sympathetic nerve responses to static contraction before and after injection of gadolinium into the arterial supply of the statically contracting triceps surae muscles of decerebrate unanesthetized and chloralose-anesthetized cats. Gadolinium has been shown to be a selective blocker of mechanogated channels in thin-fiber muscle afferents, which comprise the afferent arm of the exercise pressor reflex arc. In decerebrate (n = 15) and chloralose-anesthetized (n = 12) cats, we found that gadolinium (10 mM; 1 ml) significantly attenuated the renal sympathetic nerve and pressor responses to static contraction (60 s) after a latent period of 60 min; both responses recovered after a latent period of 120 min. We conclude that thin-fiber mechanoreceptors supplying contracting muscle are involved in some of the renal vasoconstriction evoked by the exercise pressor reflex.     

Effect of phenamine and gutimine and gutimine on adaptive changes in arterial pressure occurring during skeletal muscle contraction]

Effects of amphetamine (0,1--11 mg/kg) and gutimin (5--50 mg/kg) on the pressor reflex originating in the exercising muscle were studied on nonanesthetized decerebrate cats. Isometric exercise of the hind limb muscles was elicited by stimulating the spinal ventral roots L6--S1. Amphetamine (0.1 mg/kg) increased the level of arterial pressure and the amplitude of the pressor reflex. Higher doses of amphetamine decreased the pressor reflex to exercises and there was a fall of arterial pressure. Gutimin elevated the arterial pressure and failed to alter the pressor reflex to exercises.     

Tempol attenuates the exercise pressor reflex independently of neutralizing reactive oxygen species in femoral artery ligated rats

In decerebrate rats, we reported previously that the exercise pressor reflex arising from a limb whose femoral artery was occluded for 72 h before the experiment was significantly higher than the exercise pressor reflex arising from a contralateral freely perfused limb. These findings prompted us to examine whether reactive oxygen species contributed to the augmented pressor reflex in rats with femoral artery occlusion. We found that the pressor reflex arising from the limb whose femoral artery was occluded for 72 h before the experiment (31 ± 5 mmHg) was attenuated by tempol (10 mg), a superoxide dismutase (SOD) mimetic (18 ± 5 mmHg, n = 9, P < 0.05), that was injected into the arterial supply of the hindlimb. In contrast, the pressor reflex arising from a freely perfused hindlimb (20 ± 3 mmHg) was not attenuated by tempol (17 ± 4 mmHg, n = 10, P = 0.49). Nevertheless, we found no difference in the increase in 8-isoprostaglandin F(2α) levels, an index of reactive oxygen species, in response to contraction between freely perfused (3.76 ± 0.82 pg/ml, n = 19) and 72-h occluded (3.51 ± 0.92 pg/ml, n = 22, P = 0.90) hindlimbs. Moreover, tempol did not reduce the 8-isoprostaglandin F(2α) levels during contraction in either group (P > 0.30). A second SOD mimetic, tiron (200 mg/kg), had no effect on the exercise pressor reflex in either the rats with freely perfused hindlimbs or in those with occluded femoral arteries. These findings suggest that tempol attenuated the exercise pressor reflex in the femoral artery-occluded hindlimb by a mechanism that was independent of its ability to scavenge reactive oxygen species.     

Attenuation of reflex pressor and ventilatory responses to static muscular contraction by intrathecal opioids

We have tested the hypothesis that intrathecal injections of opioid peptides attenuate the reflex pressor and ventilatory responses to static contraction of the triceps surae muscles of chloralose-anesthetized cats. We found that before intrathecal injections of [D-Ala2]Met-enkephalinamide (100 micrograms in 0.2 ml), static contraction increased mean arterial pressure and ventilation by 32 +/- 5 (SE) mmHg and 227 +/- 61 (SE) ml/min, whereas after injection of this opioid peptide, static contraction increased mean arterial pressure and ventilation by only 15 +/- 5 mmHg and 37 +/- 33 ml/min, respectively. The attenuation of both the pressor and ventilatory responses to static contraction by [D-Ala2]Met-enkephalinamide were statistically significant (P less than 0.05). Moreover, the attenuation was probably not caused by an opioid-induced withdrawal of sympathetic outflow because [D-Ala2]Met-enkephalinamide had no effect on the pressor and ventilatory responses evoked by high-intensity electrical stimulation of the central cut end of the sciatic nerve. In addition, intrathecal injection of peptides that were highly selective agonists for either the opioid mu- or delta-receptor attenuated the reflex responses to static contraction. Naloxone (1,000 micrograms), injected intrathecally, prevented the attenuation of the reflex responses to contraction by opioid peptides. We speculate that the opioid-induced attenuation of the reflex pressor and ventilatory responses to static contraction may have been due to suppression of substance P release from group III and IV muscle afferents.     

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.     

Attenuating effects of intrathecal clonidine on the exercise pressor reflex

We tested the hypothesis that intrathecal injection of clonidine, an alpha 2-adrenergic agonist, attenuated the reflex cardiovascular and ventilatory responses to static muscular contraction in cats. Before clonidine (1 microgram in 0.2 ml), contraction-induced reflex increases (n = 10) in mean arterial pressure and ventilation averaged 25 +/- 3 mmHg and 359 +/- 105 ml/min, respectively, whereas after clonidine these increases averaged 8 +/- 4 mmHg and 200 +/- 114 ml/min, respectively (P less than 0.05). Clonidine had no effect on the heart rate response to contraction. Intrathecal injection of yohimbine (10 micrograms; n = 5), an alpha 2-adrenergic antagonist, but not prazosin (10 micrograms; n = 3), an alpha 1-adrenergic antagonist, prevented the attenuating effects of clonidine on the reflex pressor and ventilatory responses to contraction. Our findings were not due to the spread of clonidine to the medulla, because the reflex pressor and ventilatory responses to contraction were not attenuated by injection of clonidine (1 microgram) onto the medulla (n = 3). In addition, our findings were not due to a clonidine-induced withdrawal of sympathetic outflow, because intrathecal injection of clonidine (1 microgram) did not attenuate increases in arterial pressure and ventilation evoked by high-intensity electrical stimulation of the cut central end of the sciatic nerve (n = 5). Furthermore, our findings were not due to a local anesthetic action of clonidine, because application of this agent to the dorsal roots had no effect on the discharge of group IV muscle afferents. We conclude that stimulation of alpha 2-adrenergic receptors in the spinal cord attenuates the reflex pressor and ventilatory responses to static contraction.     

Role played by acid-sensitive ion channels in evoking the exercise pressor reflex

The exercise pressor reflex arises from contracting skeletal muscle and is believed to play a role in evoking the cardiovascular responses to static exercise, effects that include increases in arterial pressure and heart rate. This reflex is believed to be evoked by the metabolic and mechanical stimulation of thin fiber muscle afferents. Lactic acid is known to be an important metabolic stimulus evoking the reflex. Until recently, the only antagonist for acid-sensitive ion channels (ASICs), the receptors to lactic acid, was amiloride, a substance that is also a potent antagonist for both epithelial sodium channels as well as voltage-gated sodium channels. Recently, a second compound, A-317567, has been shown to be an effective and selective antagonist to ASICs in vitro. Consequently, we measured the pressor responses to the static contraction of the triceps surae muscles in decerebrate cats before and after a popliteal arterial injection of A-317567 (10 mM solution; 0.5 ml). We found that this ASIC antagonist significantly attenuated by half (P<0.05) the pressor responses to both contraction and to lactic acid injection into the popliteal artery. In contrast, A-317567 had no effect on the pressor responses to tendon stretch, a pure mechanical stimulus, and to a popliteal arterial injection of capsaicin, which stimulated transient receptor potential vanilloid type 1 channels. We conclude that ASICs on thin fiber muscle afferents play a substantial role in evoking the metabolic component of the exercise pressor reflex.     

MLR stimulation and exercise pressor reflex activate different renal sympathetic fibers in decerebrate cats.

Although mesencephalic locomotor region (MLR) stimulation and the exercise pressor reflex have been shown to increase whole nerve renal sympathetic activity, it is not known whether these mechanisms converge onto the same population of renal sympathetic postganglionic efferents. In decerebrate cats, we examined the responses of single renal sympathetic postganglionic efferents to stimulation of the MLR and the exercise pressor reflex (i.e., static contraction of the triceps surae muscles). We found that, in most instances (24 of 28 fibers), either MLR stimulation or the muscle reflex, but not both, increased the discharge of renal postganglionic sympathetic efferents. In addition, we found that renal sympathetic efferents that responded to static contraction while the muscles were freely perfused responded more vigorously to static contraction during circulatory arrest. Moreover, stretch of the calcaneal (Achilles) tendon stimulated the same renal sympathetic efferents as did static contraction. These findings suggest that MLR stimulation and the exercise pressor reflex do not converge onto the same renal sympathetic postganglionic efferents.     

Attenuation of reflex pressor and ventilatory responses to static contraction by an NK-1 receptor antagonist.

The chemical messengers released onto second-order dorsal horn neurons from the spinal terminals of contraction-activated group III and IV muscle afferents have not been identified. One candidate is the tachykinin substance P. Related to substance P are two other tachykinins, neurokinin A (NKA) and neurokinin B (NKB), which, like substance P, have been isolated in the dorsal horn of the spinal cord and have receptors there. Whether NKA or NKB plays a transmitter/modulator role in the spinal processing of the exercise pressor reflex is unknown. Therefore, we tested the following hypotheses. After the intrathecal injection of a highly selective NK-1 (substance P) receptor antagonist onto the lumbosacral spinal cord, the reflex pressor and ventilatory responses to static muscular contraction will be attenuated. Likewise, after the intrathecal injection either of an NK-2 (NKA) receptor antagonist or an NK-3 (NKB) receptor antagonist onto the lumbrosacral spinal cord, the reflex pressor and ventilatory responses to static contraction will be attenuated. We found that, 10 min after the intrathecal injection of 100 micrograms of the NK-1 receptor antagonist, the pressor and ventilatory responses to contraction were significantly (P < 0.05) attenuated. Mean arterial pressure was attenuated by 13 +/- 3 mmHg (48%) and minute volume of ventilation by 120 +/- 38 ml/min (34%). The cardiovascular and ventilatory responses to contraction before either 100 micrograms of the NK-2 receptor antagonist or 100 micrograms of the NK-3 receptor antagonist were not different (P > 0.05) from those after the NK-2 or the NK-3 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)