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.     

Comparison between the effect of static contraction and tendon stretch on the discharge of group III and IV muscle afferents.

The exercise pressor reflex is evoked by both mechanical and metabolic stimuli. Tendon stretch does not increase muscle metabolism and therefore is used to investigate the mechanical component of the exercise pressor reflex. An important assumption underlying the use of tendon stretch to study the mechanical component of the exercise pressor reflex is that stretch stimulates the same group III mechanosensitive muscle afferents as does static contraction. We have tested the veracity of this assumption in decerebrated cats by comparing the responses of group III and IV muscle afferents to tendon stretch with those to static contraction. The tension-time indexes as well as the peak tension development for both maneuvers did not significantly differ. We found that static contraction of the triceps surae muscles stimulated 18 of 30 group III afferents and 8 of 11 group IV afferents. Similarly, tendon stretch stimulated 14 of 30 group III afferents and 3 of 11 group IV afferents. However, of the 18 group III afferents that responded to static contraction and the 14 group III afferents that responded to tendon stretch, only 7 responded to both stimuli. On average, the conduction velocities of the 18 group III afferents that responded to static contraction (11.6 +/- 1.6 m/s) were significantly slower (P = 0.03) than those of the 14 group III afferents that responded to tendon stretch (16.7 +/- 1.5 m/s). We have concluded that tendon stretch stimulated a different population of group III mechanosensitive muscle afferents than did static contraction. Although there is some overlap between the two populations of group III mechanosensitive afferents, it is not large, comprising less than half of the group III afferents responding to static contraction.     

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.     

Blockade of purinergic 2 receptors attenuates the mechanoreceptor component of the exercise pressor reflex

The finding that pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS), a P2 antagonist, attenuated the pressor response to calcaneal tendon stretch, a purely mechanical stimulus, raises the possibility that P2 receptors sensitize mechanoreceptors to static contraction of the triceps surae muscles. The mechanical component of the exercise pressor reflex, which is evoked by static contraction, can be assessed by measuring renal sympathetic nerve activity during the first 2-5 s of this maneuver. During this period of time, group III mechanoreceptors often discharge explosively in response to the sudden tension developed at the onset of contraction. In decerebrated cats, we, therefore, examined the effect of PPADS (10 mg/kg) injected into the popliteal artery on the renal sympathetic and pressor responses to contraction and stretch. We found that PPADS significantly attenuated the renal sympathetic response to contraction, with the effect starting 2 s after its onset and continuing throughout its 60-s period. PPADS also significantly attenuated the renal sympathetic nerve response to stretch, but did so after a latency of 10 s. Our findings lead us to conclude that P2 receptors sensitize group III muscle afferents to contraction. The difference in the onset latency between the PPADS-induced attenuation of the renal sympathetic response to contraction and the renal sympathetic response to stretch is probably due to the sensitivities of different populations of group III afferents to ATP released during contraction and stretch.     

Increasing gracilis muscle interstitial potassium concentrations stimulate group III and IV afferents

Static muscular contraction reflexly increases arterial blood pressure and heart rate. One possible mechanism evoking this reflex is that potassium accumulates in the interstitial space of a working muscle to stimulate group III and IV afferents whose activation in turn evokes a pressor response. The responses of group III and IV muscle afferents to increases in interstitial potassium concentrations within the range evoked by static contraction are unknown. Thus we injected potassium chloride into the gracilis artery of anesthetized dogs while we measured both gracilis muscle interstitial potassium concentrations with potassium-selective electrodes and the impulse activity of afferents in the gracilis nerve. We found that increasing interstitial potassium concentrations to levels similar to those seen during static contraction stimulated 14 of 16 group III and 29 of 31 group IV afferents. The responses of the afferents to potassium were concentration dependent. The typical response to potassium consisted of a burst of impulses, an effect that returned to control firing rates within 26 s, even though interstitial potassium concentrations remained elevated for several minutes. Although our results suggest that potassium may play a role in initiating the reflex cardiovascular responses to static muscular contraction, the accumulation of this ion does not appear to be solely responsible for maintaining the pressor response for the duration of the contraction.     

Exercise training prevents skeletal muscle afferent sensitization in rats with chronic heart failure

An exaggerated exercise pressor reflex (EPR) contributes to exercise intolerance and excessive sympathoexcitation in the chronic heart failure (CHF) state, which is prevented by exercise training (ExT) at an early stage in the development of CHF. We hypothesized that ExT has a beneficial effect on the exaggerated EPR by improving the dysfunction of muscle afferents in CHF. We recorded the discharge of mechanically sensitive (group III) and metabolically sensitive (group IV) afferents in response to static contraction, passive stretch, and hindlimb intra-arterial injection of capsaicin in sham+sedentary (Sed), sham+ExT, CHF+Sed, and CHF+ExT rats. Compared with sham+Sed rats, CHF+Sed rats exhibited greater responses of group III afferents to contraction and stretch, whereas the responses of group IV afferents to contraction and capsaicin were blunted. ExT prevented the sensitization of group III responses to contraction or stretch and partially prevented the blunted group IV responses to contraction or capsaicin in CHF rats. Furthermore, we investigated whether purinergic 2X (P2X) and transient receptor potential vanilloid 1 (TRPV1) receptors mediate the altered sensitivity of muscle afferents by ExT in CHF. We found that the upregulated P2X and downregulated TRPV1 receptors in L4/5 dorsal root ganglia of CHF rats were normalized by ExT. Hindlimb intra-arterial infusion of a P2X antagonist attenuated the group III response to contraction or stretch in CHF rats to a greater extent than in sham rats, which was normalized by ExT. These findings suggest that ExT improves the abnormal sensitization of muscle afferents in CHF at least, in part, via restoring the dysfunction of P2X and TRPV1 receptors.     

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.     

Group III muscle afferents evoke reflex depressor responses to repetitive muscle contractions in rabbits

Repetitive-twitch contraction of the hindlimb muscles in anesthetized rabbits consistently evokes a reflex depressor response, whereas this type of contraction in anesthetized cats evokes a reflex pressor response in about one-half of the preparations tested. Rapidly conducting group III fibers appear to comprise the afferent arm of the reflex arc, evoking the depressor response to twitch contraction in rabbits because electrical stimulation of their axons reflexly decreases arterial pressure. In contrast, electrical stimulation of the axons of slowly conducting group III and group IV afferents reflexly increases arterial pressure in rabbits. In the present study, we examined the discharge properties of group III and IV muscle afferents and found that the former (i.e., 13 of 20), but not the latter (i.e., 0 of 10), were stimulated by 5 min of repetitive-twitch contraction (1 Hz) of the rabbit triceps surae muscles. Moreover, most of the group III afferents responding to contraction appeared to be mechanically sensitive, discharging in synchrony with the muscle twitch. On average, rapidly conducting group III afferents responded for the 5-min duration of 1-Hz repetitive-twitch contraction, whereas slowly conducting group III afferents responded only for the first 2 min of contraction. We conclude that rapidly conducting group III afferents, which are mechanically sensitive, are primarily responsible for evoking the reflex depressor response to repetitive-twitch contractions in anesthetized rabbits.     

Muscle mechanosensitive receptors close to the myotendinous junction of the Achilles tendon elicit a pressor reflex.

Feedback regulation by activation of mechanosensitive afferents in the exercising muscle causes the cardiovascular and sympathetic nerve responses, which follow tension development and are almost identical between static contraction and passive stretch. The precise location of the mechanoreceptors contributing to the exercise pressor reflex, however, remained unknown. To test the hypothesis that the mechanoreceptors will be located around the myotendinous junction to monitor a change in muscle tension than a change in muscle length, we examined the reflex cardiovascular responses to passive stretch of the triceps surae muscle in anesthetized rats with three interventions; systemic injection of gadolinium, cutting the Achilles tendon, and local injection of lidocaine into the myotendinous junction. Gadolinium (42 micromol/kg iv) blunted the increases in heart rate and mean arterial blood pressure during passive stretch by 36 and 22-26%, respectively, suggesting that the reflex cardiovascular responses were evoked by stimulation of muscle mechanosensitive receptors. The cardiovascular responses to passive stretch were not different between the cut Achilles tendon and the intact tendon in the same rats, suggesting that any mechanoreceptors, terminated in the more distal part of the tendon, did not contribute to the reflex cardiovascular responses. Lidocaine (volume, 0.04-0.1 ml) injected into the myotendinous junction blunted the stretch-induced increases in heart rate and mean arterial blood pressure by 37-49 and 27-34%, respectively. We conclude that the muscle mechanosensitive receptors evoking the reflex cardiovascular responses at least partly locate at or close to the myotendinous junction of the Achilles tendon.     

Effects of hypoxia on the discharge of group III and IV muscle afferents in cats.

The reflex pressor response evoked by static muscular contraction is widely believed to be caused by the stimulation of group III and IV afferents. Although the specific nature of the contraction-induced stimulus to these thin-fiber afferents is unknown, they are thought to be stimulated in part by a condition arising from a mismatch between blood supply and demand in the exercising muscle. Hypoxia, a condition found in skeletal muscle during such a mismatch, may stimulate these afferents. We have therefore tested the hypothesis that perfusion of the triceps surae muscles with hypoxic blood stimulates group III and IV afferents in barbiturate-anesthetized cats. We found that 3-3.5 min of hypoxia with the triceps surae muscles at rest significantly (P < 0.05) increased the average discharge rate of contraction-sensitive group IV afferents but had no effect on the average discharge rate of contraction-sensitive group III afferents. Hypoxia had only trivial effects on the discharge of contraction-insensitive group III and IV afferents. Hypoxia stimulated 4 of 11 contraction-sensitive group IV afferents and 2 of 13 contraction-sensitive group III afferents. The responses of the afferents stimulated by hypoxia were small in magnitude. Hypoxia with the muscles at rest appeared to have no effect on either hydrogen or lactate ion concentrations in the femoral venous blood. In addition, hypoxia increased the responses to contraction in only 3 of 22 group III and 4 of 21 group IV afferents tested. We conclude that muscle tissue hypoxia is a minor stimulus to afferents that sense a mismatch between blood supply and demand during static contraction.     

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.     

Spinal P2X receptor modulates reflex pressor response to activation of muscle afferents

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 S1 ventral roots. Blockade of P2X receptor attenuated the contraction induced-pressor response [change in mean arterial pressure (delta MAP): 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 (delta MAP: 27 +/- 5 mmHg after PPADS vs. 49 +/- 8 mmHg in control; P < 0.05). Finally, activation of P2X receptor by microdialyzing 0.5 mM alpha,beta-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.     

Spinal vasopressin modulates the reflex cardiovascular response to static contraction.

Recent evidence has demonstrated that arginine vasopressin (AVP) may modulate primary afferent activity of nociceptors in the dorsal horn of the spinal cord. Because nociceptors are group III and IV afferents, spinal AVP also may modulate the activity of group III and IV afferents that cause reflex cardiovascular responses to muscle contraction. Thus, we compared the pressor (mean arterial pressure), myocardial contractile (dP/dt), and heart rate (HR) responses to electrically induced static contraction of the cat hindlimb before and after lumbar intrathecal (IT) injection (L1-L7) of AVP (n = 9), the V1 receptor antagonist d(CH2)5Tyr(Me)AVP (n = 6), the V2 receptor antagonist d(CH2)5[D-Ile2,Ile4,Ala-NH2(9)]AVP (n = 6), and the V2 agonist [Val4,D]AVP (n = 8). After IT injection of AVP (0.1 or 1 nmol) the pressor and contractile responses to static contraction were attenuated by 55 and 44%, respectively. HR was unchanged. Forty-five to 60 min after AVP injection, the contraction-induced pressor and contractile responses were restored to control levels. V1 receptor blockade augmented contraction-induced increases in mean arterial pressure (36%) and dP/dt (49%) but not HR. V2 receptor blockade had no effect on the cardiovascular response to contraction, whereas selective V2 stimulation attenuated the dP/dt (-20%) and HR (-33%) responses but not the pressor response. These results suggest that AVP attenuates the reflex cardiovascular response to contraction by modulating sensory nerve transmission from contracting muscle primarily via a V1 receptor mechanism in the lumbar spinal cord.     

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.     

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.     

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.     

Activation of thin-fiber muscle afferents by a P2X agonist in cats.

The responses of group III and IV triceps surae muscle afferents to intra-arterial injection of alpha,beta-methylene ATP (50 microg/kg) was examined in decerebrate cats. We found that this P2X(3) agonist stimulated only three of 18 group III afferents but 7 of 9 group IV afferents (P < 0.004). The three group III afferents stimulated by alpha,beta-methylene ATP conducted impulses below 4 m/s. Pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid, a P2-receptor antagonist, prevented the stimulation of these afferents by alpha,beta-methylene ATP. We conclude that P2X(3) agonists stimulate only the slowest conducting group III muscle afferents as well as group IV afferents.     

Role played by P2X and P2Y receptors in evoking the muscle chemoreflex.

The role played by purinergic 2Y receptors in evoking the muscle chemoreflex is not well defined. To shed light on this issue, we compared the pressor responses with popliteal arterial injection of UTP (1 mg/kg), a selective P2Y agonist, with those to popliteal arterial injection of ATP (1 mg/kg), a P2X and P2Y agonist, and to alpha,beta-methylene ATP (50 mug/kg), a selective P2X1 and P2X3 agonist, in decerebrate unanesthetized cats. We found that injection of ATP and alpha,beta-methylene ATP increased mean arterial pressure by 19 +/- 2 and 15 +/- 4 mmHg, whereas UTP had no affect on arterial pressure. In addition, the pressor responses to injection of ATP and alpha,beta-methylene ATP were abolished by section of the sciatic nerve, demonstrating that they were reflex in origin. We conclude that P2Y receptors on thin fiber muscle afferents play no role in evoking the muscle chemoreflex.     

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)     

VR-1 receptor blockade attenuates the pressor response to capsaicin but has no effect on the pressor response to contraction in cats

Vanilloid type 1 (VR-1) receptors are stimulated by capsaicin and hydrogen ions, the latter being a by-product of muscular contraction. We tested the hypothesis that activation of VR-1 receptors during static contraction contributes to the exercise pressor reflex. We established a dose of iodoresinaferatoxin (IRTX), a VR-1 receptor antagonist, that blocked the pressor response to capsaicin injected into the arterial supply of muscle. Specifically, in eight decerebrated cats, we compared pressor responses to capsaicin (10 mug) injected into the right popliteal artery, which was subsequently injected with IRTX (100 mug), with those to capsaicin injected into the left popliteal artery, which was not injected with IRTX. The pressor response to capsaicin injected into the right popliteal artery averaged 49 +/- 9 mmHg before IRTX and 9 +/- 2 mmHg after IRTX (P < 0.05). In contrast, the pressor response to capsaicin injected into the left popliteal artery averaged 46 +/- 10 mmHg "before" and 43 +/- 6 mmHg "after" (P > 0.05). We next determined whether VR-1 receptors mediated the pressor response to contraction of the triceps surae. During contraction without circulatory occlusion, the pressor response before IRTX (100 mug) averaged 26 +/- 3 mmHg, whereas it averaged 22 +/- 3 mmHg (P > 0.05) after IRTX (n = 8). In addition, during contraction with occlusion, the pressor responses averaged 35 +/- 3 mmHg before IRTX injection and 49 +/- 7 mmHg after IRTX injection (n = 7). We conclude that VR-1 receptors play little role in evoking the exercise pressor reflex.