Search

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 [alpha],[beta]-methylene ATP ([alpha],[beta]-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, [alpha],[beta]-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 [alpha],[beta]-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 DRG neurons of small diameter fibers in six healthy control rats, five small MI, and five large MI rats. The percentage of P2X immunostaining-positive neurons in the DRG 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. exercise; blood pressure; sympathetic nervous system; dorsal root ganglion; heart failure

Previous work demonstrated that [Na.sup.+]-[K.sup.+] pump activity within skeletal muscle is attenuated in myocardial infarction (MI). This may lead to enhanced interstitial [K.sup.+] concentration ([[[K.sup.+]].sub.o]) in the muscle. We tested the hypothesis that [[[K.sup.+]].sub.o] rises with muscle contraction and that, in rats with MI, the rate of rise in [[[K.sup.+]].sub.o] is greater than it is in control animals. Microdialysis probes were inserted in the skeletal muscle of six healthy control and six MI rats. The ends of the probes were then attached to the [K.sup.+] electrodes, and [[[K.sup.+]].sub.o] was continuously measured. Muscle contraction was induced by electrical stimulation of the sciatic nerves for 1 min. Stimulation at 1 and 3 Hz increased muscle [[[K.sup.+]].sub.o] by 14.2% and 44.7% in controls and by 22.9% and 62.8% in MI rats (P < 0.05 vs. controls), respectively. When ouabain, an inhibitor of [Na.sup.+]-[K.sup.+] pump, was added to the perfusate, muscle [[[K.sup.+]].sub.o] rose significantly. This effect of ouabain was significantly attenuated in MI animals. In conclusion, when compared with that in control animals, an increase of [[[K.sup.+]].sub.o] in exercising muscle is augmented in MI rats, likely due to an attenuation of [Na.sup.+]-[K.sup.+] pump activity. sympathetic nervous system; exercise; blood flow

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 30 s 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 [micro]A), the sympathetic responses were not significantly different in the control (RSNA: +18 [+ or -] 4%; LSNA: +3 [+ or -] 2%) and MI rats (RSNA: + 16 [+ or -] 5%; LSNA: +8 [+ or -] 3%). With intense stimulation of the MLR (50 [micro]A), the responses were significantly greater in MI rats (RSNA: +127 [+ or -] 15%; LSNA: +57 [+ or -] 10%) than in the control rats (RSNA: +62 [+ or -] 5%; LSNA: +21 [+ or -] 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. congestive heart failure; mesencephalic locomotor region; renal sympathetic nerve activity; lumbar sympathetic nerve activity

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, [alpha],[beta]-Methylene ATP ([alpha],[beta]-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 [alpha],[beta]-MeATP was injected in 10 anesthetized cats. Femoral arterial injection of [alpha],[beta]-MeATP (1.0 mM) increased mean arterial pressure (MAP) by 35 [+ or -] 5 (35[degrees]C), 26 [+ or -] 3 (37[degrees]C), and 19 [+ or -] 3 mmHg (39[degrees]C; P < 0.05 vs. 35[degrees]C), respectively. Muscle stretch (2 kg) elevated MAP. The MAP response was significantly enhanced 34% and 36% when [alpha],[beta]-MeATP (0.2 mM) was arterially infused 5 min before muscle stretch at 35[degrees] and 37[degrees]C, respectively. However, as muscle temperature reached 39[degrees]C, the stretch-evoked response was augmented only 6% by [alpha],[beta]-MeATP injection, and the response was significantly attenuated compared with the response with muscle temperature of 35[degrees] and 37[degrees]C. In addition, we also examined effects of muscle temperature on [alpha],[beta]-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[degrees]C, arterial injections of [alpha],[beta]-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[degrees]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. adenosine 5'-triphosphate; muscle stretch; muscle temperature; muscle pressor reflex; blood pressure doi:10.1152/ajpheart.01303.2005

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 (AMAP): 16 [+ or -] 4 mmHg after 10 mM PPADS vs. 42 [+ or -] 8 mmHg in control; P < 0.05]. In addition, the pressor response to muscle stretch was also blunted by PPADS ([DELTA]MAP: 27 [+ or -] 5 mmHg after PPADS vs. 49 [+ or -] 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. adenosine 5'-triphosphate; dorsal horn; muscle contraction; blood pressure