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 α,β-methylene ATP (50 μg/kg), a selective P2X1 and P2X3 agonist, in decerebrate unanesthetized cats. We found that injection of ATP and α,β-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 α,β-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.

Ideas about control of skeletal and cardiac muscle blood flow (1876–2003): cycles of revision and new vision

This perspective examines origins of some key ideas central to major issues to be addressed in five subsequent mini-reviews related to Skeletal and Cardiac Muscle Blood Flow. The questions discussed are as follows. 1) What causes vasodilation in skeletal and cardiac muscle and 2) might the mechanisms be the same in both? 3) How important is muscle's mechanical contribution (via muscle pumping) to muscle blood flow, including its effect on cardiac output? 4) Is neural (vasoconstrictor) control of muscle vascular conductance and muscle blood flow significantly blunted in exercise by muscle metabolites and what might be a dominant site of action? 5) What reflexes initiate neural control of muscle vascular conductance so as to maintain arterial pressure at its baroreflex operating point during dynamic exercise, or is muscle blood flow regulated so as to prevent accumulation of metabolites and an ensuing muscle chemoreflex or both?

Venous occlusion to the lower limb attenuates vasoconstriction in the nonexercised limb during posthandgrip muscle ischemia

We investigated the effects of increases in calf volume on cardiovascular responses during handgrip (HG) exercise and post-HG exercise muscle ischemia (PEMI). Seven subjects completed two trials: one control (no occlusion) and one venous occlusion (VO) session. Both trials included a baseline measurement followed by 15 min of rest (REST), 2 min of HG, and 2 min of PEMI. VO was applied at 100 mmHg via cuffs placed around both distal thighs during REST, HG, and PEMI. Mean arterial pressure, heart rate, forearm blood flow (FBF) in the nonexercised arm, and forearm vascular resistance (FVR) in the nonexercised arm (FVR) were measured. During REST and HG, there were no significant differences between trials in all parameters. During PEMI in the control trial, mean arterial pressure and FVR were significantly greater and FBF was significantly lower than baseline values ( P < 0.05 for each). In contrast, in the VO trial, FBF and FVR responses were different from control responses. In the VO trial, FBF was significantly greater than in the control trial (4.7 ± 0.5 vs. 2.5 ± 0.3 ml·100 ml-1·min-1, P < 0.05) and FVR was significantly lower (28.0 ± 4.8 vs. 49.1 ± 4.6 units, respectively, P < 0.05). These results indicate that increases in vascular resistance in the nonexercised limb induced by activation of the muscle chemoreflex can be attenuated by increases in calf volume.

Muscle chemoreflex elevates muscle blood flow and O2 uptake at exercise onset in nonischemic human forearm

We tested the hypothesis that increases in forearm blood flow (FBF) during the adaptive phase at the onset of moderate exercise would allow a more rapid increase in muscle O2 uptake (V˙o 2 mus). Fifteen subjects completed forearm exercise in control (Con) and leg occlusion (Occ) conditions. In Occ, exercise of ischemic calf muscles was performed before the onset of forearm exercise to activate the muscle chemoreflex evoking a 25-mmHg increase in mean arterial pressure that was sustained during forearm exercise. Eight subjects who increased FBF during Occ compared with Con in the adaptation phase by >30 ml/min were considered “responders.” For the responders, a higherV˙o 2 mus accompanied the higher FBF only during the adaptive phase of the Occ tests, whereas there was no difference in the baseline or steady-state FBF orV˙o 2 mus between Occ and Con. Supplying more blood flow at the onset of exercise allowed a more rapid increase in V˙o 2 mussupporting our hypothesis that, at least for this type of exercise, O2 supply might be limiting.

Muscle chemoreflex-induced increases in right atrial pressure

When oxygen delivery to active muscle is too low for the ongoing rate of metabolism, metabolites accumulate and stimulate sensory nerves within the muscle leading to sympathetic activation (muscle chemoreflex). To date, studies on this reflex have focused primarily on its ability to increase arterial pressure or on the activity of the nerves that mediate this response. Clearly, a rise in cardiac output (CO) constitutes an important adjustment, because it increases the total blood flow available to be distributed among organs competing for flow. However, increments in heart rate and contractility provide limited means of raising CO because of the inverse relationship that exists between CO and right atrial pressure (RAP) in the intact circulation. Our goal was to test whether muscle chemoreflex activation, achieved via graded reductions in hindlimb blood flow by partial vascular occlusion, elicits peripheral vascular adjustments that raise RAP. In four conscious dogs exercising on a treadmill at 3.2 km/h 0% grade, RAP was well maintained during reflex activation despite increases in CO and arterial pressure that are expected to reduce RAP. Thus peripheral vascular adjustments elicited by the reflex successfully defend RAP in a setting where it would otherwise fall. To isolate the effects of the reflex on RAP, CO was maintained constant by ventricular pacing in conjunction with β1-adrenergic blockade with atenolol. When the reflex was activated by reducing hindlimb blood flow from 0.6 to 0.3 l/min, RAP rose from 5.1 ± 0.8 to 7.4 ± 0.4 mmHg ( P < 0.05) despite continued large (40 mmHg) increases in arterial pressure. During heavier exercise (6.4 km/h 10% grade) in five dogs with normal ventricular function, the reflex raised RAP from 5.7 ± 0.9 to 6.6 ± 0.8 mmHg ( P < 0.05) despite increases in CO and arterial pressure. We conclude that the muscle chemoreflex is capable of eliciting substantial increases in RAP.

Skeletal muscle chemoreflex and pHi in exercise ventilatory control

Oelberg, David A., Allison B. Evans, Mirko I. Hrovat, Paul P. Pappagianopoulos, Samuel Patz, and David M. Systrom. Skeletal muscle chemoreflex and pHi in exercise ventilatory control. J. Appl. Physiol. 84(2): 676–682, 1998.—To determine whether skeletal muscle hydrogen ion mediates ventilatory drive in humans during exercise, 12 healthy subjects performed three bouts of isotonic submaximal quadriceps exercise on each of 2 days in a 1.5-T magnet for 31P-magnetic resonance spectroscopy (31P-MRS). Bilateral lower extremity positive pressure cuffs were inflated to 45 Torr during exercise (BLPPex) or recovery (BLPPrec) in a randomized order to accentuate a muscle chemoreflex. Simultaneous measurements were made of breath-by-breath expired gases and minute ventilation, arterialized venous blood, and by 31P-MRS of the vastus medialis, acquired from the average of 12 radio-frequency pulses at a repetition time of 2.5 s. With BLPPex, end-exercise minute ventilation was higher (53.3 ± 3.8 vs. 37.3 ± 2.2 l/min; P < 0.0001), arterialized[Formula: see text] lower (33 ± 1 vs. 36 ± 1 Torr; P = 0.0009), and quadriceps intracellular pH (pHi) more acid (6.44 ± 0.07 vs. 6.62 ± 0.07; P = 0.004), compared with BLPPrec. Blood lactate was modestly increased with BLPPex but without a change in arterialized pH. For each subject, pHi was linearly related to minute ventilation during exercise but not to arterialized pH. These data suggest that skeletal muscle hydrogen ion contributes to the exercise ventilatory response.

Muscle chemoreflex increases renal sympathetic nerve activity during exercise

O’Hagan, Kathleen P., Susan M. Casey, and Philip S. Clifford. Muscle chemoreflex increases renal sympathetic nerve activity during exercise. J. Appl. Physiol. 82(6): 1818–1825, 1997.—Activation of the muscle chemoreflex increases sympathetic drive to skeletal muscle in humans. This study investigated whether activation of the muscle chemoreflex augments the renal sympathetic nerve activity (RSNA) response to dynamic exercise in rabbits. The muscle chemoreflex was evoked by hindlimb ischemia during exercise on a motorized treadmill. Seven New Zealand White rabbits performed a nonischemic control protocol and a hindlimb ischemia protocol in which terminal aortic blood flow (Q˙ta) was reduced to 51 ± 2% of preocclusion Q˙ta by partial aortic occlusion after 1.5 min of exercise. Mean arterial pressure (MAP), heart rate, RSNA andQ˙ta increased in response to exercise and were similar between trials during the first 1.5 min of exercise. In the control trial, Q˙ta, MAP, and RSNA were stable at an elevated level through an additional 3.5 min of exercise. Hindlimb ischemia produced a potent pressor response that plateaued after 2.5 min (Δ+17 ± 4 mmHg, where Δ designates change). RSNA began to increase after 1.5 min of ischemic exercise and was significantly elevated relative to preocclusion RSNA at 2.5 (Δ+25 ± 9%) and 3.5 (Δ+47 ± 12%) min of occlusion. These results suggest that the muscle chemoreflex can augment sympathoexcitatory drive to the kidney during dynamic exercise.