In decerebrated rats, we determined the pressor and cardioaccelerator reflex responses to static contraction of hindlimb muscles whose femoral arteries were either occluded 72 h before contraction, occluded 3 min before contraction, or freely perfused. We found that the pressor reflex arising from the limb whose femoral artery was occluded for 72 h before contraction (32 +/- 5 mmHg, n = 16) was significantly higher than the pressor reflex arising from the contralateral freely perfused limb (15 +/- 3 mmHg, n = 16, P < 0.001) or than that arising from the contralateral limb whose femoral artery was occluded for only 3 min (17 +/- 4 mmHg, n = 16, P < 0.001). Moreover, the pressor reflex arising from the limb whose femoral artery was occluded for 3 min before the start of contraction was not significantly different than that arising from the contralateral freely perfused limb (n = 16, P = 0.819). The pressor component of the reflex arising from the limb whose femoral artery was occluded for 72 h was not changed by transient receptor potential vanilloid (TRPV) 1 receptor blockade with iodo-resiniferatoxin (n = 15, P = 0.272), although the cardioaccelerator component was significantly reduced (P = 0.005). In addition, the pressor response evoked by capsaicin injection in the femoral artery of the 72-h occluded limb was more than double that evoked from the freely perfused limb (P = 0.026). We conclude that chronic (i.e., 72 h) but not acute (3 min), femoral arterial occlusion augments pressor reflex arising from contraction of hindlimb muscles and that TRPV1 receptors play little role in this augmentation.

In sedentary individuals, H(1) receptors mediate the early portion of postexercise skeletal muscle hyperemia, whereas H(2) receptors mediate the later portion. It is not known whether postexercise hyperemia also presents in endurance-trained individuals. We hypothesized that the postexercise skeletal muscle hyperemia would also exist in endurance-trained individuals and that combined blockade of H(1) and H(2) receptors would abolish the long-lasting postexercise hyperemia in trained and sedentary individuals. We studied 28 sedentary and endurance trained men and women before and through 90 min after a 60-min bout of cycling at 60% peak O(2) uptake on control and combined H(1)- and H(2)-receptor antagonist days (fexofenadine and ranitidine). We measured arterial pressure (brachial auscultation) and femoral blood flow (Doppler ultrasound). On the control day, femoral vascular conductance (calculated as flow/pressure) was elevated in all groups 60 min after exercise (sedentary men: Delta86 +/- 35%, trained men, Delta65 +/- 18%; sedentary women, Delta61 +/- 19%, trained women: Delta59 +/- 23%, where Delta is change; all P < 0.05 vs. preexercise). In contrast, on the histamine antagonist day, femoral vascular conductance was not elevated in any of the groups after exercise (sedentary men: Delta21 +/- 17%, trained men: Delta9 +/- 5%, sedentary women: Delta19 +/- 4%, trained women: Delta11 +/- 11%; all P > 0.16 vs. preexercise; all P < 0.05 vs. control day). These data suggest postexercise skeletal muscle hyperemia exists in endurance trained men and women. Furthermore, histaminergic mechanisms produce the long-lasting hyperemia in sedentary and endurance-trained individuals.

The early (approximately 30 min) postexercise hypotension response after a session of aerobic exercise is due in part to H1-receptor-mediated vasodilation. The purpose of this study was to determine the potential contribution of H2-receptor-mediated vasodilation to postexercise hypotension. We studied 10 healthy normotensive men and women (ages 23.7 +/- 3.4 yr) before and through 90 min after a 60-min bout of cycling at 60% peak O2 uptake on randomized control and H2-receptor antagonist days (300 mg oral ranitidine). Arterial pressure (automated auscultation), cardiac output (acetylene washin) and femoral blood flow (Doppler ultrasound) were measured. Vascular conductance was calculated as flow/mean arterial pressure. Sixty minutes postexercise on the control day, femoral (delta62.3 +/- 15.6%, where Delta is change; P < 0.01) and systemic (delta13.8 +/- 5.3%; P = 0.01) vascular conductances were increased, whereas mean arterial pressure was reduced (Delta-6.7 +/- 1.1 mmHg; P < 0.01). Conversely, 60 min postexercise with ranitidine, femoral (delta9.4 +/- 9.2%; P = 0.34) and systemic (delta-2.8 +/- 4.8%; P = 0.35) vascular conductances were not elevated and mean arterial pressure was not reduced (delta-2.2 +/- 1.3 mmHg; P = 0.12). Furthermore, postexercise femoral and systemic vascular conductances were lower (P < 0.05) and mean arterial pressure was higher (P = 0.01) on the ranitidine day compared with control. Ingestion of ranitidine markedly reduces vasodilation after exercise and blunts postexercise hypotension, suggesting H2-receptor-mediated vasodilation contributes to postexercise hypotension.

Non-technical summaryIn patients with peripheral artery disease arterial blood flow to the legs is adequate at rest, but does not increase to meet metabolic demand of the muscles during exercise. Consequently, the arterial blood pressure response to exercise in these patients is greater than it is in healthy subjects. We tested the hypothesis that this exaggerated arterial pressure response to exercise is caused by the stimulation of the ion channel ASIC3 on the endings of sensory nerves in contracting skeletal muscle. We performed our experiments in decerebrated rats. Three days before the experiment, we ligated the left femoral artery, a manoeuvre which has been shown to simulate the arterial blood flow patterns to hindlimb skeletal muscles that are found in patients with peripheral artery disease. We found that blockade of ASIC3 with two different compounds attenuated the increase in arterial pressure evoked by left hindlimb muscle contraction.Abstract We found previously that static contraction of the hindlimb muscles of rats whose femoral artery was ligated evoked a larger reflex pressor response (i.e. exercise pressor reflex) than did static contraction of the contralateral hindlimb muscles which were freely perfused. Ligating a femoral artery in rats results in blood flow patterns to the muscles that are remarkably similar to those displayed by humans with peripheral artery disease. Using decerebrated rats, we tested the hypothesis that the augmented exercise pressor reflex in rats with a ligated femoral artery is attenuated by blockade of the acid sensing ion channel (ASIC) 3. We found that femoral arterial injection of either amiloride (5 and 50 μg kg −1 ) or APETx2 (100 μg kg −1 ) markedly attenuated the reflex in rats with a ligated femoral artery. In contrast, these ASIC antagonists had only modest effects on the reflex in rats with freely perfused hindlimbs. Tests of specificity of the two antagonists revealed that the low dose of amiloride and APETx2 greatly attenuated the pressor response to lactic acid, an ASIC agonist, but did not attenuate the pressor response to capsaicin, a TRPV1 agonist. In contrast, the high dose of amiloride attenuated the pressor responses to lactic acid, but also attenuated the pressor response to capsaicin. We conclude that ASIC3 on thin fibre muscle afferents plays an important role in evoking the exercise pressor reflex in rats with a compromised arterial blood supply to the working muscles. Abbreviations HR, heart rate; MAP, mean arterial pressure; TTI, tension-time index.

Leal AK, McCord JL, Tsuchimochi H, Kaufman MP. Blockade of the TP receptor attenuates the exercise pressor reflex in decerebrated rats with chronic femoral artery occlusion. Am J Physiol Heart Circ Physiol 301: H2140 -H2146, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00403.2011.-Cyclooxygenase metabolites stimulate or sensitize group III and IV muscle afferents, which comprise the sensory arm of the exercise pressor reflex. The thromboxane (TP) receptor binds several of these metabolites, whose concentrations in the muscle interstitium are increased by exercise under freely perfused conditions and even more so under ischemic conditions, which occur in peripheral artery disease. We showed that the exercise pressor reflex is greater in rats with simulated peripheral artery disease than in rats with freely perfused limbs. These findings prompted us to test the hypothesis that the TP receptor contributes to the exaggerated exercise pressor reflex occurring in a rat model of peripheral artery disease. We compared the cardiovascular responses to static contraction and stretch before and after femoral arterial injections of daltroban (80 g), a TP receptor antagonist. We performed these experiments in decerebrate rats whose femoral arteries were ligated 72 h before the experiment (a model of simulated peripheral artery disease) and in control rats whose hindlimbs were freely perfused. Daltroban reduced the pressor response to static contraction in both freely perfused (n ϭ 6; before: ⌬12 Ϯ 2 mmHg, after: ⌬6 Ϯ 2 mmHg, P ϭ 0.024) and 72-h-ligated rats (n ϭ 10; before: ⌬25 Ϯ 3 mmHg, after: ⌬7 Ϯ 4 mmHg, P ϭ 0.001). Likewise, daltroban reduced the pressor response to stretch in the freely perfused group (n ϭ 9; before: ⌬30 Ϯ 3 mmHg, after: ⌬17 Ϯ 3 mmHg, P Ͻ 0.0001) and in the ligated group (n ϭ 11; before: ⌬37 Ϯ 5 mmHg, after: ⌬23 Ϯ 3 mmHg, P ϭ 0.016). Intravenous injections of daltroban had no effect on the pressor response to contraction. We conclude that the TP receptor contributes to the pressor responses evoked by contraction and stretch in both freely perfused rats and rats with simulated peripheral artery disease. static contraction; tendon stretch; neural control of the circulation; thin fiber muscle afferents DURING EXERCISE, MEAN ARTERIAL pressure (MAP), heart rate (HR), myocardial contractility, and ventilation increase. These circulatory and ventilatory increases ensure that the working muscle is provided with adequate blood flow and oxygen. The exercise pressor reflex (30), first evidenced by Alam and Smirk (1), is one mechanism thought to be responsible for these cardiovascular and ventilatory effects. The afferent arm of the reflex is comprised of thinly myelinated group III afferents and unmyelinated group IV afferents (25). The majority of group III afferents are mechanically sensitive and are activated by distortion of their receptive fields, whereas most group IV afferents are chemically sensitive and are activated by the metabolic by-products of working muscle (17-19, 27, 28, 36).While bo...