We tested the hypothesis that rapid increases in muscle blood flow and vascular conductance (C) at onset of dynamic exercise are caused by the muscle pump. We measured arterial (AP) and central venous pressure (CVP) in nine awake dogs, eight with atrioventricular block, pacemakers, and ascending aortic flow probes for control of cardiac output (CO) (2 also had terminal aortic flow probes). One dog had only an iliac artery probe. At exercise onset (0 and 10% grade, 4 mph) C and CVP rose to early plateaus, and AP reached a nadir, all in 2-5 s. At 20% grade and 4 mph, C increased continuously after its initial sudden rise. Timing and magnitude of initial change in conductance (delta C) were independent of CO, AP, work rate (change in grade at constant speed), or autonomic function (blocked by hexamethonium). Speed of initial delta C and its independence from work rate and blood flow ruled out metabolic vasodilation as its cause; insensitivity to AP and autonomic blockade ruled out myogenic relaxation and sympathetic vasodilation as causes of sudden delta C. Sensitivity to contraction frequency (not work per se) implicates the muscle pump. When reflexes were blocked, a large secondary rise in C, presumably caused by metabolic vasodilation, began after 10 s of mild exercise. When reflexes were intact in mild exercise, C was lowered below its initial plateau by sympathetic vasoconstriction, which partially raised AP from its nadir toward its preexercise level. Our conclusion is that dynamic exercise has a large rapid effect on C that is not explained by known neural, metabolic, myogenic, or hydrostatic influences.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

In vitro studies suggest that vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) may stimulate release of nitric oxide (NO) from endothelial cells. To investigate the hemodynamic consequences of recombinant VEGF/VPF administered in vivo, recombinant human VEGF/VPF was administered as a bolus dose of 500 micrograms to anesthetized (n = 6) or conscious (n = 5) New Zealand White rabbits, as well as anesthetized rabbits with diet-induced hypercholesterolemia (HC; n = 7). Anesthetized Yorkshire farm pigs (no specific dietary pretreatment) were studied before and after receiving 500 micrograms intravenous (IV; n = 5) or intracoronary (IC; n = 5) VEGF/VPF. In anesthetized, normal rabbits, mean arterial pressure (MAP) fell by 20.5 +/- 1.4% (P < .05 versus baseline) within 3 minutes after IV VEGF/VPF. Pretreatment with N omega-nitro-L-arginine caused a significant inhibition of VEGF/VPF-induced hypotension. In conscious, normal rabbits, VEGF/VPF produced a consistent though lesser reduction in MAP. The fall in MAP induced by VEGF/VPF in anesthetized, HC rabbits (21.5 +/- 2.5% from baseline) was no different from that observed in normal anesthetized rabbits. In pigs, both IV and IC administration of VEGF/VPF produced a prompt reduction in MAP. Heart rate increased, while cardiac output, stroke volume, left atrial pressure, and total peripheral resistance all declined to a similar, statistically significant degree in both IV and IC groups. Epicardial echocardiography disclosed neither global nor segmental wall motion abnormalities in response to VEGF/VPF. We conclude that (1) VEGF/VPF-stimulated release of NO, previously suggested in vitro, occurs in vivo; (2) this finding suggests that functional VEGF/VPF receptors are present on quiescent adult endothelium, consistent with a maintenance function for VEGF/VPF, which may include regulation of NO; and (3) the preserved response of HC rabbits suggests that endothelial cell receptors for VEGF/VPF are spared in the setting of hypercholesterolemia.

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A striking characteristic of the blood flow adaptation at exercise onset is the immediate and substantial increase in the first few (0-5 s) seconds of exercise. The purpose of this mini-review is to put into context the present evidence regarding mechanisms responsible for this phase of exercise hyperemia. One potential mechanism that has received much attention is the mechanical effect of muscle contraction (the muscle pump). The rapid vasodilatory mechanism(s) is another possible mechanism that has recently been shown to exist. This review will provide the reader with 1) an understanding of the basic physics of blood flow and the theories of muscle pump function, 2) a critical examination of evidence both for and against the contribution of the muscle pump or rapid vasodilatory mechanisms, and 3) an awareness of the limitations and impact of experimental models and exercise modes on the contribution of each of these mechanisms to the immediate exercise hyperemia. The inability to measure microvenular pressure continues to limit investigators to indirect assessments of the muscle pump vs. vasodilatory mechanism contributions to immediate exercise hyperemia in vivo. Future research directions should include examination of muscle-contraction-induced resistance vessel distortion as a trigger for rapid smooth muscle relaxation and further investigation into the exercise mode dependency of muscle pump vs. rapid vasodilatory contributions to immediate exercise hyperemia.

Graded reductions in hindlimb perfusion in dogs exercising at 2 miles/h (0% grade) elicited reflex pressor responses by what is referred to as the "muscle chemoreflex." To determine the extent to which arterial baroreceptor reflexes oppose the muscle chemoreflex, we elicited pressor responses to muscle ischemia before and after chronic surgical denervation of the arterial baroreceptors. The muscle chemoreflex showed a threshold beyond which systemic pressure rose approximately 3 mmHg for each 1-mmHg decrease in hindlimb perfusion pressure when the arterial baroreceptors were intact. Arterial baroreceptor denervation approximately doubled the pressor responses, i.e., systemic pressure rose by approximately 6 mmHg for each 1-mmHg fall in hindlimb perfusion pressure, without alteration in threshold. We conclude that during mild dynamic exercise, the arterial baroreflexes oppose the pressor response to graded reductions in hindlimb perfusion, reducing it by approximately 50%. When unopposed by the arterial baroreflexes the muscle chemoreflex exhibits a gain (ratio of change in systemic pressure to change in hindlimb perfusion pressure) of approximately -6; thus this reflex can correct by 85% the decrease in muscle perfusion pressure caused by partial vascular occlusion.

Ischemia of active skeletal muscle induces a reflex increase in sympathetic activity, heart rate, cardiac output, and arterial pressure, termed the muscle metaboreflex. Whether this pressor response contributes importantly in the regulation of blood flow to the ischemic active skeletal muscle is not well understood. If the pressor response is achieved without substantial vasoconstriction in the ischemic muscle, this increase in arterial pressure would act to improve muscle blood flow. Dogs performed treadmill exercise at mild (3.2 km/h, 0% grade) and moderate (6.4 km/h, 10% grade) workloads. During each workload, resistance to blood flow in the hindlimbs (Rh) was increased via graded partial inflation of a vascular occluder implanted on the terminal aorta. The closed-loop gain of the muscle metaboreflex (Gcl) was calculated, based on the steady-state changes in terminal aortic blood flow (TAQ). If no pressor response occurred, then TAQ should decrease in proportion to the increase in total Rh (the sum of resistance due to partial vascular occlusion and hindlimb vascular resistance); i.e., no reflex restoration of hindlimb blood flow would occur. However, with a reflex increase in systemic arterial pressure, TAQ could rise above the level predicted on the basis of the increase in Rh. We observed that with the initial increase in Rh during mild exercise, Gcl was not significantly different from zero (P > 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

At rest, central venous pressure (CVP) falls when cardiac output (CO) rises. This can be attributed to flow-dependent redistribution of blood volume from central to peripheral blood vessels. In contrast, CVP rises during dynamic exercise despite a rise in CO. Therefore peripheral circulatory changes during exercise must counteract the factors that lower CVP when CO rises during rest. Our objectives were to determine the importance of blood flow, the muscle pump, and reflexes on changes in ventricular filling pressure during dynamic exercise. In seven dogs with a surgically produced atrioventricular (AV) block, normal relationships between CO and CVP were established by AV-linked pacing (normal heart rates) during rest and exercise. Cardiac output was altered during rest and treadmill exercise (4 miles/h at 0, 10, or 20% grade) by changing ventricular pacing rate to establish curves relating delta CVP to delta CO. These curves were displaced rightward (higher CO) and upward (higher CVP) by exercise because of the muscle pump. Changing CO by pacing during rest and exercise revealed a constant slope for delta CVP/delta CO of -2.7 mmHg.l-1.min-1. Blockade of reflex vasoconstriction and venoconstriction with hexamethonium at rest and during mild exercise (to isolate effects of the muscle pump) did not alter these slopes or the displacement of the curves by exercise, although CVP was 4.3 mmHg lower at a given CO after blockade.(ABSTRACT TRUNCATED AT 250 WORDS)