Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle

Abstract

Crecelius AR, Kirby BS, Luckasen GJ, Larson DG, Dinenno FA. Mechanisms of rapid vasodilation after a brief contraction in human skeletal muscle. Am J Physiol Heart Circ Physiol 305: H29-H40, 2013. First published May 3, 2013 doi:10.1152/ajpheart.00298.2013.-A monophasic increase in skeletal muscle blood flow is observed after a brief single forearm contraction in humans, yet the underlying vascular signaling pathways remain largely undetermined. Evidence from experimental animals indicates an obligatory role of vasodilation via K ϩ -mediated smooth muscle hyperpolarization, and human data suggest little to no independent role for nitric oxide (NO) or vasodilating prostaglandins (PGs). We tested the hypothesis that K ϩ -mediated vascular hyperpolarization underlies the rapid vasodilation in humans and that combined inhibition of NO and PGs would have a minimal effect on this response. We measured forearm blood flow (Doppler ultrasound) and calculated vascular conductance 10 s before and for 30 s after a single 1-s dynamic forearm contraction at 10%, 20%, and 40% maximum voluntary contraction in 16 young adults. To inhibit K ϩ -mediated vasodilation, BaCl2 and ouabain were infused intraarterially to inhibit inwardly rectifying K ϩ channels and Na ϩ -K ϩ -ATPase, respectively. Combined enzymatic inhibition of NO and PG synthesis occurred via N G -monomethyl-L-arginine (L-NMMA; NO synthase) and ketorolac (cyclooxygenase), respectively. In protocol 1 (n ϭ 8), BaCl 2 ϩ ouabain reduced peak vasodilation (range: 30 -45%, P Ͻ 0.05) and total postcontraction vasodilation (area under the curve, ϳ55-75% from control) at all intensities. Contrary to our hypothesis, L-NMMA ϩ ketorolac had a further impact (peak: ϳ60% and area under the curve: ϳ80% from control). In protocol 2 (n ϭ 8), the order of inhibitors was reversed, and the findings were remarkably similar. We conclude that K ϩ -mediated hyperpolarization and NO and PGs, in combination, significantly contribute to contraction-induced rapid vasodilation and that inhibition of these signaling pathways nearly abolishes this phenomenon in humans.hyperemia; exercise; potassium THE REGULATION of skeletal muscle hyperemia during muscle contractions is complex and involves a variety of signals that control both the arteriovenous perfusion pressure gradient and arteriolar caliber (10, 13). In an attempt to isolate the local mechanisms underlying exercise hyperemia, early experiments used a single brief muscle contraction to allow for contractioninduced hyperemia without the continuous interruption of the blood flow response or further stimulus for hyperemia, as occurs with repeated contractions (16). In this regard, the single contraction model can serve as a tool to examine feedforward mechanisms of hyperemia that are largely independent of changes in tissue oxidative metabolism (48). The typical response is characterized by an intensity-dependent, rapid, monophasic increase in blood flow that occurs immediately (within one cardiac cycle) after contraction, achieves full magni...

Positional differences in reactive hyperemia provide insight into initial phase of exercise hyperemia

“…Regardless of the initiating event, the relaxation of vascular smooth muscle in the resistance vessels appears to be due in part to activation of inwardly rectifying potassium channels (K IR ) (9). The results of most (8,11,27,32) but not all (10, 23) studies have found that endothelium signaling pathways make little or no contribution to peak reactive hyperemia in humans. In isolated vessels, endothelium removal or inhibition of nitric oxide synthase partially blocked both peak reactive dilation and the duration of dilation (17,18).…”

“…Additionally, experiments measuring blood flow to the canine hindlimbs (14,15) indicate that vasodilation is necessary for the immediate hyperemia at the onset of muscle contraction. Studies published over the last decade have provided evidence for the involvement of adenosine (2), potassium (8,9), and vascular compression (6,16,37) in rapid vasodilation of the skeletal muscle resistance vasculature.…”

Regulation of Increased Blood Flow (Hyperemia) to Muscles During Exercise: A Hierarchy of Competing Physiological Needs

“…Armstrong et al (11) originally demonstrated that the initial vasodilation in the hamster cremaster muscle in response to muscle contractions was attenuated when 1) release of K ϩ from voltage-dependent K ϩ channels in skeletal muscle were inhibited, 2) inwardly rectifying K ϩ (K IR ) channels in smooth muscle were blocked, or 3) Na ϩ -K ϩ pump in smooth muscle was inhibited. More recently, inhibition of K ϩ -mediated vascular hyperpolarization in the human forearm effectively attenuates the peak and total vasodilator response to various intensities of single muscle contractions (107).…”

“…Emerging evidence in young humans also suggests a potential role of NO in contraction-induced rapid vasodilation (54,85,107). NOS inhibition alone (85), in combination with muscarinic receptor blockade (54), or cyclooxygenase inhibition (107) significantly reduces the peak and total postcontraction vasodilation.…”

Attenuated rapid onset vasodilation with greater force production in skeletal muscle of caveolin-2−/− mice

“…In contrast, vasodilation occurs near-instantaneously with single brief contractions in rodents (23, 34, 51), as well as humans (9 -11, 48). While several mechanisms have been proposed to initiate ROV (10,48,51), as well the inhibition of ROV through ␣AR activation (5,23), no studies have investigated whether there may be a role for Cav2 in this regard. A key finding here is that loss of Cav2 depressed ROV by approximately half throughout the resistance network (Fig.…”