Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans

Abstract

Medow MS, Taneja I, Stewart JM. Cyclooxygenase and nitric oxide synthase dependence of cutaneous reactive hyperemia in humans. Am J Physiol Heart Circ Physiol 293: H425-H432, 2007. First published March 16, 2007; doi:10.1152/ajpheart.01217.2006.-We tested the hypothesis that cyclooxygenases (COXs) or COX products inhibit nitric oxide (NO) synthesis and thereby mask potential effects of NO on reactive hyperemia in the cutaneous circulation. We performed laser-Doppler flowmetry (LDF) with intradermal microdialysis in 12 healthy volunteers aged 19 -25 yr. LDF was expressed as the percent cutaneous vascular conduction (%CVC) or as the maximum %CVC (%CVCmax) where CVC is LDF/mean arterial pressure. We tested the effects of the nonisoform-specific NO synthase inhibitor nitro-L-arginine (NLA, 10 mM), the nonspecific COX inhibitor ketorolac (Keto, 10 mM), combined NLA ϩ Keto, and NLA ϩ sodium nitroprusside (SNP, 28 mM) on baseline and reactive hyperemia flow parameters. We also examined the effects of isoproterenol, a ␤-adrenergic agonist that causes prostaglandin-independent vasodilation to correct for the increase in baseline flow caused by Keto. When delivered directly into the intradermal space, Keto greatly augments all aspects of the laser-Doppler flow response to reactive hyperemia: peak reactive hyperemic flow increased from 41 Ϯ 5 to 77 Ϯ 7%CVCmax, time to peak flow increased from 17 Ϯ 3 to 56 Ϯ 24 s, the area under the reactive hyperemic curve increased from 1,417 Ϯ 326 to 3,376 Ϯ 876%CVCmax ⅐ s, and the time constant for the decay of peak flow increased from 100 Ϯ 23 to 821 Ϯ 311 s. NLA greatly attenuates the Keto response despite exerting no effects on baseline LDF or on reactive hyperemia when given alone. Low-dose NLA ϩ SNP duplicates the Keto response. Isoproterenol increased baseline and peak reactive flow. These results suggest that COX inhibition unmasks NO dependence of reactive hyperemia in human cutaneous circulation. microdialysis; prostaglandin; skin REACTIVE HYPEREMIA (RH) is the sudden rise in muscle and skin blood flow that can be measured after release of ischemic arterial occlusion. It has been used as a clinical tool to evaluate both micro-and macrovascular function in normal subjects, as well as those with various disease states (11,31,33,34). Following release of the occlusion, postischemic vasodilation occurs in most tissues (30), but the precise vasodilatory response differs from one vascular bed to another. RH has been studied most often in skeletal muscle vasculature where it is currently thought that hyperemia is due to a combination of the myogenic response (4) and local vasoactive tissue-related substances, notably prostaglandins (PGs). Other factors that appear to strongly relate to the peak flow of the hyperemic response are the local concentration of potassium (17), nitric oxide (NO) (24), adenosine (9), and endothelium-dependent hyperpolarizing factor (EDHF) (37), which have been proposed as potential mediators for the excess cumulative blood flow, i.e., the total amount of bloo...

Assessment of Human Skin Microcirculation and Its Endothelial Function Using Laser Doppler Flowmetry

“…The results were substantiated by the study of Zhao et al, who assessed the concentration of NO in the microdyalisate using a NO selective amperometric electrode (Zhao et al, 2004). Other studies have confirmed an involvement of NO in the PRH response (Bingelli et al, 2003;Medow et al, 2007), yet it seems only of minor importance compared to other mechanisms. A conceivable speculation has been made by Medow et al: they propose that the COX inhibition unmasks the NO dependence of PRH in human skin (Medow et al, 2007).…”

“…Other studies have confirmed an involvement of NO in the PRH response (Bingelli et al, 2003;Medow et al, 2007), yet it seems only of minor importance compared to other mechanisms. A conceivable speculation has been made by Medow et al: they propose that the COX inhibition unmasks the NO dependence of PRH in human skin (Medow et al, 2007). The results could strengthen the hypothesis on the crosstalks between various endothelial vasodilators in human skin.…”

“…Yet, the results on the contribution of different endotehlial vasodilators are unequivocal (Bingelli et al, 2003;DalleAve et al, 2004;Durand et al, 2004;;Medow et al, 2007;Wong et al, 2003).…”

“…As for the role of NO and prostaglandins in the PRH, the results are controversial too (DalleAve et al, 2004;Medow et al, 2007;Wong et al, 2003,). The role of NO seems less important than it was predicted.…”

Endothelial Dysfunction in Children With Obstructive Sleep Apnea Is Associated With Epigenetic Changes in the eNOS Gene

“…7,28 Indeed, the mechanisms that have been suggested to contribute to the process of postocclusive hyperemic responses include increase in the vasodilator NO following increases in shear stress associated with the increased blood fl ow after an ischemic period, 29 and likely the accumulation of metabolic vasodilators such as adenosine and prostaglandins. 30 The selection of the arterial occlusion time at 60 s rather than 5 min, which is typically used in most ischemic challenges in adult studies, was dictated by the priority of ensuring the children's comfort during testing, thus preventing motion-induced artifacts and preserving the validity of the tests.…”