Reflex vasoconstriction in aged human skin increasingly relies on Rho kinase-dependent mechanisms during whole body cooling

Abstract

WL. Reflex vasoconstriction in aged human skin increasingly relies on Rho kinase-dependent mechanisms during whole body cooling. Am J Physiol Heart Circ Physiol 297: H1792-H1797, 2009. First published August 28, 2009 doi:10.1152/ajpheart.00509.2009.-Primary human aging may be associated with augmented Rho kinase (ROCK)-mediated contraction of vascular smooth muscle and ROCK-mediated inhibition of nitric oxide synthase (NOS). We hypothesized that the contribution of ROCK to reflex vasoconstriction (VC) is greater in aged skin. Cutaneous VC was elicited by 1) whole body cooling [mean skin temperature (Tsk) ϭ 30.5°C] and 2) local norepinephrine (NE) infusion (1 ϫ 10 Ϫ6 M). Four microdialysis fibers were placed in the forearm skin of eight young (Y) and eight older (O) subjects for infusion of 1) Ringer solution (control), 2) 3 mM fasudil (ROCK inhibition), 3) 20 mM N G -nitro-L-arginine methyl ester (NOS inhibition), and 4) both ROCK ϩ NOS inhibitors. Red cell flux was measured by laser-Doppler flowmetry over each site. Cutaneous vascular conductance (CVC) was calculated as flux/mean arterial pressure and normalized to baseline CVC (%⌬CVCbaseline). VC was reduced at the control site in O during cooling (Y, Ϫ34 Ϯ 3; and O, Ϫ18 Ϯ 3%⌬CVCbaseline; P Ͻ 0.001) and NE infusion (Y, Ϫ53 Ϯ 4, and O, Ϫ41 Ϯ 9%⌬CVCbaseline; P ϭ 0.006). Fasudil attenuated VC in both age groups during mild cooling; however, this reduction remained only in O but not in Y skin during moderate cooling (Y, Ϫ30 Ϯ 5; and O, Ϫ7 Ϯ 1%⌬CVCbaseline; P ϭ 0.016) and was not altered by NOS inhibition. Fasudil blunted NE-mediated VC in both age groups (Y, Ϫ23 Ϯ 4; and O, Ϫ7 Ϯ 3%⌬CVCbaseline; P Ͻ 0.01). Cumulatively, these data indicate that reflex VC is more reliant on ROCK in aged skin such that approximately half of the total VC response to whole body cooling is ROCK dependent. skin blood flow; aging; temperature regulation; norepinephrine PERIPHERAL CUTANEOUS VESSELS constrict in response to cold exposure through distinct reflex and locally regulated mechanisms. Localized cooling of skin induces vasoconstriction (VC) that is partly mediated by both stimulation of ␣ 2 -adrenoreceptors by norepinephrine (NE) (9, 11) and upregulation of the downstream intracellular messenger Rho kinase (ROCK) (30, 31), whereas reflex sympathetically mediated VC relies on NE (ϳ60% of the VC response) and other coreleased sympathetic neurotransmitters (ϳ40%) (29,34).In aged skin (Ͼ60 yr), the reflex VC response is not only blunted but relies entirely on an already compromised adrenergic mechanism (18,(32)(33)(34). Furthermore, the vascular signaling pathways that couple adrenoreceptor activation to VC may be altered (20,31). During localized cooling in aged skin, the magnitude of the VC response is not diminished but relies more on ROCK and less on other adrenergically stimulated protein kinase signaling cascades (31-33). ROCK can be stimulated by NE or mitochondrial superoxide generated in response to localized cooling (2, 28). Activated ROCK elicits VC through two distinct mec...

Muscle sympathetic nerve activity during cold stress and isometric exercise in healthy older adults

“…Although the reason for these disparate findings remains unclear, differences may be related to varied methodology of the cooling perturbation, because the intensity and populations of thermal and/or pain receptors stimulated by the cooling para- digm are known to influence sympathetic outflow. To this end, the present investigation examined sympathetic nervous system activation in healthy young and older adults using a standardized whole body skin surface cooling protocol via water-perfused suit (3,30,51,55). Consistent with a wide body of literature examining MSNA at rest in older adults at thermoneutrality (27,39,53), older adults in the present study exhibited increases in basal muscle sympathetic outflow.…”

“…Importantly, whole body cooling elicits significant visceral (celiac, superior mesenteric, and renal vascular conductance indexes) and peripheral (brachial artery, total forearm, and CVC) vasoconstriction that contributes to sustained increases in BP throughout cooling in young adults (62). Reflex peripheral cutaneous vasoconstriction is significantly impaired in aged adults (30,51,55). While the visceral vasoconstrictor responses to cold stress have not been examined in older adults, it is interesting to note that the splanchnic vasoconstrictor responses to upright tilt are greater in older compared with young subjects (36).…”

“…Reflex cutaneous vasoconstriction is markedly attenuated in healthy older adults, likely mediated by impairments in both end-organ responsiveness (30,51,55) and the thermoregulatory control of skin sympathetic nerve activity (19). In young adults, whole body cold stress elicits a pronounced systemic pressor response (3,4,9,23,62), and this pressor response to mild cold stress (i.e., with no reduction in core body temperature) is exaggerated in aged humans (23,60).…”

Tetrahydrobiopterin does not affect end-organ responsiveness to norepinephrine-mediated vasoconstriction in aged skin

“…Deficits in noradrenergic function have also been identified in adrenoreceptor and second messenger systems of vascular smooth muscle (7,18,26,34,36). Conflicting accounts exist regarding the effect of age on the cutaneous VC response to NE: one study showed no difference (40) and another demonstrated a blunted VC response in aged skin (36).…”

“…This may be particularly relevant to aged skin considering recent evidence indicating that rho-kinase, which is directly stimulated by ROS, mediates ϳ50% of the reflex VC response in older adults (26). Additionally, BH 4 minimizes NOS-derived ROS by preventing enzymatic uncoupling (19,29).…”