Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin

Thompson-Torgerson, Caitlin S.; Holowatz, Lacy A.; Flavahan, Nicholas A.; Kenney, W. Larry

doi:10.1152/ajpheart.01078.2006

Cited by 103 publications

(115 citation statements)

References 44 publications

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“…In vitro data suggest that ROS can induce vasoconstriction through Rho kinase-dependent mechanisms (3). Rho kinase has been shown to have an increasingly important role in cold-induced vasoconstriction (29) and connects well with a hypothesis including increased ROS (33). Angiotensin also directly affects smooth muscle function (30) and can potentiate adrenergic nerve activity and facilitate norepinephrine release (6).…”

Section: Blunting Is Improved By the Ascorbatementioning

confidence: 74%

Intradermal angiotensin II administration attenuates the local cutaneous vasodilator heating response

Stewart

Taneja²,

Raghunath³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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The vasodilation response to local cutaneous heating is nitric oxide (NO) dependent and blunted in postural tachycardia but reversed by angiotensin II (ANG II) type 1 receptor (AT1R) blockade. We tested the hypothesis that a localized infusion of ANG II attenuates vasodilation to local heating in healthy volunteers. We heated the skin of a calf to 42°C and measured local blood flow to assess the percentage of maximum cutaneous vascular conductance (%CVCmax) in eight healthy volunteers aged 19.5-25.5 years. Initially, two experiments were performed; in one, Ringer solution was perfused in three catheters, the response to heating was measured, 2 g/l losartan, 10 mM nitro-L-arginine (NLA), or NLA ϩ losartan was added to perfusate, and the heat response was remeasured; in another, 10 M ANG II was given, the heat response was measured, losartan, NLA, or NLA ϩ losartan was added to ANG II, and the heat response was reassessed. The heat response decreased with ANG II, particularly the plateau phase (47 Ϯ 5 vs. 84 Ϯ 3 %CVC max). Losartan increased baseline conductance in both experiments (from 8 Ϯ 1 to 20 Ϯ 2 and 12 Ϯ 1 to 24 Ϯ 3). Losartan increased the ANG II response (83 Ϯ 4 vs. 91 Ϯ 6 in Ringer). NLA decreased both angiotensin and Ringer responses (31 Ϯ 4 vs. 43 Ϯ 3). NLA ϩ losartan blunted the Ringer response (48 Ϯ 2), but the ANG II response (74 Ϯ 5) increased. In a second set of experiments, we used dose responses to ANG II (0.1 nM to 10 M) with and without NLA ϩ losartan to confirm graded responses. Sodium ascorbate (10 mM) restored the ANG II-blunted heating plateau. NO synthase and AT 1R inhibition cause an NO-independent angiotensin-mediated vasodilation with local heating. ANG II mediates the AT1R blunting of local heating, which is not exclusively NO dependent, and is improved by antioxidant supplementation. lasers; conductance; skin THE VASODILATION RESPONSE of nonglabrous skin to local heating can be described in terms of distinct phases including an initial thermal peak, a decrease to a nadir, and an increase to a plateau (17,19). The plateau phase is nitric oxide (NO) dependent (17,19). It has been used to evaluate NO bioavailability (15,26,32). Recently, we observed that plasma angiotensin II (ANG II) is increased in a subset of patients with postural tachycardia syndrome (POTS) (25,27) in whom we demonstrated blunted cutaneous microvascular NO-dependent vasodilation to local heat (18). We further demonstrated that ANG II type 1 receptor (AT 1 R) blockade with losartan corrects the cutaneous NO deficit in these patients (26). This is consistent with ANG II vasoconstrictive capabilities including the ability to produce direct smooth muscle vasoconstriction (30). However, one of the most potent vasoconstrictive actions of ANG II is mediated by AT 1 R-dependent interactions with NADPH oxidase, resulting in an enhanced production of reactive oxygen species (ROS) (11-13). One such ROS is superoxide, which scavenges and combines with NO to produce peroxynitrite (21). Thus a potent oxidative/nitrative agent i...

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Section: Blunting Is Improved By the Ascorbatementioning

confidence: 74%

Intradermal angiotensin II administration attenuates the local cutaneous vasodilator heating response

Stewart

Taneja²,

Raghunath³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…Knowledge about the mechanisms underlying the microvascular response to local cooling has greatly improved in the past few years, especially through the work by the Johnson, Kel- logg, Flavahan, and Kenney groups (18,31). Briefly, direct cooling of the skin (on the forearm) first induces an initial vasoconstriction followed by a transient vasodilation, within the first 10 -15 min after cooling onset, followed by prolonged vasoconstriction.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro, Furspan et al (13) showed increased cooling-induced ␣ 2 -adrenergic constriction of arterioles isolated from patients with primary RP compared with controls, suppressed by protein tyrosine kinase inhibitors. The role of the RhoA/Rho kinase (ROCK) pathway in mediating vasoconstriction after local cooling in healthy subjects has been confirmed in vivo (31). Indeed, cold-induced activation of ROCK may initiate constriction, mediated by both ␣ 2C -adrenoreceptors (through their mobilization from the Golgi apparatus to the vascular smooth muscle plasma membrane) and direct calcium sensitization (10).…”

mentioning

confidence: 93%

“…The initial vasoconstriction would be mainly dependent on norepinephrine and mediated by the ROCK pathway (by translocating ␣ 2C -adrenoreceptors; Ref. 31), whereas the prolonged vasoconstriction probably involves both the ROCK and the nitric oxide (NO) pathways (18). On the other hand, sensory nerves could play a role in the transient vasodilation, which is less well understood (18).…”

mentioning

confidence: 99%

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Impaired transient vasodilation and increased vasoconstriction to digital local cooling in primary Raynaud's phenomenon

Roustit

Blaise

Millet

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Raynaud's phenomenon (RP) is defined as episodic ischemia of the extremities in response to cold. Although the structure of skin capillaries is normal in primary RP, some data suggest impairment of microvascular function. We aimed at testing whether digital skin blood flow was lower in RP than in controls while cooling locally. We further evaluated the contribution of sensory nerves in the response. We recruited 21 patients with primary RP and 20 healthy volunteers matched on age and gender. After a 10-min baseline at 33°C, skin temperature was cooled at 15 or 24°C during 30 min on the forearm and the finger while monitoring perfusion with a custom-design laser Doppler flowmetry probe. Perfusion was also assessed after topical anesthesia. Blood flow was expressed as cutaneous vascular conductance (CVC). Data were subsequently expressed as area above the curve (AAC0 -30) of the percentage decrease from baseline CVC (%BL). CVC on the dorsum of the finger was lower in RP patients compared with controls at 15°C (AAC0 -30 were 106,237.2 and 69,544.3%BL·s, respectively; P ϭ 0.02) and at 24°C (AAC0 -30 were 86,915 and 57,598%BL·s, respectively; P ϭ 0.04) whereas we observed no significant difference on the finger pad and the forearm. Topical anesthesia increased CVC in patients with RP (P ϭ 0.05), whereas it did not affect reactivity in controls (P ϭ 0.86). Our study shows exaggerated skin microvascular vasoconstriction to local cooling on the dorsum of the finger in primary RP compared with controls. Part of this abnormal response in primary RP depends on sensitive nerves. microcirculation; skin blood flow FIRST DESCRIBED BY MAURICE RAYNAUD in 1862 (25), Raynaud's phenomenon (RP) is defined as episodic ischemia of the extremities in response to cold or emotional stimuli, often accompanied by pain. It presents clinically as pallor, cyanosis, and often rubor of the skin. Pallor indicates vasospasm and decreased blood flow, and cyanosis is a sign of deoxygenation of the static venous blood, while rubor implies reactive hyperemia (2). RP can be primary (i.e., idiopathic) or secondary to a connective tissue disease. The pathophysiology of primary RP is multifactorial and complex, with both vascular and neural abnormalities (7,15). Although available evidence suggests that microvascular function is impaired in primary RP, the exact mechanism of such dysfunction remains poorly understood.

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“…After the transient vasodilation a progressive sustained vasoconstriction is observed (Minson, 2010). The mechanism is complex but appears to be mediated by an adrenergic response (Thompson-Torgerson et al, 2007) in combination with decreased nitric oxide synthase (NOS) activity (Hodges et al, 2006). …”

Section: Local Coolingmentioning

confidence: 99%

Assessment of microvascular and metabolic responses in the skin

Iredahl¹

2016

Linköping University Medical Dissertations

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The general aim of this project was to develop experimental in vivo models that allow for minimally invasive investigations of responses in the skin to microvascular and metabolic provocations. The cutaneous microvasculature has emerged as a valuable model and been proposed to mirror the microcirculation in other organs. Dysfunction in the cutaneous microcirculation has thus been linked to systemic diseases such as hypertension and diabetes mellitus. Models for investigating skin responses could facilitate the understanding of pathophysiological mechanisms as well as effects of drugs. In the first study, three optical measurement techniques (laser Doppler flowmetry (LDF), laser speckle contrast imaging (LSCI) and tissue viability imaging (TiVi)) were compared against each other and showed differences in their ability to detect microvascular responses to provocations in the skin. TiVi was found more sensitive for measurement of noradrenaline-induced vasoconstriction, while LSCI was more sensitive for measurement of vascular occlusion. In the second study, microvascular responses in the skin to iontophoresis of vasoactive drugs were found to depend on the drug delivery protocol. Perfusion half-life was defined and used to describe the decay in the microvascular response to a drug after iontophoresis. In the third study, the role of nitric oxide (NO) was assessed during iontophoresis of insulin. The results showed a NO-dependent vasodilation in the skin by insulin. In the fourth study the vasoactive and metabolic effects of insulin were studied after both local and endogenous administration. Local delivery of insulin increased skin blood flow, paralleled by increased skin concentrations of interstitial pyruvate and lactate, although no change in glucose concentration was observed. An oral glucose load resulted in an increased insulin concentration in the skin paralleled by an increase in blood flow, as measured using the microdialysis urea clearance technique, although no changes in perfusion was measured by LSCI. The thesis concludes that when studying skin microvascular responses, the choice of measurement technique and the drug delivery protocol has an impact on the measurement results, and should therefore be carefully considered. The thesis also concludes that insulin has metabolic and vasodilatory effects in the skin both when administered locally and as an endogenous response to an oral glucose load. The vasodilatory effect of insulin in the skin is mediated by nitric oxide

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Cold-induced cutaneous vasoconstriction is mediated by Rho kinase in vivo in human skin

Cited by 103 publications

References 44 publications

Intradermal angiotensin II administration attenuates the local cutaneous vasodilator heating response

Intradermal angiotensin II administration attenuates the local cutaneous vasodilator heating response

Impaired transient vasodilation and increased vasoconstriction to digital local cooling in primary Raynaud's phenomenon

Assessment of microvascular and metabolic responses in the skin

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