Abstract
A decrease in environmental temperature can directly affect the contractility of cutaneous vasculature, mediated in part by alpha(2)-adrenoceptors. Most of the cellular mechanisms underlying the cooling-enhanced contractility to alpha(2)-adrenoceptor agonists have been reported in cutaneous arteries but little information is available on cutaneous veins. To investigate the cellular mechanisms associated with the cooling-enhanced contraction to UK-14304 (alpha(2)-adrenoceptor agonist), isolated equine digital veins (EDVs) were studied at 30 degrees C and 22 degrees C. The effects of inhibitors were studied on the contractile response to UK-14304 (0.1 microM). The cooling-enhanced responses were inhibited by Rho kinase inhibitors [maximum response to UK-14304 95.2 +/- 8% of response to depolarizing Krebs solution (DKS) in control vessels cooled to 22 degrees C, compared with 31.4 +/- 6% in the presence of fasudil 1 microM and 75.8 +/- 6% with Y-27632 0.1 microM] and the effects of these inhibitors were considerably less at 30 degrees C (control response 56.4 +/- 5% of DKS; 34.9 +/- 6% with fasudil 1 microM and 50.6 +/- 9% with Y-27632 0.1 microM). Furthermore, Western blotting showed that one of the downstream targets for Rho kinase activity, ezrin/radixin/moesin, was phosphorylated after cooling and reduced by fasudil (1 microM) only at 22 degrees C. The activation of protein kinase C contributed to the contractile response, but predominantly at 30 degrees C (maximum response 82.3 +/- 9% of DKS for control; 57.7 +/- 10% in the presence of chelerythrine 10 microM) with no significant effect at 22 degrees C. The reduction of the response at 22 degrees C by antioxidants, rotenone (14% reduction), and tempol (21% reduction) suggested the contribution of reactive oxygen species (ROS). No evidence was obtained to support the participation of tyrosine kinase. These data demonstrate that Rho kinase activation and the production of ROS contributes to the cooling-enhanced contraction in these cutaneous digital veins.
Highlights
EQUINE LAMINITIS is a condition of the equine digit that compromises the integrity of the anatomical relationship between the third phalanx and the hoof and may be linked to peripheral vasoconstriction and ischaemia
Effect of Rho kinase inhibitors in the augmented response to cooling mediated by UK-14304 in equine digital veins
The cooling-enhanced contraction to UK-14304 in equine digital veins was reduced by specific inhibitors of Rho kinase or by inhibiting the production of reactive oxygen species (ROS)
Summary
EQUINE LAMINITIS is a condition of the equine digit that compromises the integrity of the anatomical relationship between the third phalanx and the hoof and may be linked to peripheral vasoconstriction and ischaemia. Cooling-enhanced responses to UK-14304 (an ␣2-adrenoceptor agonist) in the mouse tail artery have been reported to be mediated by the ␣2C-adrenoceptor subtype, which may translocate from the Golgi compartment to the extracellular membrane Such a mechanism involves the cooling-induced production of reactive oxygen species (ROS) and the activation of the Rho/Rho kinase pathway [4, 8, 12]. It is possible that a moderate reduction of temperature can activate both the Rho and/or tyrosine kinase pathways in the vascular smooth muscle and might be involved in the cooling-enhanced effect observed in the cutaneous equine digital vasculature. The aims of this study were to determine 1) whether cooling enhances the activity of Rho kinase in rings of equine digital veins, 2) the role of the Rho/Rho kinase pathway in the cooling-enhanced functional response to UK-14304 using selective Rho kinase inhibitors, and 3) the role of protein kinase C (PKC), tyrosine kinase, and the production of ROS in the http://www.jap.org
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