title: Rho-Kinase activity and cutaneous vasoconstriction is upregulated in essential hypertensive humans.
abstract: Essential hypertension (HT) is associated with endothelial dysfunction augmented vasoconstriction (VC) which may be secondary to increased Rho/Rho-Kinase (ROCK)-dependent mechanisms. Our aim was to assess the in vivo magnitude of cutaneous VC to local cooling as a ROCK specific stimulus, and in vitro evaluate ROCK activity in the skin from HT humans. Four microdialysis fibers were placed in the forearm of 9 pre- to stage I hypertensive (MAP: 106±3 mm Hg) and 11 normotensive (NT; 86±1 mm Hg) men and women: Ringers (control), 3mM fasudil (ROCK inhibited), 5mM yohimbine+1mM proprananol (α- and β-adrenoceptor inhibited; Y+P), Y+P+3mM fasudil (ROCK and adrenocepor inhibited). Skin blood flow was measured during local cooling (Tskl 24°C) and ROCK activity in the skin biopsy samples was determined with western blot. In vitro phosphorylated myosin phosphatase target subunit 1 (pMYPT-1)/ROCK was increased in the HT skin samples (p=0.0018). Functionally, no difference in basal vasomotor tone (Tskl 34°C) was observed between the groups (HT: 0.36±0.07 vs. NT: 0.31±0.07 CVC), nor at the control site during local cooling. Pre- to stage 1 hypertensives show greater ROCK-mediated vasoconstriction at early (1-5 min; HT: -0.8±0.2 versus NT: -0.3±0.2 ΔCVC baseline 1; P<0.0001) and late (36-40 min; HT: -0.9±0.1 versus NT: -0.5±0.2 ΔCVC baseline 1; P<0.0001) phases of local cooling. These data suggest that the magnitude of cutaneous vasoconstriction to local cooling does not differ in normotensive and pre- to stage I essential hypertensive humans; however, ROCK activity is increased and functional vasoconstriction is increasingly dependent upon Rho/ROCK mechanisms with essential hypertension.
authors.affiliation: Department of Kinesiology, The Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Santhanam
authors.forename: Lacy M
authors.initials: LM
authors.lastname: Alexander
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage; D000704:Analysis of Variance; D001706:Biopsy; D001783:Blood Flow Velocity; D015153:Blotting, Western; D016022:Case-Control Studies; D003080:Cold Temperature; D005260:Female; D006801:Humans; D006973:Hypertension / Q000201:enzymology* / Q000503:physiopathology*; D017078:Laser-Doppler Flowmetry; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D010766:Phosphorylation; D058246:Prehypertension / Q000201:enzymology* / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D012039:Regional Blood Flow; D012867:Skin / Q000098:blood supply* / Q000187:drug effects / Q000201:enzymology*; D013997:Time Factors; D015854:Up-Regulation; D014661:Vasoconstriction / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000319:Adrenergic beta-Antagonists; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human