Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans.

Caroline J. Smith, Lakshmi Santhanam, Rebecca S. Bruning, Anna Stanhewicz, Dan E Berkowitz, Lacy A. Holowatz

Research output: Contribution to journalArticle

Abstract

Essential hypertension is a proinflammatory, proconstrictor disease coinciding with endothelial dysfunction and inward vessel remodeling. Using the skin circulation, our aim was to determine whether inducible NO synthase (iNOS) upregulation attenuates NO-dependent cutaneous vasodilation in hypertensive humans. We hypothesized that, with hypertension, localized iNOS inhibition would restore vasodilation in response to NO-dependent stimuli, and iNOS expression would be increased and phosphorylated vasodilator-stimulated phosphoprotein would be decreased. For, in vivo protocols, 4 intradermal microdialysis fibers were placed in 9 hypertensive and 10 normotensive men and women (systolic blood pressure: 146±4 versus 113±2 mm Hg; P<0.001). Microdialysis fibers served as control, iNOS inhibited (1400 W), neuronal NO synthase inhibited (N(ω)-propyl-l-arginine), and nonselective NOS inhibited (N(G)-nitro-l-arginine methyl ester). Cutaneous vascular conductance was calculated (percentage of sodium nitroprusside) during standardized local heating (42°C) and acetylcholine dose-response protocols (0.01, 0.10, 1.00, 5.00, 10.00, 50.00, 100.00 mmol/L). The NO-dependent local heating response was attenuated at control (95±2% versus 76±2% cutaneous vascular conductance; P<0.05) and neuronal NO synthase-inhibited sites (94±4% versus 77±3% cutaneous vascular conductance; P<0.01) in hypertensives. iNOS inhibition augmented the NO-dependent local heating response (93±2% versus 89±10% cutaneous vascular conductance). Acetylcholine-induced vasodilation was attenuated in control sites at doses ≥0.1 mmol/L of acetylcholine in hypertensives and was restored with iNOS inhibition (0.1 mmol/L, P<0.05; 1, 5, and 10 mmol/L, P<0.001; 50 and 100 mmol/L, P<0.01). In vitro iNOS expression was increased (P=0.006) and phosphorylated vasodilator-stimulated phosphoprotein was decreased in skin from hypertensive humans (P=0.04). These data suggest that iNOS is upregulated in essential hypertensive humans and contributes to reduced NO-dependent cutaneous vasodilation.

Original languageEnglish (US)
Pages (from-to)935-942
Number of pages8
JournalHypertension
Volume58
Issue number5
StatePublished - 2011
Externally publishedYes

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Nitric Oxide Synthase Type II
Vasodilation
Nitric Oxide Synthase
Up-Regulation
Skin
Blood Vessels
Heating
Acetylcholine
Microdialysis
Blood Pressure
Nitroprusside
Arginine
Hypertension

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Smith, C. J., Santhanam, L., Bruning, R. S., Stanhewicz, A., Berkowitz, D. E., & Holowatz, L. A. (2011). Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans. Hypertension, 58(5), 935-942.

Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans. / Smith, Caroline J.; Santhanam, Lakshmi; Bruning, Rebecca S.; Stanhewicz, Anna; Berkowitz, Dan E; Holowatz, Lacy A.

In: Hypertension, Vol. 58, No. 5, 2011, p. 935-942.

Research output: Contribution to journalArticle

Smith, CJ, Santhanam, L, Bruning, RS, Stanhewicz, A, Berkowitz, DE & Holowatz, LA 2011, 'Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans.', Hypertension, vol. 58, no. 5, pp. 935-942.
Smith, Caroline J. ; Santhanam, Lakshmi ; Bruning, Rebecca S. ; Stanhewicz, Anna ; Berkowitz, Dan E ; Holowatz, Lacy A. / Upregulation of inducible nitric oxide synthase contributes to attenuated cutaneous vasodilation in essential hypertensive humans. In: Hypertension. 2011 ; Vol. 58, No. 5. pp. 935-942.
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abstract = "Essential hypertension is a proinflammatory, proconstrictor disease coinciding with endothelial dysfunction and inward vessel remodeling. Using the skin circulation, our aim was to determine whether inducible NO synthase (iNOS) upregulation attenuates NO-dependent cutaneous vasodilation in hypertensive humans. We hypothesized that, with hypertension, localized iNOS inhibition would restore vasodilation in response to NO-dependent stimuli, and iNOS expression would be increased and phosphorylated vasodilator-stimulated phosphoprotein would be decreased. For, in vivo protocols, 4 intradermal microdialysis fibers were placed in 9 hypertensive and 10 normotensive men and women (systolic blood pressure: 146±4 versus 113±2 mm Hg; P<0.001). Microdialysis fibers served as control, iNOS inhibited (1400 W), neuronal NO synthase inhibited (N(ω)-propyl-l-arginine), and nonselective NOS inhibited (N(G)-nitro-l-arginine methyl ester). Cutaneous vascular conductance was calculated (percentage of sodium nitroprusside) during standardized local heating (42°C) and acetylcholine dose-response protocols (0.01, 0.10, 1.00, 5.00, 10.00, 50.00, 100.00 mmol/L). The NO-dependent local heating response was attenuated at control (95±2{\%} versus 76±2{\%} cutaneous vascular conductance; P<0.05) and neuronal NO synthase-inhibited sites (94±4{\%} versus 77±3{\%} cutaneous vascular conductance; P<0.01) in hypertensives. iNOS inhibition augmented the NO-dependent local heating response (93±2{\%} versus 89±10{\%} cutaneous vascular conductance). Acetylcholine-induced vasodilation was attenuated in control sites at doses ≥0.1 mmol/L of acetylcholine in hypertensives and was restored with iNOS inhibition (0.1 mmol/L, P<0.05; 1, 5, and 10 mmol/L, P<0.001; 50 and 100 mmol/L, P<0.01). In vitro iNOS expression was increased (P=0.006) and phosphorylated vasodilator-stimulated phosphoprotein was decreased in skin from hypertensive humans (P=0.04). These data suggest that iNOS is upregulated in essential hypertensive humans and contributes to reduced NO-dependent cutaneous vasodilation.",
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AU - Santhanam, Lakshmi

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AU - Stanhewicz, Anna

AU - Berkowitz, Dan E

AU - Holowatz, Lacy A.

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