Skin blood flow and nitric oxide during body heating in type 2 diabetes mellitus.

Individuals with type 2 diabetes mellitus (T2DM) often exhibit microvascular dysfunction that may contribute to impaired thermoregulation, but potential mechanisms remain unclear. Our goals were to quantify skin blood flow responses and nitric oxide-mediated vasodilation during body heating in individuals with T2DM compared with nondiabetic control subjects of similar age. We measured skin blood flow (laser-Doppler flowmetry) in conjunction with intradermal microdialysis of N(G)-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase inhibitor) or vehicle during 45-60 min of whole body heating (WBH) in 10 individuals with T2DM and 14 control subjects. In six individuals from each group, we also measured forearm blood flow (FBF) by venous occlusion plethysmography on the contralateral forearm. FBF responses showed diminished absolute cutaneous vasodilation during WBH in the T2DM group (P(ANOVA) < 0.01; peak FBF in control 13.1 +/- 1.7 vs. T2DM 9.0 +/- 1.6 ml.100 ml(-1).min(-1)). However, the relative contribution of nitric oxide to the cutaneous vasodilator response (expressed as % of maximal cutaneous vascular conductance) was not different between groups (P > 0.05). We conclude that cutaneous vasodilator responses to WBH are decreased in individuals with T2DM, but the contribution of nitric oxide to this smaller vasodilation is similar between T2DM and control individuals. This decrease in cutaneous vasodilation is likely an important contributor to impaired thermoregulation in T2DM.

Effects of testosterone and estradiol on cutaneous vasodilation during local warming in older men.

Microvascular vasodilation in humans can become impaired with age, leading to cardiovascular diseases ranging from mild to life-threatening. Reproductive hormones may confer some protection on the vascular system in women; however, it is unclear whether the same is true in men. Our goal was to evaluate the impact of four hormonal conditions (testosterone only, estradiol only, testosterone and estradiol, no testosterone and no estradiol) on microvascular vasodilator responsiveness in the skin of older men. We hypothesized that in older healthy men estradiol promotes cutaneous microvascular dilation during local warming of the skin and that testosterone inhibits this dilation. We measured skin blood flow using laser Doppler flowmetry during 35 min of cutaneous local warming to 42 degrees C in 52 healthy men (average age 67 +/- 1 yr). Subjects were randomized to one of the four hormonal conditions and were studied before and after hormone treatments. The endothelium-dependent vasodilator response to local warming was not different among groups either before or after hormone treatment. For example, with testosterone-only treatment this vasodilator response was 220 +/- 13 AU, and with estrogen only the response averaged 246 +/- 12 AU (P > 0.05). We conclude that, within the doses employed in the present study, testosterone and estradiol did not consistently alter cutaneous vasodilator responsiveness in healthy older men.

Contribution of nitric oxide to cutaneous microvascular dilation in individuals with type 2 diabetes mellitus.

Microvascular pathophysiology associated with type 2 diabetes mellitus (T2DM) contributes to several aspects of the morbidity associated with the disease. We quantified the contribution of nitric oxide (NO) to the cutaneous vasodilator response to nonpainful local warming in subjects with T2DM (average duration of diabetes mellitus 7 +/- 1 yr) and in age-matched control subjects. We measured skin blood flow in conjunction with intradermal microdialysis of N(G)-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) or vehicle during 35 min of local warming to 42 degrees C. Microdialysis of sodium nitroprusside (SNP) was used for assessment of maximum cutaneous vascular conductance (CVC). Resting CVC was higher in T2DM subjects at vehicle sites (T2DM: 19 +/- 2 vs. control: 11 +/- 3%maxCVC; P < 0.05); this difference was abolished by l-NAME (T2DM: 10 +/- 1 vs. control: 8 +/- 1%maxCVC; P > 0.05). The relative contribution of NO to the vasodilator response to local warming was not different between groups (T2DM: 46 +/- 4 vs. control: 44 +/- 6%maxCVC; P > 0.05). However, absolute CVC during local warming was approximately 25% lower in T2DM subjects (T2DM: 1.79 +/- 0.15 AU/mmHg; controls: 2.42 +/- 0.20 AU/mmHg; P < 0.01), and absolute CVC during SNP was approximately 20% lower (T2DM: 1.91 +/- 0.12 vs. control: 2.38 +/- 0.13 AU/mmHg; P < 0.01). We conclude that the relative contribution of NO to vasodilation during local warming is similar between subjects with T2DM and control subjects, although T2DM was associated with a lower absolute maximum vasodilation.

Beta-2 adrenergic receptor polymorphisms and the forearm blood flow response to mental stress.

Circulating epinephrine plays an important role in skeletal muscle vasodilation during mental stress. Normotensive adults homozygous for glycine (Gly) of the Arg16/Gly beta2-adrenergic receptor polymorphism have a greater forearm beta2-receptor mediated vasodilation and a higher cardiac output response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the Arg16/Gly beta2-adrenergic receptor polymorphism affects the forearm blood flow (FBF) and hemodynamic response to mental stress, and whether venous catecholamine concentrations predicted these responses, we measured venous epinephrine, norepinephrine, heart rate (HR), arterial pressure (Finapres), and FBF during mental stress in healthy subjects homozygous for Gly16 (n = 30; mean age +/- SE: 30 +/- 1.2, 13 women) and Arg16 (n = 17, age 30 +/- 1.6, 11 women). Resting HR, blood pressure, and FBF responses to mental stress were similar between genotype groups. There were positive correlations between epinephrine and peak FBF (r = 0.694, P < 0.001), peak forearm vascular conductance (r = 0.677, P < 0.001) and the change in epinephrine to the change in HR (r = 0.456, P = 0.002) in all subjects. These correlations were not significantly different in the Gly16 and Arg16 groups. We conclude that venous epinephrine predicts the FBF response to mental stress, and the increase in epinephrine is also correlated with the increase in HR. Furthermore, the Arg16/Gly beta2-receptor polymorphism has no significant influence on the FBF or cardiovascular responses to mental stress.

Arg16/Gly beta2-adrenergic receptor polymorphism alters the cardiac output response to isometric exercise.

Normotensive adults homozygous for glycine (Gly) of the Arg16/Gly beta2-adrenergic-receptor polymorphism have 1) greater forearm beta2-receptor mediated vasodilation and 2) a higher heart rate (HR) response to isometric handgrip than arginine (Arg) homozygotes. To test the hypothesis that the higher HR response in Gly16 subjects serves to maintain the pressor response [increased cardiac output (CO)] in the setting of augmented peripheral vasodilation to endogenous catecholamines, we measured continuous HR (ECG), arterial pressure (Finapres), and CO (transthoracic echocardiography) during isometric, 40% submaximal handgrip to fatigue in healthy subjects homozygous for Gly (n = 30; mean age +/- SE: 30 +/- 1.2, 13 women) and Arg (n = 17, age 30 +/- 1.6, 11 women). Resting data were similar between groups. Handgrip produced similar increases in arterial pressure and venous norepinephrine and epinephrine concentrations; however, HR increased more in the Gly group (60.1 +/- 4.3% increase from baseline vs. 45.5 +/- 3.9%, P = 0.03), and this caused CO to be higher (Gly: 7.6 +/- 0.3 l/m vs. Arg: 6.5 +/- 0.3 l/m, P = 0.03), whereas the decrease in systemic vascular resistance in the Gly group did not reach significance (P = 0.09). We conclude that Gly16 homozygotes generate a higher CO to maintain the pressor response to handgrip. The influence of polymorphic variants in the beta2-adrenergic receptor gene on the cardiovascular response to sympathoexcitation may have important implications in the development of hypertension and heart failure.