Sokolnicki LA, Roberts SK, Wilkins BW, Basu A, Charkoudian N. Contribution of nitric oxide to cutaneous microvascular dilation in individuals with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 292: E314 -E318, 2007. First published September 5, 2006; doi:10.1152/ajpendo.00365.2006.-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 Ϯ 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°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 Ϯ 2 vs. control: 11 Ϯ 3%maxCVC; P Ͻ 0.05); this difference was abolished by L-NAME (T2DM: 10 Ϯ 1 vs. control: 8 Ϯ 1%maxCVC; P Ͼ 0.05). The relative contribution of NO to the vasodilator response to local warming was not different between groups (T2DM: 46 Ϯ 4 vs. control: 44 Ϯ 6%maxCVC; P Ͼ 0.05). However, absolute CVC during local warming was ϳ25% lower in T2DM subjects (T2DM: 1.79 Ϯ 0.15 AU/mmHg; controls: 2.42 Ϯ 0.20 AU/mmHg; P Ͻ 0.01), and absolute CVC during SNP was ϳ20% lower (T2DM: 1.91 Ϯ 0.12 vs. control: 2.38 Ϯ 0.13 AU/ mmHg; P Ͻ 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. skin blood flow; vasodilation; local warming; thermoregulation THE PANDEMIC GROWTH of type 2 diabetes mellitus (T2DM) has made it increasingly important for clinicians and researchers to understand mechanisms of pathophysiology associated with the disease (19). A well-recognized area of dysfunction involves impaired microvascular control and reduced vasodilator responsiveness (2,10,16,18). For example, forearm vasodilator responses to brachial arterial infusion of endotheliumdependent or -independent vasodilators are diminished in patients with T2DM (18).It is unclear the extent to which vasodilator responsiveness in the cutaneous circulation is impaired in individuals with T2DM. Local application of ACh and nitroprusside in the skin caused less vasodilation [suggesting impaired nitric oxide (NO)-dependent vasodilation] in some groups of diabetic subjects (2), but not in others (16). In some studies, only individuals with T2DM involving significant peripheral neuropathy exhibited diminished cutaneous vasodilation (1, 16), whereas, in others (2, 17), T2DM subjects without signs of neuropathy showed decreased vasodilation in the skin. The diversity in results could reflect the variability inherent in the disease itself, inclu...

. Interactions of plasma osmolality with arterial and central venous pressures in control of sympathetic activity and heart rate in humans. Am J Physiol Heart Circ Physiol 289: H2456 -H2460, 2005. First published September 30, 2005 doi:10.1152/ajpheart.00601.2005.-Plasma osmolality alters control of sympathetic activity and heart rate in animal models; however, it is unknown whether physiological increases in plasma osmolality have such influences in humans and what effect concurrent changes in central venous and/or arterial pressures may have. We tested whether physiological increases in plasma osmolality (similar to those during exercise dehydration) alter control of muscle sympathetic nerve activity (MSNA) and heart rate (HR) in humans. We studied 17 healthy young adults (7 women, 10 men) at baseline and during arterial pressure (AP) transients induced by sequential injections of nitroprusside and phenylephrine, under three conditions: control (C), after 1 ml/kg intravenous hypertonic saline (HT1), and after 2 ml/kg hypertonic saline (HT2). We continuously measured HR, AP, central venous pressure (CVP; peripherally inserted central catheter) and MSNA (peroneal microneurography) in all conditions. Plasma osmolality increased from 287 Ϯ 1 mosmol/kg in C to 290 Ϯ 1 mosmol/kg in HT1 (P Ͻ 0.05) but did not increase further in HT2 (291 Ϯ 1 mosmol/kg; P Ͼ 0.05 vs. C). Mean AP and CVP were similar between C and HT1, but both increased slightly in HT2. HR increased slightly but significantly during both HT1 and HT2 vs. C (P Ͻ 0.05). Sensitivity of baroreflex control of MSNA was significantly increased vs. C in HT1 [Ϫ7.59 Ϯ 0.97 (HT1) vs. Ϫ5.85 Ϯ 0.63 (C) arbitrary units (au) ⅐ beat Ϫ1 ⅐ mmHg Ϫ1 ; P Ͻ 0.01] but was not different in HT2 (Ϫ6.55 Ϯ 0.94 au ⅐ beat Ϫ1 ⅐ mmHg Ϫ1 ). We conclude that physiological changes in plasma osmolality significantly alter control of MSNA and HR in humans, and that this influence can be modified by CVP and AP. baroreflex; sympathetic nervous system; hydration; plasma volume CHANGES IN HYDRATION ELICIT important alterations in neural mechanisms controlling arterial pressure (AP) via the baroreflex (5, 6, 17). Influences of increased plasma osmolality, which can accompany decreases in volume seen with certain types of dehydration (such as with prolonged exercise), may also interact with changes in volume to alter autonomic mechanisms that have important implications for control of blood pressure in these conditions.Because increased plasma osmolality often accompanies dehydration, physiological responses to hyperosmolality are generally those that would tend to defend plasma volume and AP. In animal models, these have been shown to include sympathoexcitation (2, 7) and decreased urine output (20). Furthermore, hyperosmolality has been shown to alter arterial baroreflex control of both heart rate (HR) and sympathetic activity in rats (1, 7). Such influences of osmolality on baroreflex control mechanisms may also involve osmolality-induced increases in circulating volume-regulatory hormones ...

Delayed threshold for active cutaneous vasodilation in patients with Type 2 diabetes mellitus. J Appl Physiol 100: 637-641, 2006. First published October 6, 2005 doi:10.1152/japplphysiol.00943.2005.-Epidemiological evidence suggests decreased heat tolerance in patients with Type 2 diabetes mellitus (T2DM), but it is not known whether the mechanisms involved in thermoregulatory control of skin blood flow are altered in these patients. We tested the hypothesis that individuals with T2DM have a delayed internal temperature threshold for active cutaneous vasodilation during whole body heating compared with healthy control subjects. We measured skin blood flow using laser-Doppler flowmetry (LDF), internal temperature (T or) via sublingual thermocouple, and mean arterial pressure via Finometer at baseline and during whole body heating in 9 T2DM patients and 10 control subjects of similar age, height, and weight. At one LDF site, sympathetic noradrenergic neurotransmission was blocked by local pretreatment with bretylium tosylate (BT) to isolate the cutaneous active vasodilator system. Whole body heating was conducted using a water-perfused suit. There were no differences in preheating T or between groups (P Ͼ 0.10). Patients with T2DM exhibited an increased internal temperature threshold for the onset of vasodilation at both untreated and BT-treated sites. At BT-treated sites, T or thresholds were 36.28 Ϯ 0.07°C in controls and 36.55 Ϯ 0.05°C in T2DM patients (P Ͻ 0.05), indicating delayed onset of active vasodilation in patients. Sensitivity of vasodilation was variable in both groups, with no consistent difference between groups (P Ͼ 0.05). We conclude that altered control of active cutaneous vasodilation may contribute to impaired thermoregulation in patients with T2DM. temperature regulation; sweating; metabolic disorders IN RECENT YEARS, THE INCIDENCE of Type 2 diabetes mellitus (T2DM) has reached epidemic proportions in the United States and other developed countries (24), leading to increasing interest in mechanisms of metabolic, cardiovascular, and neurological dysfunction in this disease. Importantly, dysfunction in some or all of these areas can lead to significant impairment in mechanisms of thermoregulation, which itself can cause increased morbidity and mortality in patients with T2DM. Epidemiological data indicate that individuals with diabetes are at significantly higher risk for heat illness during heat waves compared with the general population (19,20). Although physiological/pathophysiological mechanisms are not well understood, some existing data are consistent with the potential for impaired thermoregulation. For example, diabetic patients with length-dependent peripheral neuropathy exhibit impaired sweating in affected areas (7,14). Furthermore, individuals with diabetes have been shown to have decreased vasodilator responsiveness to pharmacological stimuli in vascular beds, including the skin (3,11,21,22). Such peripheral impairments could lead to a decrease in the ability of the cutaneous vascu...

Key pointsr Theoretical models suggest there is no benefit of high affinity haemoglobin to preserve maximal oxygen uptake in acute hypoxia but the comparative biology literature has many examples of species that are evolutionarily adapted to hypoxia and have high affinity haemoglobin.r We studied humans with high affinity haemoglobin and compensatory polycythaemia. These subjects performed maximal exercise tests in normoxia and hypoxia to determine how their altered haemoglobin affinity impacts hypoxic exercise tolerance.r The high affinity haemoglobin participants demonstrated an attenuated decline in maximal aerobic capacity in acute hypoxia.r Those with high affinity haemoglobin had no worsening of pulmonary gas exchange during hypoxic exercise but had greater lactate and lower pH than controls for all exercise bouts.r High affinity haemoglobin and compensatory polycythaemia mitigated the decline in exercise performance in acute hypoxia through a higher arterial oxygen content and an unchanged pulmonary gas exchange.Abstract The longstanding dogma is that humans exhibit an acute reduction in haemoglobin (Hb) binding affinity for oxygen that facilitates adaptation to moderate hypoxia. However, many animals have adapted to high altitude through enhanced Hb binding affinity for oxygen. The objective of the study was to determine whether high affinity haemoglobin (HAH) affects maximal and submaximal exercise capacity. To accomplish this, we recruited individuals (n = 11, n = 8 females) with HAH (P 50 = 16 ± 1 mmHg), had them perform normoxic and acute hypoxic (15% inspired oxygen) maximal exercise tests, and then compared their results to matched controls (P 50 = 26 ± 1, n = 14, n = 8 females). Cardiorespiratory and arterial blood gases were collected Paolo Dominelli is an Assistant Professor at the University of Waterloo. He completed his post-doctoral fellowship at the Mayo Clinic with Dr Michael Joyner. His research seeks to understand the integrative mechanisms underpinning the oxygen cascade under physiologically relevant conditions of exercise and hypoxia. He accomplishes this by studying the conductance of oxygen across multiple physiological systems (pulmonary, cardiac and muscle) and their interaction. P. B. Dominelli and others J Physiol 598.8throughout both exercise tests. Despite no difference in end-exercise arterial oxygen tension in hypoxia (59 ± 6 vs. 59 ± 9 mmHg for controls and HAH, respectively), the HAH subjects' oxyhaemoglobin saturation (S a,O 2 ) was ß7% higher. Those with HAH had an attenuated decline in maximal oxygen uptake (V O 2 max ) (4 ± 5% vs. 12 ± %, p < 0.001) in hypoxia and the change inV O 2 max between trials was related to the change in S aO 2 (r = −0.75, p < 0.0001). Compared to normoxia, the controls' alveolar-to-arterial oxygen gradient significantly increased during hypoxic exercise, whereas pulmonary gas exchange in HAH subjects was unchanged between the two exercise trials. However, arterial lactate was significantly higher and arterial pH significantly lower in the HAH s...

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.