The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching

Significance: a mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow - 'hypoxic vasodilation' - occur in an attempt to restore oxygen supply. Nitric oxide is a major signalling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent advances: this review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of nitric oxide, and mechanisms underlying the involvement of nitric oxide in hypoxic vasodilation. Recent insights into nitric oxide metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite reductases, and release of nitric oxide from storage pools. The processes through which nitric oxide levels are elevated during hypoxia are presented, namely (i) increased synthesis from nitric oxide synthases, increased reduction of nitrite to nitric oxide by heme- or pterin-based enzymes and increased release from nitric oxide stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical issues: several reviews covered modulation of energetic metabolism by nitric oxide, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression Future directions: we identify a key position for nitric oxide in the body's adaptation to an acute energy supply-demand mismatc

Additive effect of non-alcoholic fatty liver disease on metabolic syndrome-related endothelial dysfunction in hypertensive patients

Metabolic syndrome (MS) is characterized by an increased risk of incident diabetes and cardiovascular (CV) events, identifying insulin resistance (IR) and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD) is bidirectionally linked with MS as a consequence of metabolic and inflammatory abnormalities. We addressed the question if the evolution in NAFLD might worsen endothelium-dependent vasodilating response in MS hypertensives. We recruited 272 Caucasian newly-diagnosed never-treated hypertensive outpatients divided into three groups according to the presence/absence of MS alone or in combination with NAFLD. MS and NAFLD were defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and non-invasive fatty liver index, respectively. We determined IR by using the homeostasis model assessment (HOMA) index. Vascular function, as forearm blood flow (FBF), was determined through strain-gauge plethysmography after intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside. MS+NAFLD+ group showed worse metabolic, inflammatory and vascular profiles compared with MS-NAFLD- and MS+NAFLD-. HOMA resulted in being the strongest predictor of FBF both in the MS+NAFLD- and in the MS+NAFLD+ groups, accounting for 20.5% and 33.2% of its variation, respectively. In conclusion, we demonstrated that MS+NAFLD+ hypertensives show a worse endothelium-dependent vasodilation compared with MS+NAFLD-, allowing for consideration of NAFLD as an early marker of endothelial dysfunction in hypertensives

The Role of Sex Hormones in Inducing Maternal Uterine Remodeling and Vasodilation During Pregnancy

Uterine vascular adaptations such as vessel growth and vasodilation are needed to facilitate the more than 10-fold increase of uteroplacental blood flow (UPBF) during pregnancy. Adverse adaptations may result in pregnancy complications such as preeclampsia and intrauterine growth restriction. Pregnancy milieu, placentation and the attendant change in wall shear stress are major regulators of uterine vascular adaptation. In this study, we aimed at delineating : (1) the contribution of these regulators in vascular remodeling and (2) the effects of pregnancy milieu (estrogen and progesterone) alone and in combination with wall shear stress on the vascular reactivity. Using Sprague Dawley rats as the animal model, three surgical methods were utilized: (1) unilateral oviductal ligation (OHL) that restricts pregnancy to one uterine horn; (2) cervical-end main uterine artery and vein ligation (VL) that alters the hemodynamic pattern of the UPBF and wall shear stress; and (3) ovariectomy (OVX) with the implant of estrogen + progesterone pellet (0.5 and 100 mg, respectively). A segment of ovarian-end main uterine artery from each uterine horn was dissected, cannulated, and pressurized in an arteriograph system. Lumen diameters in response to phenylephrine (vasoconstrictor) and acetylcholine (vasodilator) were measured. Passive lumen diameters, wall thickness, vessel cross-sectional area, and distensibility were also measured under a microscope. Significant remodeling was seen in OVX rats in response to hormone replacement (p=0.0457); however, the extent of remodeling did not reach that seen in the nonpregnant horn of OHL rats. No significant change in wall thickness, cross-sectional area or wall: lumen ratio was found in OVX (+pellet), compared to OVX (-pellet) rats. Estrogen + progesterone had no significant effect on the sensitivity to phenylephrine or acetylcholine. In conclusion, estrogen + progesterone does have a significant effect on vascular remodeling. The presence of other factors, such as placentation, likely augment this process

Additive effect of non-alcoholic fatty liver disease on metabolic syndrome-related endothelial dysfunction in hypertensive patients

Metabolic syndrome (MS) is characterized by an increased risk of incident diabetes and cardiovascular (CV) events, identifying insulin resistance (IR) and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD) is bidirectionally linked with MS as a consequence of metabolic and inflammatory abnormalities. We addressed the question if the evolution in NAFLD might worsen endothelium-dependent vasodilating response in MS hypertensives. We recruited 272 Caucasian newly-diagnosed never-treated hypertensive outpatients divided into three groups according to the presence/absence of MS alone or in combination with NAFLD. MS and NAFLD were defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and non-invasive fatty liver index, respectively. We determined IR by using the homeostasis model assessment (HOMA) index. Vascular function, as forearm blood flow (FBF), was determined through strain-gauge plethysmography after intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside. MS+NAFLD+ group showed worse metabolic, inflammatory and vascular profiles compared with MS-NAFLD- and MS+NAFLD-. HOMA resulted in being the strongest predictor of FBF both in the MS+NAFLD- and in the MS+NAFLD+ groups, accounting for 20.5% and 33.2% of its variation, respectively. In conclusion, we demonstrated that MS+NAFLD+ hypertensives show a worse endothelium-dependent vasodilation compared with MS+NAFLD-, allowing for consideration of NAFLD as an early marker of endothelial dysfunction in hypertensives

Impaired endothelial function of the retinal vasculature in hypertensive patients

<p><b>Background and Purpose:</b> Arterial hypertension constitutes a central factor in the pathogenesis of stroke. We examined endothelial function of the retinal vasculature as a model of the cerebral circulation.</p> <p><b>Methods:</b> Thirty-eight young subjects (19 hypertensive and 19 normotensive) were treated with the AT1-receptor blocker candesartan cilexetil and placebo, each over 7 days. Retinal capillary flow and blood flow velocity in the central retinal artery were assessed with scanning laser Doppler flowmetry and pulsed Doppler ultrasound, respectively. NG-monomethyl-L-arginine (L-NMMA) was infused to inhibit nitric oxide (NO) synthesis. Diffuse luminance flicker was applied to stimulate NO release.</p> <p><b>Results:</b> In normotensive subjects, L-NMMA decreased retinal capillary flow by 8.2%±13% (P<0.05) and flickering light increased mean blood flow velocity in the central retinal artery by 19%±29% (P<0.01). In contrast, no significant change to these provocative tests was seen in hypertensive subjects. Treatment with candesartan cilexetil restored a normal pattern of reactivity in retinal capillaries (L-NMMA: decrease in perfusion by 10%±17%, P<0.05) and the central retinal artery (flicker: increase in mean blood flow velocity by 42%±31%, P<0.001) in hypertensive patients.</p> <p><b>Conclusions:</b> Endothelial function of the retinal vasculature is impaired in early essential hypertension but can be improved by AT1-receptor blockade.</p&gt

Effects of acute consumption of fruit and vegetable puree-based drinks on vasodilation and oxidative status

Epidemiological studies indicate that diets rich in fruits and vegetables (F&V) are protective against cardiovascular diseases (CVD). Pureed \&V products retain many beneficial components, including flavonoids, carotenoids, vitamin C and dietary fibres. This study aimed to establish the physiological effects of acute ingestion of F&V puree-based drink (FVPD) on vasodilation, antioxidant status, phytochemical bioavailability and other CVD risk factors. 24 Subjects, aged 30-70 years, completed the randomised, single-blind, controlled, crossover test meal study. Subjects consumed 400 ml FVPD, or fruit-flavoured sugar-matched control, after following a low-flavonoid diet for 5 days. Blood and urine samples were collected throughout the study day and vascular reactivity was assessed at 90-minute intervals using laser Doppler iontophoresis (LDI). FVPD significantly increased plasma vitamin C (P=0.002) and total nitrate/nitrite (P=0.001) concentrations. There was a near significant time by treatment effect on ex vivo LDL oxidation (P=0.068), with a longer lag phase after consuming FVPD. During the 6 hours after juice consumption the antioxidant capacity of plasma increased significantly (P=0.003) and there was a simultaneous increase in plasma and urinary phenolic metabolites (P=0.05). There were significantly lower glucose and insulin peaks after ingestion of FVPD compared with control (P=0.019 and P=0.003) and a trend towards increased endothelium-dependent vasodilation following FVPD consumption (P=0.061). Overall, FVPD consumption significantly increased plasma vitamin C and total nitrate/nitrite concentrations, with a trend towards increased endothelium-dependent vasodilation. Pureed F&V products are useful vehicles for increasing micronutrient status, plasma antioxidant capacity and in vivo NO generation, which may contribute to CVD risk reduction

Altering temperature in a mammalian body

The present application relates to systems and methods for altering temperature in a mammalian body. Optionally, the systems and methods can be used to lower or raise core body temperature of a mammalian subject. Optionally, the systems and methods can be used to lower or raise the temperature of glabrous skin of a mammalian subject.Board of Regents, University of Texas Syste

Aging and aerobic fitness affect the contribution of noradrenergic sympathetic nerves to the rapid cutaneous vasodilator response to local heating

Sedentary aging results in a diminished rapid cutaneous vasodilator response to local heating. We investigated whether this diminished response was due to altered contributions of noradrenergic sympathetic nerves; assessing 1) the age-related decline and, 2) the effect of aerobic fitness. We measured skin blood flow (SkBF)(laser-Doppler flowmetry) in young (24±1 yr) and older (64±1 yr) endurance-trained and sedentary men (n=7 per group) at baseline and during 35 min of local skin heating to 42 °C at three forearm sites: 1) untreated; 2) bretylium tosylate (BT), preventing neurotransmitter release from noradrenergic sympathetic nerves; and 3) yohimbine and propranolol (YP), antagonising α- and β-adrenergic receptors. SkBF was converted to cutaneous vascular conductance (CVC) (SkBF/mean arterial pressure) and normalized to maximal CVC (%CVCmax) achieved by skin heating to 44 °C. Pharmacological agents were administered using microdialysis. In the young trained, the rapid vasodilator response was reduced at the BT and YP sites (P0.05) but treatment with BT did (P>0.05). Neither BT nor YP treatments affected the rapid vasodilator response in the older sedentary group (P>0.05). These data suggest that the age-related reduction in the rapid vasodilator response is due to an impairment of sympathetic-dependent mechanisms, which can be partly attenuated with habitual aerobic exercise. Rapid vasodilation involves noradrenergic neurotransmitters in young trained men, and non-adrenergic sympathetic cotransmitters (e.g., neuropeptide Y) in young sedentary and older trained men, possibly as a compensatory mechanism. Finally, in older sedentary men, the rapid vasodilation appears not to involve the sympathetic system

Diabetes mellitus and ischemic heart disease. the role of ion channels

Diabetes mellitus is one the strongest risk factors for cardiovascular disease and, in particular, for ischemic heart disease (IHD). The pathophysiology of myocardial ischemia in diabetic patients is complex and not fully understood: some diabetic patients have mainly coronary stenosis obstructing blood flow to the myocardium; others present with coronary microvascular disease with an absence of plaques in the epicardial vessels. Ion channels acting in the cross-talk between the myocardial energy state and coronary blood flow may play a role in the pathophysiology of IHD in diabetic patients. In particular, some genetic variants for ATP-dependent potassium channels seem to be involved in the determinism of IH