Christine A. Sinkey

Xanthine Oxidase Inhibition Reverses Endothelial Dysfunction in Heavy Smokers

Background—Cigarette smoking causes endothelial dysfunction, possibly through increased oxidant stress. The enzyme xanthine oxidase produces oxidative free radicals. We tested the hypothesis that xanthine oxidase contributes to endothelial dysfunction in cigarette smokers by administering the inhibitor allopurinol. Methods and Results—Fourteen cigarette smokers (31±4 pack years) and 14 age- and sex-matched healthy non-smoking control subjects participated in a single-blinded, randomized, 2-phase crossover study. All subjects had no other risk factors for atherosclerosis. Inhibition of xanthine oxidase was achieved by a single oral dose of 600 mg of allopurinol on the day of the study. Stimulated nitric oxide endothelial responses were assessed by forearm blood flow responses to intraarterial administration of acetylcholine and bradykinin 4 to 7 hours later; basal nitric oxide was assessed using the nitric oxide synthase inhibitor NG-monomethyl-l-arginine (L-NMMA); and nitroprusside was used to assess sensitivity to nitric oxide. Dilatation produced by acetylcholine was significantly less in smokers (254±57%) than healthy controls (390±55%) (P =0.009). Allopurinol reversed endothelial dysfunction in smokers (acetylcholine, 463±78%, P =0.001) without affecting responses in non-smokers (401±80%). Bradykinin responses were also impaired in smokers (P =0.003), and improved with allopurinol, though not significantly (P =0.06). Responses to nitroprusside and L-NMMA were not significantly different between smokers and controls and were not altered by allopurinol. Conclusions—Smoking-induced endothelial dysfunction of resistance vessels is rapidly reversed with oral allopurinol. These data suggest that xanthine oxidase contributes importantly to endothelial dysfunction caused by cigarette smoking.

Dissociation of sympathoexcitatory and vasodilator actions of modestly elevated plasma insulin levels

Objective: To determine sympathetic and vascular responses to modest increases in plasma insulin level. Background: Most studies of sympathetic and vascular actions of insulin have evaluated high plasma insulin levels (>50µU/ml). Those levels increase sympathetic nerve activity but also cause vasodilation. Hypertension and obesity are associated with only modestly elevated fasting insulin levels. Methods: We investigated the effects of a 90min low-dose hyperinsulinemic euglycemic clamp on muscle sympathetic nerve activity (microneurography), forearm vascular resistance (plethysmography), heart rate, blood pressure and central venous pressure. Insulin and vehicle sessions were performed in 12 normal subjects. Results: Plasma insulin levels were elevated from values of 10±2 in the fasting state to 25±3µU/ml during insulin infusion. Insulin levels did not change during vehicle administration. Muscle sympathetic nerve activity increased from 16±2 to 25±3 bursts/min during the insulin session and did not change during vehicle administration. In contrast to muscle sympathetic nerve activity, forearm vascular resistance did not change during insulin administration (from 50±3 to 51±4U). Forearm vascular resistance tended to fall during vehicle administration (from 45±2 to 37 ±3 U). There were no changes in heart rate, blood pressure and central venous pressure that could be attributed to insulin. Conclusion: Modest elevations of plasma insulin levels produce sympathetic activation similar to that caused by high levels, but, in contrast to high levels, modest elevations in plasma insulin level do not decrease forearm vascular resistance. The present findings suggest a dissociation between sympathoexcitatory and vascular actions of insulin at low plasma levels.

Dietary salt produces abnormal renal vasoconstrictor responses to upright posture in borderline hypertensive subjects.

We studied the effect of high and low NaCl diets in normotensive and borderline hypertensive subjects to determine if a high NaCl diet produces abnormal renal vasoconstriction during the stress of upright posture in borderline hypertensive subjects. We studied 13 normotensive young men with diastolic blood pressures below 85 mm Hg and nine borderline hypertensive young men defined by diastolic blood pressures intermittently above 90 mm Hg. The subjects achieved comparable sodium balance during 6 days of low NaCl (10 mEq Na, 40 mEq Cl, 100 mEq K) and high NaCl (400 mEq Na, 400 mEq Cl, 100 mEq K) diets. In the normotensive subjects, standing for 30 minutes resulted in a tendency for diastolic blood pressure to fall during both diets. In contrast, during standing borderline hypertensive subjects showed no change in diastolic blood pressure during the low salt diet and a tendency for diastolic blood pressure to increase after the high salt diet. Standing reduced renal plasma flow in both groups during both diets. However, only during the high NaCl diet did the absolute decrease and percent decrease in renal plasma flow during standing differ significantly (p less than 0.05 and p less than 0.01, respectively) between the borderline hypertensive (-151 +/- 24 ml/min/1.73m2; -29 +/- 4%) and normotensive subjects (-79 +/- 17 ml/min/1.73m2; -15 +/- 3%). The resultant increase in the renal vascular resistance index with standing did not differ between the two groups during the low NaCl diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired skeletal muscle and skin microcirculatory function in human obesity.

Background Obesity is associated with exaggerated blood pressure and systemic vascular resistance responses to mental stress. Objective To test the hypothesis that skin and muscle microvascular dilatation in response to mental stress is blunted in obesity. Design and methods Blood pressure, heart rate and forearm and skin blood flow responses to mental stress were compared in 23 obese and 23 age- and sex-matched lean normotensive individuals. Results Blood pressure was almost identical in both obese (mean 94 ± 1 mmHg) and lean (93 ± 2 mmHg) individuals. The increase in blood pressure during mental stress was similar in obese and lean individuals (2.0 ± 0.9% compared with 3.1 ± 4.0%;P = 0.8). Forearm vascular resistance decreased during mental stress in both groups, but this decrease was significantly blunted in obese individuals compared with controls (decreases of 14 ± 4% and 26 ± 3%;P < 0.01). Skin microcirculatory dilatation was also significantly blunted in obese individuals compared with controls (decreases of 5 ± 2 and 17 ± 4%;P = 0.02). Conclusions Normotensive obese individuals exhibit markedly impaired muscle and skin microcirculatory responses to mental stress. The increased propensity of obese individuals to develop hypertension under conditions of chronic psychosocial stress may underlie obesity-related hypertension and cardiovascular disease.

Blood Vessel Function and Cognition in Elderly Patients With Atherosclerosis

Background and Purpose— Although a strong relationship has been established between vascular disease and cognitive decline, the current challenge is to identify vascular risk factors and mechanisms that are associated with cognitive function before the development of severe dysfunction (eg, vascular dementia). This study was conducted to determine the relationship between blood vessel function and cognition in elderly patients with atherosclerosis. Methods— Participants were 14 elderly individuals with atherosclerotic vascular disease, who had no history of stroke, cardiac surgery, or dementia diagnosis. Forearm blood flow was measured before and after brachial artery infusion of 3 vasoactive agents (verapamil, acetylcholine, nitroprusside), and these measures of vessel function were then correlated with neuropsychological performance (total scale score on the Repeatable Battery for the Assessment of Neuropsychological Status). Results— Positive correlations were found between neuropsychological performance and vasodilation in response to all 3 agents, with 2 reaching statistical significance (verapamil: &rgr;=0.78, P=0.001; nitroprusside: &rgr;=0.56, P=0.038) and the third showing a strong trend toward significance (acetylcholine: &rgr;=0.49, P=0.076). Correlations between neuropsychological performance and more conventional vascular-related variables were much weaker. Conclusions— These data provide preliminary evidence of a relationship between resistance vessel function and neuropsychological performance. With further research, measures of vessel dysfunction may be useful in identifying individuals at risk for cognitive decline and vascular dementia.

What Is the Most Appropriate Methodology for Detection of Conduit Artery Endothelial Dysfunction

Background—Use of upper-arm arterial occlusion to induce reactive hyperemia, and endothelium-dependent flow-mediated dilation (FMD) of the brachial artery, induces greater conduit vessel dilatation than lower-arm occlusion. However, brachial artery ischemia after upper arm arterial occlusion may make this approach unreliable. We studied whether upper or lower arm occlusions differ in their ability to detect endothelial dysfunction in cigarette smokers, and its improvement with an antioxidant strategy. Methods and Results—Ten cigarette smokers with a >20 pack year history and 10 age- and gender-matched healthy controls participated in a 2-phase randomized controlled study of xanthine oxidase inhibition, using a 600-mg oral dose of allopurinol administered beforehand. Endothelium-dependent dilatation was assessed using ultrasound-Doppler after lower and upper arm occlusion. After lower arm occlusion, FMD was significantly impaired in smokers compared with controls (3.8±1.1% versus 8.7±2.2%; P=0.001). However, after upper arm occlusion, brachial artery dilatation in smokers was higher (11.8±2.7%; P<0.0001 versus lower arm) and did not differ from controls (9.4±2.9%; P=0.3). There was no difference in endothelium-independent dilatation to sublingual nitroglycerin between smokers and controls. Inhibition of xanthine oxidase with allopurinol improved lower arm FMD (3.8±1.1 to 10.1±1.9%; P<0.0001), but did not improve upper arm FMD (11.8±2.7 to 14.1±3.7%; P=0.4). Conclusions—Although upper arm occlusion induces robust brachial vasodilatation, it cannot detect endothelial dysfunction induced by smoking or its improvement by inhibition of xanthine oxidase. The increase in brachial artery diameter with upper arm occlusion may be confounded by ischemia of the artery. Conduit artery FMD after release of lower arm occlusion appears to be a more valid method for assessment of endothelial function in humans.

Dissociation between sympathetic nerve traffic and sympathetically mediated vascular tone in normotensive human obesity.

Obesity increases the risk of hypertension and its cardiovascular complications. This has been partly attributed to increased sympathetic nerve activity, as assessed by microneurography and catecholamine assays. However, increased vasoconstriction in response to obesity-induced sympathoactivation has not been unequivocally demonstrated in obese subjects without hypertension. We evaluated sympathetic &agr;-adrenergic vascular tone in the forearm by brachial arterial infusion of the &agr;-adrenoreceptor antagonist phentolamine (120 &mgr;g/min) in normotensive obese (daytime ambulatory arterial pressure: 123±1/77±1 mm Hg; body mass index: 35±1 kg/m2) and lean (daytime ambulatory arterial pressure: 123±2/77±2 mm Hg; body mass index: 22±1 kg/m2) subjects (n=25 per group) matched by blood pressure, age, and gender. Microneurographic sympathetic nerve activity to skeletal muscle was significantly higher in obese subjects (30±3 versus 22±1 bursts per minute; P=0.02). Surprisingly, complete &agr;-adrenergic receptor blockade by phentolamine (at concentrations sufficient to completely inhibit norepinephrine and phenylephrine-induced vasoconstriction) caused equivalent vasodilatation in obese (−57±2%) and lean subjects (−57±3%; P=0.9). In conclusion, sympathetic vascular tone in the forearm circulation is not increased in obese normotensive subjects despite increased sympathetic outflow. Vasodilator factors or mechanisms occurring in obese normotensive subjects could oppose the vasoconstrictor actions of increased sympathoactivation. Our findings may help to explain why some obese subjects are protected from the development of hypertension.

Effect of dehydroepiandrosterone (DHEA) on vascular function in postmenopausal women with diabetes: a randomized controlled trial

Abstract nBackground: DHEA stimulates endothelial nitric oxide (NO) production in vitro and its prolonged use in humans improves vascular function. It is believed that this effect is mediated by metabolism of DHEA to

eta-Adrenergic inhibition of leptin production is attenuated in obese individuals

Background: Leptin regulates body weight and may affect cardiovascular function. Leptin expression from adipocytes is suppressed by beta-receptor stimulation. Obese subjects have high leptin levels and are at increased risk for cardiovascular disease, We tested the hypothesis that suppression of leptin production from adipocytes following betareceptor stimulation is attenuated in obese subjects. Methods: We studied 8 obese (age 35 ± 3 yrs, BMI 35 ± 2 kg/m2) and 8 age and gender matched lean controls (age 35 ± 3 yrs, BMI 24 ± 1 kg/m2). All subjects were norrnotensire, free of disease and were not taking any medications. In a randomized fashion, subjects received either a 4 hour infusion of normal saline or isoproterenol (to increase resting heart rate by 25%) on two separate days. Blood samples for plasma leptin were drawn at baseline and at 30 minute intervals during both infusions. Results: Leptin levels decreased by 7.8 ± 1.5% at the end of isoproterenol and increased by 3.1 ± 4,8% during normal saline in obese subjects (p < 0.05). in controls, leptin decreased by 16,8 ± 3.4% and 9.0 ± 4,8% with isoproterenol and normal saline, respectively (p < 0.05). During isoproterenol, the maximum percent decrease from baseline in leptin was 10.3 ± 3.3% in obese subjects and 19.2 ± 2.1% in lean controls (p < 0.02). The area under the curve (AUC) for percent change in leptin levels with isoproterenol was significantly less in obese subjects compared to lean controls (1799 ± 287 versus 2818 ± 203, p < 0.05), The infusion rate of isoproterenol in obese subjects was 0.47 ± 0,1 rncg/ rain and 0.36 ± 0.06 mcg/min in controls (p = 0.05). Conclusion: Isoproterenol significantly decreased plasma leptin levels in both obese and tean subjects compared to normal saline. Beta-adrenergic stimulation that induced comparable increases in heart rate in both Jean and obese subjects resulted in a lower level of leptin suppression in obese subjects. This blunted suppression of leptin production is even evident dudng higher doses of isoproterenol in obese subjects. Thus, there appears to be an attenuated beta-adrenergic suppression of leptin production in obese individuals.