Impact of Mood on Endothelial Function and Arterial Stiffness in Bipolar Disorder.

BACKGROUND: Previous research in bipolar disorder demonstrates greater than expected vascular dysfunction later in the course of illness, proportionate to the cumulative burden of mood symptoms. However, little is known about the effect of acute mood states on vascular function. Here we examine the relation between vascular function and mood state in individuals with bipolar disorder. METHOD: This prospective study followed 40 individuals with bipolar disorder for up to 6 months. Participants were assessed for mood state and vascular function at baseline, 2 weeks, and 6 months. Mood state was determined using clinician-administered Montgomery-Åsberg Depression Rating Scale and Young Mania Rating Scale. Vascular function was assessed by flow-mediated dilation (FMD) of the brachial artery, forearm vascular resistance (FVR), and arterial stiffness. RESULTS: Participants had a mean age of 30.1 years and 75% were male. Primary outcome measures FMD and nitroglycerine-mediated dilation were not found to have statistically significant associations with depressive or manic symptoms. In unadjusted models, higher manic symptoms were significantly associated with increased FVR nitroprusside-mediated dilation and diastolic blood pressure. In adjusted models, higher depressive symptoms were significantly associated with increases in augmentation index adjusted for heart rate of 75 bpm, and higher manic symptoms remained associated with increases in diastolic blood pressure. CONCLUSION: FMD may have limited sensitivity as a biomarker for measuring short-term effects of mood state. Longer-term prospective studies are needed to clarify the temporal relation between chronic mood symptoms and vascular function in bipolar disorder.

Sildenafil increases sympathetically mediated vascular tone in humans.

BACKGROUND: Sildenafil, a selective phosphodiesterase-type-5 (PDE-5) inhibitor, produces vasodilation that improves erectile dysfunction and pulmonary hypertension. Sildenafil could also cause baroreflex sympathetic activation that would enhance vascular tone and oppose direct vasodilation. We tested the hypothesis that sildenafil administration increases sympathetically mediated vascular tone in healthy middle-aged men. METHODS: We randomized 9 healthy, middle-aged, male volunteers (mean age 45±2 years) in a double-blind, crossover fashion to receive a single oral dose of sildenafil 100mg or placebo on 2 separate study days. Hemodynamics and forearm blood flow responses were measured at baseline, at 30 and 45 minutes after study drug administration, and then during intra-arterial infusions of vasoactive drugs. After sildenafil and placebo administration, intrabrachial medications were infused to test forearm alpha receptor sensitivity (norepinephrine), cyclic-AMP-mediated vasodilation (isoproterenol), and sympathetically mediated vascular tone (phentolamine) (adenosine was a control vasodilator). Blood samples were taken before and 60 minutes after study drug administration and at the end of the intrabrachial infusions for measurement of plasma norepinephrine concentrations. RESULTS: Forearm vascular responses to norepinephrine, isoproterenol, and adenosine were not different after placebo and sildenafil administration. Percentage reduction in forearm vascular resistance during phentolamine was significantly lower after sildenafil than placebo (-73% ± 3% vs -63% ± 3%; P = 0.0002). Sildenafil significantly increased plasma norepinephrine compared with placebo 60 minutes after study drug administration and at the end of the study session (P = 0.02). CONCLUSIONS: Sildenafil increased sympathetically mediated vascular tone in middle-aged healthy men. Alpha-adrenergic-mediated vasoconstriction may offset vasodilation during PDE-5 inhibition and may explain the significant hypotension observed in patients taking alpha-blockers with sildenafil.

Membranous nephropathy with renal salt wasting: role of neurohumoral factors in sodium retention.

The role of neurohumoral factors in the sodium retention of nephrotic syndrome is controversial. We report a case with abrupt onset of severe nephrotic-range proteinuria and hypoalbuminemia due to membranous glomerulonephritis that was associated with renal salt wasting and hypovolemia without edema. Further evaluation showed hypoaldosteronism, hyporeninemia, and primary autonomic failure principally affecting the sympathetic nervous system, determined by the Valsalva maneuver. Administration of exogenous mineralocorticoid and oral salt caused edema and accelerated hypertension. The severe hypoaldosteronism likely was due to use of the angiotensin-converting enzyme inhibitor lisinopril, and it improved after this drug treatment was discontinued. The nephrotic proteinuria resolved after treatment with cyclosporine and prednisone, but the primary autonomic failure with hyporeninemic hypoaldosteronism persisted. The case shows that intratubular factors activated by nephrotic proteinuria are not sufficient to produce sodium retention in the absence of aldosterone and an intact sympathetic nervous system.

A CTSA-sponsored program for clinical research coordination: networking, education, and mentoring.

Upon receipt of the National Institutes of Health Clinical and Translational Science Award, the University of Iowa's Institute for Clinical and Translational Science committed to develop an infrastructure for research professionals. Three goals were established: (1) identification of research professionals within the University of Iowa, (2) development of an educational series, including orientation and continuing education, and (3) development of a mentoring system. The purpose of this paper is to describe the process of development, initiation, and outcomes of a successful networking, educational, and mentoring system crafted for research professionals at the University of Iowa.

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 alpha-adrenergic vascular tone in the forearm by brachial arterial infusion of the alpha-adrenoreceptor antagonist phentolamine (120 microg/min) in normotensive obese (daytime ambulatory arterial pressure: 123+/-1/77+/-1 mm Hg; body mass index: 35+/-1 kg/m(2)) and lean (daytime ambulatory arterial pressure: 123+/-2/77+/-2 mm Hg; body mass index: 22+/-1 kg/m(2)) 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 alpha-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.

Obesity impairs vascular relaxation in human subjects: hyperglycemia exaggerates adrenergic vasoconstriction arterial dysfunction in obesity and diabetes.

OBJECTIVES: Arterial dysfunction occurs in obesity and diabetes. However, there is uncertainty about the relative contribution of endothelial dysfunction, smooth muscle dysfunction, or adrenergic hyperresponsiveness. METHODS AND RESULTS: We examined forearm resistance vessel responses to intra-arterial vasoactive agents in matched subjects on no antihyperglycemic medications classified as (1) Type 2 diabetes, (2) impaired fasting glucose (IFG), (3) obese, and (4) nonobese. Responses to both acetylcholine and nitroprusside were impaired in obese, IFG, and diabetic subjects compared to nonobese. However, diabetic and IFG subjects had no further impairment than normoglycemic obese subjects. Gender-specific data revealed that obese, IFG, and diabetic males compared to nonobese males demonstrated impaired responses to nitroprusside. However, among females, obese, IFG, and diabetic subjects demonstrated impaired acetylcholine-mediated responses. Multivariate analyses revealed that gender and adiposity, but not glycemia, were strongly related to acetylcholine and nitroprusside responses. Vasoconstriction to norepinephrine was greater in subjects with diabetes and IFG compared to nondiabetic obese controls. CONCLUSIONS: Microvascular vasodilator function is impaired in obesity, with little further impairment in IFG and Type 2 diabetes. Females appear more sensitive to the deleterious effect of obesity on endothelium-mediated resistance vessel function, and males to smooth muscle-mediated function. There is a specific increase in adrenergic vasoconstrictor responses in IFG and Type 2 diabetes independent of obesity.

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.

Obesity and insulin resistance but not hyperandrogenism mediates vascular dysfunction in women with polycystic ovary syndrome.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is associated with biochemical evidence of early atherosclerosis; however, data regarding vascular function are controversial. We hypothesized that resistance vessel function (mediated by the endothelium or smooth muscle) would be impaired in women with PCOS and aimed to determine the contribution of hyperandrogenism, obesity, or insulin resistance to vascular dysfunction. DESIGN: Prospective study. SETTING: University practice. PATIENT(S): Women with PCOS (n = 24) and age/weight-matched controls (n = 22). INTERVENTION(S): Vascular function was assessed by measuring forearm vasodilatation in response to both endothelium-dependent (acetylcholine/bradykinin) and endothelium-independent dilators (nitroprusside/verapamil). MAIN OUTCOME MEASURE(S): Resistance vessel function. RESULT(S): Forearm vasodilatation to all four drugs was reduced (>50%) in obese PCOS compared to lean PCOS subjects. There was no significant difference in vascular function between obese or lean women with PCOS compared to corresponding controls. Androgen levels did not correlate with vascular function. Stepwise regression analysis showed that body mass index (BMI) contributed maximally to vascular dysfunction (R(2) = 0.47). CONCLUSION(S): This comprehensive study demonstrates for the first time that obese women with PCOS have markedly reduced vascular smooth muscle function compared to lean subjects with PCOS. In our study obesity and insulin resistance, but not hyperandrogenism, appeared to be significant modulators of vascular function.

Effects of aging and atherosclerosis on endothelial and vascular smooth muscle function in humans.

BACKGROUND: Nitric oxide is an endothelium dependent dilator, which may protect against atherosclerosis. Several studies have shown a decrease in nitric oxide activity with aging, however none have assessed aging and atherosclerosis separately. We tested the hypothesis that aging blunts both basal and receptor-mediated endothelial nitric oxide release in humans. METHODS: We examined whether forearm blood flow responses to intra-arterial acetylcholine, and nitroprusside, were altered with aging, with and without co-infusion of an inhibitor of nitric oxide synthase (N(G)-mono-methyl-L-arginine) in three groups of human subjects; a group with clinical atherosclerotic vascular disease (n = 31, 21 M), otherwise healthy elderly (n = 17, 13 M), and healthy young controls (n = 15, 8 M). RESULTS: There was no difference in basal flows between the three groups. There was also no difference in the dilatation to either acetylcholine or nitroprusside responses between the AVD and the healthy elderly group; however, aging significantly decreased acetylcholine or nitroprusside responses when compared to the young controls (p < 0.02). Furthermore, the ratio between acetylcholine and nitroprusside, a marker of endothelial NO synthase activity, was significantly greater in the young volunteers (0.816 +/- 0.094% vs. 0.892 +/- 0.146 % vs. 1.389 +/- 0.2%, in atherosclerotic vascular disease, healthy elderly group, and young controls respectively). CONCLUSIONS: Forearm blood flow responses to endothelium dependent and independent stimuli are blunted with aging, independent of the presence of atherosclerotic disease. Moreover, the normal aging process may induce significant global vascular dysfunction (involving the endothelium and the vascular smooth muscle); to as great a degree as clinically manifest atherosclerosis.

Effect of hyperhomocysteinemia induced by methionine administration on flow-mediated dilatation of the brachial artery in healthy subjects.

Homocysteine may contribute to systolic hypertension and cardiac events by decreasing conduit artery compliance and inducing endothelial dysfunction. The effects of the experimental induction of hyperhomocysteinemia on systemic arterial compliance and pulsewave velocity are unclear, with contradictory results from previous studies. The investigators tested whether oral methionine impairs brachial artery compliance in addition to endothelial function.

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: rho=0.78, P=0.001; nitroprusside: rho=0.56, P=0.038) and the third showing a strong trend toward significance (acetylcholine: rho=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.

Role of xanthine oxidase in conduit artery endothelial dysfunction in cigarette smokers.

Xanthine oxidase contributes to oxidant stress and has been proposed as a risk factor for endothelial dysfunction. We studied the role of xanthine oxidase in conduit artery endothelial dysfunction in 12 smokers and 12 controls. Conduit artery vasodilation was impaired in smokers (4.3%) compared with controls (7.9%) (p = 0.006) and improved with xanthine oxidase inhibition in smokers (9.2%, p <0.001).

Leptin and body fat in type 2 diabetes and monodrug therapy.

To better understand the relations among leptin, insulin, and body fat during the metabolic progression to diabetes and during drug monotherapy, metabolic parameters were examined in subjects classified as 1) type 2 diabetes; 2) impaired fasting glucose or mild diabetes mellitus; 3) nondiabetic, matched for body mass index (BMI); and 4) nonobese, nondiabetic. Diabetic subjects were also studied during no pharmacological treatment, after 3 months of randomization to metformin or glyburide, and after 3 months of cross-over to the opposite drug. Log leptin correlated more with percent body fat (slope, 0.042; confidence interval, 0.036-0.047; r(2) = 0.826; P < 0.0001) than with total fat mass, percent truncal or nontruncal fat, or BMI. When normalized to percent fat, leptin did not differ by gender. Leptin normalized to percent fat was 35% less in untreated diabetes than that in BMI-matched controls (P < 0.001). Leptin normalized to percent fat was increased by 25% (P < 0.01) as a result of glyburide therapy compared with pretreatment values, but was unchanged by therapy with metformin. Across a spectrum of subjects with diabetes, impaired fasting glucose/mild diabetes, or BMI-matched nondiabetic controls, normalized leptin significantly correlated with glucose-induced insulin release, but not with insulin sensitivity. Our data suggest that plasma leptin is reduced in untreated type 2 diabetes probably as a consequence of reduced insulin secretion and that circulating leptin concentrations are differentially affected by monodrug therapy.

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.

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.

Systemic and local adrenergic regulation of muscle glucose utilization during hypoglycemia in healthy subjects.

Adrenergic responses are crucial for hypoglycemic recovery. Epinephrine increases glucose production, lipolysis, and peripheral insulin resistance as well as blood flow and glucose delivery. Sympathetic activation causes vasoconstriction and reduces glucose delivery. To determine the effects of alpha- and beta-adrenergic activity on muscle glucose uptake during hypoglycemia, we studied forearm blood flow (FBF) (plethysmography), arteriovenous glucose difference (AV-diff), and forearm glucose uptake (FGU) during insulin infusion with 60 min of euglycemia followed by 60 min of hypoglycemia. Twelve healthy subjects (27 plus minus 5 years of age) were randomized to intravenous propranolol (IV PROP, 80 microg/min), intravenous phentolamine (IV PHEN, 500 microg/min), intra-arterial propranolol (IA PROP, 25 microg/min), intra-arterial phentolamine (IA PHEN, 12 microg/min per 100 ml forearm tissue), and saline (SAL). FBF increased during hypoglycemia with SAL (P < 0.001) but not with IA or IV PROP. FGU (P = 0.015) and AV-diff (P = 0.099) fell during hypoglycemia with IA PROP but not with IV PROP. FBF increased during hypoglycemia with IA and IV PHEN (P < 0.005). AV-diff fell during hypoglycemia with IA and IV PHEN (P < 0.01), but FGU was unchanged. Blood pressure fell (P < 0.001), and adrenergic and neuroglycopenic symptoms increased with IV PHEN (P < 0.01). Thus, systemic but not local propranolol prevents a decrease in forearm glucose extraction during hypoglycemia, suggesting that epinephrine increases peripheral muscular insulin resistance through systemic effects. alpha-Adrenergic activation inhibits vasodilation and helps maintain brain glucose delivery.