Infusion Of SNP Research Articles

Sodium nitroprusside as an adjunctive treatment for schizophrenia reduces Ndel1 oligopeptidase activity.

To assess nuclear distribution element-like 1 (Ndel1) enzyme activity following acute administration of sodium nitroprusside (sNP) in a rodent model of schizophrenia (SCZ) and in a cohort of chronic SCZ patients. Ndel1 activity was measured following sNP infusions in spontaneously hypertensive rats (SHR) (2.5 or 5.0 mg/kg) and in a double-blind randomized trial with 15 SCZ patients (0.5 µg/kg/min). Patients were randomized into two groups (group I: n=7; group II: n=8), with one group receiving placebo and the other sNP in phase A. In phase B, the groups switched treatments. sNP was administered as an infusion of 0.5 µg/kg/min, for 4 h, while placebo was a 5% glucose solution infused under the same conditions. The infusions were administered once weekly over 4 weeks. Psychopathology was assessed using the 18-item figure 5 (BPRS-18 - Bech's version) and the negative subscale of the Positive and Negative Syndrome Scale. Ndel1 activity was significantly reduced after sNP infusion in SHR and in patients receiving sNP (t = 7.756, degrees of freedom [df] = 97, p < 0.0001, dcohen=1.44) compared to placebo. Reduced Ndel1 activity from baseline to the end of infusion was only seen in patients after treatment with sNP. SCZ patients may benefit from adjunctive therapy with sNP and that the Ndel1 enzyme is a candidate biomarker of psychopathology in the disorder. Future research should look into the role of Ndel1 in SCZ and the potential effects of sNP and drugs with similar profiles of action in both animals and patients.

Increased Muscle Sympathetic Nerve Activity with Acute Hyperinsulinemia: Role of Insulin‐stimulated Peripheral Vasodilation and the Response of the Arterial Baroreflex

ObjectiveHyperinsulinemia elicits an increase sympathetic nervous system activity directed toward skeletal muscle (muscle sympathetic nerve activity, MSNA). The insulin‐mediated increase in MSNA is primarily attributed to its effect within the central nervous system. In addition to direct central effects, insulin also elicits peripheral vasodilation, which may further increase MSNA via arterial baroreflex‐mediated mechanisms in order to maintain blood pressure (BP). Herein we examined the contribution of insulin‐induced peripheral vasodilation and role for the arterial baroreflex in the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with co‐infusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized the insulin‐mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP).MethodsIn 33 healthy adults (28M/5F, 28±1 yrs, BMI 25.0±0.5 kg/m2) MSNA (microneurography) and BP (Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) was calculated at rest and during intravenous insulin (n=20) or SNP (n=13) infusion. A subset of participants receiving insulin (n=7) were co‐infused with phenylephrine. Spontaneous arterial baroreflex sensitivity was determined over 5‐min at baseline and during pharmacological intervention(s).ResultsInsulin infusion increased MSNA (p=0.05) and decreased TPR (p&lt;0.05), with no effects on arterial baroreflex sensitivity or BP (p&gt;0.05). Co‐infusion with phenylephrine returned MSNA and TPR to baseline, with no effect on baroreflex sensitivity (p&gt;0.05). Similar to insulin, SNP increased MSNA (p&lt;0.01) and decreased TPR (p&lt;0.05), with no effect on baroreflex sensitivity (p&gt;0.05).ConclusionsPresent findings reveal that acute hyperinsulinemia increases MSNA without a change in arterial baroreflex sensitivity in healthy men and women. Insulin‐mediated increases in MSNA are lost with co‐infusion of phenylephrine and can be recapitulated with infusion of SNP. Results support a dynamic interplay between central and peripheral mechanisms during hyperinsulinemia to increase MSNA and maintain BP.

Role of the arterial baroreflex in the sympathetic response to hyperinsulinemia in adult humans.

Muscle sympathetic nerve activity (MSNA) increases during hyperinsulinemia, primarily attributed to central nervous system effects. Whether peripheral vasodilation induced by insulin further contributes to increased MSNA via arterial baroreflex-mediated mechanisms requires further investigation. Accordingly, we examined baroreflex modulation of the MSNA response to hyperinsulinemia. We hypothesized that rescuing peripheral resistance with coinfusion of the vasoconstrictor phenylephrine would attenuate the MSNA response to hyperinsulinemia. We further hypothesized that the insulin-mediated increase in MSNA would be recapitulated with another vasodilator (sodium nitroprusside, SNP). In 33 young healthy adults (28 M/5F), MSNA (microneurography) and arterial blood pressure (BP, Finometer/brachial catheter) were measured, and total peripheral resistance (TPR, ModelFlow) and baroreflex sensitivity were calculated at rest and during intravenous infusion of insulin (n = 20) or SNP (n = 13). A subset of participants receiving insulin (n = 7) was coinfused with phenylephrine. Insulin infusion decreased TPR (P = 0.01) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity or BP (P > 0.05). Coinfusion with phenylephrine returned TPR and MSNA to baseline, with no effect on arterial baroreflex sensitivity (P > 0.05). Similar to insulin, SNP decreased TPR (P < 0.02) and increased MSNA (P < 0.01), with no effect on arterial baroreflex sensitivity (P > 0.12). Acute hyperinsulinemia shifts the baroreflex stimulus-response curve to higher MSNA without changing sensitivity, likely due to insulin's peripheral vasodilatory effects. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.NEW & NOTEWORTHY We hypothesized that elevation in muscle sympathetic nervous system activity (MSNA) during hyperinsulinemia is mediated by its peripheral vasodilator effect on the arterial baroreflex. Using three separate protocols in humans, we observed increases in both MSNA and cardiac output during hyperinsulinemia, which we attributed to the baroreflex response to peripheral vasodilation induced by insulin. Results show that peripheral vasodilation induced by insulin contributes to increased MSNA during hyperinsulinemia.

An optimal interval type-2 fuzzy logic control based closed-loop drug administration to regulate the mean arterial blood pressure

Background and ObjectiveThe main aim of this work is to present an optimal and robust controller design in order to improve the drug infusion to the automatic control of mean arterial blood pressure in conditions like critically-ill or post-operative or anaesthesia administration. The physiological systems also have uncertainty issues such as parameter variations with time or external disturbances and noise. Therefore, a controlled drug administration is necessary to regulate the mean arterial blood pressure of a person during surgery/observation. Over the years, the proportional-integral-derivative (PID) controller is the most commonly used controller in industries due to its easy structure and simplicity. However, this controller does not meet the desired performance with the complex and uncertain plants. Therefore, a robust controller is required to regulate the physiological variables that are uncertain in nature and can affect the human life. MethodsIn this work, a hybrid control scheme consisting of an interval type-2-fuzzy logic controller which acts as pre-compensator to the traditional PID controller is presented, to regulate the mean arterial blood pressure of a patient by administering the drug sodium nitroprusside in a controlled manner. An effective and well-established nature-inspired optimization technique namely cuckoo search algorithm is employed for obtaining the optimal parameters for the presented scheme. ResultsSimulation results are presented to show the effectiveness and robustness of proposed interval type-2-fuzzy logic controller based PID controller scheme, for maintaining the mean arterial pressure to 100 mmHg within considerable limit through SNP infusion. The results are further compared with other two controllers namely type-1 fuzzy logic based PID and traditional PID controllers for the parameter variations and external noise. ConclusionIn this study, the proposed interval type-2-fuzzy logic controller pre-compensator based PID controller provides an effective control than traditional type-1 fuzzy logic based control scheme and PID controller in terms of overshoot, settling-time and error which are the prime performance objectives of the closed-loop controlled drug delivery of human blood pressure. The presented study provides a firm base for initial design considerations for development of a low-cost closed-loop drug delivery system for blood pressure regulation.

In vivo assessment of endothelial function in small animals using an infrared pulse detector.

Objective:Endothelial dysfunction is the earliest change in atherosclerosis. Flow-mediated dilatation (FMD) is used to assess endothelial function in humans. However, this assessment is not easy in small animals. This study demonstrated the reliability and reproducibility of a proposed instrument for in vivo assessment of FMD in a rodent model using infrared pulse sensors.Materials and Methods:We used 24 adult male Wistar Kyoto rats randomly divided into three groups. FMD was measured under continuous infusion of normal saline followed by intra-arterial infusion of acetylcholine (Ach; n = 8), sodium nitroprusside (SNP; n = 8), or Nω-nitro-L-arginine methyl ester (L-NAME; n = 8).Results:The dilatation indices (DIs) of all three groups were similar before application of the vasoactive agents (1.82 ± 0.46, 1.81 ± 0.44, and 1.93 ± 0.40, P = 0.877, by one-way analysis of variance). The DI was significantly increased during infusion of Ach (2.97 ± 1.03 vs. 1.82 ± 0.46, P = 0.015), unchanged during infusion of SNP (1.81 ± 0.44 vs. 1.98 ± 0.40, P = 0.574), and attenuated during infusion of L-NAME (1.91 ± 0.40 vs. 1.42 ± 0.35; P = 0.028).Conclusion:The results of this study correlated well with those of human studies, suggesting that this method can be used for in vivo evaluation of endothelial function in small animals.

Endothelium-dependent vasodilatory signalling modulates α1 -adrenergic vasoconstriction in contracting skeletal muscle of humans.

'Functional sympatholysis' describes the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction, and is critical to ensure proper blood flow and oxygen delivery to metabolically active skeletal muscle. The signalling mechanism responsible for sympatholysis in healthy humans is unknown. Evidence from animal models has identified endothelium-derived hyperpolarization (EDH) as a potential mechanism capable of attenuating sympathetic vasoconstriction. In this study, increasing endothelium-dependent signalling during exercise significantly enhanced the ability of contracting skeletal muscle to attenuate sympathetic vasoconstriction in humans. This is the first study in humans to identify endothelium-dependent regulation of sympathetic vasoconstriction in contracting skeletal muscle, and specifically supports a role for EDH-like vasodilatory signalling. Impaired functional sympatholysis is a common feature of cardiovascular ageing, hypertension and heart failure, and thus identifying fundamental mechanisms responsible for sympatholysis is clinically relevant. Stimulation of α-adrenoceptors elicits vasoconstriction in resting skeletal muscle that is blunted during exercise in an intensity-dependent manner. In humans, the underlying mechanisms remain unclear. We tested the hypothesis that stimulating endothelium-dependent vasodilatory signalling will enhance the ability of contracting skeletal muscle to blunt α1 -adrenergic vasoconstriction. Changes in forearm vascular conductance (FVC; Doppler ultrasound, brachial intra-arterial pressure via catheter) to local intra-arterial infusion of phenylephrine (PE; α1 -adrenoceptor agonist) were calculated during (1) infusion of the endothelium-dependent vasodilators acetylcholine (ACh) and adenosine triphosphate (ATP), the endothelium-independent vasodilator (sodium nitroprusside, SNP), or potassium chloride (KCl) at rest; (2) mild or moderate intensity handgrip exercise; and (3) combined mild exercise + ACh, ATP, SNP, or KCl infusions in healthy adults. Robust vasoconstriction to PE was observed during vasodilator infusion alone and mild exercise, and this was blunted during moderate intensity exercise (ΔFVC: -34±4 and -34±3 vs. -13±2%, respectively, P<0.05). Infusion of ACh or ATP during mild exercise significantly attenuated PE vasoconstriction similar to levels observed during moderate exercise (ACh: -3±4; ATP: -18±4%). In contrast, infusion of SNP or KCl during mild exercise did not attenuate PE-mediated vasoconstriction (-32±5 and -46±3%). To further study the role of endothelium-dependent hyperpolarization (EDH), ACh trials were repeated with combined nitric oxide synthase and cyclooxygenase inhibition. Here, PE-mediated vasoconstriction was blunted at rest (blockade: -20±5 vs. -31±3% vs.; P<0.05) and remained blunted during exercise (blockade: -15±5 vs. -14±5%). We conclude that stimulation of EDH-like vasodilatation can blunt α1 -adrenergic vasoconstriction in contracting skeletal muscle of humans.

The effect of sodium nitroprusside on psychotic symptoms and spatial working memory in patients with schizophrenia: a randomized, double-blind, placebo-controlled trial.

Sodium nitroprusside (SNP) has been reported to rapidly reduce psychotic symptoms in patients with schizophrenia. This has the potential to revolutionize treatment for schizophrenia. In this study, we tested the hypothesis that SNP leads to a reduction in psychotic symptoms and an improvement in spatial working memory (SWM) performance in patients with schizophrenia. This was a single-centre, randomized, double-blind, placebo-controlled trial performed from 27 August 2014 to 10 February 2016 (clinicaltrials.gov identifier: NCT02176044). Twenty patients with schizophrenia aged 18-60 years with a diagnosis of schizophrenia or schizoaffective disorder were recruited from psychiatric outpatient clinics in the South London and Maudsley NHS Trust, London, UK. Baseline symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) and the 18-item Brief Psychiatric Rating Scale (BPRS-18), and SWM was assessed using the CANTAB computerized test. Participants received either an infusion of SNP (0.5 μg/kg per min for 4 h) or placebo and were re-assessed for symptoms and SWM performance immediately after the infusion, and 4 weeks later. SNP did not lead to any reduction in psychotic symptoms or improvement in SWM performance compared to placebo. Although this study was negative, it is possible that the beneficial effects of SNP may occur in patients with a shorter history of illness, or with more acute exacerbation of symptoms.

Is The Cardiac Baroreflex Gain Altered in Spontaneously Hypertensive Rats?

There is evidence that a reduction in the baroreflex gain contributes to the high blood pressure in SHR. In the present study performed in conscious freely moving rats, we hypothesized that the baroreflex gain was not altered in SHR. To address this question we used two methods for evaluation of the cardiac baroreflex: a) the sequence analysis technique, and 2) the peak of changes in heart rate in response to increase (phenylephrine, PHE) and decrease (sodium nitroprusside, SNP) in mean arterial pressure (MAP) of Wistar (n=15) and SHR (n=21). The sequence analyses were used to evaluate the cardiac baroreflex function over the natural range of variation of arterial pressure, without any pharmacological tools. Considering that the sequence analyses are restricted to a narrow range of arterial pressure variability, we also evaluated the maximal bradycardic response (peak) to pressor response to PHE (i.v.) as well the maximal tachycardic response (peak) to fall in pressure in response to SNP (i.v). All experimental protocols were performed in conscious freely moving rats, previously anesthetized for catheterization of the femoral artery (arterial pressure recordings) and vein (i.v. injections), which were approved by the institutional ethical committee (#187/2011). The peak of reflex bradycardia in SHR in response to PHE was evaluated during the normalization of the MAP by continuous infusion of SNP (from 140 ± 2 to 101 ± 1 mmHg). The data from the sequence analyses show that the slopes of these sequences in both groups were similar (1.89 ± 0.2 vs 2.03 ± 0.2 ms mmHg−1), while the data from changes in MAP in response to PHE (49 ± 4 vs 39 ± 2 mmHg) show that the peak of bradycardic response in SHR was similar to Wistar (−107 ± 13 vs −91 ± 5 bpm). With respect to the reflex tachycardia to fall in MAP in response to SNP (−39 ± 3 vs −51 ± 12 mmHg) it was observed that the peak of tachycardia in SHR was also similar to Wistar (+107 ± 7 vs +112 ± 15 bpm). The data of this study, using two different experimental approaches, are showing that the gain of the cardiac baroreflex in SHR is not altered when compared to Wistar rats. We conclude that changes in the autonomic cardiac components of the baroreflex are not contributing to the high level of MAP observed in SHR.Support or Funding InformationFAPESP and CNPq

Continuous minimally invasive cardiac output monitoring with the COstatus in a neonatal swine model: recalibration is necessary during vasoconstriction and vasodilation.

The COstatus monitor measures cardiac output via the transpulmonary ultrasound dilution method (COTPUD ) after injection of normal saline, and can calculate continuous cardiac output (CCO) from the arterial pressure waveform. The relationship between arterial waveform and COTPUD however, might be degraded during vasoconstriction/vasodilation. To examine if recalibration of arterial waveform-derived CCO is required during mild vasoconstriction/vasodilation. In 10 anesthetized piglets (6.6-10.1kg), two COstatus monitors calculated the CCO from the same femoral arterial waveform before and during infusions of phenylephrine (PE; 1 or 3mg·kg(-1) ·min(-1) ) and sodium nitroprusside (SNP; 1 or 5mg·kg(-1) ·min(-1) ), administered in random order. One monitor was recalibrated (CCORecal ) after each intervention, while the other monitor was not (CCONon-Recal ). Recalibration was performed with COTPUD with 1ml·kg(-1) normal saline as indicator. The effects of each infusion on hemodynamic parameters were compared with baseline using paired t-tests. The bias, limits of agreement (LOA), and percentage error between simultaneous measurements (CCORecal and CCONon-Recal ) were examined with Bland-Altman plots. Infusion of PE significantly increased COTPUD , heart rate (HR), and arterial pressures but not systemic vascular resistance (SVR). Infusion of SNP decreased arterial pressures without affecting COTPUD , HR, and SVR. There was no bias between CCORecal and CCONon-Recal at the baseline, but a small bias was observed during PE and SNP infusions. The LOA increased approximately 10 fold during vasoconstriction and vasodilation. Thepercentage error increased from ≤ 5% to 32% and 27% during PE and SNP infusions, respectively. Continuous cardiac output (CO) measured with the COstatus monitor requires recalibration during vasoconstriction and vasodilation, even if changes in COTPUD or SVR are not substantial.

Abstract 631: Maternal Separation (msep) Alters Baroreflex Function And Renal Blood Flow Responsiveness

An impairment of the baroreflex buffering has been shown to precede the development of hypertension. Formerly, we reported that MSep, a model of behavioral stress during early life, impairs chronic blood pressure control and renal filtration capacity. Thus, the aim of this study was to study the baroreflex function and renal blood flow regulation in MSep rats. We used 3 month-old MSep male rats, anesthetized with isoflurane. Femoral vein catheter was fitted to infuse saline (3 ml/hr, baseline), PE (phenylephrine, 1 ug/ml, 9 ml/hr) or SNP (sodium nitroprusside, 0.5 ug/ml, 9 ml/hr). Femoral artery catheter was fitted to collect blood pressure and HR data (ADInstruments). In addition, a flow probe was placed in the left renal artery for renal blood flow (RBF) assessment (Transonic). After 45 minutes of baseline, PE infusion (2 min) was performed. Following 30-minute recovery period, SNP infusion (2 min) was achieved. Delta heart rate (HR)/Delta mean arterial pressure (MAP) relationship shows a significant difference in the slopes between MSep vs. control rats (-0.5 ±0.07 vs. -1.08 ±0.08, p&lt;0.05). PE-induced decrease in RBF was attenuated in a dose dependent manner in MSep rats (max. delta RBF -4.8±0.8 ml/min) compared to controls (max. delta RBF -7±1.5 ml/min, p&lt;0.05, respectively). Yet, renal vascular resistance (MAP/RBF) was not different between MSep and control rats along the 2-min period (slope: 0.43±0.02 vs. 0.42±0.03 mmHg/ml/min, respectively). These data suggest that MSep rats fail to increase HR in response to a vasodilatory agent and lower HR in response to vasoactive stimulus. Furthermore, attenuated alpha-adrenergic-induced renal vascular responses support the existence of a compensatory mechanism in response to an increased sympathetic outflow to the kidney, as previously suggested. The contribution of the different components of the autonomic nervous system is the focus of ongoing studies.

Is functional sympatholysis (FS) altered in chronically hypoxic (CH) rats?

Muscle sympathetic vasoconstriction is blunted in CH, however, there is no change in the modulatory role of NO. Exercise intolerance and CH are features of diseases such as COPD, this may reflect alterations in FS and fatigability. In accordance with UK legislation, experiments were performed on anaesthetised CH rats (3 weeks acclimation to 12% O2). Lumbar sympathetic chain stimulation was used to induce sympathetic vasoconstriction. Peroneal nerve stimulation evoked EDL contraction and tension was recorded. Femoral vascular resistance was calculated from recordings of arterial blood pressure and femoral blood flow. Sympathetic vasoconstriction was evoked during baseline and graded muscle contraction (10–30% max twitch) under control conditions, after NOS inhibition (L‐NAME) and again following restoration of background NO levels (SNP infusion). Compared to normal (N) rats, peak muscle tension was not different but CH rats fatigued more such that plateau tension was lower (even when O2 delivery was similar to N rats). FS was not different in CH and N rats and was not affected by either L‐NAME or SNP infusion. Muscle fatigue is greater in CH than N rats but it is not due to differences in O2 delivery. FS is unchanged despite sympathetic vasoconstriction being blunted in CH rats, and there appears to be no role for NO in mediating FS. Changes in FS are unlikely to explain exercise intolerance in diseases such as COPD.

Functional sympatholysis (FS) in rats is graded with exercise but is not NO‐mediated

FS is the exercise attenuation of sympathetic vasoconstriction. It is unclear if NO is the major mediator of FS or if the size of FS is graded to the level of exercise. Experiments were performed on anaesthetised rats (under UK legislation). Sympathetic vasoconstriction was induced by stimulation of the lumbar sympathetic chain (LSC). EDL contraction was evoked and tension recorded; femoral vascular resistance (FVR) was calculated. Vasoconstriction was evoked during baseline and graded muscle contraction (10–30% max twitch) under control conditions, after NOS inhibition (L‐NAME) and following restoration of baseline (SNP infusion). LSC‐evoked vasoconstriction (an increase in FVR) was attenuated at all levels of muscle contraction. FS was graded and correlated to the peak force at each level. L‐NAME increased baseline FVR and the vasoconstriction, but had no effect on FS at any level of muscle contraction. SNP restored baseline FVR and the vasoconstriction ‐ FS was similar to control conditions. FS was graded to the peak level of muscle contraction, not the force recorded during the sympathetic stimulation per se. Manipulation of endogenous levels of NO changes the magnitude of sympathetic vasoconstriction but does not alter the extent of FS during any of the muscle contractions used. These results are similar to human studies (no role for NO) but differ from animal studies (role for NO; see Saltin et al, 2012).

Abstract 1693: Bevacizumab acutely decreases endothelium dependent vasodilation in healthy volunteers

Abstract Introduction: Angiogenesis inhibitors have remarkably improved the outcome of patients with several types of cancer. One of the most reported side effects of angiogenesis inhibitors is hypertension. In patients treated with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), hypertension has an overall incidence up to 32%. Understanding the pathogenesis of this side effect is essential for optimal treatment with this class of drugs. Microvascular endothelial dysfunction is involved in the pathogenesis of hypertension. Our hypothesis is that bevacizumab (BVZ) induced hypertension is caused by an acute reduction of endothelium-mediated vasodilation. Methods: BVZ was infused intra-arterially to separate direct local effects of VEGF inhibition from systemic actions, such as hypertension, that could indirectly interfere with endothelial function. At first, in seven volunteers the acute vasomotor effect of BVZ was studied. During 15 minutes BVZ 144 μg/dl forearm volume/min was infused in the brachial artery of the non-dominant arm while assessing forearm blood flow (FBF) with venous strain gauge plethysmography. During BVZ infusion venous blood was collected from both arms to measure local and systemic concentrations of BVZ. Subsequently the acute vasodilator response to intra-arterial acetylcholine (Ach, endothelium-dependent vasodilator) alone and during simultaneous infusion of BVZ was studied, in another group of 12 volunteers. Finally, the effect of BVZ on the response to an endothelium-independent vasodilator nitroprusside (SNP) was studied in a similar experimental set up, in a third group of 12 volunteers. Results: In the experimental arm during infusion BVZ reached a concentration of 135±10,7μg/ml (± SD; n=8), resembling systemic exposure to BVZ in patients treated with 5mg BVZ i.v./kg. BVZ concentration in the control arm was 6,7±1,1 μg/ml (n=10). Intra-arterial BVZ did not directly alter forearm vascular tone. Infusion of BVZ significantly reduced the percentage increase in forearm blood flow during infusion of two dosages of acetylcholine from (mean±SE) 440±157 and 926±252 to 169±154 and 612±40 (p&amp;lt;0,05, ANOVA for repeated measures on log-transformed data). In the absence of BVZ, the vasodilator response to SNP equaled the response to ACh. BVZ did not alter the percentage increase in forearm blood flow during infusion of SNP (n=12). Conclusion: Although BVZ did not alter baseline forearm vascular tone, it acutely and specifially reduced endothelium-mediated vasodilation. Although this observation suggests a minor role for the muscle vascular bed, a similar acute effect in other organs such as the kidney could very well be involved in the pathogenesis of BVZ-induced hypertension. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1693. doi:1538-7445.AM2012-1693

Exaggerated sympathetic mediated responses to behavioral or pharmacological challenges following antenatal betamethasone exposure

Glucocorticoid administration to women at risk for preterm delivery is standard practice to enhance neonatal survival. However, antenatal betamethasone exposure (β-exposure) increases mean arterial pressure (MAP) in adult sheep (1.8 yr old) and results in impaired baroreflex sensitivity (BRS) for control of heart rate (HR). In the current studies we tested the hypothesis that enhanced sympathetic nervous system and hypothalamo-pituitary-adrenal (HPA) axis-mediated responses are evident at an early age in β-exposed sheep. Pregnant ewes were administered betamethasone (0.17 mg/kg twice over 24 h) or vehicle (Veh-control) on the 80th day of gestation, and offspring were delivered at full term. Female β-exposed and control offspring instrumented at age 42 ± 3 days for conscious continuous recording of MAP and HR had similar resting values at baseline. However, BRS was ~45% lower in β-exposed offspring. β-Exposed lambs allowed to suckle for 10 min had a greater elevation in MAP than Veh-control lambs (19 ± 1 vs 12 ± 2 mmHg; n = 4-5, P < 0.05). MAP was reduced by 20% from baseline via sodium nitroprusside infusion (SNP) over 10 min, which triggered a rebound increase in MAP only in β-exposed lambs. HR increased with the reduction in MAP during SNP infusion in Veh-control lambs, whereas there was no change in HR with the reduction in MAP in β-exposed lambs. Combined vasopressin-CRF injection caused greater increases in MAP in the β-exposed lambs. Cortisol and ACTH responses were higher in response to SNP hypotension in the β-exposed lambs. The data reveal enhanced sympathetic and HPA axis responses associated with impaired BRS preceding differences in resting MAP in preweanling female lambs exposed in utero to glucocorticoids. The consequences of these alterations at an early age include eventual development of higher blood pressure in this ovine model of fetal programming.

Oral nitrate therapy does not affect glucose metabolism in healthy men

1. Previously, we demonstrated that nitric oxide (NO) may be an important mediator of peripheral glucose disposal. The aim of the present study was to determine whether acute oral nitrate therapy improves glucose metabolism in healthy individuals. 2. Healthy men (n = 10), aged between 19 and 46 years, participated in a randomized cross-over placebo-controlled study. During Visit 1, participants received a dose-graded intravenous infusion of sodium nitroprusside (SNP; titrated from a dose of 0.5 microg/kg per min to a maximum of 2 microg/kg per min and delivered at a rate of 2 mL/min over 30 min). On Visits 2, 3 and 4, participants received oral extended-release isosorbide mononitrate (120 mg), pentaerythritol tetranitrate (160 mg) and placebo in a randomized Latin square design (one treatment per visit). The main outcome measures were plasma glucose and insulin levels and glucose tolerance determined by an oral glucose tolerance test following the SNP infusion and 3 h after nitrate/placebo administration. Exhaled NO, cGMP and pulmonary blood flow were also measured for 3 h after administration of nitrate/placebo and after SNP infusion. 3. None of the nitrate interventions influenced measures of glucose metabolism. Following SNP infusion, there was no change in plasma glucose (P = 0.42) or insulin (P = 0.25) levels, and the response to a glucose load did not different from baseline (P = 0.46). Similarly, neither of the oral nitrates altered plasma glucose (P = 0.24) or insulin levels (P = 0.90) or glucose tolerance (P = 0.56) compared with placebo. 4. In conclusion, these results indicate that acute oral nitrate therapy does not influence glucose metabolism. Studies using NO donors in a chronic setting are required to clarify the role of NO in mediating peripheral glucose uptake.

Saphenous Vein Grafts Display Poor Endothelium-Dependent and Endothelium-Independent Dilation—Implications for the Pathogenesis of Vein Graft Atherosclerosis

As endothelial dysfunction has been implicated in the pathogenesis of late failure of saphenous vein grafts (SVG), we assessed endothelium-dependent and endothelium-independent vascular responses of SVG in humans. Subjects undergoing angiography after bypass grafting had selective infusions of acetylcholine (ACh, an endothelium-dependent dilator) and sodium-nitroprusside (SNP, an endothelium-independent dilator) into a non-obstructed vein graft. SVG diameters were measured by quantitative coronary angiography. Two matched groups of control subjects, with or without coronary artery disease (CAD), were studied after similar infusions into their femoral arteries. We assessed 10 subjects with SVG, 8 controls with and 8 without CAD. SVG dilatation to high-dose ACh was 5+/-3%, similar to the femoral arteries of subjects with CAD (10+/-5%), but significantly less than the ACh-related arterial dilatation in the non-CAD group (16+/-2%, p=0.02). Similarly, dilatation of SVG after SNP infusion was 9+/-3%, which was not significantly different from the nitrate responses of femoral arteries in the CAD group (21+/-5%), but significantly poorer than in the non-CAD subjects (27+/-5%, p=0.02). Saphenous vein bypass grafts display poor endothelium-dependent and endothelium-independent vascular responses in vivo, compared with healthy systemic arteries. This may contribute to the pathogenesis of accelerated atherosclerosis seen in SVG.

Cytochrome P450 2C9 is involved in flow‐dependent vasodilation of peripheral conduit arteries in healthy subjects and in patients with chronic heart failure

Flow-mediated dilation (FMD) of human conduit arteries is, in part, related to shear stress-induced release of endothelium-derived nitric oxide (NO). However, NO synthase inhibitors do not completely abolish this FMD-response. Recently, a cytochrome P450 (CYP) epoxygenase of the 2C family was linked to NO- and prostacyclin-independent relaxation of conduit arteries. We therefore evaluated the contribution of CYP 2C9 to FMD in humans. FMD of the radial artery was determined in 12 healthy volunteers by high-resolution ultrasound and analyzed before and after intra-arterial infusion of sulfaphenazole, a specific CYP 2C9 inhibitor, L-NMMA (NO synthase inhibitor) and co-infusion of both. Endothelium-independent vasodilation was characterized after intra-arterial infusion of SNP. FMD was reduced after sulfaphenazole (11.5+/-0.87% vs. 7.4+/-0.95%, p<0.01), after L-NMMA (6.0+/-0.71%; p<0.01), and after co-infusion 3.9+/-0.73% (p<0.05 vs. L-NMMA; p<0.01 vs. sulfaphenazole). Sulfaphenazole had no effect on endothelium-independent vasodilation. In patients with chronic heart failure, the portion of FMD blocked by sulfaphenazole was not affected. CYP 2C was detected by immunohistochemistry in radial artery samples obtained from patients undergoing coronary bypass surgery. FMD in human conductance arteries is reduced after inhibition of CYP 2C9, supporting the concept that CYP 2C metabolites contribute to endothelium-mediated vasodilation of peripheral conduit arteries in vivo. In patients with heart failure, the CYP-dependent FMD appears to be preserved.

Vascular Dysfunction and Reduced Circulating Endothelial Progenitor Cells in Young Healthy UK South Asian Men

The objective of this study was to examine determinants of excess coronary artery disease risk in UK South Asians, more prevalent in this population than UK Caucasians, by examining differences in risk factors, vascular function, and endothelial progenitor cells (EPCs). 24 South Asian and 25 Caucasian healthy age-matched nonsmoking men were studied. Vascular function was assessed by flow-mediated and GTN brachial artery dilatation and blood flow responses to infusion of ACh, SNP, and L-NMMA. EPC number and function were measured by flow cytometry (CD34, CD133, and KDR positive cells), and CFU/migration assays. Traditional risk factors and anthropometric measurements were similar in the groups. South Asians had higher fasting insulin levels (6.01 versus 3.62 microU/mL; P = 0.02). South Asians had lower FMD (6.9 versus 8.5%; P = 0.003), L-NMMA response (0.8 versus 1.3 mL/min/100 mL; P = 0.03), mean SNP response (9.5+/-0.6 versus 11.6+/-0.6; P = 0.02), EPC number (0.046+/-0.005% versus 0.085+/-0.009%; P = < 0.001), and CFU ability (CFU 4.29+/-1.57 versus 18.86+/-4.00; P = 0.005). EPC number was the strongest predictor of FMD. Ethnicity was the strongest predictor of EPC number. Healthy South Asian men are more insulin resistant, and demonstrate endothelial dysfunction and reduced EPC number and function compared with Caucasians. These abnormalities may contribute to their increased CAD risk.

DISSOCIATION OF BLOOD PRESSURE AND SYMPATHETIC ACTIVATION OF RENIN RELEASE IN SINOAORTIC‐DENERVATED RATS

1. Blood pressure (BP) and heart rate (HR) increase 6 and 24 h after sinoaortic baroreceptor denervation (SAD), whereas plasma renin activity (PRA) and renal renin mRNA levels remain unchanged. We postulated that a simultaneous rise in BP could offset the expected activation of renin associated with an increased renal sympathetic discharge secondary to SAD. 2. To test this hypothesis, the increase in BP associated with the onset of SAD was prevented by a continuous infusion of sodium nitroprusside (SNP; 30 microg/kg per h). Changes were measured in five groups of conscious adult male Wistar rats: (i) sham; (ii) SAD; (iii) SAD rats in which the BP was prevented from increasing by infusion of SNP; (iv) sham rats in which the BP was increased by 30% by infusion of phenylephrine (PE; 1.5-2.0 mL/h); and (v) SNP + PE for 3 h by infusion as above. 3. As expected, BP and heart rate (HR) increased significantly following SAD compared with sham rats (152 +/- 4 vs 116 +/- 3 mmHg, respectively, for BP and 503 +/- 6 vs 345 +/- 13 b.p.m., respectively for HR; n = 5; P < 0.05) but remained unchanged when SNP was infused for 3 h (106 +/- 1 mmHg and 455 +/- 9 b.p.m., respectively; n = 5; P < 0.05). 4. Similarly, BP and HR increased with PE infusion compared with PE + SNP (138 +/- 9.9 vs 113 +/- 2.3 mmHg for BP, respectively, and 325 +/- 9 vs 423 +/- 18 b.p.m. for HR, respectively; n = 5; P < 0.05). 5. Plasma renin activity remained unchanged in SAD compared with sham rats (1.67 +/- 0.35 vs 1.05 +/- 0.17 ng angiotensin (Ang) I/mL per h), but increased significantly when hypertension was prevented (5.86 +/- 0.77 ng AngI/mL per h; n = 5; P < 0.05). Renin mRNA levels in the kidneys were unchanged in all groups. 6. These results show that an elevation in BP appears to offset increased renal sympathetic discharge with no change in PRA.

Nitric oxide and noradrenaline contribute to the temperature threshold of the axon reflex response to gradual local heating in human skin

The initial skin blood flow response to rapid local heating is an axon reflex, which may be mediated by calcitonin gene-related peptide and substance P released from C-fibres. We investigated the role of nitric oxide (NO) and noradrenaline on the temperature threshold for the axon reflex during gradual local heating. 36 subjects participated in two studies. Using microdialysis, we examined the following interventions: NO synthase inhibition (10 mM N(G)-nitro-L-arginine methyl ester, L-NAME); low-dose NO infusion (1.0 microM sodium nitroprusside, SNP); adrenergic blockade (10 mM bretylium tosylate); and low-dose (0.1 microM) noradrenaline infusion. Laser-Doppler flowmetry was used to measure red blood cell flux. Skin was heated at a rate of 0.1 degrees C min(-1) from 33 degrees C to 40 degrees C. Compared to control skin sites, the axon reflex response was shifted to a higher temperature in 4 subjects in the L-NAME sites (control, 37.0 +/- 0.3 degrees C, n = 16; L-NAME, 39.8 +/- 0.1 degrees C, n = 4; P < 0.001) and absent in 12 subjects. The response was also absent in L-NAME plus low-dose SNP sites and not altered by low-dose SNP infusion alone. Adrenergic blockade, with and without low-dose noradrenaline infusion, also abolished the axon reflex response in all subjects. Low-dose noradrenaline infusion alone shifted the axon reflex to a significantly lower temperature threshold compared to control sites (control, 38.2 +/- 0.5 degrees C; noradrenaline, 37.7 +/- 0.4 degrees C, P < 0.05, n = 5). These results suggest that endogenous NO and noradrenaline contribute to the temperature threshold of the axon reflex response during gradual local heating of the skin.