Infusion Of Nitroprusside Research Articles

Is robot-assisted retroperitoneal adrenalectomy safe? An investigation of perioperative hypertensive crisis among hypertensive and normotensive patients.

Objective: We examined the incidence of perioperative hypertensive crisis in robot-assisted retroperitoneal laparoscopic adrenalectomy. A consecutive series of 120 patients with adrenal tumours undergoing robot-assisted retroperitoneal laparoscopic adrenalectomy were included. Patients were divided into two groups: group A (hypertension group, 58 cases, mean age 43.59 years) and group B (normotension group, 62 cases, mean age 48.01 years). General anaesthesia was applied using endotracheal intubation and haemodynamic changes were closely monitored. A total of nine (7.5%) hypertensive crisis cases were observed. After intravenous infusion of sodium nitroprusside, seven cases of them were quickly controlled and two cases experienced transient severe hypertension. The incidence of hypertensive crisis was 13.7% and 1.6% in groups A and B, respectively (p<0.05). These findings highlight the importance of strengthening the monitoring of anaesthesia and taking various measures to effectively control the blood pressure in robot-assisted retroperitoneal laparoscopic adrenalectomy, especially among hypertensive patients.

Effective reflection distance and its association with pressure augmentation index under a variety of acute hemodynamic perturbation

Abstract Effective reflection distance (ERD), a conceptual distance to a major reflection site from the aortic root, is associated with aging and pressure augmentation index (AIx) in clinical population. However, it is poorly understood how ERD varies and associates with AIx within a subject when the hemodynamic condition is changed extensively by acute pharmacological interventions. Methods In 13 anesthetized dogs, we measured aortic pressure (AP) and flow (AF) and femoral arterial flow (FF). Using AP, AF and FF, ERD based on an arterial model comprising a tube with frequency-dependent load (ERD_TL) was determined as a physiologically valid reference. ERD was also determined by wave separation (ERD_WSA) and pressure-only analyses (ERD_AW). Hemodynamic condition was changed by administrating zatebradine (bradycardic agent), nitroprusside, noradrenaline, dobutamine, and dextran. Results ERD_TL shortened significantly in response to infusion of nitroprusside or dobutamine. ERD_TL was significantly and negatively associated with AIx in multivariate analysis (Figure/Table). Changes in ERD_WSA or ERD_AW, and their association with AIx were not necessarily concordant with those observed in ERD_TL. Conclusion For the first time, we demonstrated that under diverse hemodynamic conditions, ERD_TL can change sensitively, and associates with AIx physiologically. This substantiates importance of tight attention to medication at clinical analysis of wave reflection phenomena. ERD_WSA or ERD_AW may not be a surrogate of ERD_TL. Responses of ERD to drugs Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Japan Society for the Promotion of Science (JSPS)

Microvascular Function Is Impaired after Short-Term Immobilization in Healthy Men.

We examined whether 2 wk of one-leg immobilization would impair leg microvascular function and to what extent a subsequent period of intense aerobic cycle training could restore function. Study participants were healthy young men (n = 12; 20-24 yr of age). Leg microvascular function was determined before the intervention, after the immobilization period, and after a 4-wk exercise training period. Microvascular function was assessed as the vasodilator response to intra-arterial infusion of acetylcholine and sodium nitroprusside and as the vasoconstrictor response to endogenous noradrenaline release induced by tyramine infusion. Vasodilator enzymes as well as prooxidant and antioxidant enzymes were assessed by protein analysis in skeletal muscle samples: endothelial nitric oxide synthase, NADPH oxidase (NOX p67 and NOX gp91), and superoxide dismutase 2 (SOD2). The acetylcholine-induced change in vascular conductance was reduced after the 2 wk of immobilization (P = 0.003), tended to increase (P = 0.061), and was back to baseline levels after the subsequent 4 wk of exercise training. Plasma prostacyclin levels in response to acetylcholine infusion were lower after immobilization than before (P = 0.041). The changes in vascular conductance with sodium nitroprusside and tyramine were similar during all conditions. Skeletal muscle protein levels of endothelial nitric oxide synthase in the experimental leg were unchanged with immobilization and subsequent training but increased 47% in the control leg with training (P = 0.002). NOX p67, NOX gp91, and SOD2 in the experimental leg remained unaltered with immobilization, and SOD2 was higher than preimmobilization after 4 wk of training (P < 0.001). The study shows that 2 wk of immobilization impairs leg microvascular endothelial function and prostacyclin formation but that 4 wk of intense aerobic exercise training restores the function. The underlying mechanism may reside in the prostacyclin system.

Hemodynamic Reserve Predicts Early Right Heart Failure After LVAD Implantation

Background Right heart failure (RHF) remains a major source of morbidity and mortality after left ventricular assist device (LVAD) implantation, yet efforts to predict RHF have proved only modestly successful. Acute pharmacologic unloading of the LV to assess ventricular and hemodynamic reserve may better predict post-implant RHF. Objectives To compare pre-implant baseline and post-vasodilator hemodynamic predictors of INTERMACS defined severe or severe-acute RHF after LVAD implantation. Methods After IRB approval, we performed a retrospective analysis of all subjects implanted with a durable LVAD at our institution between February 2017 and April 2020 (n=108). Only those who underwent vasodilator testing with nitroprusside during their pre-implant right heart catheterization were ultimately included (n=29). Continuous variables were compared with t-test and Levene's test of equality of variances; categorical via Fisher's Exact test. Logistic regression was used to determine predictors of severe or severe-acute RHF. Results Ten subjects met criteria for severe or severe-acute RHF (34%) after implant. There were no significant differences in demographics, HF etiology, INTERMACS profile, echo assessment of LV/RV function, or pre-implant baseline hemodynamics including RAP:PAWP ratio and PAPi between groups (TABLE). Both groups saw a similar reduction in systemic mean arterial pressure with nitroprusside, which led to significant and similar reductions in PAWP and pulmonary pressures. Compared to the group with severe or severe-acute RHF, those without significant RHF achieved higher peak cardiac index (CI) with nitroprusside infusion, suggesting better cardiac reserve. Peak CI was a significant predictor of RHF (p= 0.022), even after controlling for baseline values (p=0.048). No subject achieving a peak CI > 2.66 L/min/m2 developed severe or severe-acute RHF, and every 0.25 L/min/m2 decrease in peak CI was associated with 2.3 fold increased risk. Mortality was higher and hospital length of stay longer in the severe or severe-acute RHF group. Conclusion Peak CI with nitroprusside infusion predicts post-implant LVAD RHF better than resting hemodynamics in this small cohort. Hemodynamic reserve measurements may prove to be an important risk stratification tool when assessing LVAD candidacy.

Abstract P082: Elevated Circulating Endothelial-Derived Microvesicles Are Associated With Obesity-Related Endothelial Dysfunction

Background: Obesity reduces the number of years lived free of cardiovascular disease (CVD) and increases the number of years lived with CVD, contributing to increased morbidity and mortality risk across all ages. Experimental and clinical studies indicate that a proatherogenic endothelial phenotype is a major consequence of increased adiposity and a primary mechanism underlying obesity-related CVD. Extracellular microvesicles, particularly endothelial cell-derived microvesicles (EMVs), are seminal functional modulators of vascular health and disease. The purpose of this study was to determine: 1) if circulating EMV levels are elevated with obesity, independent of other cardiometabolic risk factors; and if so, 2) whether circulating EMVs are associated with obesity-related endothelial vasodilator dysfunction. Methods: Thirty sedentary, middle-aged adults (45-63 years) were studied: 15 normal weight (10M/5F; age: 56±1 yr; BMI: 23.2±0.4 kg/m2; body fat: 25.1±2.4 %) and 15 obese (10M/5F; age: 54±1 yr; BMI: 31.5±0.3 kg/m2; body fat: 37.2±1.7 %). All subjects were free of other cardiometabolic risk factors and overt disease. EMV identification (CD31 + /42b - ) and concentration in peripheral blood were determined by flow cytometry. Forearm blood flow (FBF: via plethysmography) was assessed in response to intra-arterial infusions of acetylcholine (4.0, 8.0 and 16.0 μg/100 mL tissue/min) and sodium nitroprusside (1.0, 2.0 and 4.0 μg/100 mL tissue/min). Results: Circulating EMV levels were ~100% higher (P&lt;0.05) in obese (182±14 EMV/μL) compared with normal weight (91±12 EMV/μL) adults. FBF response to acetylcholine was significantly lower (~35%) in the obese (from 4.0±0.2 to 10.3±0.6 mL/100 mL tissue/min vs 4.3±0.3 to 15.4±0.8 mL/100 mL tissue/min) group. Circulating EMVs were significantly and inversely associated with total FBF response to acetylcholine (r=-0.55). Conclusions: Obesity, independent of other cardiometabolic risk factors, is associated with elevated circulating levels of EMVs. Higher circulating EMVs in obese adults may contribute to adiposity-related endothelial dysfunction and vascular disease risk. Indeed, circulating EMVs have been linked to disease risk, severity and outcome in other high-risk populations.

Nitric oxide in the insular cortex modulates baroreflex responses in a cGMP-independent pathway

Insular cortex is a brain structure involved in the modulation of autonomic activity and cardiovascular function. The nitric oxide/cyclic guanosine-3′,5′-monophosphate pathway is a prominent signaling mechanism in the central nervous system, controlling behavioral and physiological responses. Nevertheless, despite evidence regarding the presence of nitric oxide-synthesizing neurons in the insular cortex, its role in the control of autonomic and cardiovascular function has never been reported. Thus, the present study aimed to investigate the involvement of nitric oxide/cyclic guanosine-3′,5′-monophosphate pathway mediated by neuronal nitric oxide synthase (nNOS) activation within the insular cortex in the modulation of baroreflex responses in unanesthetized rats. For this, we evaluated the effect of bilateral microinjection of either the nitric oxide scavenger carboxy-PTIO, the selective neuronal nitric oxide synthase inhibitor Nω-Propyl-l-arginine or the soluble guanylate cyclase inhibitor ODQ into the insular cortex on the bradycardia evoked by blood pressure increases in response to intravenous infusion of phenylephrine, and the tachycardia caused by blood pressure decreases evoked by intravenous infusion of sodium nitroprusside. Bilateral microinjection of either NPLA or carboxy-PTIO into the insular cortex increased the reflex bradycardic response, whereas the reflex tachycardia was decreased by these treatments. Bilateral microinjection of the soluble guanylate cyclase inhibitor into the insular cortex did not affect any parameter of baroreflex function evaluated. Overall, our findings provide evidence that insular cortex nitrergic signaling, acting via neuronal nitric oxide synthase, plays a prominent role in control of baroreflex function. However, control of reflex responses seems to be independent of soluble guanylate cyclase activation.

Ischemic Preconditioning Improves Microvascular Endothelial Function in Remote Vasculature by Enhanced Prostacyclin Production.

BACKGROUNDThe mechanisms underlying the effect of preconditioning on remote microvasculature remains undisclosed. The primary objective was to document the remote effect of ischemic preconditioning on microvascular function in humans. The secondary objective was to test if exercise also induces remote microvascular effects.METHODS AND RESULTSA total of 12 healthy young men and women participated in 2 experimental days in a random counterbalanced order. On one day the participants underwent 4×5 minutes of forearm ischemic preconditioning, and on the other day they completed 4×5 minutes of hand‐grip exercise. On both days, catheters were placed in the brachial and femoral artery and vein for infusion of acetylcholine, sodium nitroprusside, and epoprostenol. Vascular conductance was calculated from blood flow measurements with ultrasound Doppler and arterial and venous blood pressures. Ischemic preconditioning enhanced (P<0.05) the remote vasodilator response to intra‐arterial acetylcholine in the leg at 5 and 90 minutes after application. The enhanced response was associated with a 6‐fold increase (P<0.05) in femoral venous plasma prostacyclin levels and with a transient increase (P<0.05) in arterial plasma levels of brain‐derived neurotrophic factor and vascular endothelial growth factor. In contrast, hand‐grip exercise did not influence remote microvascular function.CONCLUSIONSThese findings demonstrate that ischemic preconditioning of the forearm improves remote microvascular endothelial function and suggest that one of the underlying mechanisms is a humoral‐mediated potentiation of prostacyclin formation.

P0978THE EFFECTS OF CHRONIC DAPAGLIFLOZIN TREATMENT ON THE RENAL MICROVASCULATURE IN A RAT MODEL OF TYPE 2 DIABETES

Abstract Background and Aims Chronic kidney disease (CKD) is an ever-growing concern and CKD associated with diabetes accounted for ∼ 35% of new cases of end-stage renal failure. Clinical trials with insulin-independent sodium-glucose co-transporter 2 (SGLT2) inhibitors not only showed significant improvements in hyperglycemia and thus renal damage, but also reduced the risk of adverse cardiovascular events. Microvessels supply local tissue oxygen demands and are important controllers of regional perfusion. Endothelial dysfunction has been posited to be an important factor driving the pathogenesis of diabetic nephropathy, largely through impaired eNOS activity and thus reduced nitric oxide bioavailability. Thus, we aim to determine the effects of SGLT2 inhibition on vasodilator function in the renal vasculature. We hypothesize that rats chronically treated with dapagliflozin, a SGLT2 inhibitor, improves renal endothelial function and the microvessels are better able to maintain perfusion in response to the inhibition of nitric oxide synthase and prostaglandin blockade. Method Male Zucker fatty diabetic rats (8 wk old), a model of type 2 diabetes, were given daily oral gavage of 1 mg/kg dapagliflozin or its vehicle for up to 22 wks of age (n=6/group). Renal excretory function, glomerular filtration rate (GFR) and indices of renal injury was assessed before treatment and after every 4 wks up until 22 wks of age. GFR was assessed via transcutaneous clearance of FITC-sinistrin. Vasodilator function of the renal microvasculature was assessed via X-ray microangiography. We conducted successive imaging of the microvessels before and during infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) which facilitated the assessment of endothelium dependent and independent dilation respectively. After which, rats were given successive boluses of L-NAME and indomethacin to assess the vasodilatory function of the microvasculature independent of nitric oxide and prostaglandins respectively. These inhibitors were given under the conditions of SNP clamp which allowed for us to titrate the blood pressure to baseline levels. Lastly, we assessed the ability of endothelium hyperpolarizing factors (EDHFs) to maintain microvascular perfusion when SNP infusion ceased and an infusion of ACh commenced while still under the effects of L-NAME and indomethacin. Results As expected, dapagliflozin alleviated hyperglycemia across the treatment period. There was a tendency for dapagliflozin to ameliorate the decline of GFR, although this apparent effect was not statistically significant. Dapagliflozin did not appear to improve indices of renal injury. Treatment with dapagliflozin alleviated polyuria but did not appear to have an impact on urine osmolarity or sodium excretion. The responses (vessel diameter) of renal microvessels to ACh and SNP was greater in dapagliflozin than in vehicle fed rats. The microvessels of vehicle fed rats appeared to undergo relative constriction in response to L-NAME and indomethacin even under the effects of SNP clamp. In contrast, microvessels of dapagliflozin fed rats appeared to be relatively well-perfused after NOS and COX blockade. This suggests that dapagliflozin may improve endothelial dysfunction commonly associated with diabetic nephropathy. Following NOS and COX blockade, ACh was infused in rats to determine the status of vasodilatory function mediated by EDHFs. The microvessels in diabetic rats did not appear to be dilated after infusion of ACh, suggesting that vasodilatory effects of EDHFs on the vasculature is diminished in diabetic rats. Dapagliflozin appeared to improve this effect in that the renal microvessels were dilated even when NOS and COX production was blocked/inhibited. Conclusion Chronic treatment of dapagliflozin may improve endothelial dysfunction and thus retard the progression of diabetic nephropathy in a rat model of type 2 diabetes.

RETRACTED ARTICLE: A fuzzy-based adaptive multi-input–output scheme in lieu of diabetic and hypertension management for post-operative patients: an human–machine interface approach with its continuum

Here, a multi-input–output control strategy-based adaptive system is implemented to regulate the glycaemic and hypertension (HT) level concurrently for post-operative patients. The current medical research identifies the relationship between diabetes and HT, and these two diseases have possible overlap in their disease aetiology. Based on the continuum, the blood glucose and blood pressure (BP) have to be measured independently and control the infusion to maintain optimally based on the variations of diabetic mellitus and HT to avoid the major complications for the perioperative condition. Based on the analysis, the post-operative strain may increase HT and may increase the glycaemic level, and this uncertainty of disparity may lead to BP, hyperinsulinemia, cardio diseases, and osmotic diuresis along with hyperglycaemia. The proposed adaptive cascade control strategy illustrates two different types of control loops independently, and these loops adopt an adaptive control strategy with parametric compensation. This adaptive control algorithm integrates the cascade methodology along with expert knowledge to treat these diseases by using adaptation laws with the help of fuzzy logic to regulate the proper insulin and sodium nitroprusside (SNP) infusion. The output response of the plasma glucose concentration and HT regulation was shown along with insulin infusion rate and SNP infusion rate based on the extensive simulation readings. The attained simulation results demonstrate that the adaptive control strategy shows better outcomes for the infusion and may achieve potentially better control on HT and glycaemic levels for post-operative patients.

Global Reach 2018 Heightened α-Adrenergic Signaling Impairs Endothelial Function During Chronic Exposure to Hypobaric Hypoxia.

Chronic exposure to hypoxia is associated with elevated sympathetic nervous activity and reduced vascular function in lowlanders, and Andean highlanders suffering from excessive erythrocytosis (EE); however, the mechanistic link between chronically elevated sympathetic nervous activity and hypoxia-induced vascular dysfunction has not been determined. To determine the impact of heightened sympathetic nervous activity on resistance artery endothelial-dependent dilation (EDD), and endothelial-independent dilation, in lowlanders and Andean highlanders with and without EE. We tested healthy lowlanders (n=9) at sea level (344 m) and following 14 to 21 days at high altitude (4300 m), and permanent Andean highlanders with (n=6) and without (n=9) EE at high altitude. Vascular function was assessed using intraarterial infusions (3 progressive doses) of acetylcholine (ACh; EDD) and sodium nitroprusside (endothelial-independent dilation) before and after local α+β adrenergic receptor blockade (phentolamine and propranolol). Intraarterial blood pressure, heart rate, and simultaneous brachial artery diameter and blood velocity were recorded at rest and during drug infusion. Changes in forearm vascular conductance were calculated. The main findings were (1) chronic hypoxia reduced EDD in lowlanders (changes in forearm vascular conductance from sea level: ACh1: -52.7±19.6%, ACh2: -25.4±38.7%, ACh3: -35.1±34.7%, all P≤0.02); and in Andeans with EE compared with non-EE (changes in forearm vascular conductance at ACh3: -36.4%, P=0.007). Adrenergic blockade fully restored EDD in lowlanders at high altitude, and normalized EDD between EE and non-EE Andeans. (2) Chronic hypoxia had no effect on endothelial-independent dilation in lowlanders, and no differences were detected between EE and non-EE Andeans; however, EID was increased in the non-EE Andeans after adrenergic blockade (P=0.012), but this effect was not observed in the EE Andeans. These data indicate that chronic hypoxia reduces EDD via heightened α-adrenergic signaling in lowlanders and in Andeans with EE. These vascular mechanisms have important implications for understanding the physiological consequences of acute and chronic high altitude adaptation.

Essential hypertension is associated with blunted smooth muscle cell vasodilator responsiveness and is reversed by 10-20-30 training in men

Essential hypertension is associated with impairments in vascular function and sympathetic nerve hyperactivity; however, the extent to which the lower limbs are affected remains unclear. We examined the leg vascular responsiveness to infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and phenylephrine (PEP) in 10 hypertensive men [HYP: age 59.5 ± 9.7 (means ± SD) yr; clinical and nighttime blood pressure: 142 ± 10/86 ± 10 and 141 ± 11/83 ± 6 mmHg, respectively; and body mass index (BMI): 29.2 ± 4.0 kg/m2] and 8 age-matched normotensive counterparts (NORM: age 57.9 ± 10.8 yr; clinical and nighttime blood pressure: 128 ± 9/78 ± 7 and 116 ± 3/69 ± 3 mmHg, respectively; and BMI: 26.3 ± 3.1 kg/m2). The vascular responsiveness was evaluated before and after 6 wk of 10-20-30 training, consisting of 3 × 5 × 10-s sprint followed by 30 and 20 s of low- to moderate-intensity cycling, respectively, interspersed by 3 min of rest. Before training, the vascular responsiveness to infusion of SNP was lower (P < 0.05) in HYP compared with NORM, with no difference in the responsiveness to infusion of ACh and PEP. The vascular responsiveness to infusion of SNP and ACh improved (P < 0.05) with training in HYP, with no change in NORM. With training, intra-arterial systolic blood pressure decreased (P < 0.05) by 9 mmHg in both HYP and NORM whereas diastolic blood pressure decreased (5 mmHg; P < 0.05) in HYP only. We provide here the first line of evidence in humans that smooth muscle cell vasodilator responsiveness is blunted in the lower limbs of hypertensive men. This impairment can be reversed by 10-20-30 training, which is an effective intervention to improve the responsiveness of smooth muscle cells in men with essential hypertension.

Circulating endothelial cell derived microvesicles are elevated with hypertension and associated with endothelial dysfunction.

The purpose of this study was to determine (1) if circulating endothelial microvesicles (EMVs) are elevated in hypertensive adults and (2) whether circulating EMVs are associated with hypertension-related endothelial vasodilator dysfunction. Circulating EMVs (CD31+/42b-) were determined in 30 middle-aged adults (55 ± 1 years): 15 normotensive (10 males, 5 females; blood pressure 114/71 ± 2/1 mm Hg) and 15 hypertensive (10 males, 5 females; blood pressure 142/87 ± 2/2 mm Hg). Forearm blood flow (FBF) (via plethysmography) was assessed by intra-arterial infusion of acetylcholine and sodium nitroprusside. Circulating EMVs were ∼65% higher (P < 0.05) in hypertensive (157 ± 10 EMVs/μL) than in normotensive (96 ± 10 EMVs/μL) adults. FBF to acetylcholine was significantly lower (∼30%) in the hypertensive group (from 5.0 ± 0.4 to 11.8 ± 0.8 mL·100 mL tissue-1·min-1 versus from 4.4 ± 0.2 to 15.6 ± 0.8 mL·100 mL tissue-1·min-1). Circulating EMVs were inversely associated with vasodilation (r = -0.65; P < 0.05). Hypertension is associated with elevated circulating levels of EMVs. EMVs may serve as a biomarker of, and contribute to, blood pressure related endothelial dysfunction.

Exercise Hyperemia is Preserved During Augmented Basal Oxygen Delivery in Humans

The coupling between skeletal muscle blood flow and metabolic demand is largely attributed to feedback regulation of oxygen delivery. However, the relative importance of feedforward mechanisms in increasing blood flow in proportion to contractile work is unknown. We hypothesized that the change in blood flow following initiation of exercise is preserved independent of the level of baseline oxygen delivery, and that reciprocal reductions in oxygen extraction occur during elevations in resting blood flow. In 6 young healthy adults (4M/2F, 22±1 y) we quantified forearm blood flow (FBF; Doppler ultrasound), oxygen extraction (O2 extraction; based on venous O2 content), and forearm oxygen consumption (mVO2; Fick equation). Measurements were taken at rest and during 5 minutes of rhythmic handgrip exercise under control conditions and during intra‐arterial infusion of the vasodilator sodium nitroprusside (SNP) to pharmacologically manipulate oxygen delivery (O2D) prior to initiation of contractions. We elevated resting blood flow to levels that matched (MAT) and exceeded (EXC) steady‐state hyperemia during control (CON) exercise trials. Steady‐state FBF and O2D during dynamic forearm contractions at an intensity equivalent to 10% of participants maximal voluntary contraction under CON conditions were 159 ± 24 ml · min−1 and 32 ± 4.9 ml O2 · min−1, respectively. As intended, SNP infusion increased resting FBF (152 ± 26 ml · min−1) and O2D (31 ± 5.3 ml O2 · min−1) to levels similar to those observed during CON exercise in MAT (both P = NS), and further elevated FBF (196 ± 19 ml · min−1) and O2D (40 ± 4.0 ml O2 · min−1) to levels exceeding CON exercise in EXC (both P &lt; 0.05). However, resting O2 extraction decreased in MAT (9 ± 5 %) and EXC (7 ± 4 %) compared to CON (49 ± 7 %; P &lt; 0.05), and thus resting mVO2 was not different between conditions (range: ~2–3 ml O2 · min−1; P = NS). Despite elevating resting FBF and O2D to levels adequate to sustain muscle contractile work, the change in FBF in response to exercise remained intact during MAT (Δ FBF; 112 ± 20 ml · min−1) and EXC (Δ FBF; 133 ± 18 ml · min−1) compared to CON (Δ FBF; 123 ± 24 ml · min−1; all P = NS). As predicted, O2 extraction remained lower during steady‐state exercise in the MAT (45 ± 7 %) and EXC (39 ± 7 %) conditions compared to CON (66 ± 3 %; P &lt; 0.05). However, the change in O2 extraction from rest to steady‐state exercise was not reduced (Δ O2 extraction: CON; 17 ± 5, MAT; 36 ± 5, EXC; 32 ± 5 %; P = NS), and thus mVO2 was not different between conditions (CON; 21 ± 2.9, MAT; 24 ± 4.5, EXC; 27 ± 5.6 ml O2 · min−1; P = NS). We conclude that changes in blood flow and oxygen extraction remain intact when oxygen delivery is artificially elevated prior to exercise, which highlights the importance of feedforward mechanisms capable of initiating changes in skeletal muscle blood flow independent of oxygen delivery.Support or Funding InformationNIH HL119337

Blunted Cutaneous Thermal Reactivity in Black Women and the Relationship with Endothelin‐1 and L‐arginine

The black population (BL) has elevated rates of hypertension and cardiovascular disease relative to other populations. However, research specific to the mechanisms for these conditions in BL women (BW) remains remarkably devoid. Our group recently demonstrated impaired microvascular function in young, BL men (BM) and BW. Further, inhibition of oxidative stress from xanthine and NADPH oxidases restored microvascular function in BM, while no such effect was observed in BW suggesting divergent mechanisms of microvascular dysfunction between these populations. Two possible candidate mechanisms are heightened endothelin‐1 (ET‐1) activity and/or reduced L‐arginine (L‐ARG) bioavailability, both of which have been noted in BW, but not specifically linked to microvascular dysfunction. Therefore, this study tested the hypothesis that ET‐1 overactivity and/or L‐ARG insufficiency contribute to the blunted microvascular function observed in young, BW. To test this hypothesis, four intradermal microdialysis membranes were placed in the dorsal forearm of 4 white women (WW) and 6 BW (mean±SD; age: 22 ± 2 vs. 21 ± 3) and the cutaneous vascular conductance (CVC: cutaneous blood flow/mean arterial pressure) response to a standard local heating protocol was assessed. Following trauma resolution, each site received one of four, 30‐min infusions: lactated Ringer’s (control), BQ‐123 (500nM; ET receptor type A antagonist), BQ‐788 (300nM; ET receptor type B antagonist), or L‐ARG (10mM). After a 10‐min baseline at 33°C, skin temperature was elevated to 39°C for ~30‐min to assess local cutaneous thermal reactivity. L‐NAME (20mM) was then infused at all sites to inhibit nitric oxide (NO) synthase and quantify the NO contribution to the CVC response. Site‐specific maximal cutaneous blood flow was then determined via combined sodium nitroprusside (28mM) infusion and 43°C heating. The CVC response during each stage was calculated as a percent of site‐specific maximum (%CVCmax) while the NO contribution was calculated as a delta between the 39°C plateau and the L‐NAME nadir (Δ%CVCmax). During local heating, BW exhibited blunted CVC responses compared to WW (control: 35.3 ± 28.7 vs. 50.6 ± 8.1 %CVC‐max; BQ‐123: 41.6 ± 12.0 vs. 64.5 ± 9.2 %CVCmax; BQ‐788: 25.9 ± 18.9 vs. 59.5 ± 13.9 %CVCmax; L‐ARG: 29.6 ± 12.1 vs. 54.6 ± 11.9 %CVCmax; respectively; main effect: P = 0.03). BW also exhibited a reduced NO contribution to vasodilation relative to WW (control: 19.4 ± 8.6 vs. 37.6 ± 7.4 Δ%CVCmax; BQ‐123: 30.8 ± 11.8 vs. 47.8 ± 7.6 Δ%CVCmax; BQ‐788: 17.3 ± 14.7 vs. 44.0 ± 14.2 Δ%CVCmax; L‐ARG: 21.5 ± 9.2 vs. 40.0 ± 12.3 Δ%CVCmax; respectively; main effect: P &lt; 0.01). No interactions were noted for either race‐by‐drug comparison (P &gt; 0.05). These preliminary data suggest that BW exhibit blunted NO‐mediated vasodilation to local heating compared to WW. However, individual ET‐1 receptor activity and reduced L‐ARG bioavailability do not appear to influence the blunted dilatory response.Support or Funding InformationResearch Support: ACSM, Texas ACSM, and The University of Texas at Arlington CONHI (JDA)

MPTP-Induced Impairment of Cardiovascular Function.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies and loss of dopaminergic neurons in the substantia nigra pars compacta (SNpC). MPTP is widely used to generate murine PD model. In addition to classical motor disorders, PD patients usually have non-motor symptoms related to autonomic impairment, which precedes decades before the motor dysfunction. This study's objective is to examine the effects of MPTP on noradrenergic neurons in the hindbrain, thereby on the cardiovascular function in mice. Adult mice received 10mg/kg/day of MPTP (4 consecutive days) to generate PD model. Systolic blood pressure was measured by tail cuff system in conscious mice, and baroreflex sensitivity was evaluated by heart rate alteration in response to a transient increase or decrease in blood pressure induced by intravenous infusion of phenylalanine (PE) or sodium nitroprusside (SNP) in anesthetized condition, respectively. Baseline heart rate and heart rate variability were analyzed in both sham and MPTP-treated mice. Dopamine, norepinephrine, and related metabolites in the plasma and brain tissues including SNpC, locus coeruleus (LC), rostroventrolateral medulla (RVLM), and nucleus tractus solitarii (NTS) were measured by liquid chromatography-mass spectrometry (LC-MS). Tyrosine hydroxylase-positive (TH+) neurons in above nuclei were quantified by immunoreactivities. We found that in addition to the loss of TH+ neurons in SNpC, MPTP treatment induced a dramatic reduction of TH+ cell counts in the LC, RVLM, and NTS. These are associated with significant decreases of dopamine, norepinephrine, and epinephrine in above nuclei. Meanwhile, MPTP induced a lasting effect of baroreflex desensitization, tachycardia, and decreased heart rate variability compared to the sham mice. Notably, MPTP treatment elevated sympathetic outflow and suppressed parasympathetic tonicity according to the heart rate power spectrum analysis. Our results indicate that the loss of TH+ neurons in the brainstem by MPTP treatment led to impaired autonomic cardiovascular function. These results suggest that MPTP treatment can be used to study the autonomic dysfunction in murine model.

Comprehensive analysis of effective reflection distance and its association with wave reflection strength under diverse hemodynamic conditions in anesthetized dogs

Pressure wave reflection is associated with cardiovascular risk. The conceptual distance to a theoretical major reflection site, termed effective reflection distance (ERD), has been associated with aging and augmentation index (AIx) clinically. However, it remains unclear whether and how ERD varies and associates with AIx when the hemodynamic condition is acutely perturbed in a patient. The objective of this study was to address this issue in rigorously controlled animal experiments. In 13 anesthetized dogs, we measured arterial pressure, aortic flow and femoral arterial flow, while altering the hemodynamic condition over wide ranges by administering zatebradine (bradycardic agent), nitroprusside (vasodilator), noradrenaline (vasoconstrictor), dobutamine (inotrope), and dextran (volume-expander). Using the measured data, we determined ERD based on an arterial model comprising a tube with a complex frequency-dependent load (ERDTL), which has been considered a physiologically valid model. We also determined ERD based on wave separation (ERDWSA) and pressure-based analyses (ERDAW). ERDTL was shortened significantly in response to nitroprusside or dobutamine infusion, and was significantly and negatively associated with AIx in multiple regression analysis using pooled data. ERDWSA or ERDAW did not necessarily correlate with ERDTL in terms of responses to drug administration or association with AIx. In conclusion, under diverse hemodynamic conditions, ERDTL changes sensitively and shows physiologically reasonable association with AIx. This result substantiates the importance of paying close attention to medications during clinical analysis of wave reflection. Caution is required when using ERDWSA or ERDAW as an alternative to ERDTL.

New non-invasive approach to detect cardiac contractility using the first sound of phonocardiogram.

AimDuring surgery, a non‐invasive and easy‐to‐use method is required for evaluating left ventricular status. The systolic time interval, including pre‐ejection period (PEP), of left ventricle has been known to be correlated with cardiac contractility. In this study, we focused on the non‐invasive time interval from the Q wave of an electrocardiogram to the third component in the first heart sound (QS1‐3rd) and evaluated the correlation between PEP and peak differentiated left ventricular pressure (LV dp/dt).MethodsSix adult anesthetized pigs were intubated. Mechanical ventilation was started. An electrocardiogram, carotid artery blood pressure, left ventricular pressure, and phonocardiogram on the fourth left intercostal space were monitored using a polygraph system. Cardiac output was measured by the thermodilution method. Data were simultaneously measured at baseline and after the infusion of noradrenaline, nitroprusside, esmolol sulfate, and dobutamine, respectively. Data were analyzed by Spearman’s rank correlation coefficient using four‐quadrant plot analysis.ResultsA total of 270 points were simultaneously measured. The QS1‐3rd showed a significant correlation with PEP (QS1‐3rd = 7.62 + 0.92 PEP; ρ = 0.91, P < 0.0001). Concordance rate was 92% between PEP and QS1‐3rd (excluded zones were set within ± 5 ms). Both PEP and QS1‐3rd showed a good correlation with LV dp/dt (LV dp/dt = 3861.3–24.4 PEP; ρ = 0.85, P < 0.0001, LV dp/dt = 3763.6–23.5 QS1‐3rd; ρ = 0.82, P < 0.0001).ConclusionThis non‐invasive and easy‐to‐use hemodynamic parameter (QS1‐3rd) could be helpful for continuous monitoring of left cardiac contraction performance.

Sodium Nitroprusside Infusion for the Treatment of Schizophrenia

Abstract One previous small single-center clinical trial showed that a single intravenous administration of sodium nitroprusside added-on to antipsychotics improved a wide spectrum of schizophrenia (SCZ) symptoms more than placebo, and the improvement persisted for 4 weeks after infusion even though no additional drug was given. Our study attempted to replicate these data in a 4-week, add-on, double-blind, randomized, placebo-controlled trial on 20 patients performed in a site in Romania and a site in Moldova. This study’s sample size and protocol were identical to the previous trial, including patients with a diagnosis of SCZ, within the first 5 years after diagnosis. Patients recruited needed to have a baseline total positive and negative syndrome scale (PANSS) score of 60 or above. Ten participants received a single dose of 0.5 µg/kg/min intravenous sodium nitroprusside over 4 hours, and 10 participants received matching placebo infusion, added-on to antipsychotics. The primary outcomes were the PANSS total score and the PANSS negative subscale. There were no significant between-group differences in PANSS total scores or negative subscale scores during the infusion on daily evaluations for the next 7 days nor on weekly evaluations at weeks 2, 3, and 4. No significant differences were found between the 2 study groups in adverse events. Meta-analyses including all 5 published randomized controlled trials on the topic, representing 155 subjects, do not show a statistically significant benefit of sodium nitroprusside. We conclude that the current evidence does not support the efficacy of sodium nitroprusside in the treatment of SCZ.

Effects of moderate and severe hypocapnia on intracerebral perfusion and brain tissue oxygenation in piglets.

Hypocapnia is a common alteration during anesthesia in neonates. To investigate the effects of hypocapnia and hypocapnia combined with hypotension (HCT) on cerebral perfusion and tissue oxygenation in anesthetized piglets. Thirty anesthetized piglets were randomly allocated to groups: moderate hypocapnia (mHC), severe hypocapnia (sHC), and HCT. Cerebral monitoring comprised a tissue oxygen partial pressure and a laser Doppler probe inserted into the brain tissue as well as a near-infrared spectroscopy (NIRS) sensor placed on the skin, measuring regional oxygen saturation. Hypocapnia was induced by hyperventilation (target PaCO2 mHC: 3.7-4; sHC: 3.1-3.3kPa) and hypotension by blood withdrawal and nitroprusside infusion (mean blood pressure: 35-38mmHg). Data were analyzed at baseline, during (Tr20, Tr40, Tr60) and after (Post20, Post40, Post60) treatment. Compared to baseline, tissue oxygen partial pressure decreased significantly and equally during all treatments (mean [SD] at baseline: mHC 35.7 [32.45]; sHC: 28.1 [20.24]; HCT 25.4 [10.3] and at Tr60: mHC: 29.9 [27.36]; sHC: 22.2 [18.37]; HCT: 18.4 [9.5] mmHg). Decreased laser Doppler flow was detected with all treatments at Tr20 (mHC: 0.9 [0.18]; sHC: 0.88 [0.15]; HCT: 0.97 [0.13] proportion from baseline). Independently of group, regional oxygen saturation varied only after reverting and not during treatment. Blood lactate, pH, HCO3- , and PaO2 increased during treatment with no differences between groups. This animal model revealed reduced cerebral blood flow and brain tissue oxygenation during hypocapnia without detectable changes in regional oxygen saturation as measured by NIRS. Changes occurred as early as during moderate hypocapnia.

Augmentation index in the assessment of wave reflections and systolic loading

BackgroundAugmentation index (AIx) is used to quantify the augmented systolic aortic pressure that impedes ventricular ejection. Its use as an index of wave reflections is questionable. We hypothesize that AIx is quantitatively different from the reflection coefficient under varied physiological conditions. Methods42 datasets of aortic pressure and flow waveforms were obtained during induced hypertension (methoxamine infusion) and vasodilation (nitroprusside infusion) in our mongrel dog experiments (n = 5) and from Mendeley data during various interventions (vasoconstrictors, vasodilators, pacing, stimulation, hemorrhage and hemodilution). Wave reflections and principal components of reflection coefficients were computed for comparison to AIx and heart rate normalized AIx. ResultsPrincipal reflection coefficient, Γ1, increased in hypertension and decreased in vasodilation, hemorrhage and hemodilution. AIx followed the trend in many cases but was consistently lower than Γ1 in almost all the subjects. The Bland-Altman analysis also showed that both AIx and normalized AIx underestimated Γ1. The relationship between augmentation index and reflection coefficient was explained by a linear regression model (r2 = 0.23, p < 0.01) in which AIx followed directional changes in Γ1 and the normalization of AIx resulted in a linear model that explained less variation in the relationship between AIx and Γ1. ConclusionAIx is a reasonable clinical trend indicator, albeit not an accurate surrogate measure of the amount of wave reflections.