Reduction In Systemic Blood Pressure Research Articles

Comparison of dexmedetomidine versus propofol-based anaesthesia for controlled hypotension in functional endoscopic sinus surgery

Background: Increased intraoperative bleeding during functional endoscopic sinus surgery (FESS) affects operative field visibility, which increases both duration of surgery and frequency of complications. Controlled hypotension is an anaesthetic technique in which there is deliberate reduction of systemic blood pressure during anaesthesia. The aim of the study was to compare the efficacy of dexmedetomidine against propofol infusion when used for controlled hypotension during FESS. Methods: A randomised, prospective, and single-blinded study was carried out, which included 80 patients of either sex of ASA grade І & ІІ who underwent elective FESS. Patients were randomly assigned to two groups: Group A (dexmedetomidine), Group B (propofol). Intraoperative mean arterial pressure (MAP), heart rate (HR), surgical grade of bleeding (based on the Fromme– Boezzart scale), and amount of bleeding were recorded. Results: Groups were well matched for their demographic data. There was a statistically significant difference (p < 0.05) between Group A and Group B in heart rate, mean arterial pressure (MAP) and mean total blood loss, with Group A being effectively in controlled on all three parameters during FESS. However, there was no significant difference (p > 0.05) in terms of surgical grade of bleeding between Group A and Group B. Conclusions: Both dexmedetomidine and propofol infusion are efficacious to facilitate controlled hypotension and haemodynamic stability intraoperatively.

Morphine for Refractory Dyspnea in Interstitial Lung Disease: A Phase I Study (JORTC-PAL 05).

Background: Dyspnea is common in interstitial lung disease (ILD) patients and often refractory to conventional treatment. Little is known regarding the safety of systemic morphine in ILD patients. Objective: The objective of this study is to evaluate the safety of a single subcutaneous morphine injection and to determine the recommended dose of morphine for alleviating dyspnea in ILD patients. Design: We conducted a dose-escalation Phase I study for investigating the recommended dose of a single subcutaneous morphine injection to alleviate dyspnea in ILD patients. Setting/Subjects: Eligible subjects were ILD inpatients with dyspnea at rest who were refractory to conventional dyspnea treatment. The morphine doses used were 1 mg and 2 mg in cohort 1 and cohort 2, respectively. The primary endpoint was dose-limiting toxicity, which was defined as (1) respiratory depression, that is, 30% reduction of respiratory rate and 10 Torr increase of PaCO2 compared with baseline; (2) hypotension, that is, 20% reduction of systemic blood pressure compared with baseline and presentation of hypotension-related symptoms; or (3) grade 3, 4, or 5 treatment-emergent adverse events graded by Common Terminology Criteria for Adverse Events (version 4). Results: A total of six patients were enrolled, with three patients each in cohorts 1 and 2. No dose-limiting toxicities were observed; three patients experienced worsened somnolence, but no patients experienced sedation. Conclusion: We conclude that 2 mg of morphine has a tolerable safety profile in ILD patients with dyspnea, and can be tested in further clinical trials.

New Innovations in Treatment and Monitoring of Heart Failure With Guidelines on the Use of Sacubitril/Valsartan and Ivabradine

Background: Heart failure is a clinical syndrome that carries a significant burden of morbidity and is associated with poor long-term prognosis. Treatment of heart failure is constantly evolving, with large amounts of research going into the development of new medications, in the hopes of improving symptom management as well as reducing morbidity and mortality. Area of Uncertainty: One of the major areas of uncertainty regarding recent advances in heart failure management is the applicability of data from existing trials to the geriatric population. The majority of current research focuses on patients in a younger age group with a median age around 60, and there is a lack of randomized control trials assessing efficacy in the geriatric population specifically. Therapeutic Advances: Three new medications are examined in this review: sacubitril/valsartan, ivabradine, and nesiritide. Sacubitril/valsartan is a combination of neprilysin inhibitor and angiotensin receptor blocker that acts to increase natriuretic peptides and block the effect of angiotensin, leading to diuresis and vasodilation. The resultant reduction in systemic blood pressure and intravascular volume leads to decreased cardiac stress. This drug has Class 1B recommendation for the treatment of heart failure with reduced ejection fraction, with superior improvement in cardiovascular mortality and hospitalization rate compared with enalapril. Ivabradine is an If channel inhibitor that allows for selective reduction in heart rate without hindering cardiac contractility. This drug has Class IIa-B recommendation for heart failure with reduced ejection fraction with evidence of reduction in hospital admission rate. Nesiritide is a recombinant human brain natriuretic peptide that causes arterial and venous dilation and suppression of the renin–angiotensin–aldosterone system. Clinical trials have shown that this medication has some positive effect with patients in acute heart failure exacerbation; however, no benefit in long-term management has been shown. Conclusion: As the population of the United States continues to age, the number of patients with heart failure will continue to rise. Understanding the wide range of treatment options available to elderly patients is increasingly important for clinicians. Determining whether any of the new therapeutic options is appropriate for a patient will be a collaborative effort between a clinician and patient and will depend heavily on the patient's comorbidities, functional status, and goals of care.

Enhanced oral bioavailability of nisoldipine-piperine-loaded poly-lactic-co-glycolic acid nanoparticles

AbstractBackground:Piperine helps in the improvement of bioavailability through pharmacokinetic interaction by modulating metabolism when administered with other drugs. Nisoldipine is a substrate for cytochrome P4503A4 enzymes. The study was undertaken to assess the influence of piperine on the pharmacokinetics and pharmacodynamics of nisoldipine nanoparticles in rats.Methods:Optimization studies of nanoparticles were performed using Taguchi L9 orthogonal array, and the nanoparticles were formulated by the precipitation method. The influence of piperine and nanoparticles was evaluated by means of in vivo kinetic and dynamic studies by oral administration in rats.Results:The entrapment efficiency, drug loading, ζ potential, and average particle size of optimized nisoldipine-piperine nanoparticles was 89.77±1.06%, 13.6±0.56%, −26.5 mV, and 132±7.21 nm, respectively. The in vitro release in 0.1 n HCl and 6.8 pH phosphate buffer was 96.9±0.48% and 98.3±0.26%, respectively. Pharmacokinetic studies showed a 4.9-fold increase in oral bioavailability and a >28.376±1.32% reduction in systemic blood pressure by using nanoparticles as compared to control (nisoldipine suspension) in Wistar rats.Conclusion:The results revealed that piperine being an inhibitor of cytochrome P4503A4 enzymes enhanced the bioavailability of nisoldipine by 4.9-fold in nanoparticles.

Feeding during dialysis-risks and uncertainties.

Allowing dialysis patients to eat during the treatment is controversial. It is, therefore, no surprise that practices and policies with respect to intradialytic food consumption vary considerably from unit to unit and from country to country. Those who defend the position of feeding during dialysis reason that intradialytic meals offer a supervised and effective therapy for protein-energy wasting. Those who take the opposite view argue that intradialytic food intake should be avoided for the following three reasons. First, interventional studies show that eating during dialysis causes a clinically significant reduction in systemic blood pressure during the postprandial period and elevates the risk of symptomatic intradialytic hypotension; the latter is associated with increased mortality risk. Second, clinical studies have shown that eating during dialysis interferes with the adequacy of the delivered dialysis, whereas eating 2-3 h before the dialysis session has no impact on the efficiency of the subsequent dialysis treatment. And third, randomized studies show that eating during dialysis focus on the positive outcomes but do not adequately balance this potential benefit against the risk of intradialytic hemodynamic instability and poor quality of delivered dialysis. Even after half a century of providing long-term dialysis, definitive randomized trials that balance risks and benefits of eating during dialysis are missing. These knowledge gaps require randomized trials. Since there is a real possibility of harm with eating during dialysis, we caution that instead of encouraging the widespread use of intradialytic meals, practices and policies should focus on adequate nutrient intake during the interdialytic interval.

Plasma ET-1 Concentrations are Elevated in Patients with Hypertension – Meta-Analysis of Clinical Studies

Background/Aims: A recent study revealed that global overexpression of ET-1 causes a slight reduction in systemic blood pressure. Moreover, heterozygous ET-1 knockout mice are hypertensive. The role of ET-1 in human hypertension was so far not addressed by a strict meta-analysis of published human clinical studies. Methods: We included studies published between January 1, 1990 and February 28, 2017. We included case control studies analyzing untreated essential hypertension or hypertensive patients where antihypertensive medication was discontinued for at least two weeks. Based on the principle of Cochrane systematic reviews, case control studies (CCSs) in PubMed (Medline) and Google Scholar designed to identify the role of endothelin-1 (ET-1) in the pathophysiological of hypertension were screened. Review Manager Version 5.0 (Rev-Man 5.0) was applied for statistical analysis. Mean difference and 95% confidence interval (CI) were shown in inverse variance (IV) fixed-effects model or IV random-effects models. Results: Eleven studies fulfilling our in- and exclusion criteria were eligible for this meta-analysis. These studies included 450 hypertensive patients and 328 controls. Our meta-analysis revealed that ET-1 plasma concentrations were higher in hypertensive patients as compared to the control patients [mean difference between groups 1.57 pg/mL, 95%CI [0.47∼2.68, P = 0.005]. These finding were driven by patients having systolic blood pressure higher than 160 mmHg and diastolic blood pressure higher than 100 mmHg. Conclusions: This meta-analysis showed that hypertensive patients do have elevated plasma ET-1 concentrations. This finding is driven by those patients with high systolic/diastolic blood pressure. Given that the ET-1 gene did not appear in any of the whole genome association studies searching for hypertension associated gene loci, it is very likely that the elevated plasma ET-1 concentrations in hypertensive patients are secondary to hypertension and may reflect endothelial cell damage.

Abstract 119: Anti-hypertensive Effect of Thiazides Shifts From Salt Excretion to Vasorelaxation During Salt Restriction or Volume Depletion

Thiazide derivatives, including hydrochlorothiazide (HCTZ), are specific inhibitors of the Na+-Cl- Co-transporter (NCC) in the kidney distal tubules, and the most commonly used diuretic for the treatment of mild to moderate hypertension. Both renal (natriuretis) and extra renal (vasorelaxation) mechanisms have been proposed as major mediators of blood pressure reduction by HCTZ but the circumstances under which the renal or extra renal mechanism predominates remain unknown . To address these issues, systemic blood pressure was monitored by intra-arterial catheter and computerized tail cuff in transgenic mice lacking NCC under varying conditions. For comparison, mice with pendrin ablation or double deletion of pendrin and NCC were used to ascertain the compensatory role of pendrin in salt reabsorption in response to HCTZ. Pendrin KO mice were the only group which showed enhanced salt excretion in response to HCTZ, with salt excretion increasing by ~30% in pendrin KO vs. WT mice (p<0.05). In mice lacking NCC, HCTZ significantly reduced the systemic blood pressure only during salt restriction and without enhancing salt excretion. In volume depleted but not in volume resuscitated NCC/pendrin dKO mice, HCTZ caused dramatic reduction in systemic blood pressure, with systolic blood pressure decreasing from 72.13± 5.1 at baseline to 51.06 ± 6.6 mm Hg in dKO mice within 20 minutes of HCTZ administration (p<0.01 vs. baseline) with no significant effect in WT mice (p>0.5 vs. baseline) or in salt resuscitated NCC/pendrin dKO mice. There was no enhancement in salt excretion and no reduction in echocardiography-monitored cardiac output in pendrin/NCC dKO mice in response to HCTZ. The antihypertensive effects of HCTZ were abrogated in the presence of paxilline, a specific blocker of BK channel, which is upregulated in arterial vasculature of volume depleted mutant mice. We propose that thiazides reduce blood pressure predominantly via vasorelaxation during salt restriction/volume depletion; whereas, they enhance salt excretion during salt replete state and specifically in conditions associated with pendrin downregulation/inactivation.

Abstract P617: Actions on the Splanchnic Venous System Contribute to 5-HT-induced Hypotension

Infusion of serotonin (5-hydroxytryptamine, 5-HT) into conscious normotensive and hypertensive rats causes a sustained reduction in systemic blood pressure. Imaging studies reveal that the blood pressure fall is closely associated with dilation of the large splanchnic veins (mesenteric, portal and abdominal vena cava), suggesting that active venodilation contributes to the fall in blood pressure. In fact, isolated splanchnic veins dilate directly to 5-HT via activation of the 5-HT 7 receptor, and a 5-HT 7 receptor antagonist prevents the 5-HT induced fall in blood pressure. To determine if the splanchnic venodilation caused by 5-HT is active or passive, anesthetized male Sprague Dawley rats were instrumented with arterial and venous lines for pressure measurements and 5-HT administration, respectively, while splanchnic veins were imaged using the Vevo® 2100 Ultrasound system. Measures were made relative to baselines measures. Within 5 minutes of infusion, 5-HT (25 ug/kg/min) caused an initial fall in portal vein pressure (~8-10% reduction) accompanied by dilation of the portal vein (~40% increase). No changes were seen in the dimensions or pressure of the abdominal vena cava at this time. Mean arterial blood pressure was reduced (>40% reduction). All of these changes were prevented by pretreatment with the 5-HT 7 receptor antagonist SB269970. SB269970 during 5-HT infusion also caused an immediate reversal of changes in blood pressure and venous dimensions. Thus, active dilation of the pre-hepatic splanchnic venous system may be an early cause of 5-HT-induced hypotension. A more chronic experiment was performed in rats that were instrumented with a new dual channel radiotelemeter for concomitant measure of systemic and portal pressure in the conscious state. Within one hour after initiation of 5-HT infusion, portal venous pressure was elevated 38±0.2% above baseline (n=3) versus vehicle infused animals (4±0.3% above baseline; n=3), suggesting an action of 5-HT on intrahepatic venous resistance. Within 24 hours, portal pressure elevation resolved but blood pressure remained reduced. Collectively these data highlight the portal venous circulation as an important site of action for 5-HT in causing acute and chronic falls in systemic blood pressure.

Cardiovascular function, compliance, and connective tissue remodeling in the turtle, Trachemys scripta, following thermal acclimation.

Low temperature directly alters cardiovascular physiology in freshwater turtles, causing bradycardia, arterial hypotension, and a reduction in systemic blood pressure. At the same time, blood viscosity and systemic resistance increase, as does sensitivity to cardiac preload (e.g., via the Frank-Starling response). However, the long-term effects of these seasonal responses on the cardiovascular system are unclear. We acclimated red-eared slider turtles to a control temperature (25°C) or to chronic cold (5°C). To differentiate the direct effects of temperature from a cold-induced remodeling response, all measurements were conducted at the control temperature (25°C). In anesthetized turtles, cold acclimation reduced systemic resistance by 1.8-fold and increased systemic blood flow by 1.4-fold, resulting in a 2.3-fold higher right to left (R-L; net systemic) cardiac shunt flow and a 1.8-fold greater shunt fraction. Following a volume load by bolus injection of saline (calculated to increase stroke volume by 5-fold, ∼2.2% of total blood volume), systemic resistance was reduced while pulmonary blood flow and systemic pressure increased. An increased systemic blood flow meant the R-L cardiac shunt was further pronounced. In the isolated ventricle, passive stiffness was increased following cold acclimation with 4.2-fold greater collagen deposition in the myocardium. Histological sections of the major outflow arteries revealed a 1.4-fold higher elastin content in cold-acclimated animals. These results suggest that cold acclimation alters cardiac shunting patterns with an increased R-L shunt flow, achieved through reducing systemic resistance and increasing systemic blood flow. Furthermore, our data suggests that cold-induced cardiac remodeling may reduce the stress of high cardiac preload by increasing compliance of the vasculature and decreasing compliance of the ventricle. Together, these responses could compensate for reduced systolic function at low temperatures in the slider turtle.

Endovascular treatment of acquired atheromatous aortic arch coarctation.

Acquired aortic coarctation is a rare condition. Its treatment using a percutaneous approach can be challenging, especially when severe calcifications and concomitant aneurysmal disease are present. We report a patient with symptomatic thoracic aorta acquired coarctation and aneurysm that was successfully treated using endovascular technique. After left subclavian artery transposition, a self-expanding endograft was implanted percutaneously, with complete abolishment of the transaortic gradient. Follow-up evaluation at 12 months revealed perfect position of the endograft, persistent reduction of the coarctation, and exclusion of the concomitant aneurysm. A noninvasive pressure reading demonstrated significant systemic blood pressure reduction, with no change in antihypertensive medications.

The role of O-GlcNAc transferase in regulating the gene transcription of developing and failing hearts.

Heart failure treatment currently centers on symptom management, primarily through reductions in systemic blood pressure and fluid retention. The O-linked attachment of β-N-acetylglucosamine to cardiac proteins is increased in cardiovascular disease and heart failure, and O-GlcNAc transferase (OGT) is the enzyme that catalyzes this addition. Deletion of OGT is embryonically lethal, and cardiomyocyte-specific OGT knockdown causes the exacerbation of heart failure. Stem cell therapy is currently a major focus of heart failure research, and it was recently discovered that OGT is intricately involved with stem cell differentiation. This article focuses on the relationship of OGT with epigenetics and pluripotency, and integrates OGT with several emerging areas of heart failure research, including calcium signaling.

GW25-e1549 Effects of apocynin and allopurinol on exercise training-upregulated NOS in the kidney of SHR

It has been recently reported that the exercise training (Ex) increases nitric oxide (NO) production and NO synthase (NOS) expression not only in vasculatures but also in the kidney of spontaneously hypertensive rats (SHR) with the reduction of systemic blood pressure. H2O2, which is metabolized by

Cerebral oxygenation and hyperthermia

Hyperthermia is associated with marked reductions in cerebral blood flow (CBF). Increased distribution of cardiac output to the periphery, increases in alveolar ventilation and resultant hypocapnia each contribute to the fall in CBF during passive hyperthermia; however, their relative contribution remains a point of contention, and probably depends on the experimental condition (e.g., posture and degree of hyperthermia). The hyperthermia-induced hyperventilatory response reduces arterial CO2 pressure (PaCO2) causing cerebral vasoconstriction and subsequent reductions in flow. During supine passive hyperthermia, the majority of recent data indicate that reductions in PaCO2 may be the primary, if not sole, culprit for reduced CBF. On the other hand, during more dynamic conditions (e.g., hemorrhage or orthostatic challenges), an inability to appropriately decrease peripheral vascular conductance presents a condition whereby adequate cerebral perfusion pressure may be compromised secondary to reductions in systemic blood pressure. Although studies have reported maintenance of pre-frontal cortex oxygenation (assessed by near-infrared spectroscopy) during exercise and severe heat stress, the influence of cutaneous blood flow is known to contaminate this measure. This review discusses the governing mechanisms associated with changes in CBF and oxygenation during moderate to severe (i.e., 1.0°C to 2.0°C increase in body core temperature) levels of hyperthermia. Future research directions are provided.

Measuring cerebrovascular reactivity: what stimulus to use?

Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasodilatory or vasoconstrictive stimulus. Measuring variations of cerebrovascular reactivity between different regions of the brain has the potential to not only advance understanding of how the cerebral vasculature controls the distribution of blood flow but also to detect cerebrovascular pathophysiology. While there are standardized and repeatable methods for estimating the changes in cerebral blood flow in response to a vasoactive stimulus, the same cannot be said for the stimulus itself. Indeed, the wide variety of vasoactive challenges currently employed in these studies impedes comparisons between them. This review therefore critically examines the vasoactive stimuli in current use for their ability to provide a standard repeatable challenge and for the practicality of their implementation. Such challenges include induced reductions in systemic blood pressure, and the administration of vasoactive substances such as acetazolamide and carbon dioxide. We conclude that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time. We suggest that carbon dioxide is the most suitable vasoactive stimulus. We describe recently developed computer-controlled MRI compatible gas delivery systems which are capable of administering reliable and repeatable vasoactive CO2 stimuli.

Abstract 373: Impacts of Apocynin and Allopurinol on Exercise Training-increased Nitric Oxide Synthase Activity and Expression in the Kidney of SHR and WKY

It has been recently reported that the exercise training (Ex) increases nitric oxide (NO) production and NO synthase (NOS) expression not only in vasculatures but also in the kidney of spontaneously hypertensive rats (SHR) with the reduction of systemic blood pressure. To clarify the mechanism of the Ex-increased NOS expression, the impacts of inhibitors of NADPH oxidase and xanthine oxidase on the Ex-increased NOS activity and expression were examined in SHRs and Wistar-Kyoto rats (WKY). Five week-old, male SHR or WKY were trained with treadmill running. Apocynin (2 mmol/L in drinking water), an inhibitor of NADPH oxidase or allopurinol (1.5 mmol/L in drinking water), an inhibitor of xanthine oxidase was given for drug treatments. After 8 weeks, H2O2 and NO2/NO3 (NOx) in plasma and urine were measured. The NOS activity and expression were examined in the kidney cortex, the outer medulla, the inner medulla and thoracic aorta. In both SHR and WKY, the Ex significantly increased H2O2 and NOx in plasma and urine, NOS activity and endothelial and neuronal NOS (eNOS and nNOS) expressions in the kidney cortex, the outer medulla, the inner medulla and thoracic aorta (p<0.01 in each). Apocynin significantly decreased basal levels of H2O2 and NOx in plasma and urine, NOS activity and eNOS and nNOS expressions (p<0.01 in each) in the kidney sections and aorta of SHR, but did not affect all parameters in those of WKY. Apocynin blocked the Ex-induced changes of H2O2 and NOx levels and renal and aortic NOS activity and expression in WKY and aortic NOS activity and expression in SHR, but it did not block the Ex-induced changes of H2O2 and NOx levels or renal NOS activity and expression in SHR. In contrast to apocynin, allopurinol did not affect basal levels of all these parameters in SHR or WKY. Allopurinol blocked the Ex-induced changes of H2O2 and NOx levels and renal NOS expression in SHR but did not block the Ex- induced changes of aortic NOS expression in SHR or all parameters in WKY. These results indicate that the Ex-increased NOS activity and expression in aorta were mediated through NADPH oxidase in both SHR and WKY. The Ex-induced NOS activity and expression in the kidney were mediated through NADPH oxidase in WKY but through xanthine oxidase in SHR.

Acute hemodynamic effects of erythropoietin do not mediate its cardioprotective properties

SummaryActivation of nitric oxide (NO) signaling is considered, at list partially, a mechanistic basis for EPO-induced cardioprotection. Surprisingly, hemodynamic response subsequent to NO activation after EPO administration has never been reported. The objectives of this study were to evaluate the acute hemodynamic and cardiovascular responses to EPO administration, to confirm their NO genesis, and to test the hypothesis that EPO-induced cardioprotection is mediated through cardiovascular changes related to NO activation. In Experiment 1, after 3000 U/kg of rhEPO was administered intravenously to Wistar rats, arterial blood pressure, monitored via indwelling catheter, progressively declined almost immediately until it leveled off 90 minutes after injection at 20% below control level. In Experiment 2 the 25% reduction of mean blood pressure, compared to control group, was observed 2 hours after intravenous injection of either 3000 or 150 U/kg of rhEPO. Detailed pressure–volume loop analyses of cardiac performance (Experiment 3) 2 hours after intravenous injection of human or rat recombinant EPO (3000 U/kg) revealed a significant reduction of systolic function (PRSW was 33% less than control). Reduction of arterial blood pressure and systolic cardiac function in response to rhEPO were blocked in rats pretreated with a non-selective inhibitor of nitric oxide synthase (L-NAME). In Experiment 4, 24 hours after a permanent ligation of a coronary artery, myocardial infarction (MI) measured 26±3.5% of left ventricle in untreated rats. MI in rats treated with 3000 U/kg of rhEPO immediately after coronary ligation was 56% smaller. Pretreatment with L-NAME did not attenuate the beneficial effect of rhEPO on MI size, while MI size in rats treated with L-NAME alone did not differ from control. Therefore, a single injection of rhEPO resulted in a significant, NO-mediated reduction of systemic blood pressure and corresponding reduction of cardiac systolic function. However, EPO-induced protection of myocardium from ischemic damage is not associated with NO activation or NO-mediated hemodynamic responses.

Dietary Nitrate Ameliorates Pulmonary Hypertension

Background— Pulmonary hypertension (PH) is a multifactorial disease characterized by increased pulmonary vascular resistance and right ventricular failure; morbidity and mortality remain unacceptably high. Loss of nitric oxide (NO) bioactivity is thought to contribute to the pathogenesis of PH, and agents that augment pulmonary NO signaling are clinically effective in the disease. Inorganic nitrate (NO 3 − ) and nitrite (NO 2 − ) elicit a reduction in systemic blood pressure in healthy individuals; this effect is underpinned by endogenous and sequential reduction to NO. Herein, we determined whether dietary nitrate and nitrite might be preferentially reduced to NO by the hypoxia associated with PH, and thereby offer a convenient, inexpensive method of supplementing NO functionality to reduce disease severity. Methods and Results— Dietary nitrate reduced the right ventricular pressure and hypertrophy, and pulmonary vascular remodeling in wild-type mice exposed to 3 weeks of hypoxia; this beneficial activity was mirrored largely by dietary nitrite. The cytoprotective effects of dietary nitrate were associated with increased plasma and lung concentrations of nitrite and cGMP. The beneficial effects of dietary nitrate and nitrite were reduced in mice lacking endothelial NO synthase or treated with the xanthine oxidoreductase inhibitor allopurinol. Conclusions— These data demonstrate that dietary nitrate, and to a lesser extent dietary nitrite, elicit pulmonary dilatation, prevent pulmonary vascular remodeling, and reduce the right ventricular hypertrophy characteristic of PH. This favorable pharmacodynamic profile depends on endothelial NO synthase and xanthine oxidoreductase -catalyzed reduction of nitrite to NO. Exploitation of this mechanism (ie, dietary nitrate/nitrite supplementation) represents a viable, orally active therapy for PH.

Renal sympathetic nerve ablation for the treatment of difficult-to-control or refractory hypertension in a haemodialysis patient

Haemodialysis patients show sympathetic hyperactivity. Hyperactivation of the sympathetic nervous system aggravates hypertension and it is related to left ventricular hypertrophy, heart failure, arrhythmias and atherogenesis. We report the first use of renal sympathetic nerve ablation for correction of uncontrolled hypertension in an end-stage renal disease patient on maintenance dialysis. We observed a progressive and sustained reduction of systemic blood pressure. Our case demonstrates the safety, the feasibility and the efficacy of this procedure. These findings suggest, however, that further clinical trials are needed into renal nerve radiofrequency ablation therapy for the treatment of hypertension and for the improvement of cardiovascular prognosis in this high-risk patient group.

Hemodynamic Stability After Intraarterial Injection of Verapamil for Cerebral Vasospasm

Vasospasm after subarachnoid hemorrhage is a common and potentially life-threatening complication. Treatment of vasospasm may include intraarterial (IA) injections of verapamil into the cerebral vasculature. Clinical experience suggests that the average patient experiences an acute reduction in systemic blood pressure after IA verapamil. Our study objective was to (1) identify the effects of IA injection of verapamil on mean arterial blood pressure (MAP) and heart rate (HR) in patients with cerebral vasospasm and (2) determine the effect of verapamil dose on change in MAP and HR. We hypothesized that (1) selective IA injection of verapamil for treatment of cerebral vasospasm is associated with a reduction in MAP and an increase in HR and (2) the change in MAP and HR are linearly related to the dose of verapamil administered. We prospectively studied subjects with vasospasm scheduled for cerebral angiography with possible IA injection of verapamil. All subjects were given a general anesthetic. Invasive arterial blood pressure and HR were monitored continuously and recorded at 10-second intervals throughout the procedure. We identified the lowest MAP and highest HR before and after verapamil injection. The association between IA verapamil and change in MAP and HR was determined using repeated-measures multivariate regression analysis, adjusting for potential confounding factors (weight, preoperative vasopressor use, and preinjection MAP). Data are reported as adjusted coefficients and 95% confidence intervals (CI). We included 20 subjects who underwent a total of 46 injections of IA verapamil. On the basis of our multivariate model, on average, each 5 mg of IA verapamil was associated with a 3.5 mm Hg reduction in MAP (95% CI -5.0 to -2.0, P < 0.001). HR was not significantly altered by IA verapamil on both unadjusted and adjusted analyses (nonsignificant increase of 0.4 beats per minute for each 5 mg of IA verapamil, 95% CI -1.6 to 2.4, P = 0.70). Under general anesthesia, injection of IA verapamil into cerebral arteries reduces MAP but does not change HR in the average patient. Further research is required to determine the clinical significance of these results.

Immunotherapy for Acute Kidney Injury

Acute renal failure, now referred to as acute kidney injury, is a common and clinically important problem. Acute kidney injury frequently occurs as a result of acute tubular necrosis (ATN), which is often caused by a reduction in systemic blood pressure or renal blood flow (e.g., as observed in severe sepsis or during renal transplantation). The disease course in ATN is variable, including prolonged dialysis-dependence and chronic renal dysfunction, but there is currently no specific therapy for ATN. There is increasing evidence that the inflammatory response in ATN significantly contributes to disease severity and outcome. In this review, we summarize recent developments in the understanding of how the immune system responds to dying cells, and the relevance of these discoveries to ATN. In particular, NLRP3 inflammasome activation and IL-1β-mediated neutrophil recruitment are likely to play a key role and may provide novel therapeutic targets for immunotherapy in ATN.