Peripheral Arterial Vasodilation Research Articles

Impairment of microvascular endothelial Kir2.1 channels contributes to endothelial dysfunction in human hypertension.

Hypertension is associated with decreased endothelial function through reduced contributions of nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K+ (Kir2.1) channels. The goal of this study was to establish whether these channels contribute to the impairment of endothelial function, measured by flow-induced vasodilation (FIV) in peripheral resistance arteries of humans with hypertension. We measured FIV in vessels isolated from subcutaneous fat biopsies from 32 subjects: normotensive [n = 19; 30.6 ± 9.8 yr old; systolic blood pressure (SBP): 115.2 ± 7 mmHg; diastolic blood pressure (DBP): 75.3 ± 5.7 mmHg] and hypertensive (n = 13; 45.3 ± 15.3 yr old; SBP: 146.1 ± 15.2 mmHg; DBP: 94.4 ± 6.9 mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive adults as demonstrated by a significant reduction in FIV when compared with the normotensive adults. Furthermore, our data suggest that the impairment of FIV in hypertensive adults is partially attributed to a reduction in Kir2.1-dependent vasodilation. Specifically, we show that blocking Kir2.1 with ML133 or functionally downregulating Kir2.1 with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (dnKir2.1) result in a significant reduction in FIV in normotensive subjects but with a smaller effect in hypertensive adults. The Kir2.1-dependent vasodilation was negatively correlated to both SBP and DBP, indicating that the Kir2.1 contribution to FIV decreases as blood pressure increases. In addition, we show that exposing vessels from normotensive adults to acute high-pressure results in loss of Kir2.1 contribution, as high pressure impairs vasodilation. No effect is seen when these vessels were incubated with dnKir2.1. Overexpressing wtKir2.1 in the endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive adults. Our data suggest that hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.NEW & NOTEWORTHY Impairment of endothelial function under high blood pressure is linked to the loss of inwardly rectifying K+ (Kir2.1) channels activity in human resistance arteries, leading to a reduction in flow-induced vasodilation and possibly leading to a vicious cycle between elevation of blood pressure, and further impairment of Kir2.1 function and flow-induced vasodilation.

A Comparative Study of Infusion of Ephedrine and Phenylephrine on Hemodynamic Stability After Spinal Anesthesia in Elderly Patients Undergoing Lower Limb Orthopedic Surgeries.

Background Hypotension during spinal anesthesia occurs due to sympathetic nervous system blockade, resulting in decreased systemic vascular resistance and reduced cardiac output. Due to reduced sympathetic tone, peripheral arterial vasodilatation and blood pooling in lower limbs due to venodilatation occur, reducing preload to the heart and stroke volume. The elderly patients have reduced cardiovascular compensatory mechanisms, increasing the frequency and severity of hypotension due to sympathetic blockade after spinal anesthesia significantly. Vasopressors correct hypotension during the intraoperative period to maintain organ perfusion. Fluids can be administered, and if given excessively, can cause fluid overload and urinary retention. This study aimed to compare the effectiveness of vasopressors, phenylephrine, and ephedrine in maintaining hemodynamic stability intraoperatively through prophylactic infusion after spinal anesthesia in elderly patients for lower limb orthopedic surgeries. Methodology A total of 174 elderly patients aged 60 years and above with American Society of Anesthesiologists (ASA) Classification I and II, undergoing lower limb orthopedic surgeries, enrolled in a randomized comparative study, were allocated into three groups: Group P (phenylephrine, n=58) received 250 mcg phenylephrine in 30 ml normal saline using infusion syringe pump, Group E (ephedrine, n=58) received 30 mg ephedrine in 30 ml normal saline using infusion syringe pump, and Group C (control group, n=58) received mephentermine I/V (6 mg bolus) when the fall in blood pressure was below 30% of baseline without any placebo infusion. Hemodynamic parameters (systolic and diastolic blood pressure, mean arterial pressure (MAP), heart rate) at 15, 10, and 5-minute intervals before spinal anesthesia, and at 3, 6, 9, 12, 15, 20, 25, and 30-minute intervals after spinal anesthesia. The need for rescue doses to treat hypotension after spinal anesthesia was recorded. Result At all time intervals following spinal anesthesia, Group E reported heart rate and systolic blood pressure better than Groups P and C, significantly. At 3, 6, 9, 12, 15, and 25-minute intervals following spinal anesthesia, the diastolic blood pressure in Group E was enhanced significantlythan Groups P and C. The MAP in Group E was substantially higher than in other groups at 3, 6, 15, and 20-minute intervals following spinal anesthesia, which was statistically significant. Compared to Groups P and C, Group E required lesser rescue doses to treat intraoperative fall in hypotension 30% below baseline and lesser events of bradycardia. Conclusion Following spinal anesthesia, the preload to the heart is to be maintained with intravenous (crystalloid or colloidal) solutions to maintain cardiac output adequately. Intraoperative use of phenylephrine and ephedrine as a low-dose prophylactic infusion can be used, as it increases both systemic vascular resistance and preload without cardiac stimulation along with intravenous solutions to maintain hemodynamic parameters such as systolic and diastolic blood pressure, MAP, heart rate effectively but preferably ephedrine in elderly patients.

Abstract 13315: Recurrent Cardiac Tamponade Due to Minoxidil Associated Drug Induced Lupus Erythematosus

Case description A 59 year old man with history of MGUS, CKD stage 2, DM, HTN, and OSA presented with gradual worsening of dyspnea and intermittent dizziness over the past few days. Echocardiography showed diastolic collapse of the RV, RA collapse, IVC plethora, marked tricuspid in-flow velocities, and pericardial effusion suggestive of cardiac tamponade (CT). Subxiphoid pericardial window was emergently performed. Serosanguineous fluid 900 mL was drained, and fluid analysis was negative for malignancy or infection. Pericardial biopsy revealed fibro-connective tissue with mild peri-vascular chronic inflammation. He significantly improved and was discharged after 5 days. One month later, he presented again with 1 day symptom of severe dyspnea due to recurrent pericardial effusion with CT physiology. Emergent pericardiocentesis was performed to remove 1,800 ml of serous fluid. Serologic workup for autoimmune disease was strongly positive for anti-histone antibody. ESR (124 mm/hr) and c-reactive protein (5.8 mg/dL) were elevated. Upon review of prescription list, he had been treated for HTN in the past 5 years with minoxidil, amlodipine, lisinopril, and carvedilol. Discussion The use of topical minoxidil, a potent peripheral arterial vasodilator, has been approved for androgenetic alopecia in both men and women for decades, whereas oral minoxidil is limited to refractory hypertension due to side effects such as reflex tachycardia, fluid retention, hypertrichosis, and, rarely, idiosyncratic pericardial effusion. Pericardial effusion was reported in approximately 3-5% of patients receiving minoxidil therapy, which could be attributed to volume overload associated with underlying renal insufficiency. Besides hydralazine, another direct arterial vasodilator commonly implicated in drug-induced lupus erythematosus (DILE), minoxidil also carries a trivial risk of DILE, as suggested by a positive anti-histone antibody and biopsy-proven serositis. Although the association between topical minoxidil and pericardial effusion has never been reported, receding hairline has become a major cosmetic concern and the clinicians should be aware of this rare, but serious, complication associated with minoxidil due to its widespread use.

Overview of the Incidence of Hypotension After Spinal Anesthesia Induction in Sectio Caesarea Patients During Intra Anesthesia at Juanda Kuningan Hospital West Java

Purpose: This study aimed to identify the incidence of hypotension after spinal anesthesia induction in SC patients during intra-anesthesia based on Body Mass Index (BMI), age, and baseline systolic blood pressure at Juanda Kuningan Hospital. Methods: This study used a quantitative descriptive method with a cross sectional approach. The sample in this study were all SC patients with spinal anesthesia techniques who met the criteria. The sampling technique used was purposive sampling with the slovin formula resulting in 90 respondents. And data analysis using univariate analysis. Findings: The results showed that the majority of respondents who experienced mild hypotension with excessive BMI status were 50 respondents (58.8%), the majority of respondents who experienced mild hypotension with early adulthood were 52 respondents (61.2%) and the majority of respondents who experienced mild hypotension with initial systolic blood pressure were at initial systolic blood pressure <120 mmHg and 120-130 mmHg as many as 31 respondents (36.5%). Conclusions: The results of this study illustrate that the majority of respondents will experience hypotension after spinal anesthesia induction. This is because spinal anesthesia can block sympathetic nerves, resulting in a decrease in circulating arterial tone, this condition causes peripheral arterial vasodilation. This vasodilating effect can result in a decrease in vascular resistance (hypotension). For further researchers to be able to develop this study to look for other variables that may be associated with the incidence of hypotension after induction of spinal anesthesia in SC patients so that the results of the study will show more variation.

The Role of Nitric Oxide in the Micro- and Macrovascular Response to a 7-Day High-Salt Diet in Healthy Individuals.

This study aimed to investigate the specific role of nitric oxide (NO) in micro- and macrovascular response to a 7-day high-salt (HS) diet, specifically by measuring skin microvascular local thermal hyperemia and the flow-mediated dilation of the brachial artery, as well as serum NO and three NO synthase enzyme (NOS) isoform concentrations in healthy individuals. It also aimed to examine the concept of non-osmotic sodium storage in the skin following the HS diet by measuring body fluid status and systemic hemodynamic responses, as well as serum vascular endothelial growth factor C (VEGF-C) concentration. Forty-six young, healthy individuals completed a 7-day low-salt diet, followed by a 7-day HS diet protocol. The 7-day HS diet resulted in impaired NO-mediated endothelial vasodilation in peripheral microcirculation and conduit arteries, in increased eNOS, decreased nNOS, and unchanged iNOS concentration and NO serum level. The HS diet did not change the volume of interstitial fluid, the systemic vascular resistance or the VEGF-C serum level. These results indicate that the 7-day HS-diet induces systemic impairment of NO-mediated endothelial vasodilation, while dissociation in the eNOS and nNOS response indicates complex adaptation of main NO-generating enzyme isoforms to HS intake in healthy individuals. Our results failed to support the concept of non-osmotic sodium storage.

Albumin administration in patients with cirrhosis: Current role and novel perspectives.

Mortality in cirrhosis is mostly associated with the development of clinical decompensation, characterized by ascites, hepatic encephalopathy, variceal bleeding, or jaundice. Therefore, it is important to prevent and manage such complications. Traditionally, the pathophysiology of decompensated cirrhosis was explained by the peripheral arterial vasodilation hypothesis, but it is currently understood that decompensation might also be driven by a systemic inflammatory state (the systemic inflammation hypothesis). Considering its oncotic and nononcotic properties, albumin has been thoroughly evaluated in the prevention and management of several of these decompensating events. There are formal evidence-based recommendations from international medical societies proposing that albumin be administered in individuals with cirrhosis undergoing large-volume paracentesis, patients with spontaneous bacterial peritonitis, those with acute kidney injury (even before the etiological diagnosis), and those with hepatorenal syndrome. Moreover, there are a few randomized controlled trials and meta-analyses suggesting a possible role for albumin infusion in patients with cirrhosis and ascites (long-term albumin administration), individuals with hepatic encephalopathy, and those with acute-on-chronic liver failure undergoing modest-volume paracentesis. Further studies are necessary to elucidate whether albumin administration also benefits patients with cirrhosis and other complications, such as individuals with extraperitoneal infections, those hospitalized with decompensated cirrhosis and hypoalbuminemia, and patients with hyponatremia.

Hepatorenal syndrome: new insights about pathogenesis (part 1))

An analysis of literature reviews, clinical studies, experimental research, clinical recommendations from pubmed / Medline and ELIBRARY databases on keywords for“liver cirrhosis”and“hepatorenal syndrome”was carried out. In accordance with modern studies, the idea of the pathophysiology of hepatorenal syndrome was revised in recent years, departing from the assumption that the development of this pathology is associated only with renal hypoperphusion due to the development of peripheral systemic arterial vasodilation. Today, the effect of cardiovascular, immune, endocrine systems, coagulation systems, hematological changes, endothelial dysfunction, reception of drugs and other factors for the development of renal dysfunction is studied.

Cirrhotic ascites: A review of pathophysiology and management

Ascites describes the condition of pathologic fluid accumulation in the peritoneal cavity. Cirrhosis is the most common cause of ascites worldwide, with a half of cirrhotic patients developing ascites within 10 years of diagnosis. The “underfill” and “overflow” theories have traditionally been used to explain the pathogenesis of ascites in cirrhosis. However, with advances in hemodynamic and neurohumoral studies, it has been shown that neither of these theories fully explains the pathophysiologic mechanisms involved. The key roles of portal hypertension and vasodilators such as nitric oxide (NO) in the process of ascites formation have now been recognized. This led to the proposal of the peripheral arterial vasodilatation theory which includes components of both the “underfill” and “overflow” theories. Recently, the role of gut bacteria in the pathogenesis of ascites has been demonstrated. Bacterial translocation is now known to be a key event preceding the onset of ascites. Bacterial DNA and endotoxin have been shown to stimulate NO synthesis. This led to the proposal of a modified version of the vasodilatation hypothesis, “the systemic inflammation hypothesis,” which proposes that translocated bacteria or their products stimulate the release of proinflammatory cytokines which in turn stimulate NO synthesis. Cardiac dysfunction (cirrhotic cardiomyopathy) has also been described in cirrhosis and is believed to contribute to the reduction in effective circulating volume which stimulates renal sodium and water retention. Initial treatment measures include salt restriction and diuretics. Drugs known to reduce glomerular perfusion or directly toxic to the kidneys must be stopped. Initial therapeutic paracentesis should be done in those presenting with tense ascites. There is no need for albumin infusion if the amount of fluid removed is less than 5 liters. For those with refractory ascites, beta-blockers should be stopped. Treatment options include aquaretics; serial large-volume paracentesis with albumin infusion or midodrine in place of albumin; transjugular intrahepatic portosystemic shunt; peritoneovenous shunt; low-flow ascites pump; and liver transplantation.

Abstract 445: Monitoring the Hemodynamic Status During Three Trimesters of Pregnancy and Non-pregnancy Periods

Pregnancy is an important stage in women and is associated with delicate cardiovascular adaptation from non-pregnancy to pregnancy. Maternal hemodynamic changes are made to provide sufficient nutrients and oxygen to support the normal growth of the developing fetus. This study was designed to assess maternal hemodynamic status during three trimesters of pregnancy and non-pregnancy periods. Total 326 women (84 pregnant women and 242 age-matched non-pregnant women of childbearing age) between the ages of 20 and 44 participated in this non-invasive observational study. In this cross-sectional study, enrolled participants underwent blood pressure and radial pressure pulse measurements. In order to compare the hemodynamic status of different subjects, we recorded the systolic and diastolic blood pressure and calculated the first five harmonic amplitudes(C1~C5) and phases(P1~P5) of radial pulse wave using Fourier transform method. Compared with non-pregnant women, the maternal systolic and diastolic blood pressures were lower, and heart rate, C2, C4, and P1 were higher in pregnant women (Table 1). Those hemodynamic changes may be due to decreased arterial stiffness and peripheral arterial vasodilatation in pregnancy. In summary, a series of changes in maternal hemodynamic status can be observed during the trimesters of pregnancy, including lowering blood pressure and increasing harmonics of radial pulse. This study demonstrates the feasibility of non-invasive monitoring of the hemodynamic status of pregnant women, which could be used for early detection of pregnancy disorder.

Apelin and Acetylcholine Activate Distinct Nitric Oxide Signaling Pathways to Cause Endothelium‐Dependent Relaxation of Isolated Coronary Arteries

The peptide, apelin, is expressed in fat cells, endothelial cells, and CNS neurons. Increasing evidence (e.g. inotropic and vasomotor effects) supports a role for apelin in the regulation of the cardiovascular system. Apelin is reported to cause vasodilation in peripheral arteries but the underlying molecular mechanisms are not well understood. In the present study, we investigated the role of nitric oxide (NO) in apelin‐induced relaxation of isolated rat coronary arteries, and compared it with the classic endothelium‐dependent vasodilator, acetylcholine. Receptors for apelin (APJ receptors) were expressed in coronary arteries, as determined by Western blot and RT‐PCR analysis (n=3). Immunofluorescence staining and confocal microscopy demonstrated the presence of APJ receptors on endothelial and smooth muscle cells in the coronary arterial wall. In freshly isolated coronary endothelial cells, apelin (10−6 M) caused an increase in DAF‐2 fluorescence that was abolished by nitro‐l‐arginine (3 × 10−5 M; NLA) and F13A (10−7 M), an APJ receptor antagonist, consistent with an increase in NO production. In coronary arterial rings contracted with 5‐HT (10−7 M), apelin caused endothelium‐dependent relaxations (pD2=6.90 ± 0.1; Emax=45 ± 6%; n=9) that were abolished in the presence of NLA, F13A, or iberiotoxin (10−7 M; IBTx), as well as in rings contracted with a depolarizing concentration of K+ (40 mM). Neither ODQ (10−5 M) nor DT‐2 (10−6 M), a protein kinase G (PKG) inhibitor, had any effect on apelin‐induced relaxations, and apelin (10−6 M) itself had no effect on intracellular cGMP accumulation in coronary arteries (0.09 ± 0.03 vs 0.05 ± 0.01 pmol/mg; n=4; p>0.05). By contrast, endothelium‐dependent relaxations to acetylcholine (pD2=6.89 ± 0.1; Emax=97 ± 2%; n=8) were inhibited by NLA, ODQ, and DT‐2. Acetylcholine (10−6 M) increased DAF‐2 fluorescence in isolated endothelial cells, and increased cGMP accumulation (0.08 ± 0.04 vs 0.26 ± 0.02 pmol/mg; n=4; p<0.05) in coronary arteries in an NLA‐ and ODQ‐sensitive manner. Patch clamp studies in freshly isolated coronary smooth muscle cells demonstrated that the NO donor, DEA NONOate (10−6 M) caused an increase in large conductance, calcium‐activated K (BKCa) current (peak current density (+80mV) = 53.02 ± 10.4 vs. 90.42 ± 8.6 pA/pF without and with DEA NONOate, respectively; n=6; p<0.05), that was inhibited by IBTx (peak current density = 33.8 ± 5.3 pA/pF; n=6; p<0.05 vs DEA NONOate alone) but not by ODQ (peak current density = 90.2 ± 7.9 pA/pF; n=6; p>0.05 vs DEA NONOate alone). Taken together, the data demonstrate that, in coronary arteries, endothelium‐derived NO causes arterial relaxation via two distinct signaling pathways: 1) which is activated by apelin, is sensitive to changes in membrane potential and requires activation of BKCa channels; this pathway is independent of cGMP formation and may be due to direct activation of BKCa channels by NO; and 2) which is activated by acetylcholine, is cGMP‐dependent and is mediated by activation of PKG. Differential regulation of distinct NO‐signaling pathways may provide opportunities for developing novel therapeutic strategies for the treatment of the coronary arterial dysfunction that often occurs in cardiovascular disease.Support or Funding InformationSupported by a grant from the NIH National Heart, Lung and Blood Institute (HL124338)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The pathophysiology of arterial vasodilatation and hyperdynamic circulation in cirrhosis.

Patients with cirrhosis and portal hypertension often develop complications from a variety of organ systems leading to a multiple organ failure. The combination of liver failure and portal hypertension results in a hyperdynamic circulatory state partly owing to simultaneous splanchnic and peripheral arterial vasodilatation. Increases in circulatory vasodilators are believed to be due to portosystemic shunting and bacterial translocation leading to redistribution of the blood volume with central hypovolemia. Portal hypertension per se and increased splanchnic blood flow are mainly responsible for the development and perpetuation of the hyperdynamic circulation and the associated changes in cardiovascular function with development of cirrhotic cardiomyopathy, autonomic dysfunction and renal dysfunction as part of a cardiorenal syndrome. Several of the cardiovascular changes are reversible after liver transplantation and point to the pathophysiological significance of portal hypertension. In this paper, we aimed to review current knowledge on the pathophysiology of arterial vasodilatation and the hyperdynamic circulation in cirrhosis.

Clinical profile of ascites in children at tertiary care hospital, North Karnataka

Introduction: Ascites is a common clinical problem in children with liver and renal disease. The peripheral arterial vasodilation hypothesis is mostly accepted as the patho-physiological basis of ascites. The most important complication is spontaneous ascitic fluid infection in the form of spontaneous bacterial peritonitis (SBP) and its variants. Objective: To know the incidence, etiology, associated clinical co-morbidities & the outcome (morbidity & mortality) of the hospitalized children with ascites. Materials and Methods: After informed written consent from parents/ guardian, 102 children admitted with ascites irrespective of primary diagnosis were studied at department of Pediatrics, S. Nijalingappa Medical College, Bagalkot. The study was a prospective study and subjects were enrolled consecutively. Detailed history, complete physical examination & routine investigations were done in all patients and were recorded in predesigned proforma. A detailed etiological workup was done. Results: The most common symptoms were abdominal distension (100%), facial puffiness (62.74%), pedal edema (46.08%), & generalized swelling (35.29 %). The most common signs were facial puffiness in 62.74%, pedal edema in 46.07% & anasarca in 35.29% the most common etiology of ascites was dengue fever, followed by nephrotic syndrome. Of the 102 children with ascites, 2 expired (Gaucher’s disease & Wilson’s disease). Conclusion: Prompt and early diagnosis and appropriate management of ascites is warranted to prevent related morbidity and mortality in children.

Nitroglycerine-induced vasodilation in coronary and brachial arteries in patients with suspected coronary artery disease

BackgroundNitroglycerine-induced vasodilation, an index of endothelium-independent vasodilation, is measured for the assessment of vascular smooth muscle cell function or alterations of vascular structure. Both coronary and brachial artery responses to nitroglycerine have been demonstrated to be independent prognostic markers of cardiovascular events. The purpose of this study was to evaluate the nitroglycerine-induced vasodilation in coronary and brachial arteries in the same patients. MethodsWe measured nitroglycerine-induced vasodilation in coronary and brachial arteries in 30 subjects with suspected coronary artery disease who underwent coronary angiography (19 men and 11 women; mean age, 69.0±8.8years; age range, 42–85years). Results and conclusionsThe mean values of nitroglycerine-induced vasodilation in the brachial artery, left anterior descending coronary artery, and left circumflex coronary artery were 12.6±5.2%, 11.6±10.3%, and 11.9±11.0%, respectively. Nitroglycerine-induced vasodilation in the brachial artery correlated significantly with that in the left anterior descending coronary artery (r=0.43, P=0.02) and that in the left circumflex coronary artery (r=0.49, P=0.006). There was also a significant correlation between nitroglycerine-induced vasodilation in the left anterior descending coronary artery and that in the left circumflex coronary artery (r=0.72, P<0.001). These findings suggest that vascular smooth muscle cell dysfunction is a systemic disorder and thus impairment of endothelium-independent vasodilation in peripheral arteries and that in coronary arteries are simultaneously present. Nitroglycerine-induced vasodilation in the brachial artery could be used as a surrogate for that in a coronary artery and as a prognostic marker for cardiovascular events.

Ascites in Children.

Ascites is an accumulation of serous fluid within the peritoneal cavity. It is the most common complication of liver cirrhosis. In children, hepatic, renal and cardiac disorders are the most common causes. Portal hypertension and sodium and fluid retention are key factors in the pathophysiology of ascites. Peripheral arterial vasodilatation hypothesis is the most accepted mechanism for inappropriate sodium retention and formation of ascites. Diagnostic paracentesis is indicated in children with newly diagnosed ascites and in children with suspected complications of ascites. Ascitic fluid is evaluated for cell count, protein level, and culture. The serum-ascites albumin gradient (SAAG) is the best single test for classifying ascites into portal hypertensive (SAAG >1.1g/dl) and non-portal hypertensive (SAAG <1.1g/dl). A neutrophil count ≥250 cells/mm3 is highly suggestive of bacterial peritonitis. The treatment of ascites due to non-liver disease depends on the underlying condition. In liver disease, diuretics as monotherapy or dual therapy and salt restriction form the mainstay of treatment in children with mild to moderate ascites. Fluid restriction is helpful in children with hyponatremia. In non-responsive ascites or in children with large ascites, large volume paracentesis (LVP) with albumin infusion should be performed. In children with refractory ascites, LVP with albumin administration, transjugular intrahepatic porto-systemic shunt (TIPS), peritoneo-venous shunting and liver transplantation are other therapeutic modalities that need to be considered.

Hyponatremia in Patients with Cirrhosis of the Liver.

Hyponatremia is common in cirrhosis. It mostly occurs in an advanced stage of the disease and is associated with complications and increased mortality. Either hypovolemic or, more commonly, hypervolemic hyponatremia can be seen in cirrhosis. Impaired renal sodium handling due to renal hypoperfusion and increased arginine-vasopressin secretion secondary to reduced effective volemia due to peripheral arterial vasodilation represent the main mechanisms leading to dilutional hyponatremia in this setting. Patients with cirrhosis usually develop slowly progressing hyponatremia. In different clinical contexts, it is associated with neurological manifestations due to increased brain water content, where the intensity is often magnified by concomitant hyperammonemia leading to hepatic encephalopathy. Severe hyponatremia requiring hypertonic saline infusion is rare in cirrhosis. The management of asymptomatic or mildly symptomatic hyponatremia mainly rely on the identification and treatment of precipitating factors. However, sustained resolution of hyponatremia is often difficult to achieve. V2 receptor blockade by Vaptans is certainly effective, but their long-term safety, especially when associated to diuretics given to control ascites, has not been established as yet. As in other conditions, a rapid correction of long-standing hyponatremia can lead to irreversible brain damage. The liver transplant setting represents a condition at high risk for the occurrence of such complications.

Comparison of peripheral arterial tonometry and flow-mediated vasodilation for assessment of the severity and complexity of coronary artery disease

Noninvasive flow-mediated vasodilation (FMD) is a widely used method to assess endothelial function, but its technical difficulty and problems remain obstacles for use in clinical practice. Reactive hyperemia-peripheral arterial tonometry (RH-PAT) was developed as a simpler and more reproducible method. We compared FMD and RH-PAT in patients with stable angina. Furthermore, the differences in these two techniques according to coronary artery disease (CAD) severity and complexity were also assessed. We consecutively enrolled 80 patients who underwent elective coronary angiography. Endothelial function was assessed before angiography using brachial artery FMD and RH-PAT. The complexity and extent of the coronary lesions were assessed angiographically. The extent of CAD was defined as the number of diseased coronary arteries (>70%) and complexity of CAD was assessed by the SYNTAX score algorithm. In the overall study group (61±9 years, 57% men), the mean FMD was 8.5±5.1% and the mean reactive hyperemia index (RHI) measured by RH-PAT was 1.7±0.4. A significant correlation was observed between FMD and RHI irrespective of sex, diabetes, or presence of CAD. FMD and RHI were significantly lower in patients with multivessel and complex CAD. A receiver-operating characteristic curve analysis showed that both techniques were comparable in terms of predicting the presence of CAD and complexity. Assessment of RH-PAT could be a less operator-dependent and noninvasive method of evaluating vascular endothelial function in patients with stable angina.

G Protein–Coupled Bile Acid Receptor 1 Stimulation Mediates Arterial Vasodilation through a KCa1.1 (BKCa)–Dependent Mechanism

Bile acids (BAs) and BA receptors, including G protein-coupled bile acid receptor 1 (GPBAR1), represent novel targets for the treatment of metabolic and inflammatory disorders. However, BAs elicit myriad effects on cardiovascular function, although this has not been specifically ascribed to GPBAR1. This study was designed to test whether stimulation of GPBAR1 elicits effects on cardiovascular function that are mechanism based that can be identified in acute ex vivo and in vivo cardiovascular models, to delineate whether effects were due to pathways known to be modulated by BAs, and to establish whether a therapeutic window between in vivo cardiovascular liabilities and on-target efficacy could be defined. The results demonstrated that the infusion of three structurally diverse and selective GPBAR1 agonists produced marked reductions in vascular tone and blood pressure in dog, but not in rat, as well as reflex tachycardia and a positive inotropic response, effects that manifested in an enhanced cardiac output. Changes in cardiovascular function were unrelated to modulation of the levothyroxine/thyroxine axis and were nitric oxide independent. A direct effect on vascular tone was confirmed in dog isolated vascular rings, whereby concentration-dependent decreases in tension that were tightly correlated with reductions in vascular tone observed in vivo and were blocked by iberiotoxin. Compound concentrations in which cardiovascular effects occurred, both ex vivo and in vivo, could not be separated from those necessary for modulation of GPBAR1-mediated efficacy, resulting in project termination. These results are the first to clearly demonstrate direct and potent peripheral arterial vasodilation due to GPBAR1 stimulation in vivo through activation of large conductance Ca(2+) activated potassium channel K(Ca)1.1.

Enhanced external counterpulsation improves peripheral resistance artery blood flow in patients with coronary artery disease

Enhanced external counterpulsation (EECP) increases coronary artery perfusion and improves endothelium-dependent vasodilation in peripheral muscular conduit arteries. It is unknown whether vasodilatory capacity is improved in the peripheral resistance vasculature. Here we provide novel evidence from the first randomized, sham-controlled study that EECP increases peak limb blood flow and improves endothelium-dependent vasodilation in both calf and forearm resistance arteries in patients with coronary artery disease.

Cardiac and renal effects of a transjugular intrahepatic portosystemic shunt in cirrhosis

Refractory ascites and recurrent variceal bleeding are among the serious complications of portal hypertension and cirrhosis for which a transjugular intrahepatic portosystemic shunt (TIPS) can be used. Cirrhotic patients have varying degrees of haemodynamic derangement, mainly characterized by peripheral arterial vasodilatation, central underfilling and activation of several vasoactive systems. These changes affect the heart, the lungs and the kidneys in particular. The cardiac effects of TIPS are immediate and are related to the redirection of blood from the splanchnic circulation into the systemic circulation, resulting in worsening of the hyperdynamic circulation with increasing cardiac output and decreasing systemic vascular resistance; further, TIPS may unmask a latent diastolic dysfunction of the heart. However, the renal effects of TIPS seem to be beneficial as renal function tends to improve in patients with the hepatorenal syndrome. The clinical and haemodynamic effects of TIPS have been studied intensively and will be reviewed in the present paper. Considerable knowledge on the effects of TIPS on the pathophysiology of cirrhosis has been gained, but studies on the central haemodynamic effects are warranted to refine the already applied treatments and develop new treatment modalities.

Postmarketing study of efficacy and safety of losartan during the treatment of patients with mild and moderate hypertension: Lothar study

Losartan, the angiotensin type 1 receptor blocker (ARB) exercises its main antihypertensive effect by vasodilatation of peripheral arteries. The aim of this study was to evaluate the antihypertensive effect and safety of losartan in patients with mild and moderate arterial hypertension (AH). This was an open post-marketing study with losartan as monotherapy in previously treated or untreated patients with AH. Primary efficacy parameter was the percentage of patients that achieved target blood pressure after 8-week treatment with a single daily dose of losartan of 50-100 mg. Safety parameters were assessed according to the percentage of adverse events and metabolic effects of therapy. The study included 550 patients with AH (59% female and 41% male), mean age 56.8 +/-11.4 years, BMI = 27 +/- 4 kg/m2. Losartan was applied in 31% of untreated and 69% of previously treatment-resistant patients After 8 weeks target blood pressure was achieved in 67.8% (SBP) and in 81.1% (DBP) of patients, respectively. The mean decrease was 21.8% for SBP and 21.1% for DBP (p < 0.001). Out of all, 65% of patients achieved both target SBP and DBP values. Hydrochlorothiazide was added to the therapy in 11.6% of patients. There were no significant differences in drug efficacy between the entire group and subgroups of patients with diabetes mellitus and impaired renal function (p = ns). Adverse events were rare and metabolic effect was favorable. Monotherapy with losartan in a dosage of 50-100 mg applied during 8 weeks resulted in achieving target values of blood pressure in 65% of patient with mild and moderate hypertension, also including the patients with diabetes mellitus and impaired renal function. Losartan is a safe and metabolically neutral medication.