Vasodilators in the treatment of acute heart failure: what we know, what we don’t

Although we have recently witnessed substantial progress in management and outcome of patients with chronic heart failure, acute heart failure (AHF) management and outcome have not changed over almost a generation. Vasodilators are one of the cornerstones of AHF management; however, to a large extent, none of those currently used has been examined by large, placebo-controlled, non-hemodynamic monitored, prospective randomized studies powered to assess the effects on outcomes, in addition to symptoms. In this article, we will discuss the role of vasodilators in AHF trying to point out which are the potentially best indications to their administration and which are the pitfalls which may be associated with their use. Unfortunately, most of this discussion is only partially evidence based due to lack of appropriate clinical trials. In general, we believe that vasodilators should be administered early to AHF patients with normal or high blood pressure (BP) at presentation. They should not be administered to patients with low BP since they may cause hypotension and hypoperfusion of vital organs, leading to renal and/or myocardial damage which may further worsen patients’ outcome. It is not clear whether vasodilators have a role in either patients with borderline BP at presentation (i.e., low-normal) or beyond the first 1–2 days from presentation. Given the limitations of the currently available clinical trial data, we cannot recommend any specific agent as first line therapy, although nitrates in different formulations are still the most widely used in clinical practice

Cantharidin Enhances Norepinephrine-Induced Vasoconstriction in an Endothelium-Dependent Fashion 1

ABSTRACT In this study we characterized the effects of the protein phosphatase (PP) type 1 and type 2A inhibitor cantharidin (Cant) and its structural analogs cantharidic acid and endothall on PP activity, force of contraction, and myosin light chain phosphorylation in rat aorta. All compounds inhibited PP activity in homogenates of rat aorta with a rank order of potency of Cant ϭ cantharidic acid Ͼ endothall. However, only Cant increased force of contraction and myosin light chain phosphorylation in intact isolated rat aortic rings. Based on these findings, we investigated the effects of Cant on ␣-adrenoceptormediated vasoconstriction. Cant (1 and 3 M) enhanced norepinephrine-induced contraction in endothelium-intact rat aorta. In contrast, Cant did not affect norepinephrine-induced contraction in endothelium-denuded rat aorta. We suggest that inhibition of PP1 and/or PP2A activities by Cant enhances vascular contractility in endothelium-intact rat aorta by increasing the phosphorylation state of endothelial regulatory proteins

Expression of constitutive nitric oxide synthase in rat and human gastrointestinal tract

AbstractThe aim of this study was to determine the expression of constitutive NO synthases (ecNOS and bNOS) at the protein level in rat and human gastrointestinal tract. We established a quantitative Western blotting method for detection and quantification of ecNOS and bNOS in both species. Human gastric fundus was further analyzed by immunohistochemistry. EcNOS expression at the protein level could be quantified in different organs of the rat gastrointestinal tract and in human gastric mucosal biopsies. Immunohistochemistry of gastric fundus revealed that immunoreactivity for ecNOS was localized mainly in the endothelium of small vessels. In rats, expression of bNOS at the protein level was highest in esophagus. By means of immunohistochemistry of human gastric fundus, immunoreactivity was detected mainly in the plexus of Auerbach. We conclude that isoforms of constitutive nitric oxide synthase can be identified and quantified at the protein level both in rat and human gastrointestinal tract. The presence of bNOS in nerve tissue supports previous observations that NO serves as a transmitter in non-adrenergic, non-cholinergic nerves in human esophagus and stomach. The observation that ecNOS has been found mainly in endothelial cells suggests the involvement of NO in the regulation of mucosal blood flow

Renal effects of ularitide in patients with decompensated heart failure

Background: Renal function frequently deteriorates in decompensated heart failure (DHF) patients, and one determinant is reduced renal blood flow. This may, in part, result from low cardiac output (CO), reduced mean arterial pressure (MAP), and venous congestion. The combined impact of both venous congestion (elevated right atrial pressure [RAP]) and low MAP are reflected by a reduced pressure gradient MAP-RAP. This study investigated the renal effects of ularitide, a synthetic version of the renal natriuretic peptide urodilatin in DHF patients. Methods: In SIRIUS II, a double-blind phase II trial, 221 patients hospitalized for DHF (with dyspnea at rest or minimal activity, cardiac index ≤2.5 L/min per square meter, and pulmonary artery wedge pressure ≥18 mm Hg) were randomized to a single 24-hour infusion of ularitide (7.5, 15, or 30 ng/kg per minute) or placebo added to standard therapy. Results: Estimated glomerular filtration rate, serum creatinine, creatinine clearance, and blood urea nitrogen (BUN) were not impaired by ularitide throughout infusion and during a 2-day follow-up period. At 24 hours, 15 ng/kg per minute ularitide reduced BUN levels (-4.07 ± 12.30 vs -0.20 ± 7.50 for placebo, P < .05). Ularitide at 15 and 30 ng/kg per minute rapidly elevated CO with sustained effects. Although 15 ng/kg per minute ularitide preserved the pressure gradient MAP-RAP, 30 ng/kg per minute ularitide reduced MAP-RAP by -7.8 ± 10.6 mm Hg vs -2.4 ± 9.8 mm Hg for placebo (P < .01, at 6 hours). A strong inverse correlation between MAP-RAP and BUN levels (Corr = -0.50579, P = .00015) was observed with 15 ng/kg per minute ularitide. Conclusions: Single 24-hour infusions of ularitide at 15 ng/kg per minute preserved short-term renal function in DHF patients possibly by both elevating CO and maintaining the MAP-RAP pressure gradient. © 2008 Mosby, Inc. All rights reserved