Inhibitions of late INa and CaMKII act synergistically to prevent ATX-II-induced atrial fibrillation in isolated rat right atria.

Aims: Increases in late Na(+) current (late INa) and activation of Ca(2+)/calmodulin-dependent protein kinase (CaMKII) are associated with atrial arrhythmias. CaMKII also phosphorylates Nav1.5, further increasing late INa.

Ambrisentan and tadalafil synergistically relax endothelin-induced contraction of rat pulmonary arteries.

Endothelin receptor antagonists and phosphodiesterase type 5 inhibitors are used to treat pulmonary arterial hypertension. We tested the hypothesis that a selective endothelin type A receptor antagonist (ambrisentan) and a phosphodiesterase type 5 inhibitor (tadalafil) may act synergistically to relax endothelin-constricted pulmonary arteries. Rat isolated intrapulmonary arterial rings contracted with 8 nmol/L endothelin-1 were relaxed by 10 nmol/L ambrisentan and 30 nmol/L tadalafil alone by 26±3% and 21±1%, respectively, whereas both drugs in combination acted synergistically to relax arterial rings by 83±6%.

Darusentan is a potent inhibitor of endothelin signaling and function in both large and small arteries.

Endothelin is a potent vasoconstrictor often up-regulated in hypertension. Endothelin vasoconstriction is mediated via the G-protein coupled endothelin A (ETA) receptor present on vascular smooth muscle. Endothelin receptor antagonists (ERAs) have been shown to antagonize ET-induced vasoconstriction.

Atrial natriuretic peptide suppresses endothelin gene expression and proliferation in cardiac fibroblasts through a GATA4-dependent mechanism.

Aims: Atrial natriuretic peptide (ANP) is a hormone that has both antihypertrophic and antifibrotic properties in the heart. We hypothesized that myocyte-derived ANP inhibits endothelin (ET) gene expression in fibroblasts.

Methods And Results: We have investigated the mechanism(s) involved in the antiproliferative effect of ANP on cardiac fibroblasts in a cell culture model.

B-Type natriuretic peptide inhibited angiotensin II-stimulated cholesterol biosynthesis, cholesterol transfer, and steroidogenesis in primary human adrenocortical cells.

In this study, we demonstrate that B-type natriuretic peptide (BNP) opposed angiotensin II (Ang II)-stimulated de novo cholesterol biosynthesis, cellular cholesterol uptake, cholesterol transfer to the inner mitochondrial membrane, and steroidogenesis, which are required for biosynthesis of steroid hormones such as aldosterone and cortisol in primary human adrenocortical cells. BNP dose-dependently stimulated intracellular cGMP production with an EC(50) of 11 nm, implying that human adrenocortical cells express the guanylyl cyclase A receptor. cDNA microarray and real-time RT-PCR analyses revealed that BNP inhibited Ang II-stimulated genes related to cholesterol biosynthesis (acetoacetyl coenzyme A thiolase, HMG coenzyme A synthase 1, HMG coenzyme A reductase, isopentenyl-diphosphate Delta-isomerase, lanosterol synthase, sterol-4C-methyl oxidase, and emopamil binding protein/sterol isomerase), cholesterol uptake from circulating lipoproteins (scavenger receptor class B type I and low-density lipoprotein receptor), cholesterol transfer to the inner mitochondrial membrane (steroidogenic acute regulatory protein), and steroidogenesis (ferredoxin 1,3beta-hydroxysteroid dehydrogenase, glutathione transferase A3, CYP19A1, CYP11B1, and CYP11B2).

Evidence for functional heterogeneity of circulating B-type natriuretic peptide.

Objectives: These studies describe molecular forms of circulating B-type natriuretic peptide (BNP) as well as their biological activity.

Background: Increased circulating levels of immunoreactive BNP correlate with the severity of heart failure and are considered a sensitive biomarker. However, little is known about the molecular forms of circulating BNP and their biological activity.

B-type natriuretic peptide exerts broad functional opposition to transforming growth factor-beta in primary human cardiac fibroblasts: fibrosis, myofibroblast conversion, proliferation, and inflammation.

The natriuretic peptides, including human B-type natriuretic peptide (BNP), have been implicated in the regulation of cardiac remodeling. Because transforming growth factor-beta (TGF-beta) is associated with profibrotic processes in heart failure, we tested whether BNP could inhibit TGF-beta-induced effects on primary human cardiac fibroblasts. BNP inhibited TGF-beta-induced cell proliferation as well as the production of collagen 1 and fibronectin proteins as measured by Western blot analysis.

Peroxisome proliferator activated receptor (PPAR)alpha agonists inhibit hypertrophy of neonatal rat cardiac myocytes.

The peroxisome proliferator activated receptors (PPARs) appear to have beneficial effects in the cardiovascular system. PPAR gamma has been shown previously to exert an inhibitory effect on cardiac myocyte hypertrophy in vivo and in vitro. Using endothelin to activate the hypertrophic program in neonatal rat cardiac myocytes, we demonstrate that PPAR alpha ligands (fenofibrate and WY14,643) suppress hypertrophy-dependent increases in protein synthesis, cell surface area, and sarcomeric organization in vitro.

Triiodothyronine increases brain natriuretic peptide (BNP) gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes.

Brain natriuretic peptide (BNP) gene expression is a well documented marker of hypertrophy in the cardiac myocyte. Triiodothyronine (T(3)), the bioactive form of thyroid hormone, triggers a unique form of hypertrophy in cardiac myocytes that accompanies the selective activation or suppression of specific gene targets. In this study, we show that the BNP gene is a target of T(3) action.