Journal of Cardiovascular Pharmacology最新文献

Abstract: Postural orthostatic tachycardia syndrome (POTS) is a clinical syndrome of tachycardia on standing leading to palpitations, dizziness, chest pain, and/or fatigue. An exaggerated norepinephrine response with standing is often present in POTS, but it remains unclear whether the tachycardia is compensatory for a reduced stroke volume or whether the tachycardia is itself causing the symptoms of POTS. We herein report the effects of heart rate (HR) lowering with ivabradine, a selective I f channel blocker, on symptom burden in patients with POTS. After ivabradine treatment, there was a significant reduction in the change in HR with standing in all patients from 40 (30-70) to 15 (8-19) bpm ( P = 0.011), without significant changes in blood pressure. The Malmö score was significantly reduced in all patients from 86 (74-92) to 39 (32-66) ( P = 0.005). A correlation between change in HR with standing and the change in Malmö score (R = +0.828; R 2 quadratic = 0.635; P < 0.001) was present. The parallel improvement in HR response and symptoms with ivabradine suggests that the tachycardia response in POTS may not be considered compensatory but rather central to the pathophysiology of POTS symptoms.

Abstract: Flavin adenine dinucleotide (FAD), a cofactor that catalyzes the reaction of flavin protein, participates in fatty acid β-oxidation, which has been shown to inhibit pathological cardiac hypertrophy and fibrosis in spontaneously hypertensive rats. However, the therapeutic advantage of FAD for heart failure (HF) treatment has not been investigated. This study aimed to explore the effects and underlying mechanisms of FAD in a transverse aortic constriction-induced HF mouse model and in vitro tert-butyl hydroperoxide (tBHP)-induced cardiomyocyte apoptosis model experiments. FAD considerably inhibited tBHP-induced cardiomyocyte apoptosis. In addition, FAD significantly increased the activity and expression of the short-chain acyl-CoA dehydrogenase enzyme and adenosine triphosphate (ATP) content while reducing the content of free fatty acids and reactive oxygen species both in vitro and in vivo. Meanwhile, FAD increased the mitochondrial membrane potential, suppressed mitochondrial membrane swelling, and decreased myocardial fibrosis and TUNEL-positive apoptosis cells in the TAC-induced HF mice. In conclusion, our results indicate that FAD plays a positive role in preventing and treating HF, which can be attributed in part to the activation of short-chain acyl-CoA dehydrogenase.

Abstract: Oxytocin (OT) has been shown to provide myocardial protection against ischemia-reperfusion (I/R) injury. This study investigates the involvement of muscarinic receptors in the OT-induced cardioprotection, focusing on its potential mechanisms and effects on myocardial infarction (MI) and ischemic arrhythmias. Male rats anesthetized with pentobarbital sodium were subjected to 25-minute ischemia followed by 120-minute reperfusion after intraperitoneal administration of OT (0.01 μg), atropine (1.5 µg/kg), or saline. Cardioprotection was evaluated by monitoring lactate dehydrogenase, malondialdehyde, and cardiac creatine kinase isoenzyme levels, infarct size, arrhythmia severity, ventricular fibrillation (VF), and mortality. OT markedly reduced infarct size, oxidative stress, and the severity of ischemic arrhythmias, including ventricular tachycardia and VF, compared with saline-treated I/R animals. OT also significantly improved survival rates. Pretreatment with atropine abolished most protective effects of OT but did not significantly alter its suppression of VF, suggesting the involvement of muscarinic receptor-independent mechanisms. These findings highlight that the OT-induced cardioprotection, mediated in part by acetylcholine locally released in the left ventricle, extends beyond infarct limitation to include potent antiarrhythmic effects. The dual impact of OT on MI and arrhythmias provides insights into the mechanisms underlying its preconditioning effect and its potential application in MI management.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Dissociation of tetrameric transthyretin (TTR) is the triggering event in the pathogenic mechanism; destabilizing TTR mutations accelerate the process. The TTR stabilizers, tafamidis and acoramidis, are the only FDA approved treatments for patients with ATTR-CM. By mimicking the stabilizing characteristics of the super-stabilizing, disease-protecting variant T119M, we hypothesize that acoramidis displays differential TTR binding, kinetic stability, and tetramer stabilization compared with other TTR stabilizers, such as tafamidis and diflunisal. The TTR binding affinity and thermodynamic stability of TTR interaction of acoramidis and tafamidis were assessed by surface plasmon resonance (SPR) and microscale thermophoresis (MST). Tetrameric TTR stabilization by acoramidis, tafamidis, and diflunisal in the presence of plasma proteins against acidic denaturation was measured by immune blots. In kinetic studies, SPR demonstrated 4 times longer residence time for acoramidis bound to TTR compared with tafamidis. The dissociation constants were consistent with those determined by equilibrium measurements in MST. The affinity of acoramidis for purified TTR, as measured by MST, was 4 times higher than that of tafamidis. When tested at clinically relevant plasma concentrations, acoramidis stabilized TTR against acidic denaturation to a much higher extent (≥90%) than tafamidis or diflunisal. Of note, both tafamidis and diflunisal demonstrated partial stabilization of tetrameric TTR. Relative to other stabilizers, acoramidis is more potent as independently assessed by TTR binding affinity, kinetic stability, and acid-mediated denaturation. These properties may contribute to the ability of acoramidis to achieve near-complete stabilization of TTR in plasma samples.

Abstract: Hydrogen sulfide (H 2 S), an important gaseous signaling molecule, plays a critical role in maintaining vascular homeostasis. H 2 S participates in numerous biological functions, including redox regulation, interactions with other signaling molecules, and post-translational modifications of proteins through sulfhydration. Additionally, H 2 S influences key pathological processes such as inflammation, oxidative stress, and cell apoptosis. Dysregulation of endogenous H 2 S metabolism has been closely linked to the development of various vascular diseases, including aortic aneurysms, aortic dissection, atherosclerosis, and thrombotic conditions. Various endogenous and exogenous H 2 S donors have been developed, and these donors have demonstrated promising effects in preclinical models of vascular diseases such as atherosclerosis, pulmonary hypertension, and thrombosis by modulating oxidative stress, inflammatory pathways, and vascular remodeling. This review consolidates the current knowledge on the effects of H 2 S on vascular function and offers a comprehensive summary of recent advancements in the development and application of H 2 S donors in vascular disease research.

To identify the functional roles of human H1-histamine and H2-histamine receptors when they coexist in the heart, we crossbred mice that overexpressed human H1-histamine receptors only in the heart (H1-TG) with mice that overexpressed human H2-histamine receptors only in the heart (H2-TG) to obtain double transgenic mice (H1xH2-TG) and compared them with wild type (WT) mice. We measured the force of contraction (FOC) in isolated, electrically stimulated left atrial (LA) preparations and spontaneously beating right atrial (RA) preparations. We noted that when cumulatively applied (1 nM - 30 µM), histamine did not affect the force of contraction in the LA of WT mice. In H1xH2-TG mice, low concentrations (30 nM - 1 µM) of histamine increased the FOC in the LA, whereas higher concentrations (3 µM, 10 µM, 30 µM) of histamine reduced the FOC in the LA. Likewise, histamine in low concentrations (10 nM and higher) increased the beating rate in the RA, while higher concentrations of histamine (3 µM, 10 µM) reduced the beating rate in the RA. Dimaprit, an H2-histamine receptor agonist increased the force of contraction in the LA of H1xH2-TG mice but not in the LA of WT mice. 2-2-thiazol-ethan-amine (ThEA) an H1-histamine receptor agonist, increased the FOC in the LA of H1xH2-TG mice but not in the LA of WT mice. These data indicate that histamine, at least under our experimental conditions, at lower concentrations activates cardiac H2-histamine receptors, and at higher concentrations activated H1-histamine receptors.

Cardiac hypertrophy, initially referred to as an adaptive response, would gradually transit to decompensated states over time, contributing to hypertension, and ultimately heart failure under salt overload. The cellular and molecular mechanisms driving salt-induced cardiac hypertrophy, as well as the signaling pathways responsible for this shift from compensation to decompensation, still remain insufficiently understood. Transient receptor potential vanilloid 4 (TRPV4) is ubiquitously expressed in cardiomyocytes, participating in cardiac remodeling and dysfunction. This study investigated TRPV4-relevant mechanisms in salt-induced cardiac hypertrophy. Knockdown of TRPV4 with cardiac gene transfer of Lv-shTRPV4 attenuated salt-induced cardiac hypertrophy, ROS generation, perivascular fibrosis and Akt & mTOR phosphorylation in adult rats. The in vitro results suggest that exposing cardiomyocytes to high-salt induced a concentration-dependent increase in autophagy, which was initially a rising phase and later followed by a declining phase. Salt-induced autophagic activity was enhanced by inhibiting Class I PI3-Kinase (PI3KC1) with LY294002 or Akt with AZD5363, but got undermined by AMPK inhibition with Compound C (CC) or SIRT1 inhibition with EX-527. Additionally, blockade of PI3KC1/Akt pathway significantly attenuated high salt-induced ROS generation and cardiac hypertrophy, whilst blockade of AMPK/SIRT1 pathway exacerbated high salt-induced cardiac hypertrophy via ROS accumulation. Thus, both PI3KC1 and AMPK signaling pathways participate in salt-induced cardiac hypertrophy via shared upstream component of TRPV4: lower salt triggers AMPK, scavenges ROS, preventing cardiac hypertrophy, whilst higher salt activates PI3KC1 with opposite effects. Our findings illuminate potential therapeutic effects of interfering TRP-related channels on high salt-induced hypertrophy and other mechanical stretch force-associated diseases.