Canadian journal of physiology and pharmacology最新文献

Hypertrophic cardiomyopathy (HCM) is a relatively common heritable cardiac condition (~1 in 500) that can significantly reduce quality and quantity of life. Severe symptoms are often from dynamic left ventricular outflow tract (LVOT) obstruction which may result in dyspnea, chest pain, fatigue, and (pre)syncope. This obstructive phenotype is present in more than half of cases. Traditional pharmacological therapies used to treat symptomatic LVOT obstruction are ineffective in many patients thereby necessitating septal reduction therapy in the form of alcohol septal ablation or surgical myectomy. In recent years, the demand for improved HCM treatment without surgical intervention has led to the development of a new class of drugs called cardiac myosin inhibitors. Mavacamten represents the first-in-class cardiac myosin inhibitor, which is now approved in Canada, available for special authorization cost coverage in most provinces, and is increasingly being prescribed in both specialized HCM programs and general cardiology clinics. As such, many general cardiologists, internists, and family physicians will need to be familiar with these agents. This review on the myosin inhibitors, particularly mavacamten, provides a perspective for more general cardiovascular providers by summarizing the key mechanisms, clinical trials, expected outcomes, and potential impacts on the Canadian healthcare system.

Hyperhomocysteinemia can induce significant alterations in the cardiovascular system, and vitamin B6 is one of the primary cofactors of enzymes involved in homocysteine metabolism. The aim of this study was to examine the effects of vitamin B6 in hyperhomocysteinemic conditions on cardiovascular biomarkers in sera, oxidative stress parameters, metabolic enzymes activities, and histological changes in rat heart and aorta. Male Wistar albino rats were divided into four groups (n = 10, per group): C: 0.9% NaCl 0.2 mL/day s.c. + 0.9% NaCl 0.5 mL i.p; H: D, L-homocysteine 0.45 mmol/g b.w./day s.c. + 0.9% NaCl 0.5 mL i.p; CB6: 0.9% NaCl 0.2 mL/day s.c. + vitamin B6 7 mg/kg b.w. i.p.; and H-B6: D, L-homocysteine 0.45 mmol/g b.w./day s.c. + vitamin B6 7 mg/kg b.w. i.p. Substances were applied s.c. for 2 weeks and i.p for 4 weeks. Level of homocysteine, activity of superoxide dismutase, concentration of malondialdehyde, and right ventricle wall thickness were significantly lower in HB6 group compared to H group, while lactate dehydrogenase activity was higher in HB6 group compared to all other groups. These findings suggest the potential beneficial effects of vitamin B6 supplementation on cardiovascular system in patients with hyperhomocysteinemia.

The Guest Editors provide highlights and overview of the eCollection which was based on the International Academy of Cardiovascular Sciences-North American Section (IACS-NAS) 2023 annual meeting. The overall impact generated by the papers published in eCollection with emphasis on cutting edge topics including FDA-Adverse Event Reporting System (FAERS), ChatGPT and physician recommendation, small molecule research, sarcopenia and aging, metabolism, and orphan receptors and weight loss. The editorial overview provides insights into the continued success of the eCollection.

The present study was designed to investigate the role of PERK in CVD risk associated with polycystic ovarian syndrome (PCOS) in experimental rat model, and the therapeutic benefits of probiotics. Eight-weeks-old female Wistar rats were assigned into four groups (n = 6): Control (CTRL), Probiotics (PROB), Letrozole (PCOS), and PCOS + PROB. Daily administration of letrozole (1 mg/kg) for 21 days was used to induce PCOS; thereafter, probiotics (3 × 10⁹ CFU) was administered daily for 6 weeks. Biochemical parameters and histological evaluations were performed with appropriate techniques. The present findings revealed that animals with PCOS were characterized with phenotypic features such as hyperandrogenemia and multiple cysts in the ovaries. In addition, PCOS rats manifested insulin resistance and increase in glucose regulatory protein (GRP78), together with increased levels of circulating corticosterone, cardiac triglyceride, inflammatory mediators (NF-κB and TNF-α), TGF-β1, Caspase-6, and HDAC2, while a decrease in HIF-1α and NrF2 was observed when compared with control animals. These were accompanied by elevated level of PERK. However, treatment with probiotics reversed these systemic, endocrine, metabolic, and cardiac anomalies. The present study suggests that probiotics attenuates CVD risk profile in experimental PCOS rat model by suppression of PERK/HDAC2-dependent pathway.

As our understanding of acute coronary syndromes (ACS) has increased, we have been able to better delineate the unique pathologies that cause ACS. This review article on the common causes of ACS in females explores the atherosclerotic pathologies of plaque rupture and plaque erosion, and non-atherosclerotic pathologies of SCAD, MINOCA, and Takotsubo cardiomyopathy. It reviews the literature on the link between estrogen and its protection against both atherosclerotic risk factors and induction of plaque vulnerability. This review also explores the mechanistic plausibility that estrogen may contribute to the increased risk of SCAD, MINOCA, and Takotsubo cardiomyopathy-although these mechanisms remain under investigation. Whilst there is still much to be researched about these pathologies, an analysis of the biological impact of sex hormones at the molecular level has helped identify links between mechanisms suggesting a possible unifying pathology between plaque erosion, MINOCA, and microvascular spasm. In this way, a new paradigm for ACS as an equilibrium between thrombus-stabilisation and thrombus-dissolution states is also explored in this article. What has become evident is that the attempt to understand the common causes of ACS in females has resulted also in a deeper understanding of atherosclerotic ACS in males, and highlighted areas of exciting further discovery.

Pharmacological targeting of ion channels represents a crucial avenue for pain management. The KCNQ family of ion channels plays a significant role in controlling neuronal excitability and the generation and propagation of pain-related nerve impulses, mitigating excessive electrical signaling and limiting the transmission of pain signals. Eugenol has a variety of biological activities, including analgesic and anti-inflammatory properties. When used in conjunction with the anti-inflammatory drug diclofenac, eugenol demonstrates enhanced analgesic efficacy in animal models. We investigated the effects of eugenol on KCNQ ion channels. Eugenol acts as a KCNQ2/3 activator, shifting the voltage dependency to negative potentials, most of the activation can be explained by the effect on the KCNQ3, molecular docking simulation and mutagenesis experiments suggest that the binding pocket of eugenol is located at the top of the voltage-sensing domain. We also show that eugenol is a weak activator of the TRPV1 channel yet inhibits the capsaicin and acidic pH-activated current. Diclofenac also inhibits the TRPV1 channel current. In cells co-expressing KCNQ2/3 and TRPV1, eugenol and diclofenac limit the extent of membrane depolarization. Altogether, we report a new target for eugenol that adds to its wide array of biological activities, including its role in modulating acute pain.

Anaplastic lymphoma kinase (ALK) inhibitors have transformed treatment for ALK-rearranged malignancies, particularly non-small cell lung cancer, by disrupting oncogenic signalling. However, hematologic adverse effects, including hemolysis, have emerged as concerns, especially with alectinib. This study evaluates the prevalence of hemolytic events associated with ALK inhibitors using FDA Adverse Event Reporting System (FAERS) data. A retrospective pharmacovigilance analysis was conducted using FAERS data (2013-2023). Disproportionality analysis with OpenVigil 2.1 assessed associations between ALK inhibitors and hemolysis-related events. Reporting odds ratios (RORs) were calculated, with statistical significance defined as ROR > 2.00 and a lower 95% confidence interval (CI) bound > 1.00. Alectinib exhibited strong associations with hemolysis (ROR 24.01, 95% CI: 17.88-32.24; 45 reports) and bilirubin increase (ROR 18.86, 95% CI: 15.92-22.34; 138 reports). Crizotinib and ceritinib showed weaker signals, while brigatinib and lorlatinib had no significant associations. The findings highlight alectinibs potential hemolytic risk, necessitating hematologic monitoring. Proposed mechanisms include immune-mediated hemolysis, direct cytotoxicity, and metabolic variability. Routine hemoglobin and bilirubin assessments, along with clinical vigilance, are essential. Further studies are needed to elucidate mechanisms of causality and optimize patient safety.

Incretin therapies have revolutionized the management of type 2 diabetes and obesity. Recent evidence suggests that these agents modulate key pathways involved in cardiovascular, renal, hepatic, neuropsychiatric, and reproductive health. In this narrative review, we examine the role of incretin-based therapies in chronic kidney disease, heart failure with preserved ejection fraction, metabolic dysfunction-associated steatotic liver disease, neurodegenerative and cognitive disorders, substance use disorder, obstructive sleep apnea, knee osteoarthritis, and polycystic ovary syndrome. The mechanisms underlying these benefits appear to extend beyond glucose and weight regulation, including anti-inflammatory, neuroprotective, and cardiorenal effects. We summarize key clinical trial data, highlight knowledge gaps, and discuss future directions for integrating incretin-based therapies into broader clinical practice.