Sulforaphane improves vasodilatory reactivity in diaphragm arterioles from rats with pulmonary hypertension

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Pulmonary hypertension (PH) is a chronic, progressive disease characterized by pulmonary vascular remodeling, respiratory muscle and cardiac impairments, and exercise intolerance. Specifically, the diaphragm displays compromised contractile and vascular function, precluding it from meeting the increased metabolic demands of PH-induced chronic hyperpnea. Oxidative stress has been implicated in vascular dysfunction and PH pathology, therefore our objective was to target the antioxidant mediator Nrf2 (Nuclear factor erythroid 2-related factor 2) using sulforaphane (SFN) to determine whether this could improve vascular function in the diaphragm. We hypothesized that incubation with SFN would increase vasodilatory responsiveness in diaphragm arterioles from PH rats. Methods: Female Sprague-Dawley rats were administered monocrotaline (MCT; 50 mg/kg, i.p.) to induce PH. Disease progression was monitored via echocardiography. Once animals developed PH (~3 wks), the diaphragm was removed and first-order arterioles from the medial costal diaphragm were isolated, cannulated, and pressurized at 90 cmH2O. After a 60 min equilibration period and spontaneous tone development, endothelium-dependent and -independent vasorelaxation responses to cumulative doses of acetylcholine (ACh) and sodium nitroprusside (SNP) (10−9 to 10−4 M) were determined. These vessels were subsequently incubated with SFN (10 μM, 20 min), then ACh and SNP dose-response measurements were repeated. Results: All PH rats displayed morphometric and echocardiographic criteria for disease (i.e., right ventricular hypertrophy and reduced pulmonary artery acceleration time). Incubation with SFN improved endothelium-dependent and -independent vasodilation (p<0.05). Maximal vasodilatory responses with SFN were 14% and 16% higher for ACh (30±2 vs 34±3%; P=0.02) and SNP (52±2 vs 60±2%; P=0.03), respectively. However, vasodilatory reactivity remains substantially lower than that of healthy animals. Conclusions: These findings suggest that Nrf2 activation using SFN may improve vascular function in the diaphragm with PH. Future investigations will focus on chronic administration of SFN to PH rats to determine the therapeutic potential of this compound in vivo. The results of these studies provide insight into novel pharmacological strategies to improve diaphragm vascular and contractile function, with the potential to help mitigate dyspnea and exercise intolerance and enhance life quality for PH patients. Sustained Momentum for Investigators with Laboratories Established Grants (TIM & DCP); National Institute on Aging 1R15AG078060 (BJB & DCP); Ruth L. Kirschstein National Research Service Awards 1F31HL167618-01 (AGH) and 1F31HL170643-01 (KMS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.