The Effects of β-Cyclodextrin on Rat Heart Rate, Systole, Diastole, and the Underlying Mechanisms

Abstract

Background: DL-3-n-Butylphthalide (NBP) sodium chloride injection is widely used in treating cerebral ischemia stroke, yet it may lead to adverse effects, including a reduction in heart rate (HR). However, the specific component responsible for affecting cardiac function remains unclear. Aim: This study aimed to elucidate the component of NBP that affects cardiac function and delineate its mechanisms of action. Methods: The Langendorff perfusion system was employed to investigate the effects of NBP and its principal components on the functional parameters of isolated rat hearts. The apoptosis/necrosis assay kit evaluated the impact of β-cyclodextrin (β-CD) on cardiomyocyte apoptosis and necrosis. Furthermore, Di-8-ANEPPS staining was performed to visualize T-tubule disruptions. Finally, patch clamp techniques were employed to examine alterations in L-type calcium channel function. Results: β-CD, rather than butylphthalide, impaired cardiac function. Higher concentrations or longer perfusion times of β-CD resulted in significant reductions in HR (p < 0.05). Moreover, increased concentrations or longer perfusion time of β-CD led to elevated left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) (p < 0.05). β-CD perfusion also decreased the maximal left ventricular pressure rising rate (dp/dt max) and -dp/dt max (p < 0.05). Treatment with different concentrations of β-CD significantly decreased B-cell lymphoma-2 associated X protein (Bax) expression levels and increased cardiomyocyte apoptosis and necrosis rates (p < 0.01). Pre-treatment and post-treatment with cholesterol significantly mitigated β-CD-induced cardiomyocyte necrosis, with post-treatment exhibiting a stronger effect than pre-treatment (p < 0.05). Di-8-ANEPPS staining revealed the stronger concentration-dependent disruption of T-tubule integrity and continuity following β-CD treatment. Furthermore, paracellular administration of β-CD did not alter the current density or activation curve trend of L-type calcium channels but caused a rightward shift in the activation curve. Conclusion: β-CD, a principal component of NBP, induces a reduction in HR, which depends on the concentration and duration of β-CD treatment. The mechanism underlying this effect may involve cardiomyocyte necrosis, T-tubule damage, and modulation of L-type calcium channel function.