Effects of Acute and Chronic Gabapentin Treatment on Cardiovascular Function of Rats
Authors: Pribil Sarah , Pendyala Ved Vashishtha , Schaal Victoria , Sharma Kanika , Jagadensan Sankarasubramanian , Yu Li , Kumar Vikas 
Published: May 2024

Gabapentin (GBP), a GABA analogue, is primarily used as an anticonvulsant to treat partial seizures and neuropathic pain. While a majority of the side effects are associated with the nervous system, emerging evidence suggests a high risk for heart disease in the patients taking GBP. Given GBP can bind with high affnity to the α2δ subunits of voltage-gated Ca2+ channels (VGCCs) to block Ca2+ influx of cardiomyocytes, we hypothesize GBP suppresses cardiac function by evoking calcium signaling dysfunction. By using a preclinical rat model treated with GBP, we investigated (1) the acute cardiovascular responses to GBP (bolus i.v. injection; 50 mg/kg, 100 mg/ml x 0.1 ml in 3 min) and (2) the effects of chronic GBP treatment (i.p. 100 mg/kg/day x 7 days) on cardiovascular function and the myocardial proteome. Under isoflurane-anesthesia, blood pressure (BP), heart rate (HR), and left ventricular (LV) hemodynamics of the rats were measured using two Millar pressure transducers; one was implanted in abdominal aorta via right femoral artery, and the another was implanted in the LV chamber via right carotid artery. The LV myocardium was analyzed by proteomics, bioinformatics, and western blot to explore the molecular mechanisms underlying GBP-induced cardiac dysfunction, with the brain cortex used as a control tissue. In experiment (1), we found that i.v. GBP treatment significantly decreased BP, HR, maximal LV pressure, and maximal and minimal dP/dt, whereas it increased IRP-AdP/dt, Tau, systolic, diastolic, and cycle durations (*p < 0.05 and **p < 0.01 vs baseline; n = 4/group). This cardiovascular inhibition started at the injection time point and lasted at least 60 min, with a maximal effect appearing at 30 min post injection. In experiment (2), we found that chronic GBP treatment resulted in hypotension, bradycardia, and LV systolic dysfunction, with no change in plasma norepinephrine. In the myocardium of these rats, we used mass spectra to identify 109 differentially expressed proteins involved in calcium pathways, cholesterol metabolism, and galactose metabolism. Particularly, we found that calmodulin, a key protein of intracellular calcium signaling, was significantly upregulated by GBP in the heart but not in the brain, suggesting a myocardium-specific dysregulation of calcium signaling pathway, which may play a critical role in GBP-induced cardiac inhibition. Subsequent bioinformatics assays revealed a reduced Ca2+ release of sarcoplasmic reticulum (SR) and increased electrophoretic Ca2+ uptake into the matrix of mitochondria in the hearts of GBP-treated rats. In summary, we found that acute and chronic GBP treatments suppressed cardiovascular function in rats, which is attributed to abnormal calcium signaling in cardiomyocytes where GBP binds to VGCCs to reduce extracellular Ca2+ influx and cytosolic Ca2+ release from SR, resulting in blockage of excitation-contraction coupling. These data reveal a novel side effect of GBP independent of the nervous system, providing important translational evidence to suggest that GBP can evoke adverse cardiovascular events by depression of myocardial function.

This project is funded by NIH R01 HL 160820.

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.