AbstractsMedical & Health Science

Pharmacological Intervention with Atenolol and Diazepam in Seizure-Induced Cardiomyopathy

by Rebecca Nicole Millen

Institution: University of Otago
Year: 0
Keywords: seizure; cardiac; kainic acid; diazepam; atenolol; cardiomyopathy
Record ID: 1307679
Full text PDF: http://hdl.handle.net/10523/5477


Seizures have become frequently associated with an increased risk of cardiomyopathy, with tachycardia and pathological structural changes commonly reported in both clinical and animal studies. This thesis examined the hypothesis that intervention with the selective β1-adrenergic receptor antagonist atenolol, in conjunction with the antiepileptic drug diazepam, would prevent cardiac injury in a kainic acid (KA)-induced seizure model. Male Sprague-Dawley rats (320 – 350 g) were instrumented with ECG/EEG transmitters and seizures induced by intrahippocampal delivery of KA (2 nmol in 1 µL saline). Saline, diazepam (5 mg/kg initial and 1 mg/kg bid., sc.), atenolol (5 mg/kg, sc.) or a combination of diazepam + atenolol interventions were administered at 1 hour post-KA and continued daily for the remainder of the study (7 or 14 days). High-level seizure behaviours were associated with tachycardia (482.3 ± 15 b.p.m., P < 0.05 vs. baseline) present up to 3 hours post-KA, and QTc prolongation up to 7 days post-KA, in the saline-treated group (P < 0.05 vs. baseline). Both tachycardia and QTc prolongation were significantly attenuated by treatment with atenolol alone and in combination with diazepam (P < 0.05 vs. saline group). Monotherapy with diazepam intervention effectively attenuated seizure behaviours but failed to reduce heart rate, QTc prolongation or markers of cardiac injury, and unexpectedly, heart rate was increased above saline-treated animal responses at both 24 and 48 hours post-KA (P < 0.05). Cardiac troponin I levels were elevated up to 5-fold at 24 hours in the saline and diazepam groups (P < 0.05 vs. baseline), and this injury marker was attenuated by atenolol and combination treatments. Histological examination confirmed the presence of micro-infarcts with evidence of oedema and significant collagen I deposition in the ventricular myocardium of the saline and diazepam intervention groups. Immunolabelling also showed significant increases in apoptotic-positive cell counts (15-fold increase above naïve control, P < 0.05) and macrophage infiltration (51.1 cells/mm2; P < 0.05 vs. naïve control) in hearts from saline and diazepam-treated animals. However, α smooth muscle actin levels, indicative of myofibroblast presence, were not altered in any treatment groups (P > 0.05 vs. naïve control). This study clearly showed that seizure induction in the rat by intrahippocampal KA delivery results in the development of ECG changes and cardiac structural injury. β1-receptor blockade is known to exert cardioprotective effects through the attenuation of sympathetic drive on heart rate, and by preventing the stimulation of pathological β1-mediated pathways including apoptosis, hypertrophy, and remodelling. The evidence of diazepam-induced heart rate increases presented here, tallies with previous reports of central- and peripheral-mediated cardiac effects of diazepam. These detrimental cardiac effects of diazepam were attenuated by the use of atenolol in the combination intervention strategy suggesting that β1…