MSc (Med), University of the Witwatersrand, Faculty of Health Sciences / Background: Males have a higher prevalence of cardiovascular diseases compared to premenopausal women. However, postmenopausal women are at equal risk to men. It has therefore been suggested that estrogen is cardioprotective. Although the exact mechanisms of the purported cardioprotective effects of estrogen are unknown, estrogen administration has been reported to suppress beta-adrenergic receptor up-regulation in ovariectomized female rats. As beta-adrenergic activation induces cardiomyocyte apoptosis and necrosis, and hence adverse cardiac remodelling and heart failure, I aimed to determine whether the extent of beta-adrenergic induced apoptosis and necrosis differs between males and females. Methods: 27 male Wistar rats were assigned to one of two groups: ISO M (n=14) receiving a beta-adrenergic receptor agonist, isoproterenol (0.02mg/kg) and CON M (n=13) receiving vehicle (saline, 0.2ml). 29 female Wistar rats were assigned to one of two groups: ISO F (n=15) receiving a beta-adrenergic receptor agonist, isoproterenol (0.02mg/kg) and CON F (n=14) receiving vehicle. Isoproterenol and saline were administered by means of daily subcutaneous injections for 5 days. On the 5th day, cardiac geometry and function were assessed before and after ISO or saline administration using echocardiography. Rats were then terminated under anaesthesia within 30 minutes of ISO (or vehicle) administration and blood samples collected for the determination of serum estrogen concentration (ELISA). Female rats were terminated in proestrus which corresponds to peak estrogen concentrations. Cardiac myocyte apoptosis was assessed histologically using the DeadEndTM Colorimetric TUNEL system (Promega, Madison, WI, USA). The number of apoptotic cardiomyocyte nuclei was expressed as a percentage of the total number of cardiomyocyte nuclei per slide (heamotoxylin and eosin stain). Necrosis and fibrosis (pathological score) were assessed by assigning a pathological score to sections stained for fibrosis (van Gieson). Groups were iii compared using two-way (gender and regimen; and including repeated measures for echocardiography data) ANOVA followed by the Tukey-Kramer post hoc test. Results: As expected estrogen concentrations were higher in female compared to male rats (mean±SEM, pg.ml-1; ISO M: 7.04±1.41; CON M: 7.14±0.53; ISO F: 23.00±3.47; CON F: 19.31±3.66; p<0.01). Five days of ISO or saline administration had no effect on cardiac function or geometry in either the male or the female rats. Inotropic effects (increased heart rate and cardiac function) were observed in response to acute ISO administration in both male and female rats. The female rats had slower heart rates (p<0.05) and showed a greater heart rate response to acute ISO administration than the male rats (p<0.05). But the acute ISO induced increments in cardiac function were similar between genders. Five days of ISO administration induced cardiomyocyte apoptosis in male rats but not in female rats (mean±SEM, % ; ISO M: 0.086±0.013; CON M: 0.030±0.004; ISO F: 0.053±0.004; CON F: 0.041±0.007; p<0.05). Furthermore, 5 days of ISO administration induced cardiomyocyte necrosis in male rats but not in female rats (mean±SEM, pathological score; ISO M: 1.21±0.21, CON M: 0.46±0.14, ISO F: 0.50±0.11, CON F: 0.68±0.12, p<0.01). Conclusion: Male rats are more susceptible than female rats to beta-adrenergic induced cardiomyocyte apoptosis and necrosis. The protective effects of estrogen against the adverse effects of beta-adrenergic activation on the heart, may explain the lower risk of cardiovascular disease in premenopausal women compare to men; however, the possible role of progesterone cannot be ignored.