106 Highly Beta-1 Selective Antagonism Preserves Cerebral Perfusion in Hemodiluted Rats

Perioperative β-blockade reduces the incidence of myocardial infarction, but is associated with an increased incidence of ischemic stroke, particularly in the context of acute surgical blood loss and fluid resuscitation (hemodilution). Metoprolol, a relatively poor β1-selective antagonist, impaired cerebral perfusion in an experimental model of acute hemodilution. The mechanism may include attenuation of the cardiac output (β1-effect) and cerebral vasodilatory response to hemodilution (β2-effect). We hypothesized that treatment with the highly β1-selective antagonist (nebivolol) will not impair cerebral perfusion during hemodilution. Anesthetised rats were randomized to receive vehicle (control) or nebivolol (1.25 or 2.5 mg/kg intravenously). Drug levels, heart rate (HR), cardiac output (CO, echocardiography), normalized cerebral blood flow (nCBF, laser Doppler), and brain microvascular PO2 (G2 oxyphor) were measured before and after hemodilution to a target hemoglobin concentration of 60 g/L. Drug levels, CO, and cerebral PO2 data were collected in a blinded fashion. Data (mean±SD) are assessed by ANOVA with significance assigned at p<0.05. Plasma drug levels reached values of 109±35 and 202±22 nM, after 1.25 and 2.5 mg/kg of nebivolol, respectively. A comparable hemoglobin nadir was achieved in all groups after hemodilution (∼60 g/L). HR decreased comparably from baseline (301±20) to 251±19 and 252±27 bpm in both treated groups (n=17, p<0.05 for both). The CO increased from control values (122±9.5 mL) after hemodilution (205±41 mL/min, n=5, p<0.05). This effect was attenuated by both nebivolol doses (161±24 and 151±13 mL/min, n=5, p<0.05). The increase in nCBF observed after hemodilution was similar in control and low dose nebivolol groups, but attenuated in the high dose group. Similarly, brain microvascular PO2 values were decreased to a greater degree after hemodilution with high dose nebivolol, relative to both control and low dose nebivolol groups. Western blot and immunostaining demonstrated increased cerebral cortical hypoxic cellular responses in hemodiluted rats treated with 2.5 mg/kg of nebivolol compared to other treatment groups. The data suggest that both doses of nebivolol impaired the cardiac output response to hemodilution (β1-effect). However, only the higher dose of nebivolol attenuated the nCBF response and was associated with a reduction in brain PO2 levels and an increase in brain HIF-1á expression, relative to other treatment groups. The reduction in brain perfusion observed in the high dose group may be consistent with increased β2-receptor antagonism and an impaired cerebral vasodilatory response to hemodilution.