Treatment with a highly selective ß1 antagonist causes dose-dependent impairment of cerebral perfusion after hemodilution in rats.

BACKGROUND: Acute ß-blockade has been associated with a dose-dependent increase in adverse outcomes, including stroke and mortality. Acute blood loss contributes to the incidence of these adverse events. In an attempt to link the risks of acute blood loss and ß-blockade, animal studies have demonstrated that acute ß-blockade impairs cerebral perfusion after hemodilution. We expanded on these findings by testing the hypothesis that acute ß-blockade with a highly ß(1)-specific antagonist (nebivolol) causes dose-dependent cerebral hypoxia during hemodilution. METHODS: Anesthetized rats and mice were randomized to receive vehicle or nebivolol (1.25 or 2.5 mg/kg) IV before hemodilution to a hemoglobin concentration near 60 g/L. Drug levels, heart rate (HR), cardiac output (CO), regional cerebral blood flow (rCBF, laser Doppler), and microvascular brain Po(2) (P(Br)O(2), G2 Oxyphor) were measured before and after hemodilution. Endothelial nitric oxide synthase (NOS), neuronal NOS (nNOS), inducible NOS, and hypoxia inducible factor (HIF)-1α were assessed by Western blot. HIF-α expression was also assessed using an HIF-(ODD)-luciferase mouse model. Data were analyzed using analysis of variance with significance assigned at P < 0.05, and corrected P values are reported for all post hoc analyses. RESULTS: Nebivolol treatment resulted in dose-specific plasma drug levels. In vehicle-treated rats, hemodilution increased CO and rCBF (P < 0.010) whereas P(Br)O(2) decreased to 45.8 ± 18.7 mm Hg (corrected P < 0.001; 95% CI 29.4-69.7). Both nebivolol doses comparably reduced HR and attenuated the CO response to hemodilution (P < 0.012). Low-dose nebivolol did not impair rCBF or further reduce P(Br)O(2) after hemodilution. High-dose nebivolol attenuated the rCBF response to hemodilution and caused a further reduction in P(Br)O(2) to 28.4 ± 9.6 mm Hg (corrected P = 0.019; 95% CI 17.4-42.7). Both nebivolol doses increased brain endothelial NOS protein levels. Brain HIF-1α, inducible NOS, and nNOS protein levels and brain HIF-luciferase activity were increased in the high-dose nebivolol group after hemodilution (P < 0.032). CONCLUSIONS: Our data demonstrate that nebivolol resulted in a dose-dependent decrease in cerebral oxygen delivery after hemodilution as reflected by a decrease in brain tissue Po(2) and an increase in hypoxic protein responses (HIF-1α and nNOS). Low-dose nebivolol treatment did not result in worsened tissue hypoxia after hemodilution, despite comparable effects on HR and CO. These data support the hypothesis that acute ß-blockade with a highly ß(1)-specific antagonist causes a dose-dependent impairment in cerebral perfusion during hemodilution.