Action and Disposition of the β3-Agonist Nebivolol in the Presence of Inflammation; An Alternative to Conventional β1-Blockers
Forough Sanaee and Fakhreddin Jamali
Affiliation: Faculty of Pharmacy & Pharmaceutical Sciences, 11361 – 87 Avenue, Edmonton, Alberta, Canada T6G 2E1.
Inflammation reduces pharmacological response to β1-blockers by down-regulating the target receptor protein. This may contribute
to the sub-optimal response to pharmacotherapy with β-blockers. Nebivolol is a third generation β-adrenoceptor (AR) blocker with
high selectivity for blocking β1 and β3-agonistitic properties. We studied whether response to nebivolol is also reduced by inflammation.
Male Sprague-Dawley rats (Inflamed; Mycobacterium butyricum induced) and Control (healthy) were orally administered single doses of
2 mg/kg nebivolol (n=5) or 25 mg/kg propranolol (positive control, n=7-8); ECG recorded for PR and RR interval measurements; serial
blood samples were collected for pharmacokinetic assessment. Subsequently, the myocardial β1, β2 and β3-AR levels were measured in
homogenized hearts. For propranolol, inflammation resulted in increased concentration but reduced response and down-regulation of β1-
AR. The action and disposition of nebivolol were, however, unaffected by inflammation despite the reduced β1-AR levels. The levels of
β2 and β3-AR were unaffected by inflammation. The consistency of response to nebivolol despite inflammation may be due to the predominance
of contribution of β2 and β3-AR. The lack of an inhibitory effect of inflammation on the clearance of nebivolol is suggestive
of mechanisms other than an efficient hepatic metabolism for its low bioavailability. If extrapolated to human, nebivolol may be a more
effective cardiovascular drug when inflammatory conditions are present.
Keywords: Inflammation, β-adrenoceptor, β3-adrenoceptor, β-blockers, arthritis, receptor downregulation, reduced response, PR interval, RR
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