Abstract
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 interval.
Current Pharmaceutical Design
Title:Action and Disposition of the β3-Agonist Nebivolol in the Presence of Inflammation; An Alternative to Conventional β1-Blockers
Volume: 20 Issue: 9
Author(s): Forough Sanaee and Fakhreddin Jamali
Affiliation:
Keywords: Inflammation, β-adrenoceptor, β3-adrenoceptor, β-blockers, arthritis, receptor downregulation, reduced response, PR interval, RR interval.
Abstract: 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.
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Cite this article as:
Sanaee Forough and Jamali Fakhreddin, Action and Disposition of the β3-Agonist Nebivolol in the Presence of Inflammation; An Alternative to Conventional β1-Blockers, Current Pharmaceutical Design 2014; 20 (9) . https://dx.doi.org/10.2174/13816128113199990550
DOI https://dx.doi.org/10.2174/13816128113199990550 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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