The l-enantiomer of nebivolol potentiates the blood pressure lowering effect of the d-enantiomer

doi:10.1016/0014-2999(90)90087-M

European Journal of Pharmacology

Volume 181, Issue 3, 8 June 1990, Pages 261-265

https://doi.org/10.1016/0014-2999(90)90087-M Get rights and content

Abstract

In this study the effect of 1-nebivolol on the blood pressure lowering action of d-nebivolol was investigated after intraperitoneal administration of the drugs to spontaneously hypertensive rats. Doses of 1-nebivolol which did not affect blood pressure when given alone potentiated the decrease in systolic and diastolic blood pressure induced by 1.25 mg · kg⁻¹ d-nebivolol. The potentiating effect of 1-nebivolol was seen at doses higher than 0.16 mg · kg⁻¹. At 1.25 mg · kg⁻¹ d-nebivolol significantly reduced the heart rate, an effect which was not potentiated by 1-nebivolol in doses up to 1.25 mg · kg⁻¹. Higher doses of 1-nebivolol (2.5 and 5.0 mg · kg⁻¹) in combination with 1.25 mg · kg⁻¹ d-nebivolol not only lowered the blood pressure further, but also significantly reduced the heart rate; thus at these doses the enantiomers together exerted more pronounced β₁-drenoceptor blocking properties. This is probably disadvantageous, because d,1-nebivolol has been shown to decrease arterial blood pressure in hypertensive patients and animals before it reaches its maximal β₁-adrenoceptor blocking effect. Therefore, the racemic mixture of 50% d-nebivolol and 50% 1-nebivolol seems to contain the two compounds in near optimal proportions for an antihypertensive effect.

References (6)

J.L. Bollman
Cage which limits the activity of rats
J. Lab. Clin. Med.
(1948)
M. Heimberger et al.
Presynaptic β-adrenoceptors in rat atria: evidence for the presence of stereoselective β₁-adrenoceptors
Br. J. Pharmacol.
(1989)
W.J. Janssens et al.
Nebivolol is devoid of intrinsic sympathomimetic activity
European J. Pharmacol.
(1989)

There are more references available in the full text version of this article.

Cited by (36)

Nebivolol has protective effect against endothelial and ileal dysfunction due to I/R
2011, Journal of Surgical Research
Citation Excerpt :
The mechanism of vasodilatation is attributed to the generation of NO, an effect that can be inhibited by NG-monomethyl-L-arginine [10]. D-nebivolol, one of its two enantiomers, shows β1-selectivity, whereas L-nebivolol lacks β1-adrenergic activity and stimulates endothelial-dependent NO release to a greater degree [9]. The L-isomer has vasodilating properties associated with increasing NO production via activation of β3 receptors at endothelial cells [11].
In this study, two enantiomers of the drug, L-nebivolol and racemic nebivolol, were used to measure and compare their ability to prevent endothelial dysfunction, disturbed ileal contractility, and ileal injury induced by I/R.
The superior mesenteric artery of male Sprague-Dawley rats was occluded for 45 min to induce ischemia, and then the clamp was removed for 60-min reperfusion. Drugs or saline were administered prior to the surgical procedure in the I/R and sham-operated groups. Vasodilation in the third branch of the mesenteric artery was evaluated with a myograph system. Isometric contractions of the ileal segments in response to acetylcholine or electrical field stimulation (EFS) (120 V, 2-ms pulse duration for 5 s, 1–20 Hz) were recorded on a polygraph. Additionally, the ileal segments were examined histopathologically.
Acetylcholine-induced relaxation of the mesenteric artery, precontracted by submaximal phenylephrine, markedly decreased after I/R. L-nebivolol pretreatment reversed this relaxation, but racemic nebivolol did not. Contractions induced by both acetylcholine and EFS were significantly reduced after I/R. L-nebivolol, but not racemic nebivolol, prevented this reduction in the acetylcholine-induced contractions. I/R-induced reduction was prevented by L-nebivolol only in response to EFS of 20 Hz. Intestinal I/R caused severe ischemic injury in the rat ileum, which was prevented by L-nebivolol, but not racemic nebivolol. Control responses were not affected by L-nebivolol or racemic nebivolol.
These results suggest that L-nebivolol had a protective effect against both endothelial dysfunction of the mesenteric artery and ileal injury induced by intestinal I/R; however, similar effects were not observed for racemic nebivolol.
Nebivolol
2007, xPharm: The Comprehensive Pharmacology Reference
Nebivolol is a cardioselective beta-1 adrenoceptor antagonist without membrane stabilizing or intrinsic sympathomimetic properties. It is a unique beta adrenoceptor antagonist because of its sparing effect on left ventricular function. It has a relatively long half-life. Because the antihypertensive effect of D-nebivolol is enhanced by concurrent administration of L-nebivolol, it is administered as a racemic mixture.
Characterization of Nitric Oxide Release by Nebivolol and Its Metabolites
2006, American Journal of Hypertension
Nebivolol is a selective β₁-adrenergic receptor antagonist that causes a direct vasodilator effect attributed to the action on vascular nitric oxide (NO). This study aimed to investigate whether nebivolol or its metabolites induces NO production and to explore the mechanisms underlying this pharmacologic effect.
Conductance and resistance arteries from Wistar-Kyoto rats (WKY) (n = 33) incubated with the fluorescent probe diaminofluorescein-2 (DAF-2) were stimulated with increasing concentrations of nebivolol or its enantiomers and metabolites, and NO release was histologically evaluated.
Nebivolol induced a dose-dependent increase in NO levels in the endothelium of both arteries. Levels of NO were significantly increased at 10⁻⁶ mol/L and reached a plateau state at 10⁻⁵ mol/L. Induction of NO is not a general action of β-adrenoceptor antagonists, as atenolol had no effects. Nebivolol action on NO release was mainly caused by the d-isomer. Moreover NO production is also maintained after hepatic metabolism, as the three main metabolites of nebivolol were able to induce a significant increase in endothelial NO release. Finally, nebivolol-activated calcium mobilization is crucial to NO production.
Our study shows the effects of d-nebivolol and its metabolites on endothelial NO production in both conductance and resistance arteries, and clarifies that this effect is realized through a calcium-dependent mechanism.
Rapid quantification of nebivolol in human plasma by liquid chromatography coupled with electrospray ionization tandem mass spectrometry
2005, Journal of Pharmaceutical and Biomedical Analysis
A simple, sensitive and rapid liquid chromatographic/electrospray ionization tandem mass spectrometric method was developed and validated for the quantitation of nebivolol in human plasma. The method involved a simple single-step liquid–liquid extraction with diethyl ether/dichloromethane (70/30). The analyte was chromatographed on Waters symmetry^® C₁₈ reversed-phase chromatographic column by isocratic elution with water:acetonitrile:formic acid (30:70:0.03, v/v) and analyzed by mass spectrometry in the multiple reaction monitoring mode. The precursor to product ion transitions of m/z 406.4–151.5 and m/z 409.1–228.1 were used to measure the analyte and the internal standard (I.S.), respectively. The chromatographic runtime was 2 min and the weighted (1/x²) calibration curves were linear over the range 50–10,000 pg/mL. The method was validated in terms of accuracy, precision, absolute recovery, freeze-thaw stability, bench-top stability and re-injection reproducibility. The limit of detection and lower limit of quantification in human plasma were 10 and 50 pg/mL, respectively. The within- and between-batch accuracy and precision were found to be well within acceptable limits (<10%). The analyte was stable after three freeze-thaw cycles (deviation <10%). The average absolute recoveries of nebivolol and tamsulosin, used as an internal standard, from spiked plasma samples were 73.4 ± 3.7 and 72.1 ± 2.0%, respectively. The assay method described here was applied to study the pharmacokinetics of nebivolol.
Lack of inverse agonistic activity of nebivolol, its D- and L-enantiomers and of in vivo metabolized nebivolol in human myocardium
2003, European Journal of Pharmacology
The pharmacological profile of nebivolol may be mediated by its enantiomers and/or its hydroxylated metabolites. Therefore, the cardiac effects of the nebivolol enantiomers as well as of serum specimens containing hydroxylated nebivolol metabolites were studied in human myocardium. For control, the β₁-adrenoceptor selective antagonist metoprolol was used. After pre-stimulation of force of contraction with forskolin (0.3 μM) or isoprenaline (0.01 μM), force developement was decreased only at high concentrations (≥300 nM) of nebivolol or its enantiomers in isolated trabeculae. Nebivolol and its enantiomers, in contrast to metoprolol (0.4 μM: −72% basal force), produced only minor negative intropic effects in isolated trabeculae under basal conditions. Basal force of contraction was not decreased by in vivo metabolized nebivolol in pharmacological concentrations. Neither d- nor l-nebivolol (30 μM) influenced myofibrillar Ca²⁺ responsiveness. Nebivolol and the d-enantiomer, but not the l-enantiomer (all 0.5 μM), improved the frequency-dependent force generation. d-Nebivolol, in contrast to l-nebivolol, was a β₁-adrenoceptor selective compound in membrane preparations from non-failing donor hearts. In conclusion, nebivolol and its enantiomers as well as in vivo metabolized nebivolol produce only minor negative inotropic effects. This and the finding that nebivolol and its d-enantiomer improve the frequency-dependent force generation may be of particular advantage when treating patients with already compromised cardiac function.
Enantioselective total synthesis of the antihypertensive agent (S,R,R,R)-Nebivolol
2000, Tetrahedron

View all citing articles on Scopus

View full text

The l-enantiomer of nebivolol potentiates the blood pressure lowering effect of the d-enantiomer

Abstract

Cage which limits the activity of rats

J. Lab. Clin. Med.

Presynaptic β-adrenoceptors in rat atria: evidence for the presence of stereoselective β1-adrenoceptors

Br. J. Pharmacol.

Nebivolol is devoid of intrinsic sympathomimetic activity

European J. Pharmacol.

Presynaptic β-adrenoceptors in rat atria: evidence for the presence of stereoselective β₁-adrenoceptors