The Α‐ AND Β‐ADRENOCEPTOR BLOCKING POTENCIES OF LABETALOL AND ITS INDIVIDUAL STEREOISOMERS IN ANAESTHETIZED DOGS AND IN ISOLATED TISSUES

Brittain, R. T.; Drew, G. M.; Levy, Gerhard

doi:10.1111/j.1476-5381.1982.tb09275.x

Cited by 103 publications

(25 citation statements)

References 25 publications

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“…The formulation used clinically and experimentally is a mixture of equal proportions of the four stereoisomers RR, SR, SS, and RS. The a-and fJ-adrenoceptor antagonist potencies of the individual stereoisomers differ considerably such that most of the a1-blocking activity of labetalol is attributable to the SR isomer, whereas most of the fil-adrenoceptor blocking activity is attributable to the RR isomer (dilevalol), while the SS and RS isomers are devoid of a,-and 41-antagonist activity (Baum et al, 1981;Brittain et al, 1982;Chrisp & Goa, 1990;Sybertz et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

The α‐ and β‐adrenoceptor blocking activities of labetalol and its RR‐SR (50:50) stereoisomers

Riva¹,

Mennini

Latini

1991

British J Pharmacology

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1 We compared the a,-, a2-and f6l-adrenoceptor blocking potencies of labetalol with those of its two stereoisomers (RR and SR) in pithed rats and in homogenized rat cerebral cortex and heart. 2 In pithed rats, labetalol and the RR-SR combination were given orally either at doses of 25 and 50mg kg-1 body wt. or intravenously at doses of 1 and 5mg kg-' body wt. Prazosin 4 and 20ug kg'-body wt. and propranolol 1 and 5 mg kg-l body wt., were given intravenously for comparison studies of potency at al-and fl1-adrenoceptors, respectively. Effects were studied before and after i.v. administration of either phenylephrine (at doses which increased the mean arterial pressure by approximately 80mmHg) or isoprenaline (at doses that increased heart rate by approximately 100 beats min 1). 3 In pithed rats, labetalol and the RR-SR combination antagonized, in a dose-dependent manner, the pressor effect of phenylephrine (P < 0.05) and the chronotropic effect of isoprenaline (P < 0.05). Following both oral and intravenous dosing, the RR-SR combination was twice potent as labetalol in terms of a,-and 161-adrenoceptor antagonism at equivalent doses. 4 Labetalol and the enantiomers lacked affinity at a2-adrenoceptors while at x1-adrenoceptors the order of potency was prazosin > RR-SR > labetalol. At fl1-adrenoceptors, the affinity of the compound RR-SR was about 3 times that of labetalol. 5 As labetalol is a mixture of active (RR and SR) and inactive (SS and SR) enantiomers (in terms of aand Preceptor actions), the combination of RR and SR may be a valuable substitute for labetalol in the treatment of systemic hypertension. Although the potential for non-specific side effects (common to all four enantiomers) could be expected to be diminished, recent reports by postmarketing surveillance indicate that the RR isomer (dilevalol) can induce liver toxicity. Interestingly, labetalol is devoid of this effect; whether the combination of RR and SR enantiomers could be of clinical importance warrants further investigation.

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Section: Introductionmentioning

confidence: 99%

The α‐ and β‐adrenoceptor blocking activities of labetalol and its RR‐SR (50:50) stereoisomers

Riva¹,

Mennini

Latini

1991

British J Pharmacology

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“…Second-generation agents such as metoprolol, atenolol, and bisoprolol are ß-receptors subtype selective agents with no ancillary properties. Third-generation agents, including bucinodolol, labetalol [1], carvedilol [2], and our previously reported vanidilol, ferulidilol, eugenodilol, isoeugenodilol, KMUP 880723, KMUP 880708, and KMUP 880602 [3][4][5][6][7][8][9] have the ancillary property of vasodilatation. They work through a variety of mechanisms including ·-receptor blockade, ß 2 -agonism, and a dilator action independent of the ·-and ß-receptors.…”

Section: Introductionmentioning

confidence: 99%

Anti-Hypertension Effect of Vanylidilol: A Phenylaldehyde α/β-Adrenoceptor Blocker with Endothelium-Dependent and K<sup>+</sup> Channels Opening-Associated Vasorelaxant Activities

Chiu¹,

Lee

et al. 2004

Pharmacology

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The antihypertensive effect of vanylidilol, a new α/β-adrenoceptor antagonist with endothelium-dependent and K⁺-channel-opening activities, was investigated in normotensive and hypertensive Wistar rats. Vanylidilol competitively antagonized (–)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in isolated rat right atria, left atria, and guinea pig tracheal strips in a concentration-dependent manner. Vanylidilol’s apparent pA₂ values were 6.36 ± 0.08 (right atria), 6.41 ± 0.07 (left atria), and 6.31 ± 0.06 (trachea). Vanylidilol also produced a competitive antagonism of phenylephrine-induced contraction in the isolated rat aorta with pA₂ values of 6.79 ± 0.18. In the radioligand binding assay, vanylidilol inhibited [³H]CGP-12177 binding to rat ventricle and lung tissues and [³H]prazosin binding to brain membranes with Ki values of 535.17, 2,066.69, and 431.11, respectively. In isolated rat thoracic aorta, vanylidilol’s vasorelaxant effects on phenylephrine (10 µmol/l)-induced contractions were attenuated by removing endothelium and by the presence of L-N^G-nitro arginine methyl ester (L-NAME; 100 µmol/l), methylene blue (10 µmol/l), 1H-[1,2,4]oxadiazolol[4,3,-a] quinoxalin-1-one (ODQ; 10 µmol/l), tetraethylammonium (10 mmol/l), glibenclamide (1 µmol/l), apamin (1 µmol/l), and charybdotoxin (0.1 µmol/l). In addition, vanylidilol, in an equally antagonistic activity, inhibited phenylephrine-induced phasic and tonic contractions. Intravenous vanylidilol further reduced mean blood pressure in pentobarbital-anesthetized normotensive Wistar rats in a dose-dependent manner. The oral administration of vanylidilol to conscious spontaneously hypertensive rats had a long-lasting hypotensive effect on the heart rate and decreased it in a dose-dependent manner. Furthermore, vanylidilol’s vasodilator effect can be attributed in part to the release of NO or NO-related substance from vascular endothelium, while the endothelium-independent mechanism involved in vanylidilol’s relaxation is probably linked to the activation of the K⁺ channels and the α-adrenoceptor blocking activity in these vessels.

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“…referred to as 'hybrid' drugs that combine in one molecule two distinct pharmacological activities (Nicolaus, 1983). The antihypertensive agents, labetalol, which combines a-and P-adrenoceptor blocking properties (Brittain et al, 1982) and prizidilol, which combines vasodilator and P-adrenoceptor-blocking properties (Taylor et al, 1981) are examples of this class of drug.…”

Section: Introductionmentioning

confidence: 99%

BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and β‐adrenoceptor‐blocking properties

Allan

Cambridge

Hardy

et al. 1987

British J Pharmacology

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) is a chemically novel agent which exhibits in a single molecule both angiotensin converting enzyme (ACE) inhibition and P-adrenoceptor-blocking properties.2 BW A575C produced a competitive blockade of heart rate responses to isoprenaline in a guinea-pig right atrial preparation (pKB 7.18 ± 0.05, cf. pindolol 8.9 ± 0.7). BW A575C inhibited a partially purified preparation of ACE obtained from rabbit lung (IC50 10.7 + 2.1 nM, cf. enalaprilat, 4.4 ± 0.8 nM).3 Intravenous administration of BW A575C (1-100 tgkg-' min-')to the pithed rat inhibited in a dose-dependent fashion both angiotensin I-induced pressor responses and isoprenaline-induced tachycardia. Dose-ratios obtained from such studies demonstrated that, in this preparation, BW A575C was approximately 100 times more active as an ACE inhibitor than as a P-adrenoceptor blocking agent. 4 Intravenous administration of BW A575C (I mg kg-') to the conscious rat inhibited angiotensin Iinduced pressor responses, being approximately equipotent to enalapril and 10 times more potent than captopril. At the same dose, BW A575C had a similar duration of action as an ACE inhibitor to enalapril. 5 Intravenous administration of BW A575C (I mg kg-') to either conscious dogs or rats inhibited both angiotensin I-induced pressor responses and isoprenaline-induced heart rate responses. Doseratios obtained from such studies demonstrated that in these species, BW A575C was 2-10 times more active as an ACE inhibitor than as a P-adrenoceptor blocking agent.

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The Α‐ AND Β‐ADRENOCEPTOR BLOCKING POTENCIES OF LABETALOL AND ITS INDIVIDUAL STEREOISOMERS IN ANAESTHETIZED DOGS AND IN ISOLATED TISSUES

Cited by 103 publications

References 25 publications

The α‐ and β‐adrenoceptor blocking activities of labetalol and its RR‐SR (50:50) stereoisomers

The α‐ and β‐adrenoceptor blocking activities of labetalol and its RR‐SR (50:50) stereoisomers

Anti-Hypertension Effect of Vanylidilol: A Phenylaldehyde α/β-Adrenoceptor Blocker with Endothelium-Dependent and K<sup>+</sup> Channels Opening-Associated Vasorelaxant Activities

BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and β‐adrenoceptor‐blocking properties

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