Effects of propranolol and a number of its analogues on sodium channels

doi:10.1016/0006-2952(82)90668-2

Biochemical Pharmacology

Volume 31, Issue 9, 1 May 1982, Pages 1681-1685

https://doi.org/10.1016/0006-2952(82)90668-2 Get rights and content

Abstract

To assess the relative contributions that the sodium channel blocking activity of propranolol may play in a variety of its therapeutic applications, its effects were examined in vitro with a sodium channel specific ²²Na⁺ uptake system, using rat brain membranes. Propranolol inhibited ²²Na⁺ uptake in the rat brain membrane preparation by acting as a competitive inhibitor of the binding of the sodium channel opening agent veratridine, with an IC₅₀ for this action of 6.5 μM. This is approximately one order of magnitude higher in concentration than that necessary for expression of the β-adrenergic antagonism of propranolol. The binding of propranolol and its action to block sodium channels were demonstrably different from those of the neurotoxins tetrodotoxin and saxitoxin. Propranolol had effects on sodium channels that are similar, although not identical to those of the local anesthetics procaine and lidocaine. The concentrations of propranolol and a number of its analogues which produced 50% inhibition of ²²Na⁺ uptake (IC₅₀ values ranging from 4 to > 100 μM) were similar to the concentrations of these same analogues which were required to produce negative inotropic and antiarrythmic effects (ED₄₀) on isolated rabbit atria [D. O. Rauls and J. K. Baker, J. med. Chem.22, 81 (1979)]. These effects showed correlations of 0.945 and 0.936, respectively, with the ²²Na⁺ uptake inhibition. It is concluded from this information that a substantial proportion of the negative inotropic and antiarrythmic effects of propranolol is due to its action on sodium channels.

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Cited by (44)

Clonidine as an adjuvant for propranolol enhances its effect on infiltrative cutaneous analgesia in rats
2016, Neuroscience Letters
Clonidine prolongs duration of analgesia when used as an adjunct to local anesthetics for infiltrative cutaneous analgesia, and propranolol produces local anesthesia. The purpose of the experiment was to evaluate clonidine as an adjuvant for propranolol on the quality and duration of cutaneous analgesia. A rat model of cutaneous trunci muscle reflex (CTMR) in response to local skin pinprick was employed to evaluate the cutaneous analgesic effect of propranolol combined with clonidine. The long-lasting local anesthetic bupivacaine was used as control. Cutaneous analgesia elicited by propranolol and bupivacaine was dose-dependent, and both propranolol (9.0 μmol) and bupivacaine (1.8 μmol) produced 100% nociceptive blockade. On an 50% effective dose (ED₅₀) basis, the relative potency was bupivacaine [0.48 (0.42–0.55) μmol] greater than propranolol [2.27 (1.98–2.54) μmol] (p < 0.01). Subcutaneous saline and clonidine (0.12 μmol) did not produce cutaneous analgesia. The mixture of an ineffective-dose clonidine (0.12 μmol) and a drug (propranolol or bupivacaine) at ED₅₀ or ED₉₅ increased the potency and extended the duration at producing cutaneous analgesia. The resulting data demonstrated that propranolol is less potent than bupivacaine as an infiltrative anesthetic. Clonidine as an adjuvant for propranolol or bupivacaine has a significant peripheral action in increasing the depth and duration of action on infiltrative cutaneous analgesia.
Propranolol combined with dopamine has a synergistic action in intensifying and prolonging cutaneous analgesia in rats
2015, Pharmacological Reports
Citation Excerpt :
Propranolol, the first clinically useful β-adrenergic receptor antagonist, was introduced to the clinical practice in the treatment of cardiovascular diseases [1,2], angina pectoris [3,4], infantile haemangiomas [5,6], many neuropsychiatric disorders [7], dental anxiety [8] and pulmonary hemangioma [9].
The purpose of the experiment was to assess interactions of dopamine with propranolol as an infiltrative anesthetic.
After injecting the rats with four doses of drugs subcutaneously, the cutaneous analgesic effect of propranolol was compared with dopamine through the blockade of cutaneous trunci muscle reflex (CTMR) in response to local skin pinprick. Drug–drug interactions were examined via an isobolographic analysis.
We demonstrated that the action of propranolol and dopamine was dose dependent to skin infiltrative analgesia. On the ED₅₀ (50% effective dose) basis, the rank of drug potency was propranolol (11.3 [10.6–12.2] μmol) > dopamine (195 [188–205] μmol) (p < 0.001). At the equi-anesthetic doses (ED₂₅, ED₅₀, ED₇₅), the block duration caused by dopamine was equal to that caused by propranolol. Coadministration of dopamine and propranolol exhibited a synergistic effect on infiltrative cutaneous analgesia.
The preclinical data showed that dopamine produced a lesser potency but a comparable duration of cutaneous analgesia compared to propranolol. Adding dopamine to propranolol potentiated and prolonged propranolol's cutaneous analgesic effect.
Epinephrine as adjuvant for propranolol produces a marked peripheral action in intensifying and prolonging analgesia in response to local dorsal cutaneous noxious pinprick in rats
2014, European Journal of Pharmacology
Citation Excerpt :
Propranolol as the first clinically useful β-adrenergic receptor antagonist was discovered in 1964 and introduced to the clinical practice in the treatment of cardiovascular diseases (Frullani et al., 1970; Matthews and Baker, 1982).
The aim of this study was to evaluate the effect of epinephrine as additive for propranolol as an infiltrative anesthetic. Using a rat model of cutaneous trunci muscle reflex (CTMR), we tested the effect of co-administration of epinephrine with propranolol on infiltrative cutaneous analgesia. Bupivacaine, a long-lasting local anesthetic, was used as control. Subcutaneous propranolol and bupivacaine elicited a dose-dependent local anesthetic effect on infiltrative cutaneous analgesia. On the 50% effective dose (ED₅₀) basis, the relative potency was bupivacaine [2.05 (1.95–2.21) μmol/kg]>propranolol [9.21 (9.08–9.42) μmol/kg] (P<0.01 for each comparison). Subcutaneous epinephrine (0.012 μmol/kg) did not produce cutaneous analgesia. Mixtures of epinephrine (0.012 μmol/kg) with drugs (propranolol or bupivacaine) at ED₅₀ or ED₉₅, respectively, intensified and prolonged drug action on infiltrative cutaneous analgesia. Intraperitoneal injection of combined drugs (propranolol or bupivacaine) at ED₉₅ with epinephrine (0.012 μmol/kg) exhibited no cutaneous analgesia. We concluded that propranolol was less potent but produced a similar duration of action when compared to bupivacaine on infiltrative cutaneous analgesia. Epinephrine as adjuvant for propranolol or bupivacaine enhanced the potency and extended the duration of action on infiltrative cutaneous analgesia.
To the Editor - Propranolol, a β-adrenoreceptor blocker, prevents arrhythmias also by its sodium channel blocking effect
2014, Heart Rhythm
Propranolol elicits cutaneous analgesia against skin nociceptive stimuli in rats
2012, Neuroscience Letters
The purpose of this study was to investigate the cutaneous analgesic effect of propranolol and compare with a local anesthetic lidocaine. The potencies and equipotent doses were determined for infiltrative cutaneous analgesia on the rat back by determination of dose–response curves for propranolol and lidocaine. Propranolol as well as lidocaine elicited dose–dependent cutaneous analgesia. On a 50% effective dose (ED₅₀) basis, the relative potency was propranolol (10.3 [8.9–11.9] μmol kg⁻¹) > lidocaine (25.8 [24.3–27.8] μmol kg⁻¹) (P < 0.01). On equianalgesic doses (ED₂₅, ED₅₀, ED₇₅), propranolol produced longer action of infiltrative cutaneous analgesia than lidocaine (P < 0.01). Coadministration of lidocaine (25.8 μmol kg⁻¹) and propranolol (1.7 μmol kg⁻¹) exhibited greater blockade and duration than lidocaine (25.8 μmol kg⁻¹) or propranolol (1.7 μmol kg⁻¹) alone. Propranolol displayed more potent and longer duration of action than lidocaine at producing cutaneous analgesia. Furthermore, propranolol may prove useful as an adjuvant for lidocaine in producing cutaneous analgesia.
Intrathecal propranolol displays long-acting spinal anesthesia with a more sensory-selective action over motor blockade in rats
2011, European Journal of Pharmacology
Citation Excerpt :
It revolutionized the medical management of angina pectoris and is considered to be one of the most important contributions to clinical medicine and pharmacology in the 20th century (Zimmermann et al., 2010). Indications for the use of propranolol are numerous, including the treatment of angina pectoris (Frishman et al., 1989; Zimmermann et al., 2010), hypertension (Frishman et al., 1989), cardiac arrhythmias (Matthews and Baker, 1982), hyperthrophic obstructive cardiomyopathy (Hess et al., 1983), migraine (Linde and Rossnagel, 2004), and in the therapy of many neuropsychiatric disorders (Tchivileva et al., 2010). Recently, propranolol has been introduced as a novel modality for the treatment of proliferating haemangiomas (Buckmiller, 2009; Maturo and Hartnick, 2010; Zimmermann et al., 2010) and dental anxiety (Heaton et al., 2010).
To prevent cardiovascular effects of peripherally administered propranolol, the aim of this study was to evaluate the spinal anesthetic effect of propranolol, a Na^± channel blocker. After rats were injected with drugs intrathecally, the spinal anesthetic effect of propranolol was compared with that of lidocaine, which is known to produce local anesthesia. We also evaluated the effect of the addition of clonidine with propranolol on spinal anesthesia. Our results showed that propranolol produced a dose-dependent spinal blockade in motor, proprioception, and nociception. On a 50% effective dose (ED₅₀) basis, the spinal anesthetic effect of propranolol in motor, proprioception, and nociception [1.16 (1.01–1.34), 1.10 (0.92–1.31), 1.05 (0.89–1.24)] was equal to lidocaine [1.03 (0.94–1.13), 0.95 (0.84–1.07), 0.87 (0.79–0.96)], respectively. On an equipotent basis (0.5, 1.0, 2.5 μmol), the sensory/nociceptive block duration caused by propranolol was longer than that caused by lidocaine (P ≤ 0.01). Co-administration of propranolol (1.1 μmol) and clonidine (0.5 μmol) produced greater spinal anesthesia than propranolol (1.1 μmol) or clonidine (0.5 μmol) alone. These preclinical findings demonstrated that propranolol produces similar spinal anesthesia to lidocaine and that α₂-adrenergic receptors also contribute to improve the quality and duration of the spinal anesthetic effect of propranolol. Propranolol with a more sensory-selective action over motor blockade elicited longer spinal blockade than did lidocaine.

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^†: Department of Medicinal Chemistry.

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Effects of propranolol and a number of its analogues on sodium channels

Abstract

Brain Res.

Life Sci.

J. biol. Chem.

Experientia

Cardiovas. Res.

Physiol. Rev.