Central Hypotensive Activity of dl- and d-Propranolol

Kelliher, Gerald J.; Buckley, Joseph P.

doi:10.1002/jps.2600590914

Cited by 100 publications

(36 citation statements)

References 39 publications

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“…Those treatments produced (parallel) rightward shifts of the dose-response curves and, consequently, marked changes in the ED 50 dose of S(−)PRO; ED 50 values of S(−)PRO shifted 2.5-and five-fold when S(−)PRO was given alone versus when it was given in the presence of 1 and 2 mg/kg of prazosin, respectively. Thus, it is possible that PRO and its stereoisomers might exert a central effect(s) that arises from an increased release or a decreased reuptake of NE into central adrenergic nerve terminals (e.g., Kelliher and Buckley 1970;Day and Roach 1974;Davies and Reid 1975;Kobinger 1978;Privitera et al 1979;Tackett et al 1981;Tuross and Patrick 1986). However, the present experiments cannot discern inhibition of reuptake and/or stimulation of release of NE by PRO, but in either, or both, case(s), the result would be an increase in adrenergic action in the synapse.…”

Section: Discussionmentioning

confidence: 99%

“…PRO also may interact with adrenoceptors in ways other than, or in addition to, antagonism of β-adrenoceptors. For instance, PRO can raise central α-adrenoceptor (primarily α 1 -adrenoceptor) activity via the release of NE and/or an inhibition of NE reuptake (e.g., Kelliher and Buckley 1970;Day and Roach 1974;Davies and Reid 1975;Kobinger 1978;Privitera et al 1979;Tackett et al 1981;Tuross and Patrick 1986). Interestingly, however, R(+)PRO is nearly as potent or slightly less potent (i.e., 1.5-to ∼3-fold) than S(−)PRO with respect to those indirect agonist actions on adrenoceptors (Daniell et al 1976;Saelens et al 1977;Tackett et al 1981;Tuross and Patrick 1986).…”

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confidence: 99%

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S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Young

Glennon

2008

Psychopharmacology

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Rationale Racemic propranolol (PRO), a β-adrenoceptor antagonist, has been evaluated as a test agent but not as a discriminative stimulus. Its S(−) stereoisomer is thought to subserve the effects of (±)PRO. Materials and methods Rats were trained to discriminate S(−)PRO (5 mg/kg) from saline in a two-lever foodreinforced operant conditioning task. Results The S(−)PRO stimulus was shown to be centrally mediated, dose-related, time dependent, and stereoselective: S(−)PRO (ED 50 =2.2 mg/kg) was twice as potent as (±)PRO and approximately four times as potent as R(+)PRO. The S(−)PRO stimulus generalized fully to the β-adrenoceptor agent pindolol, the α 1 -adrenoceptor agonist methoxamine, cocaine, and the serotonergic agents TFMPP and RU 24969; partial generalization occurred to (−)ephedrine and nisoxetine but not to fenfluramine or 5-OMe DMT. The S(−)PRO stimulus was blocked completely (and competitively) when prazosin, an α 1 -adrenoceptor antagonist, was given in combination with the training dose of S(−)PRO. Moreover, prazosin exerted antagonism of the S(−)PRO-like effect of (±)PRO or R(+)PRO but produced only partial antagonism of the S(−)PRO-like effect of cocaine. In a second study, rats were trained to discriminate 8 mg/kg of cocaine from saline. The cocaine stimulus generalized to S(−)PRO, (±)PRO, and R(+)PRO. Prazosin partially attenuated the stimulus effect of cocaine (8 mg/kg) but completely blocked the cocaine-like effects of (±), S(−), and R(+)PRO. Conclusions PRO and cocaine exhibited cross-substitution, but their stimulus effects were antagonized differentially by prazosin. PRO (and its optical isomers) can exert a stimulus effect that is based, at least in part, on increased α 1 -adrenoceptor activity. PRO might be better characterized as an adrenoceptor partial agonist.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Young

Glennon

2008

Psychopharmacology

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“…) injection of ,B-adrenoceptor blocking agents induces bradycardia in cats (Kelliher & Buckley, 1970), dogs (Srivastava, Kulshrestha, Singh & Bhargava, 1972), rabbits (Reid, Lewis, Myers & Dollery, 1974) and rats (Ito & Schanberg, 1974), whilst under the same experimental conditions, P-adrenoceptor stimulating drugs, especially isoprenaline, provoke tachycardia in dogs (Bhargava, Mishra & Tangri, 1972) cats (Gagnon & Melville, 1967) and rabbits (Toda, Matsuda & Shimamoto, 1969;Reid et al, 1974;Day & Roach, 1974a). …”

Section: Introductionmentioning

confidence: 98%

“…However, fl-blocking drugs and isoprenaline, when injected separately i.c.v., induce a fall in blood pressure (Toda et al, 1969;Kelliher & Buckley, 1970;Schmitt & Fenard, 1971;Srivastava et al, 1972;Reid et al, 1974).…”

Section: Introductionmentioning

confidence: 99%

Β‐adrenoceptor Blocking Drugs and Isoprenaline: Central Effects on Cardiovascular Parameters

Cohen

Lindenbaum

Midol-Monnet

et al. 1979

British J Pharmacology

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1 The central hypotensive activity of (+)-and (-)-propranolol (100 ig), pindolol (100 ig) and isoprenaline (1 and 4 pg) injected intracerebroventricularly (i.c.v.) was studied in rats anaesthetized with urethane and chloralose. Blood pressure, cardiac output and heart rate were measured; systolic stroke volume and peripheral vascular resistance were calculated. 2 (+)-and (-)-Propranolol and pindolol induced a fall of blood pressure but (+)-propranolol was less active. The heart rate was reduced more by (-)-propranolol than by (+)-propranolol or (-)-pindolol. The decrease of systolic stroke volume was greater for (-)-propranolol and pindolol than for (+)-propranolol. Peripheral vascular resistance was reduced to the same level but with different time courses, (-)-propranolol having a longer effect than (+)-propranolol and pindolol. 3 Isoprenaline induced a hypotensive effect, while cardiac output and heart rate increased; the systolic stroke volume remained stable but peripheral vascular resistance was significantly decreased. 4 These results suggest that different central regulatory centres are involved in the control of cardiac function and peripheral vascular tone.

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“…Early reports of inhibition of sympathetic nervous system cardiovascular reflexes during f3-adrenergic blockade, both in animals (Dunlop & Shanks, 1969) and patients with essential hypertension (Esler & Nestel, 1973), suggested that suppression of the sympathetic nervous system, perhaps at a site within the central nervous system (Kelliher & Buckley, 1970), might be an antihypertensive mechanism. This viewpoint was subsequently strengthened when it was found that administration of propranolol to rabbits reduced sympathetic nerve firing rates (Lewis & Haeusler, 1975).…”

Section: Introductionmentioning

confidence: 99%

Effect of propranolol on noradrenaline kinetics in patients with essential hypertension.

Esler¹,

Jackman²,

Leonard³

et al. 1981

Brit J Clinical Pharma

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1 The rates of noradrenaline spillover to, and removal from, plasma were measured in ten patients with essential hypertension treated with propranolol, to ascertain if long-term administration of this drug reduces sympathetic nervous system tone. 2 The plasma clearance of noradrenaline fell with propranolol, leading to a small rise in the mean plasma noradrenaline concentration. Sympathetic nervous activity in treated patients cannot be reliably gauged from plasma noradrenaline values because these are distorted by the reduction in noradrenaline clearance. 3 There was no consistent effect on noradrenaline spillover rates, which fell in six patients, but rose in the remaining four. The magnitude of the antihypertensive response was unrelated to these changes in noradrenaline release. During propranolol treatment, noradrenaline spillover rates were in every case within the normal range, much higher than in patients treated with the known sympathetic nervous systems suppressant, clonidine. 4 The principal mode of antihypertensive action of propranolol is something other than central suppression of sympathetic tone or pre-synaptic inhibition of noradrenaline release.

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Central Hypotensive Activity of dl- and d-Propranolol

Cited by 100 publications

References 39 publications

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

S(−)Propranolol as a discriminative stimulus and its comparison to the stimulus effects of cocaine in rats

Β‐adrenoceptor Blocking Drugs and Isoprenaline: Central Effects on Cardiovascular Parameters

Effect of propranolol on noradrenaline kinetics in patients with essential hypertension.

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