Complete blockade by phenoxybenzamine of ?1- but not of ?2-vascular receptors in dogs and the effects of propranolol

Constantine, Jay W.; Lebel, Wesley S.

doi:10.1007/bf00504531

Cited by 61 publications

(14 citation statements)

References 17 publications

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“…Although phenoxybenzamine is relatively selective for al-adrenoceptors (Dubocovich & Langer, 1972;Doxey et al, 1977;Constantine & Lebel, 1980), at the doses used in the present study (0.5-1.1 mg kg-') it would be expected to produce a2-adrenoceptor blockade in addition (Hamilton et al, 1981). It has been suggested that drugs which are selective postsynaptic aradrenoceptor antagonists (such as indoramin and prazosin) are less likely to increase heart rate in clinical use, as the negative feedback inhibition of NA release mediated by presynaptic a2-adrenoceptors is left intact (Hoffman & Lefkowitz, 1980).…”

Section: Discussionmentioning

confidence: 71%

Differential blockade of alpha‐adrenoceptors by indoramin.

Nicholls¹,

O'Connor²,

Harron³

et al. 1984

Brit J Clinical Pharma

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1 The effect of equihypotensive single oral doses of indoramin (mean dose 67 mg), phenoxybenzamine (mean dose 50 mg), hydralazine (mean dose 133 mg) and placebo on arterial pressure and heart rate in the supine and standing position was studied in six normal volunteers. Observations were made before and at 2 and 4 h after drug administration.2 Plasma noradrenaline (NA) was measured at each time interval in the supine position, and after 4 min of standing. Plasma renin activity (PRA) was measured at each time interval after 30 min in the standing position. 3 The three active drugs reduced systolic arterial pressure in the standing position to a similar extent (indoramin, -24 mm Hg; phenoxybenzamine, -23.4 mm Hg; hydralazine, -30.4 mm Hg). The maximum effect of indoramin and phenoxybenzamine was observed at 4 h, and of hydralazine at 2 h after drug administration. 4 The reductions of arterial pressure in the standing position were accompanied by increases in heart rate, plasma NA and PRA. Small increases were observed after indoramin (heart rate, + 9.2 beats min-'; plasma NA, + 126 pg/ml; PRA, + 0.33 ng angiotensin 1 ml-' h-1), greater increases after phenoxybenzamine (heart rate, + 20; plasma NA, + 210; PRA, + 0.47), and the greatest increases after hydralazine (heart rate, + 26; plasma NA, + 250; PRA, + 1.16). 5 In the supine position, indoramin and phenoxybenzamine produced no effect on arterial pressure, heart rate or plasma NA. Hydralazine produced small reductions in diastolic pressure, which were accompanied by an increase in heart rate of 25.5 beats min (P < 0.01 when compared to placebo) and in plasma NA of 223 pg ml-'(P < 0.05). 6 Plasma NA, PRA and heart rate increased together and may be regarded as three interdependent indices of sympathetic activity. 7 Indoramin reduced the degree of increase of plasma NA, PRA and heart rate per unit fall in pressure, when compared to phenoxybenzamine and hydralazine. The effect of phenoxybenzamine and hydralazine on the degree of increase was similar. 8 The results are consistent with the hypothesis that indoramin produces selective postsynaptic al-adrenoceptor blockade in man, and therefore produces relatively less tachycardia and NA increase than does a non-selective a-adrenoceptor antagonist (phenoxybenzamine) or an arteriolar vasodilator (hydralazine).Keywords indoramin phenoxybenzamine hydralazine a-adrenoceptors 719 720 D. P. Nicholls et al.

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Section: Discussionmentioning

confidence: 71%

Differential blockade of alpha‐adrenoceptors by indoramin.

Nicholls¹,

O'Connor²,

Harron³

et al. 1984

Brit J Clinical Pharma

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“…If one combines the observations of Constantine and Lebel (1980), that phenoxybenzamine is a more powerful postjunctional aj than postjunctional a 2 -receptor-blocking agent, with the recent observations of Holtz et al (1982), that coronary vasoconstriction is mediated by both <*i and a 2 postjunc- • % = 100 (phenoxybenzamine -control)/control. n = 7; mean ± 1 SEM.…”

Section: Discussionmentioning

confidence: 98%

Effect of coronary artery pressure on transmural distribution of adrenergic coronary vasoconstriction in the dog.

Buffington¹,

Feigl²

1983

Circulation Research

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SUMMARY. The transmural distribution of a-receptor coronary vasoconstriction was studied in 14 closed-chest, morphine-and chloralose-anesthesized dogs. The a-receptor-blocking agent, phenoxybenzamine (0.25 mg/kg), was infused into either the anterior or circumflex coronary artery while collection of coronary sinus blood mimimized recirculation. The left main coronary artery was cannulated and perfused at constant pressure. Myocardial lactate extraction and blood flow (9 nm radioactive microspheres) were measured during adrenergic activation with intracoronary norepinephrine (2 jig/min) at coronary artery pressures of 100, 70, 50, and 38 mm Hg. Flow was 15-25% less in the control region (a-receptors intact) than in the a-receptor-blocked region, in all layers of the left ventricular wall, at coronary pressures of 100 and 70 mm Hg. When coronary pressure was 50 mm Hg, lactate production resulted (-4% extraction) and significant a-receptor vasoconstriction was observed in the outer layer, but was marginal (P = 0.043) in the inner layer, of the left ventricle. Flows were not different in control and a-receptorblocked regions at a coronary pressure of 38 mm Hg (lactate extraction -49%). These data indicate a uniform transmural a-receptor vasoconstriction at normal coronary artery pressures that diminished as the heart was progressively underperfused. (Circ Res 53: 613-621, 1983)

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“…To resolve the question, experiments were carried out in which tissues were pre-exposed to the irreversible antagonist, phenoxybenzamine, a drug that is selective for ac-adrenoceptors (Dubocovich & Langer, 1974;Constantine & Lebel, 1980); a concentration was chosen that reduced the contractile response to stimulation by approximately two thirds. In the aorta, the phenoxybenzamine treatment changed neither pre-nor postsynaptic effects of rauwolscine and prazosin, further confirming the olnature of the responses in that tissue.…”

Section: Discussionmentioning

confidence: 99%

An EXAMINATION OF THE PRE‐ AND POSTSYNAPTIC Α‐ADRENOCEPTORS INVOLVED IN NEUROEFFECTOR TRANSMISSION IN RABBIT AORTA AND PORTAL VEIN

Docherty

Starke

1982

British J Pharmacology

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1 The a-adrenoceptor agonists, clonidine and xylazine, reduced and the a-antagonists, yohimbine and rauwolscine, increased the stimulation-evoked tritium overflow from rabbit aorta and portal vein pre-incubated with [3H]-noradrenaline. 2 Based on an order of agonist potency of clonidine > xylazine > phenylephrine and antagonist potency of rauwolscine = yohimbine > prazosin, the presynaptic receptor mediating these effects is of the a2-type.3 In the aorta, stimulation-evoked contractions were abolished by prazosin (0.1 pM) and potentiated by rauwolscine and yohimbine in concentrations that increased the stimulation-evoked overflow of tritium.4 In the portal vein, prazosin was less potent in reducing, and rauwolscine and yohimbine failed to potentiate, the stimulation-evoked contraction.5 In experiments in which tissues were pre-exposed to phenoxybenzamine (30 nM) to block some of the postsynaptic a-receptors, rauwolscine in concentrations that increased stimulation-evoked tritium overflow, reduced the evoked contraction in the portal vein but not in the aorta. 6 It is concluded that presynaptic a2-autoreceptors are present in both tissues and that the postsynaptic a-receptors which mediate nerve stimulation-evoked contractions are a1 in the aorta but a mixture of al and a2 in the portal vein.

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Complete blockade by phenoxybenzamine of ?1- but not of ?2-vascular receptors in dogs and the effects of propranolol

Cited by 61 publications

References 17 publications

Differential blockade of alpha‐adrenoceptors by indoramin.

Differential blockade of alpha‐adrenoceptors by indoramin.

Effect of coronary artery pressure on transmural distribution of adrenergic coronary vasoconstriction in the dog.

An EXAMINATION OF THE PRE‐ AND POSTSYNAPTIC Α‐ADRENOCEPTORS INVOLVED IN NEUROEFFECTOR TRANSMISSION IN RABBIT AORTA AND PORTAL VEIN

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