Calculated and actual changes in β-adrenoceptor number associated with increases in rat and guinea-pig cardiac sensitivity

Chess‐Williams, Russell; Broadley, Kenneth J.; Sheridan, Desmond J.

doi:10.1111/j.2042-7158.1986.tb03380.x

Cited by 11 publications

(5 citation statements)

References 11 publications

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“…The positive inotropic responses to methoctramine were unaffected by phentolamine, indicating a lack of effect at a-adrenoceptors, but were abolished by propranolol, probably implicating f-adrenoceptor agonism. This finding is consistent with the increased sensitivity observed to methoctramine after reserpine treatment; a procedure which also increases sensitivity to fi-adrenoceptor agonists (Chess-Williams et al, 1986).…”

Section: Discussionsupporting

confidence: 87%

The interaction of methoctramine and himbacine at atrial, smooth muscle and endothelial muscarinic receptors in vitro

Eglen¹,

Montgomery²,

Dainty

et al. 1988

British J Pharmacology

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1 The action of methoctramine and himbacine at muscarinic receptors has been studied using guinea-pig isolated trachea, oesophageal muscularis mucosae, paced left atria, and rat aortic preparations.2 Methoctramine (1 x 10-6-3.2 x 10-0M), but not himbacine, elicited positive inotropic responses. These responses were enhanced by pretreating the animals with reserpine. The responses in reserpine-treated animals were not antagonized by phentolamine (1 x 10-6M) but were antagonized by propranolol (1 x 10-6M).3 Methoctramine, but not himbacine, exhibited allosteric inhibitory effects at cardiac muscarinic receptors, resulting in a curvilinear Schild plot. Deviations from competitive antagonism were also observed in combination dose-ratio experiments using atropine and methoctramine. At 1 x 10-6M, the pKB value for methoctramine was 7.88 + 0.15 (mean + s.e.mean, n = 5). The pA2 value for himbacine at cardiac muscarinic receptors was 8.52 + 0.06 (n = 3). 4 At tracheal and oesophageal muscularis mucosal smooth muscle receptors, the Schild plots for both antagonists were linear. The pA2 values for methoctramine at receptors in these two preparations were similar (6.08 + 0.05 and 6.03 + 0.09 respectively, n = 4) and were approximately 60 fold less than those values observed at atrial receptors. Himbacine, also exhibited similar values at muscarinic receptors in the trachea and oesophageal muscularis mucosae (7.61 + 0.05 and 7.57 + 0.04 respectively, n = 4). 5 Muscarinic receptors mediating relaxation of the rat aortic endothelium exhibited pA2 values for methoctramine (5.87 + 0.12, n = 6) which were similar to those observed in the smooth muscle, but not the atria. The pA2 values for himbacine at endothelial muscarinic receptors were approximately 0.5 pA2 units lower than those observed at muscarinic receptors in smooth muscle (6.92 + 0.80, n = 6). In addition, the Schild slopes for methoctramine and himbacine at these receptors were significantly (P < 0.05) less than unity. 6 Methoctramine, and to a lesser extent himbacine, are potent and selective antagonists for cardiac muscarinic receptors. However, caution should be used in interpretation of the data with methoctramine in view of the inhibitory allosteric properties and direct inotropic actions of this compound.

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Section: Discussionsupporting

confidence: 87%

The interaction of methoctramine and himbacine at atrial, smooth muscle and endothelial muscarinic receptors in vitro

Eglen¹,

Montgomery²,

Dainty

et al. 1988

British J Pharmacology

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“…In the diabetic bladder the density of muscarinic receptors was significantly increased by 40% compared with the density in the control rat bladder. This change in sensitivity to carbachol would require a 6.3‐fold increase in receptor density if this were the sole mechanism responsible for the increase in tissue sensitivity (Chess‐Williams, Broadley & Sheridan, 1986). Thus, the increase in receptor density can only partially explain the tissue supersensitivity and other mechanisms must also be operating at a cellular level.…”

Section: Discussionmentioning

confidence: 99%

Muscarinic receptor function, density and G‐protein coupling in the overactive diabetic rat bladder

Stevens

Sellers

McKay

et al. 2006

Auton Autocoid Pharmacol

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1 Bladder smooth muscle sensitivity to muscarinic agonists is increased in the overactive bladder. Treatment of rats with streptozotocin induces a diabetic state in which the bladder muscle is overactive and also supersensitive to muscarinic agonists. This study has examined bladder contraction, muscarinic receptor density and receptor/G-protein coupling in the streptozotocin-induced overactive bladder of the rat. 2 Diabetes was induced by a single intraperitoneal dose of streptozotocin. Seven days later contraction of isolated detrusor muscle strips was assessed in tissue bath experiments, while receptor density was assayed in saturation experiments with [3H]-QNB (quinuclidinyl benzilate, L-[benzilic-4,4'-3H]) and receptor/G-protein coupling was determined in agonist displacement experiments with this radioligand. 3 Isolated detrusor strips from diabetic animals displayed an enhanced degree of spontaneous activity (0.060 +/- 0.016 g mg(-1), compared with 0.015 +/- 0.004 g mg(-1), P < 0.05). Carbachol produced contractile responses in tissues from both control and diabetic rats, but the diabetic tissues were more sensitive to this agonist, the pEC50 being 6.52 +/- 0.17 compared with 5.93 +/- 0.06 in controls (P < 0.001). Maximum responses to carbachol were similar in both groups of animals. The increase in carbachol potency was accompanied by a 40% increase in receptor density from 158 +/- 5 to 221 +/- 22 fmol mg(-1) protein (P < 0.05), but this was not enough to fully account for the change in tissue sensitivity. 4 In the absence of GTP-gamma-S, carbachol displaced [3H]-QNB from two binding sites, the high-affinity site (pKi = 7.06 +/- 0.26) which represents the receptors coupled to G-proteins made up 43.1 +/- 5.9% of the total binding sites in control tissues and this value was similar (41.0 +/- 4.0%) in the diabetic tissues (pKi = 6.64 +/- 0.31). In the presence of GTP-gamma-S, carbachol displaced [3H]-QNB from a single binding site which had a low-affinity, similar to the low-affinity site observed in the absence of GTP-gamma-S. 5 These data demonstrate that detrusor supersensitivity is observed after only 1 week of untreated diabetes in the rat. The overactivity is associated with an enhanced sensitivity to carbachol, which is partly explained by an increase in receptor density, but there appears to be no change in receptor/G-protein coupling.

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“…The postsynaptic sensitivity of a tissue to a transmitter is regulated by the degree of receptor stimulation. Elevating plasma catecholamine levels by infusing noradrenaline in vivo (Butterfield & Chess-Williams, 1991) or incubating tissues with notadrenaline in vitro (Chess-Williams, 1987) al., 1986), a mechanism presumably operating in the present study. The regulation of al-adrenoceptor-mediated responses has received less attention, but in most tissues, responses appear to be depressed following excessive stimulation of the receptor.…”

Section: Discussionmentioning

confidence: 99%

“…anococcygeus muscle, spleen (O'Brien & Chess-Williams, 1991) and vasculature of the rat (Colucci, Gimborne & Alexander, 1981;Lurie, Tsujimoto & Hoffman, 1985), and also the vas deferens of the guinea-pig (Takeyasu, Higuchi, Fujita, Uchida & Yoshida, 1982). The cardiac al-adrenoceptor appeqrs atypical, however, since studies in vitro and in vivo have failed to induce a desensitization with noradrenaline (Chess-Williams, 1987;Butterfield & Chess-Williams, 1991). Furthermore, chemical sympathectomy with 6-OHDA or reserpine failed to alter cardiac al-adrenoceptormediated responses, despite cardiac padrenoceptor-mediated responses being enhanced by pretreatment (Chess-Williams et al, 1987a,b).…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of cardiac α‐ and β‐adrenoceptors by the sympathetic nervous system

Chess-Williams¹,

Doubleday²,

Reynolds³

1994

Journal of Autonomic Pharmacology

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1. The effects of depressed sympathetic function on the inotropic responses of the heart to sympathomimetic amines have been examined in rats immunized against nerve growth factor (NGF) 6 weeks prior to the isolation of cardiac tissues. 2. The activity of tyrosine hydroxylase in cervical sympathetic ganglia and the levels of noradrenaline in ventricular tissue were significantly reduced in NGF-immunized rats. 3. Left atria and papillary muscles from NGF-immunized rats were supersensitive to the beta-adrenoceptor agonist isoprenaline when compared with controls. 4. The responses of cardiac tissues to the alpha-adrenoceptor agonist phenylephrine were unaffected by immunization. 5. These results support the hypothesis that cardiac beta- but not alpha-adrenoceptor sensitivity is regulated by the sympathetic nervous system.

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Calculated and actual changes in β-adrenoceptor number associated with increases in rat and guinea-pig cardiac sensitivity

Cited by 11 publications

References 11 publications

The interaction of methoctramine and himbacine at atrial, smooth muscle and endothelial muscarinic receptors in vitro

The interaction of methoctramine and himbacine at atrial, smooth muscle and endothelial muscarinic receptors in vitro

Muscarinic receptor function, density and G‐protein coupling in the overactive diabetic rat bladder

Differential regulation of cardiac α‐ and β‐adrenoceptors by the sympathetic nervous system

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