Studies on β-adrenoceptors mediating changes in mechanical events and adenosine 3′,5′-monophosphate levels. Rat atria

Buckner, Carl K.; Torphy, T. J.; Costa, D.

doi:10.1016/0014-2999(78)90233-9

Cited by 34 publications

(9 citation statements)

References 17 publications

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“…The small difference for orciprenaline was not significant. This agrees with results obtained by ourselves and others (Buckner, Torphy & Costa, 1978) in which functional antagonism was used to determine the dissociation constants. This finding is also consistent with the observations that the affinity values (pA2) of competitive antagonists are identical for the positive inotropic and positive chronotropic responses (Blinks, 1967;Bristow & Green, 1970;Horii, Kawada, Takeda & Imai, 1974;Lumley & Broadley, 1975;1977).…”

Section: Discussionsupporting

confidence: 92%

Dissociation Constants of Isoprenaline and Orciprenaline and Their Relative Efficacies on Guinea‐pig Isolated Atria Determined by Use of an Irreversible Β‐adrenoceptor Antagonist

Broadley

Nicholson

1981

British J Pharmacology

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I Dissociation constants (KA) of isoprenaline and orciprenaline were determined for the positive inotropic and chronotropic responses of guinea-pig isolated atria. Cumulative dose-response curves to the agonists were constructed before and after incubation with and washout of the irreversible ,3-adrenoceptor antagonist, Ro 03-7894 1-(5-chloracetylaminobenzfuran-2-yl)-2-isopropylaminoethanol). 2 After 20 min washout, the curves were displaced to the right with depression of the maxima. After 3 h washout, there was only depression of the maxima. 3 Dissociation constants were determined by plotting reciprocals of molar concentrations before Ro 03-7894 (1/A) against reciprocals of the equiactive concentrations after Ro 03-7894 (1/A'). KA = (slope -1)/intercept. 4 Isoprenaline had a greater affinity (KA) than orciprenaline on both rate and tension. The affinity for rate and tension was identical for both agonists, indicating that the ,B-adrenoceptors were identical. 5 Isoprenaline and orciprenaline produced identical rate response maxima when compared in the same preparation but the orciprenaline tension maximum was only 92.0 + 0.3% that of isoprenaline. 6 These dose-response curves were replotted as response against -log RA/Rt (fraction of receptors occupied) for each agonist concentration, calculated from the equation RA/Rt = (A)/(KA + (A)).

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Section: Discussionsupporting

confidence: 92%

Dissociation Constants of Isoprenaline and Orciprenaline and Their Relative Efficacies on Guinea‐pig Isolated Atria Determined by Use of an Irreversible Β‐adrenoceptor Antagonist

Broadley

Nicholson

1981

British J Pharmacology

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“…However, contrary to what is observed with isoprenaline, no significant increase in cyclic AMP level could be detected in atria in the presence of the P2-selective agonists, soterenol and terbutaline (Buckner, Torphy & Costa, 1978;Hedberg, Carlsson, Fellenius & Lundgren, 1982). Furthermore, Minneman, Hegstrand & Molinoff (1979) reported that P2-selective drugs such as soterenol, zinterol, terbutaline and salbutamol, did not stimulate adenylate cyclase in rat ventricle homogenate.…”

Section: Introductionmentioning

confidence: 66%

Comparison of the chronotropic effect and the cyclic AMP accumulation induced by β₂‐agonists in rat heart cell culture

Freyss-Beguin¹,

Griffaton²,

Lechat³

et al. 1983

British J Pharmacology

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1The chronotropic response and the variation in cyclic adenosine 3',5'-monophosphate (cyclic AMP) accumulation induced by isoprenaline and six P2-selective agonists (fenoterol, salmefamol, soterenol, zinterol, salbutamol and formoterol) were analyzed on cultured heart cells of the rat. 2 The compounds elicited an enhancement of the frequency, but the time course of the variation of the beating rate was not identical for all of them. A rapid onset was observed for isoprenaline, zinterol and formoterol while it was slower for fenoterol, salmefamol and salbutamol.3 In contrast with isoprenaline, the P2-selective agonists gave concentration-beating frequency curves which were not sigmoidal. Their effects extended up to a concentration of 5 to 6 orders of magnitude. Nevertheless, the concentration at which the maximal effect occurred and the intrinsic activities of the various compounds agrees better with the responses observed on guinea-pig atria than with those on trachea.4 All the P2-selective agonists increased the accumulation of cyclic AMP in rat heart cells with a maximal effect at 10-5M or less. The effects of 02-agonists on cyclic AMP production showed some analogies with those on beating frequency of the heart cells. The increase in cyclic AMP accumulation induced by P2-agonists also corresponded to their chronotropic effects on guinea-pig atria. Thus, the correlation coefficient between the inverse of the log of the concentration producing the half maximal cyclic AMP accumulation in cultured heart cells and the pD2 values on guinea-pig atria was 0.93.5 It is concluded that, in contrast to what was observed in other models, the P2-selective agonists induce an increase in the production of cyclic AMP in rat heart cells. Furthermore, the effects of the P2-agonists on cyclic AMP accumulation and on beating rate in the heart cells may correspond with their J1-adrenoceptor potencies.

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“…It should be noted that the stimulation of ␤-AR with sympathomimetic amines, including ISO, enhances cardiac myocyte contractility through the production of cAMP and thus cAMP-dependent kinasemediated phosphorylation of related proteins. However, the dose of ISO required for the maximal enhancement of cardiac contractility is much lower than that required for the maximal activation of cAMP production, suggesting the presence of a large cAMP reserve capacity by cardiac AC in regulating contractility (27,(33)(34)(35)(36)(37).…”

Section: Resultsmentioning

confidence: 99%

Direct Inhibition of Type 5 Adenylyl Cyclase Prevents Myocardial Apoptosis without Functional Deterioration

Iwatsubo

Minamisawa

Takemoto

et al. 2004

Journal of Biological Chemistry

101

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Adenylyl cyclase, a major target enzyme of ␤-adrenergic receptor signals, is potently and directly inhibited by P-site inhibitors, classic inhibitors of this enzyme, when the enzyme catalytic activity is high. Unlike ␤-adrenergic receptor antagonists, this is a non-or uncompetitive inhibition with respect to ATP. We have examined whether we can utilize this enzymatic property to regulate the effects of ␤-adrenergic receptor stimulation differentially. After screening multiple new and classic compounds, we found that some compounds, including 1R,4R-3-(6-aminopurin-9-yl)-cyclopentanecarboxylic acid hydroxyamide, potently inhibited type 5 adenylyl cyclase, the major cardiac isoform, but not other isoforms. In normal mouse cardiac myocytes, contraction induced by low ␤-adrenergic receptor stimulation was poorly inhibited with this compound, but the induction of cardiac myocyte apoptosis by high ␤-adrenergic receptor stimulation was effectively prevented by type 5 adenylyl cyclase inhibitors. In contrast, when cardiac myocytes from type 5 adenylyl cyclase knock-out mice were examined, ␤-adrenergic stimulation poorly induced apoptosis. Our data suggest that the inhibition of ␤-adrenergic signaling at the level of the type 5 adenylyl cyclase isoform by P-site inhibitors may serve as an effective method to prevent cardiac myocyte apoptosis induced by excessive ␤-adrenergic stimulation without deleterious effect on cardiac myocyte contraction.Adrenergic stimulation via the sympathetic nervous system is a major mechanism to regulate cardiac function (1). Norepinephrine released from the synaptic terminal binds to ␤-adrenergic receptors (␤-AR), 1 leading to the activation of adenylyl cyclase (AC) and thus the production of cAMP, which initiates a cascade of protein phosphorylation and regulation of many key signaling elements involved in muscle contraction and calcium handling. The immediate outcome of this stimulation is increased cardiac contractility and output. Pharmacological inhibition of this pathway, by the use of ␤-AR antagonists, has been widely utilized to attenuate cardiac function in the clinical setting of treating high blood pressure for several decades. Recently, ␤-AR antagonists have been used in the treatment of heart failure, i.e. in hearts with deteriorated cardiac function. This paradoxical usage of ␤-AR antagonists in heart failure has been rationalized by the protection of the heart from excessive sympathetic stimulation. Under this pathological condition, it is well known that the sympathetic activity is increased markedly (2-4), leading to the remodeling of the heart (5) and, more importantly, the induction of cardiac myocyte apoptosis, as demonstrated by both in vivo and in vitro studies (6, 7). However, a major problem in introducing ␤-AR antagonist therapy is the worsening of cardiac function (8).It is believed that regulating ␤-adrenergic signaling at the level of AC, instead of the receptor, may serve as an alternative to the common ␤-AR regulating therapy, which is most exemplified by direct ...

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Studies on β-adrenoceptors mediating changes in mechanical events and adenosine 3′,5′-monophosphate levels. Rat atria

Cited by 34 publications

References 17 publications

Dissociation Constants of Isoprenaline and Orciprenaline and Their Relative Efficacies on Guinea‐pig Isolated Atria Determined by Use of an Irreversible Β‐adrenoceptor Antagonist

Dissociation Constants of Isoprenaline and Orciprenaline and Their Relative Efficacies on Guinea‐pig Isolated Atria Determined by Use of an Irreversible Β‐adrenoceptor Antagonist

Comparison of the chronotropic effect and the cyclic AMP accumulation induced by β₂‐agonists in rat heart cell culture

Direct Inhibition of Type 5 Adenylyl Cyclase Prevents Myocardial Apoptosis without Functional Deterioration

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Studies on β-adrenoceptors mediating changes in mechanical events and adenosine 3′,5′-monophosphate levels. Rat atria

Cited by 34 publications

References 17 publications

Dissociation Constants of Isoprenaline and Orciprenaline and Their Relative Efficacies on Guinea‐pig Isolated Atria Determined by Use of an Irreversible Β‐adrenoceptor Antagonist

Dissociation Constants of Isoprenaline and Orciprenaline and Their Relative Efficacies on Guinea‐pig Isolated Atria Determined by Use of an Irreversible Β‐adrenoceptor Antagonist

Comparison of the chronotropic effect and the cyclic AMP accumulation induced by β2‐agonists in rat heart cell culture

Direct Inhibition of Type 5 Adenylyl Cyclase Prevents Myocardial Apoptosis without Functional Deterioration

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Comparison of the chronotropic effect and the cyclic AMP accumulation induced by β₂‐agonists in rat heart cell culture