Modulation of Adrenoceptor-Mediated Cardiovascular Effects by Short-Term In Vivo Infusion of Isoproterenol in Rats

Vleeming, W.; Rooij, H.H. van; Wemer, J.; Porsius, A. J.

doi:10.1097/00005344-199010000-00009

Cited by 12 publications

(15 citation statements)

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“…Desensitization of the atrial PI-receptors was not unexpected since the desensitizing/down regulatory effects upon cardiac PI-receptors of prolonged elevation of catecholamine levels in vivo is a well documented phenomenon, observed in human heart failure (Bristow et al, 1986;Michel et al, 1988;Steinfath et al, 1991) and experimentally in rats (Chang et al, 1982;Kenakin & Ferris, 1983;Hayes et al, 1986;Nanoff et al, 1989;Lu & Barnett, 1990;Vleeming et al, 1990;Butterfield & Chess-Williams, 1993); guinea-pigs (Elfellah & Reid, 1990) and cats (Hedberg et al, 1984). Equally, lack of desensitization of atrial PI-receptors following 7-day dopexamine infusion was not a surprising result since dopexamine has been reported to be only a weak agonist at the 3,-receptors of the guinea-pig right atria (Mitchell et al, 1987), with an intrinsic activity of only 0.1 relative to isoprenaline (Brown et al, 1985).…”

Section: -Adrenoceptor-mediated Atrial Responsesmentioning

confidence: 96%

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Martin

Broadley

1994

British J Pharmacology

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1 Rats received intravenous infusions of dopexamine, an agonist with selectivity for D1-dopamine receptors and P2-adrenoceptors (240 ,g kg-' h-1), isoprenaline, a P,-and P2-adrenoceptor agonist (40 fig kg- and paced left atrium (increase in tension) showed significant reductions in sensitivity to isoprenaline following isoprenaline infusion. The EC5 values were significantly increased from 5.6 to 17.7 nM in right atria and from 7.4 to 27.1 nM in left atria. The maximum rate increase of right atria was also significantly less after isoprenaline infusion compared with controls (164.0 and 251.9 beats min-', respectively) but the maximum tension responses of left atria were not significantly different. After infusion with dopexamine, however, there was no change in sensitivity of the left or right atria to PI-adrenoceptor stimulation by isoprenaline.3 P2-Adrenoceptor-mediated relaxation responses to isoprenaline of the pulmonary artery, constricted with noradrenaline (6 x 108 M), showed no significant difference in maximum response or ECm in tissue from isoprenaline-or dopexamine-infused rats compared with vehicle-infused controls. P2-Adrenoceptormediated vasodilator responses were also examined in the kidney perfused with the thromboxane A2 analogue, U46619 (7.1 x 10-8 M) to raise perfusion pressure. As with the pulmonary artery, there was no significant difference in ED50 or maximum response to isoprenaline in kidneys from isoprenalineinfused animals compared with vehicle controls.4 The DI-receptor-mediated vasodilator responses to dopamine of the kidney perfused with U46619 were reduced after infusion of rats with dopexamine. The maximum fall in perfusion pressure (16.0 mmHg) and ED50 value (5.2 rig) were significantly different from those after vehicle infusion (31.5 mmHg; 1.5 pg). 5 These results show that functional responses mediated via P1-adrenoceptors and DI-receptors are reduced by intravenous infusions of isoprenaline and dopexamine, respectively. In contrast, the P2-adrenoceptor-mediated vasodilator responses of the pulmonary artery and kidney are not reduced by these agonists. Thus, under identical conditions, there appears to be selective down-regulation of peripheral P,-and D,-receptors, but not of P2-adrenoceptors.

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Section: -Adrenoceptor-mediated Atrial Responsesmentioning

confidence: 96%

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Martin

Broadley

1994

British J Pharmacology

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“…Importantly, preserved basal LV systolic function in ISO-induced cardiac hypertrophy is associated with a profound downregulation of b-AR-mediated inotropic responses [31, 139,[144][145][146][147][148]. This downregulation is not balanced by an enhanced myocardial noradrenaline release, changes in heart rate aimed at recruiting a positive forcefrequency relationship, modifications in cardiac loads, or compensatory up-regulation of inotropic responses to non-b-adrenergic agents such as histamine, serotonin, angiotensin II, or phenylephrine [133].…”

Section: Basal Cardiac Systolic Functionmentioning

confidence: 99%

Cardiac hypertrophy induced by sustained β-adrenoreceptor activation: pathophysiological aspects

2007

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Cardiac hypertrophy is promoted by adrenergic over-activation and represents an independent risk factor for cardiovascular morbidity and mortality. The basic knowledge about mechanisms by which sustained adrenergic activation promotes myocardial growth, as well as understanding how structural changes in hypertrophied myocardium could affect myocardial function has been acquired from studies using an animal model of chronic systemic beta-adrenoreceptor agonist administration. Sustained beta-adrenoreceptor activation was shown to enhance the synthesis of myocardial proteins, an effect mediated via stimulation of myocardial growth factors, up-regulation of nuclear proto-oncogenes, induction of cardiac oxidative stress, as well as activation of mitogen-activated protein kinases and phosphatidylinositol 3-kinase. Sustained beta-adrenoreceptor activation contributes to impaired cardiac autonomic regulation as evidenced by blunted parasympathetically-mediated cardiovascular reflexes as well as abnormal storage of myocardial catecholamines. Catecholamine-induced cardiac hypertrophy is associated with reduced contractile responses to adrenergic agonists, an effect attributed to downregulation of myocardial beta-adrenoreceptors, uncoupling of beta-adrenoreceptors and adenylate cyclase, as well as modifications of downstream cAMP-mediated signaling. In compensated cardiac hypertrophy, these changes are associated with preserved or even enhanced basal ventricular systolic function due to increased sarcoplasmic reticulum Ca(2+) content and Ca(2+)-induced sarcoplasmic reticulum Ca(2+) release. The increased availability of Ca(2+) to maintain cardiomyocyte contraction is attributed to prolongation of the action potential due to inhibition of the transient outward potassium current as well as stimulation of the reverse mode of the Na(+)-Ca(2+) exchange. Further progression of cardiac hypertrophy towards heart failure is due to abnormalities in Ca(2+) handling, necrotic myocardial injury, and increased myocardial stiffness due to interstitial fibrosis.

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“…The reduction of P2AR binding sites in the gastrocnemius muscle of guinea-pigs after a 7-day infusion of isoprenaline was also greater than for the PIAR of the left ventricle (Elfellah & Reid, 1990). P2AR-mediated functional sensitivity was also shown to be attenuated in isolated vascular preparations after catecholamine infusions (Hayes, Wyss, Schenck & Cohen, 1986;Vleeming, van Rooij, Wemer & Porsius, 1990).…”

Section: Introductionmentioning

confidence: 99%

Review of mechanisms involved in the apparent differential desensitization of β₁‐ and β₂‐adrenoceptor‐mediated functional responses

Broadley

1999

Journal of Autonomic Pharmacology

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1. There has been considerable debate whether responses mediated via beta1- and beta2-adrenoceptors (beta1ARs and beta2ARs) display the same degree of desensitization after prolonged or repeated exposure to agonists. 2. Examples are provided for selective desensitization of functional responses and loss of binding sites for beta1ARs. Equally, examples are given of selective desensitization and down-regulation involving beta2ARs. 3. This review examines whether receptor subtype-selective desensitization of betaAR-mediated responses can occur and whether even within the same subtype, there may be tissue-selective desensitization. Possible reasons why apparent selectivity of desensitization of functional responses may occur are considered and are divided into methodological and non-methodological factors. 4. Methodological factors discussed are: the concentration of agonist used for inducing desensitization and the washout times before construction of the post-incubation concentration-response curve (CRC), the need for correction of CRCs from time-matched controls, and the methods adopted for plotting CRCs. 5. Four non-methodological factors are considered. Firstly, the roles of different receptor reserves for the responses of each tissue can have an important effect on whether desensitization is apparent; a large reserve will make desensitization less likely to be apparent. Secondly, there is more than one site at which desensitization occurs; receptors are uncoupled from adenylyl cyclase activation, there is an additional site at the level of stimulation of cyclic AMP-dependent protein kinase and betaARs may ultimately be down-regulated. These processes may differ depending on the tissue and conditions and this may influence whether differential desensitization occurs between tissues. Thirdly, the apparent degree of desensitization after washout of an agonist can depend upon the rate of resensitization. Experiments to overcome this problem are described which demonstrate betaAR desensitization in the continued presence of agonist. Finally, the role of up-regulation of PDE in desensitization is discussed.

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Modulation of Adrenoceptor-Mediated Cardiovascular Effects by Short-Term In Vivo Infusion of Isoproterenol in Rats

Cited by 12 publications

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Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Cardiac hypertrophy induced by sustained β-adrenoreceptor activation: pathophysiological aspects

Review of mechanisms involved in the apparent differential desensitization of β₁‐ and β₂‐adrenoceptor‐mediated functional responses

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Modulation of Adrenoceptor-Mediated Cardiovascular Effects by Short-Term In Vivo Infusion of Isoproterenol in Rats

Cited by 12 publications

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Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1‐, β1‐ and β2‐receptor‐mediated responses

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D1‐, β1‐ and β2‐receptor‐mediated responses

Cardiac hypertrophy induced by sustained β-adrenoreceptor activation: pathophysiological aspects

Review of mechanisms involved in the apparent differential desensitization of β1‐ and β2‐adrenoceptor‐mediated functional responses

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Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Effects of chronic intravenous infusions of dopexamine and isoprenaline to rats on D₁‐, β₁‐ and β₂‐receptor‐mediated responses

Review of mechanisms involved in the apparent differential desensitization of β₁‐ and β₂‐adrenoceptor‐mediated functional responses