Functional β‐adrenoceptors in the left atrium of normotensive and hypertensive rats

Doggrell, Sheila A; Surman, Ailsa J.

doi:10.1111/j.1474-8673.1994.tb00623.x

Cited by 8 publications

(11 citation statements)

References 30 publications

(13 reference statements)

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“…Circulating adrenaline can enhance the neuronal outflow of noradrenaline by stimulating presynaptic neuronal facilitatory b 2 -adrenoceptors [43]. Indeed, in pre-hypertensive and hypertensive SHR, there is increased functional b 2 -adrenoceptor response [44,45]. Furthermore, pre-weaning treatment of SHR with the b-blocker carvedilol reduced blood pressure during treatment and attenuated the subsequent development of hypertension [46].…”

Section: Discussionmentioning

confidence: 99%

α2-Adrenoceptor-Mediated Inhibition of Catecholamine Release from the Adrenal Medulla of Spontaneously Hypertensive Rats is Preserved in the Early Stages of Hypertension

Moura

Pinto

Caló

et al. 2011

Basic &Amp; Clinical Pharmacology &Amp; Toxicology

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In this study, we evaluated the effect of a 2 -adrenoceptor activation on catecholamine release from the adrenal medulla of pre-hypertensive (6-week-old) and hypertensive (16-week-old) spontaneously hypertensive rats (SHR) and of agematched normotensive control Wistar Kyoto (WKY) rats. Catecholamine overflow from isolated adrenal medullae was evoked by the nicotinic receptor agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) in the absence and presence of the a 2 -adrenoceptor agonist medetomidine (MED). The spontaneous outflow of adrenaline was similar between age-matched SHR and WKY rats. However, the spontaneous outflow of noradrenaline was significantly lower in SHR compared with agematched WKY rats. DMPP (0.1-3 mM) increased the outflow of noradrenaline and adrenaline in a concentration-dependent manner. The E max values for adrenaline overflow were similar between strains, but the E max values for noradrenaline overflow were significantly lower in SHR. The EC 50 values for noradrenaline and adrenaline overflow were significantly higher in SHR compared with age-matched WKY rats. MED (0.1-300 nM) reduced the DMPP-evoked overflow (DMPP 500 lM) of noradrenaline and adrenaline in a concentration-dependent manner and was capable of totally inhibiting this effect. The inhibitory action of MED was similar between age-matched SHR and WKY rats. In the adrenals, the a 2A -and a 2B -adrenoceptor subtypes had the highest mRNA expression levels; the a 2C -adrenoceptor subtype had the lowest mRNA expression levels. The mRNA levels for the three subtypes were similar between strains. In conclusion, in SHR during the development of hypertension, adrenal a 2 -adrenoceptor inhibitory function is conserved, accompanied by reduced noradrenaline release and unchanged adrenaline release. a 2 -Adrenoceptors are important target molecules for endogenous catecholamines and exogenous pharmacological agents. a 2 -Adrenoceptors consist of three genetically distinct subtypes, a 2A , a 2B and a 2C [1]. Presynaptic a 2 -adrenoceptors play a critical role in regulating noradrenaline release from sympathetic nerve terminals by a negative feedback mechanism [2,3]. Moreover, a 2 -adrenoceptors are solely responsible for autocrine feedback inhibition of noradrenaline and adrenaline secretion from the adrenal medulla [4][5][6][7].Increased activity of the sympathetic nervous system (SNS) accompanied by increased noradrenaline spillover has been implicated in the pathogenesis of essential hypertension in humans [8][9][10] and in an animal model of this disorder, the spontaneous hypertensive rat (SHR) [11,12]. Impairment of presynaptic a 2 -adrenoceptors by a reduced expression of the a 2A -adrenoceptor subtype has been associated with the increased noradrenaline release that is associated with the hypertensive phenotype in SHR [13,14].The adrenal medulla in combination with the SNS also plays a role in the epigenesis of hypertension in SHR. Hypertension and left ventricular hypertrophy were absent only in sympathectomized SHR tha...

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Section: Discussionmentioning

confidence: 99%

α2-Adrenoceptor-Mediated Inhibition of Catecholamine Release from the Adrenal Medulla of Spontaneously Hypertensive Rats is Preserved in the Early Stages of Hypertension

Moura

Pinto

Caló

et al. 2011

Basic &Amp; Clinical Pharmacology &Amp; Toxicology

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“…However, Doggrell and Surman [44] have shown that functional ß-adrenoceptors in the left atrium of hypertensive rats were not altered. In our left atrial strips, eugenosedin-A antagonized the isoproterenol-induced positive inotropic effects in WKY and SHR.…”

Section: Discussionmentioning

confidence: 99%

Hypotensive Effects of Eugenosedin-A with Serotonin, Alpha- and Beta-Adrenoceptor Antagonistic Activities in Spontaneously Hypertensive and Normotensive Rats

Shen

Chiu²,

Chen³

et al. 2004

Pharmacology

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Eugenosedin-A is a newly synthesized compound with special serotonergic, α- and β₁-adrenergic blocking actions. Intravenous injection of eugenosedin-A significantly caused dose-dependent decreases in the mean arterial blood pressure and heart rate in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The effects of eugenosedin-A-decreased blood pressure and heart rate in SHR were more potent than in WKY. In in vitro experiments, eugenosedin-A competitively antagonized the serotonin-, norepinephrine- and clonidine-induced vasocontraction in a concentration-dependent manner in isolated thoracic aorta of WKY and SHR. We also observed that eugenosedin-A competitively antagonized the isoproterenol-induced positive inotropic effects in a concentration-dependent manner in the isolated left atrium of WKY and SHR. These findings clearly suggested that eugenosedin-A possesses α₁/α₂, β₁ and 5-HT_2A receptor-blocking activities. The order of pA₂ values in isolated tissues of WKY was 5-HT_2A > α₁/α₂ > β₁. However, the order of pA₂ values in isolated tissues of SHR was α₁/α₂ >5-HT_2A > β₁. Similarly, we found that the in vitro functional activity of eugenosedin-A is quite different between WKY and SHR. On the other hand, in the isolated rabbit ear artery sensitized with 16 mmol/l K⁺, eugenosedin-A antagonized 5-nonyloxytryptamine- and serotonin-induced vasocontractions, indicating that it also blocked 5-HT_1B and 5-HT_2A receptors. In radioligand binding experiments, eugenosedin-A had significant binding affinities on α₁/α₂, β₁, 5-HT_1B and 5-HT_2A receptors. Finally, we suggest that the hypotensive effects of eugenosedin-A can be attributed to its multiple actions on the blockade of 5-HT_1B, 5-HT_2A, α and β₁ receptors in both WKY and SHR strains.

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“…Surprisingly, changes in the in vitro pharmacodynamic properties of β‐adrenoceptor antagonists have rarely been studied in experimental hypertension. Doggrell and Surman 20 have demonstrated that the dissociation constant of bisoprolol to left atrial β 1 ‐adrenoceptors was not altered in SHR.…”

Section: Discussionmentioning

confidence: 98%

CHANGES IN THE IN VITRO PHARMACODYNAMIC PROPERTIES OF METOPROLOL IN ATRIA ISOLATED FROM SPONTANEOUSLY HYPERTENSIVE RATS

Verniero

Höcht

Opezzo

et al. 2007

Clin Exp Pharma Physio

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1. The present study addressed possible changes in the dissociation constant of metoprolol and its inverse agonist activity in spontaneously hypertensive rats (SHR). In addition, a possible correlation between cardiac hypertrophy and the inverse agonist activity of metoprolol was explored. 2. In order to determine the dissociation constant (expressed as the pKb) of metoprolol, a cumulative concentration-response curve to noradrenaline was constructed in the absence or presence of metoprolol (0.1, 1 or 10 micromol/L). In a second experiment, a cumulative concentration-response curve to metoprolol was constructed to determine its inverse agonist activity. 3. The ventricular weight of SHR was significantly greater compared with Wistar-Kyoto (WKY) rats. A rightward shift of the concentration-response curve to noradrenaline was observed in SHR compared with WKY rats. The pKb of metoprolol was smaller in SHR compared with WKY rats (6.35 +/- 0.14 vs 6.99 +/- 0.12, respectively; P < 0.05). No difference was observed in the maximal response (Emax) of the concentration-time effect of metoprolol in WKY rats and SHR (-29.1 +/- 7.1 vs-28.2 +/- 8.5%, respectively; n = 6 for both). However, the concentration of metoprolol eliciting a half-maximal effect (expressed as the pEC50) was significantly smaller in SHR compared with WKY rats (4.82 +/- 0.07 vs 5.29 +/- 0.13, respectively; n = 6; P < 0.05). Although a significant correlation (r = -0.876) between the ventricular weight/bodyweight (VW/BW) ratio and the pEC50 of the chronotropic effect of metoprolol was found, no relationship (r = -0.257) was found between the VW/BW ratio and Emax. 4. In summary, the present study provides the first evidence of a change in the in vitro pharmacodynamic properties of metoprolol in SHR. The sympathetic overactivity present in SHR not only reduces the positive chronotropic effect of noradrenaline, but also diminishes the constant dissociation of metoprolol from atrial beta1-adrenoceptors and its inverse agonist activity. A significant correlation between the VW/BW ratio and the inverse agonist potency of metoprolol was found, suggesting a possible link between cardiac hypertrophy and the reduction of the inverse agonist activity of metoprolol.

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Functional β‐adrenoceptors in the left atrium of normotensive and hypertensive rats

Cited by 8 publications

References 30 publications

α2-Adrenoceptor-Mediated Inhibition of Catecholamine Release from the Adrenal Medulla of Spontaneously Hypertensive Rats is Preserved in the Early Stages of Hypertension

α2-Adrenoceptor-Mediated Inhibition of Catecholamine Release from the Adrenal Medulla of Spontaneously Hypertensive Rats is Preserved in the Early Stages of Hypertension

Hypotensive Effects of Eugenosedin-A with Serotonin, Alpha- and Beta-Adrenoceptor Antagonistic Activities in Spontaneously Hypertensive and Normotensive Rats

CHANGES IN THE IN VITRO PHARMACODYNAMIC PROPERTIES OF METOPROLOL IN ATRIA ISOLATED FROM SPONTANEOUSLY HYPERTENSIVE RATS

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