Cardiac Responses After Norepinephrine-Induced Ventricular Hypertrophy in Rats

Brown, Lindsay; Sernia, Conrad; Newling, Ross; Fletcher, Peter

doi:10.1097/00005344-199208000-00019

Cited by 18 publications

(10 citation statements)

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“…Cardiac responses to a-adrenoceptor agonists have been reported in several disease states. Noradrenaline infusion in vivo increased a-adrenoceptor-mediated responses in isolated atria but ventricular responses were unchanged (Brown et al 1992). Streptozotocininduced diabetes led to supersensitivity and hyperresponsiveness to phenylephrine in rat cardiac tissues (Yu & McNeill 1991); our results also show an increased phenylephrine potency.…”

Section: Discussionsupporting

confidence: 59%

“…The development of cardiac or vascular hypertrophy leads to inconsistent changes in ventricular responses to phenylephrine. An increased responsiveness was shown in hyperthyroid rats (this study), with no change in noradrenalineinfused rats (Brown et al 1992) or in SHR (this study;Bohm et al 1988) and decreased responses in renal hypertensive rats (Fouad et al 1983) yet hypertrophy is common to these models.…”

Section: Discussionsupporting

confidence: 46%

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Disease‐induced Changes in Α‐adrenoceptor‐mediated Cardiac and Vascular Responses in Rats

Brown

Amos

Miller

1994

Clin Exp Pharma Physio

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1. The physiological relevance of cardiac and vascular alpha-adrenoceptors may increase in disease states in which beta-adrenoceptors are altered. To test this, positive inotropic and vasoconstrictor responses to phenylephrine were measured in isolated tissues from rats with experimentally-induced hyperthyroidism, hypothyroidism and diabetes as well as in genetically spontaneous hypertensive rats (SHR). 2. In left atria, positive inotropic responses to phenylephrine were increased in hypothyroid and diabetic rats and abolished in hyperthyroid and SHR. 3. In contrast, phenylephrine produced increased positive inotropy in left ventricular papillary muscles from hyperthyroid rats, increased potency in diabetic rats and negative inotropic responses in hypothyroid rats. 4. The potency of phenylephrine as a vasoconstrictor in thoracic aortic rings was increased in hyperthyroid and SHR and decreased in hypothyroid rats. 5. Thus, disease states which alter beta-adrenoceptor responsiveness can independently regulate atrial, ventricular and vascular responses to the alpha 1-adrenoceptor agonist, phenylephrine. Therefore, these disease states may alter the physiological control of the cardiovascular system by noradrenaline and adrenaline as well as the responsiveness in disease states to therapeutic agents acting via alpha-adrenoceptors.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionsupporting

confidence: 46%

Disease‐induced Changes in Α‐adrenoceptor‐mediated Cardiac and Vascular Responses in Rats

Brown

Amos

Miller

1994

Clin Exp Pharma Physio

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“…Further, isolated ventricular tissues from L-NAME-treated rats were more likely to develop arrhythmias with noradrenaline, as we have previously shown in rats with hypertrophy associated with chronic noradrenaline infusion 21 and isolated thoracic aortic rings showed decreased contractile responses. Treatment of L-NAME hypertensive rats with candesartan returned all functional and structural parameters towards control values, although normalisation was not achieved.…”

Section: Papersupporting

confidence: 67%

Reversal of cardiovascular remodelling with candesartan

Brown

Fenning

Shek

et al. 2001

J Renin Angiotensin Aldosterone Syst

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Cardiovascular remodelling, defined as ventricular and vascular hypertrophy together with fibrosis, characterises hypertension following inhibition of the production of the endogenous vasodilator, nitric oxide (NO). This study has determined whether the cardiovascular remodelling following chronic NO synthase inhibition can be reversed by administration of the selective angiotensin II AT 1 -receptor antagonist, candesartan. Male Wistar rats were treated with L-nitroarginine methyl ester (L-NAME, 400 mg/l in drinking water) for eight weeks and with candesartan cilexetil (2 mg/kg/day by oral gavage) for the last four weeks. L-NAME-treated rats became hypertensive with systolic blood pressure increasing from 110±4 mmHg (control) to 170±10 mmHg. Rats developed left ventricular hypertrophy (control 1.70±0.06; L-NAME 2.10±0.04 mg/kg body wt) with markedly increased deposition of perivascular and interstitial collagen. Candesartan returned blood pressure, left ventricular weights and collagen deposition to control values. Echocardiographic assessment showed concentric hypertrophy with an increased fractional shortening; this was reversed by candesartan treatment. Heart failure was not evident. In the isolated Langendorff heart, diastolic stiffness increased in L-NAME-treated rats while the rate of increase in pressure (+dP/dt) increased after eight weeks only; candesartan reduced collagen deposition and normalised +dP/dt. In isolated left ventricular papillary muscles, the potency (negative log EC 50 ) of noradrenaline as a positive inotropic compound was unchanged, (control 6.56±0.14); maximal increase in force before ectopic beats was reduced from 5.0±0.4 mN to 2.0±0.2 mN. Noradrenaline potency as a vasoconstrictor in thoracic aortic rings was unchanged, but maximal contraction was markedly reduced from 25.2±2.0 mN to 3.0±0.3 mN; this was partially reversed by candesartan treatment. Thus, chronic inhibition of NO production with L-NAME induces hypertension, hypertrophy and fibrosis with increased toxicity and significant decreases in vascular responses to noradrenaline. These changes were at least partially reversible by treatment with candesartan, implying a significant role of AT 1 -receptors in L-NAME-induced cardiovascular changes.

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“…Likewise, reduced chronotropic and contractile responses of isolated guinea-pig atria to selective b 1 -and b 2 -AR agonists were noted following chronic b-AR activation [174]. Moreover, reduced inotropic responses to noradrenaline were observed after prior chronic noradrenaline administration to rats [177,178]. The abovementioned studies, however, did not show a downregulation of a-AR-mediated inotropic effects.…”

Section: Cardiac Electrophysiologymentioning

confidence: 83%

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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Cardiac Responses After Norepinephrine-Induced Ventricular Hypertrophy in Rats

Cited by 18 publications

References 0 publications

Disease‐induced Changes in Α‐adrenoceptor‐mediated Cardiac and Vascular Responses in Rats

Disease‐induced Changes in Α‐adrenoceptor‐mediated Cardiac and Vascular Responses in Rats

Reversal of cardiovascular remodelling with candesartan

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

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