Beta adrenergic receptor blockade of feline myocardium. Cardiac mechanics, energetics, and beta adrenoceptor regulation.

Th, Grasela; Kent, Robert L.; McGonigle, Paul; Watanabe, August M.

doi:10.1172/jci112323

Cited by 11 publications

(2 citation statements)

References 81 publications

(56 reference statements)

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“…A variety of substrate pro teins are phosphorylated in a cAMP-dependent manner in response to (B-adrenergic ago nists [11]. These effects increase myocardial O2 consumption [34,35], which leads to an increase in coronary blood flow. In addi tion, (3-agonists cause relaxation of vascular smooth muscle and can directly increase coro nary blood flow [36], It is not clear whether the increased correlation between coronary blood flow and cAMP is related to the direct or metabolic vasodilator effects of isoprotere nol.…”

Section: Discussionmentioning

confidence: 99%

Effect of Isoproterenol on the Relationship between Regional Cyclic AMP and Local Coronary Blood Flow in the Canine Myocardium

Ramirez¹,

Rodriguez²,

Weiss³

1994

Pharmacology

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This study was designed to test in the dog heart the hypothesis that local levels of myocardial cyclic AMP (cAMP) would exhibit significant heterogeneity; that this heterogeneity would correlate with local coronary blood flow, and that this association would be increased with isoproterenol stimulation. Anesthetized open-chest dogs were studied during control (n = 7) or isoproterenol (0.5 µg/kg/min) infusion (n = 7) to test this hypothesis. Coronary blood flow was measured with radioactive microspheres, and cAMP was determined with a competitive binding assay using ³H-cAMP. Significant heterogeneity in cAMP existed during basal [592 pmol/g, within-animal coefficient of variation (100 × mean/SD) = 45.2%] and isoproterenol stimulated [872 (27.3%)] conditions. Method variability could account for only 28% of the total basal variability. No correlation between local blood flow [87 ml/min/ 100 g (12.9%)] and local cAMP was found under control conditions. Both coronary blood flow [206 (20.8%)] and cAMP levels increased significantly with isoproterenol stimulation. There was a significant correlation between normalized stimulated blood flow and cAMP: % flow = 0.39 (% cAMP) + 61.3 (r = 0.48, p < 0.0001). We conclude that significant heterogeneity in myocardial cAMP levels exists, and that this heterogeneity correlates with coronary blood flow heterogeneity during isoproterenol stimulation.

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Section: Discussionmentioning

confidence: 99%

Effect of Isoproterenol on the Relationship between Regional Cyclic AMP and Local Coronary Blood Flow in the Canine Myocardium

Ramirez¹,

Rodriguez²,

Weiss³

1994

Pharmacology

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“…Cardiocyte cell surface ␤-AR density was assayed in terms of the binding of 4-(3-tertiarybutylamino-2-hydroxypropoxy)-benzimidazole-2-on hydrochloride ([ 3 H]CGP-12177; Perkin-Elmer; Boston, MA; specific activity 45 Ci/mmol), which is specific to cell surface ␤-ARs (27). Following established methods (7,15), the binding assays were performed at 4°C to avoid both receptor endocytosis and reappearance of the receptors on the cell surface after agonist-induced internalization. Nonspecific binding was determined by the addition of 10 M propranolol, a ␤-AR antagonist, to triplicate wells and represented Ͻ10% of total counts.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of β-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules

Cheng

Qiao

Gallien

et al. 2005

American Journal of Physiology-Heart and Circulatory Physiology

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.-Decreased ␤-adrenergic receptor (␤-AR) number occurs both in animal models of cardiac hypertrophy and failure and in patients. ␤-AR recycling is an important mechanism for the ␤-AR resensitization that maintains a normal complement of cell surface ␤-ARs. We have shown that 1) in severe pressure overload cardiac hypertrophy, there is extensive microtubule-associated protein 4 (MAP4) decoration of a dense microtubule network; and 2) MAP4 microtubule decoration inhibits muscarinic acetylcholine receptor recycling in neuroblastoma cells. We asked here whether MAP4 microtubule decoration inhibits ␤-AR recycling in adult cardiocytes. [3 H]CGP-12177 was used as a ␤-AR ligand, and feline cardiocytes were isolated and infected with adenovirus containing MAP4 (AdMAP4) or ␤-galactosidase (Ad␤-gal) cDNA. MAP4 decorated the microtubules extensively only in AdMAP4 cardiocytes. ␤-AR agonist exposure reduced cell surface ␤-AR number comparably in AdMAP4 and Ad␤-gal cardiocytes; however, after agonist withdrawal, the cell surface ␤-AR number recovered to 78.4 Ϯ 2.9% of the pretreatment value in Ad␤-gal cardiocytes but only to 56.8 Ϯ 1.4% in AdMAP4 cardiocytes (P Ͻ 0.01). This result was confirmed in cardiocytes isolated from transgenic mice having cardiac-restricted MAP4 overexpression. In functional terms of cAMP generation, ␤-AR agonist responsiveness of AdMAP4 cells was 47% less than that of Ad␤-gal cells. We conclude that MAP4 microtubule decoration interferes with ␤-AR recycling and that this may be one mechanism for ␤-AR downregulation in heart failure. myocardium; hypertrophy; tubulin; adenovirus TEN YEARS AGO (32), we reported that the progressive contractile abnormalities characteristic of severe pressure overload cardiac hypertrophy are attributable to a remarkable extent to a densification of the microtubule component of the cardiocyte extramyofilament cytoskeleton. In subsequent work reviewed elsewhere (6), we and others observed that increased microtubule network density, which imposes a viscous load on active myofilaments, is seen in myocardium hypertrophying in response to pressure overloading of either ventricle in each of the five mammalian species examined to date, including humans. This microtubule network densification, which in our hands has tight specificity for severe pressure overload hypertrophy, which fails to maintain normal ventricular wall stress, appears to have a major role in the contractile dysfunction found in this distinct but common hemodynamic setting, because in each of our animal models microtubule depolymerization restored normal contractile function on the levels of the isolated cell, isolated tissue, and in vivo intact heart.We have now found several potentially synergistic bases for this microtubule network densification (6): 1) there is transcriptional upregulation of the two genes encoding the ␤ 1 -and ␤ 2 -tubulin isoforms, whose expression is ordinarily minor in the heart of the adult, accounting for the persistent increase in ␤-tubulin synthesis in pressure overload hypertrophy, ...

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Evidence that reversal of mouse aggression is not related to beta blockade

DaVanzo

McConnaughey

Brooks

et al. 1988

Drug Development Research

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The ED, & for reversal of mouse aggression were determined for nine beta adrenergic receptor blockers: metoprolol, nadolol, pindolol, propranolol, acebutolol, penbutolol, labetalol, timolol, and atenolol. Propranolol and penbutolol generated linear doseresponse curves, suggesting easy access to brain. To determine if beta blockade was actually occurring at the receptor level, upregulation of beta receptors after 10 days of chronic treatment with the ED, & was determined in the limbic system as well as other areas of brain. These areas included: olfactory bulbs, hypothalamus, septum, amygdala, cortex, midbrain, cerebellum, pons, and medulla. Upregulation occurred in all areas of the brain in animals treated with propranolol and penbutolol, suggesting that at the dose required to block aggressing in fighting mice, beta receptors were also effectively blocked. With other drugs (timolol, atenolol, pindolol, metoprolol, nadolol, and acebutolol) the ED, , s produced localized upregulation of beta receptors, but nothing consistent in the limbic areas. The beta blocker labetalol at the ED50 for reversal of mouse aggression produced virtually no upregulation of brain receptors, suggesting no correlation between antiaggression and beta blockade.

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Beta adrenergic receptor blockade of feline myocardium. Cardiac mechanics, energetics, and beta adrenoceptor regulation.

Cited by 11 publications

References 81 publications

Effect of Isoproterenol on the Relationship between Regional Cyclic AMP and Local Coronary Blood Flow in the Canine Myocardium

Effect of Isoproterenol on the Relationship between Regional Cyclic AMP and Local Coronary Blood Flow in the Canine Myocardium

Inhibition of β-adrenergic receptor trafficking in adult cardiocytes by MAP4 decoration of microtubules

Evidence that reversal of mouse aggression is not related to beta blockade

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