Response of Failing Canine and Human Heart Cells to β
            <sub>2</sub>
            -Adrenergic Stimulation

Altschuld, Ruth A.; Starling, Randall C.; Hamlin, Robert L.; Billman, George E.; Hensley, James; Castillo, Lourdes; Fertel, Richard H.; Hohl, Charlene M.; Robitaille, Pierre‐Marie; Jones, Larry R.; Xiao, Rui; Lakatta, Edward G.

doi:10.1161/01.cir.92.6.1612

Cited by 119 publications

(83 citation statements)

References 27 publications

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“…Evidence for the involvement of cAMP is given only for high ␤ 2 -agonist concentrations; indeed, activation by 10 M zinterol of both contraction (32) and L-type Ca 2ϩ current (2) is blocked by (Rp)-cAMPS, the specific inhibitory cAMP analog. Second, in electrically stimulated dog myocytes, ␤ 2 -AR activation is ineffective in stimulating adenylyl cyclase, whereas it produces increases in [Ca 2ϩ ] i transient and twitch amplitudes (13). In this regard, we show here that, in embryonic chick heart cells, ␤ 2 -AR stimulation by zinterol triggers a positive inotropic effect, independent of adenylyl cyclase activation (Figs.…”

Section: Discussionmentioning

confidence: 56%

Evidence for a β2-Adrenergic/Arachidonic Acid Pathway in Ventricular Cardiomyocytes

Pavoine

Magne

Sauvadet

et al. 1999

Journal of Biological Chemistry

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The signaling pathway mediating the contractile effect of ␤ 2 -adrenergic receptors (␤ 2 -AR) in the heart is still matter of debate. By using embryonic chick ventricular cardiomyocytes that express both functional ␤ 1 -and ␤ 2 -ARs, we show here that the specific ␤ 2 -AR agonist, zinterol, increases the amplitude of Ca 2؉ transients and cell contraction of electrically stimulated cells. Zinterol, up to 10 M, did not stimulate adenylyl cyclase activity, and its effect on Ca ␤ 1 -and ␤ 2 -Adrenergic receptors (␤ 1 -and ␤ 2 -ARs) 1 coexist in the hearts of various animal species, including humans. However, their relative amount and their respective participation in the positive chronotropic and inotropic effects of adrenaline and noradrenaline vary depending on the cardiac tissue, the animal species, and/or the pathophysiological state (1, 2). In the non-failing human left ventricle, ␤ 1 -ARs represent 80% of the total ␤-ARs but mediate about 60% only of ␤-adrenergicinduced ventricular contractility (3). In the human failing heart, the ␤ 1 /␤ 2 -AR ratio decreases, and the contribution of ␤ 2 -AR to the contractile responses becomes predominant over that of ␤ 1 -AR, in particular at low adrenaline concentrations (3, 4). For these reasons, the potential role of ␤ 2 -AR for improving cardiac performance has received considerable attention. In fact, the myocardial-targeted overexpression of ␤ 2 -ARs in transgenic mice significantly enhanced myocardial left ventricular contractility (5).It is well documented that ␤ 1 -AR and ␤ 2 -AR subtypes are coupled to adenylyl cyclase activation and that stimulation of both receptors generally leads to an increase in cellular cAMP (4, 6, 7). In human healthy heart, ␤ 2 -ARs are more efficiently coupled to adenylyl cyclase than ␤ 1 -ARs (6 -10). However, during cardiac failure, ␤ 2 -AR subtypes are partially uncoupled from adenylyl cyclase (6, 7), whereas their contribution to the positive inotropic effects of adrenaline and noradrenaline is increased to 63% (7). In addition, studies in the rat heart (11, 12) and in the non-failing and failing canine heart (13) have demonstrated a dissociation between the inotropic effect of ␤ 2 -AR and cellular cAMP increase. Based on those observations, Xiao et al. (12) proposed that unidentified signal transduction pathway(s), other than adenylyl cyclase and cAMP, could be involved in the cardiac inotropic response to ␤ 2 -AR stimulation.Angiotensin II (14,15), bradykinin (16,17), and endothelin (15, 18), which exert positive inotropic responses, evoke AA release in heart. Furthermore, in a recent study, we have demonstrated that glucagon action relies not only on cAMP but also on the synergistic support of AA, by activation of the cPLA 2 which hydrolyzes the sn-2 fatty acyl ester bonds of membranous phospholipids (15).The aim of the present study was to investigate the respective role of cAMP and AA in the cardiac response to ␤-adrenergic agonists. We used the model of embryonic chick ventricular cardiomyocytes that has been widely exploited ...

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Section: Discussionmentioning

confidence: 56%

Evidence for a β2-Adrenergic/Arachidonic Acid Pathway in Ventricular Cardiomyocytes

Pavoine

Magne

Sauvadet

et al. 1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

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“…In this context, it has been reported that activation of myocardial ␤ 2 -adrenoecptors increases contractility and under certain circumstances may facilitate the development of ventricular arrhythmias. [23][24][25] The potential clinical importance of the myocardial ␤ 2 -adrenoceptor in the failing heart has been highlighted by observations that it does not undergo downregulation, as displayed by the ␤ 1 -adrenoceptor. The ␤ 2 -adrenoceptor has also been identified both experimentally and clinically in sympathetic ganglia and in postganglionic sympathetic nerve terminals, 1,26 -30 where it appears to facilitate the release of norepinephrine.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Carvedilol Action in Human Congestive Heart Failure

et al. 2001

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Abstract-The precise mechanism by which ␤-adrenoceptor blockers exert their beneficial actions in patients with heart failure remains unclear. Several possibilities have been proposed, including heart rate reduction, ␤2-adrenoceptormediated modulation of catecholamine release, antagonism of the receptor-mediated toxic actions of norepinephrine on the myocardium, and favorable effects on myocardial energetics. In the present study we evaluated the effect of 3 months of carvedilol therapy on hemodynamics, total systemic and cardiac norepinephrine spillover (isotope dilution method), and myocardial metabolism (myocardial oxygen consumption and carbon dioxide release) in 10 patients with severe congestive heart failure. Although carvedilol treatment was associated with a significant improvement in left ventricular ejection fraction (17Ϯ1% to 28Ϯ3%; PϽ0.01) and left ventricular stroke work (87Ϯ13 to 119Ϯ21 g ⅐ m per beat; PϽ0.05), this effect was unrelated to changes in total systemic or cardiac norepinephrine spillover.

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“…Evidently, this pathway is compromised in heart failure. Because of the clear-cut evidence that ␤ 2 -adrenoceptors mediate acute functional effects in human cardiomyocyte in vitro (1,2) and in vivo (3), a rationale for ␤ 2 -adrenoreceptor gene therapy exists (4)(5)(6). Whether and where ␤ 2 -adrenoreceptor stimulation or inhibition, by pharmacological or genetic means, will have its place in heart failure therapy is an open question (7)(8)(9).…”

mentioning

confidence: 99%

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

Foerster

Groner

Matthes

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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Two subtypes of ␤-adrenoceptors, ␤1 and ␤2, mediate cardiac catecholamine effects. These two types differ qualitatively, e.g., regarding G protein coupling and calcium channel stimulation. Transgenic mice overexpressing human ␤2-adrenoceptors survive high-expression levels, unlike mice overexpressing ␤1-adrenoceptors. We examined the role of inhibitory Gi proteins, known to be activated by ␤2-but not ␤1-adrenoceptors, on the chronic effects of human ␤2-adrenoreceptor overexpression in transgenic mice. These mice were crossbred with mice where G␣i2, a functionally important cardiac Gi ␣-subunit, was inactivated by targeted gene deletion. Survival of ␤2-adrenoreceptor transgenic mice was reduced by heterozygous inactivation of G␣i2. Homozygous knockout͞␤2-adrenoreceptor transgenic mice died within 4 days after birth. Heterozygous knockout͞␤2-adrenoreceptor transgenic mice developed more pronounced cardiac hypertrophy and earlier heart failure compared with ␤2-adrenoreceptor transgenic mice. Single calcium-channel activity was strongly suppressed in heterozygous knockout͞␤2-adrenoreceptor transgenic mice. In cardiomyocytes from these mice, pertussis toxin treatment in vitro fully restored channel activity and enhanced channel activity in cells from homozygous G␣i2 knockout animals. Cardiac G␣i3 protein was increased in all G␣i2 knockout mouse strains. Our results demonstrate that G␣i2 takes an essential protective part in chronic signaling of overexpressed ␤2-adrenoceptors, leading to prolonged survival and delayed cardiac pathology. However, reduction of calcium-channel activity by ␤2-adrenoreceptor overexpression is due to a different pertussis-toxin-sensitive pathway, most likely by G␣i3. This result indicates that subtype-specific signaling of ␤2-adrenoreceptor functionally bifurcates at the level of Gi, leading to different effects depending on the G␣ isoform.L-type calcium channel ͉ single channel recording ͉ mouse genetics ͉ survival curve ͉ pertussis toxin C ardiac stimulatory catecholamine effects are mediated by both ␤ 1 -and ␤ 2 -adrenergic receptors (␤-adrenoceptors), mainly through cAMP-dependent protein kinase A-catalyzed phosphorylation of cardiac proteins involved in calcium homeostasis, such as phospholamban and the L-type calcium channel. Evidently, this pathway is compromised in heart failure. Because of the clear-cut evidence that ␤ 2 -adrenoceptors mediate acute functional effects in human cardiomyocyte in vitro (1, 2) and in vivo (3), a rationale for ␤ 2 -adrenoreceptor gene therapy exists (4-6). Whether and where ␤ 2 -adrenoreceptor stimulation or inhibition, by pharmacological or genetic means, will have its place in heart failure therapy is an open question (7-9).Inherent in the clinical discussion is recent molecular insight into differences between cardiac ␤ 1 -and ␤ 2 -adrenoreceptor stimulation at the signal-transduction level (10, 11). In rat cardiomyocytes, a ␤ 2 -agonist, zinterol, was shown to increase calcium current in a manner qualitatively distinct from ␤ 1 -adrenoreceptor stimu...

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Response of Failing Canine and Human Heart Cells to β ₂ -Adrenergic Stimulation

Cited by 119 publications

References 27 publications

Evidence for a β2-Adrenergic/Arachidonic Acid Pathway in Ventricular Cardiomyocytes

Evidence for a β2-Adrenergic/Arachidonic Acid Pathway in Ventricular Cardiomyocytes

Mechanisms of Carvedilol Action in Human Congestive Heart Failure

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors

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Response of Failing Canine and Human Heart Cells to β 2 -Adrenergic Stimulation

Cited by 119 publications

References 27 publications

Evidence for a β2-Adrenergic/Arachidonic Acid Pathway in Ventricular Cardiomyocytes

Evidence for a β2-Adrenergic/Arachidonic Acid Pathway in Ventricular Cardiomyocytes

Mechanisms of Carvedilol Action in Human Congestive Heart Failure

Cardioprotection specific for the G protein G i2 in chronic adrenergic signaling through β 2 -adrenoceptors

Contact Info

Product

Resources

About

Response of Failing Canine and Human Heart Cells to β ₂ -Adrenergic Stimulation

Cardioprotection specific for the G protein G _i2 in chronic adrenergic signaling through β ₂ -adrenoceptors