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1.
Acta Physiol (Oxf) ; 231(3): e13564, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33002334

RESUMO

AIM: There is an increasing awareness of the impact of age and sex on cardiovascular diseases (CVDs). Differences in physiology are suspected. Beta-adrenoceptors (beta-ARs) are an important drug target in CVD and potential differences might have significant impact on the treatment of many patients. To investigate whether age and sex affects beta-AR function, we analysed a large data set on beta-AR-induced inotropy in human atrial trabeculae. METHODS: We performed multivariable analysis of individual atrial contractility data from trabeculae obtained during heart surgery of patients in sinus rhythm (535 trabeculae from 165 patients). Noradrenaline or adrenaline were used in the presence of the beta2 -selective antagonist (ICI 118 551, 50 nmol/L) or the beta1 -selective antagonist (CGP 20712A, 300 nmol/L) to stimulate beta1 -AR or beta2 -AR respectively. Agonist concentration required to achieve half-maximum inotropic effects (EC50 ) was taken as a measure of beta-AR sensitivity. RESULTS: Impact of clinical variables was modelled using multivariable mixed model regression. As previously reported, chronic treatment with beta-blockers sensitized beta-AR. However, there was no significant interaction between basal force, maximum force and beta-AR sensitivity when age and sex were modelled continuously. In addition, there was no statistically significant effect of body mass index or diabetes on atrial contractility. CONCLUSION: Our large, multivariable analysis shows that neither age nor sex affects beta-AR-mediated inotropy or catecholamine sensitivity in human atrial trabeculae. These findings may have important clinical implications because beta-ARs, as a common drug target in CVD and heart failure, do not behave differently in women and men across age decades.


Assuntos
Contração Miocárdica , Receptores Adrenérgicos beta 2 , Antagonistas Adrenérgicos beta/farmacologia , Feminino , Átrios do Coração , Direitos Humanos , Humanos , Masculino , Norepinefrina
3.
Br J Pharmacol ; 173(16): 2478-89, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27238373

RESUMO

BACKGROUND AND PURPOSE: 5-HT increases force and L-type Ca(2) (+) current (ICa,L ) and causes arrhythmias through 5-HT4 receptors in human atrium. In permanent atrial fibrillation (peAF), atrial force responses to 5-HT are blunted, arrhythmias abolished but ICa,L responses only moderately attenuated. We investigated whether, in peAF, this could be due to an increased function of PDE3 and/or PDE4, using the inhibitors cilostamide (300 nM) and rolipram (1 µM) respectively. EXPERIMENTAL APPROACH: Contractile force, arrhythmic contractions and ICa,L were assessed in right atrial trabeculae and myocytes, obtained from patients with sinus rhythm (SR), paroxysmal atrial fibrillation (pAF) and peAF. KEY RESULTS: Maximum force responses to 5-HT were reduced to 15% in peAF, but not in pAF. Cilostamide, but not rolipram, increased both the blunted force responses to 5-HT in peAF and the inotropic potency of 5-HT fourfold to sevenfold in trabeculae of patients with SR, pAF and peAF. Lusitropic responses to 5-HT were not decreased in peAF. Responses of ICa,L to 5-HT did not differ and were unaffected by cilostamide or rolipram in myocytes from patients with SR or peAF. Concurrent cilostamide and rolipram increased 5-HT's propensity to elicit arrhythmias in trabeculae from patients with SR, but not with peAF. CONCLUSIONS AND IMPLICATIONS: PDE3, but not PDE4, reduced inotropic responses to 5-HT in peAF, independently of lusitropy and ICa,L , but PDE3 activity was the same as that in patients with SR and pAF. Atrial remodelling in peAF abolished the facilitation of 5-HT to induce arrhythmias by inhibition of PDE3 plus PDE4.


Assuntos
Arritmias Cardíacas/metabolismo , Fibrilação Atrial/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Serotonina/metabolismo , Idoso , Feminino , Humanos , Masculino , Inibidores de Fosfodiesterase/farmacologia
4.
Proc Natl Acad Sci U S A ; 111(30): 11193-8, 2014 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-25024212

RESUMO

Atrial fibrillation (AF) is the most common heart rhythm disorder. Transient postoperative AF can be elicited by high sympathetic nervous system activity. Catecholamines and serotonin cause arrhythmias in atrial trabeculae from patients with sinus rhythm (SR), but whether these arrhythmias occur in patients with chronic AF is unknown. We compared the incidence of arrhythmic contractions caused by norepinephrine, epinephrine, serotonin, and forskolin in atrial trabeculae from patients with SR and patients with AF. In the patients with AF, arrhythmias were markedly reduced for the agonists and abolished for forskolin, whereas maximum inotropic responses were markedly blunted only for serotonin. Serotonin and forskolin produced spontaneous diastolic Ca(2+) releases in atrial myocytes from the patients with SR that were abolished or reduced in myocytes from the patients with AF. For matching L-type Ca(2+)-current (ICa,L) responses, serotonin required and produced ∼ 100-fold less cAMP/PKA at the Ca(2+) channel domain compared with the catecholamines and forskolin. Norepinephrine-evoked ICa,L responses were decreased by inhibition of Ca(2+)/calmodulin-dependent kinase II (CaMKII) in myocytes from patients with SR, but not in those from patients with AF. Agonist-evoked phosphorylation by CaMKII at phospholamban (Thr-17), but not of ryanodine2 (Ser-2814), was reduced in trabeculae from patients with AF. The decreased CaMKII activity may contribute to the blunting of agonist-evoked arrhythmias in the atrial myocardium of patients with AF.


Assuntos
Fibrilação Atrial/metabolismo , Catecolaminas/farmacologia , Contração Miocárdica/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Serotonina/farmacologia , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiotônicos/farmacologia , Doença Crônica , Colforsina/farmacologia , AMP Cíclico/metabolismo , Feminino , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Rianodina/metabolismo
5.
Naunyn Schmiedebergs Arch Pharmacol ; 387(7): 629-40, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24668024

RESUMO

The ß-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 µM) or PDE4-selective inhibitor rolipram (1 µM) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through ß1-adrenoceptors (ß2-adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through ß2-adrenoceptors (ß1-adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of the PDE inhibitors. The inotropic potency, estimated from -logEC50s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-ß-blocker-treated patients, consistent with the previously reported ß2-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular ß2-adrenoceptors compared to ß1-adrenoceptors. The ß2-adrenoceptor-selectivity of carvedilol may provide protection against ß2-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control ß1- and ß2-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Carbazóis/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/fisiologia , Insuficiência Cardíaca/fisiopatologia , Propanolaminas/farmacologia , Receptores Adrenérgicos beta 1/fisiologia , Receptores Adrenérgicos beta 2/fisiologia , Adulto , Carvedilol , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/fisiologia , Epinefrina/farmacologia , Feminino , Transplante de Coração , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/farmacologia , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Quinolonas/farmacologia , Rolipram/farmacologia
6.
Br J Pharmacol ; 169(3): 528-38, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23489141

RESUMO

BACKGROUND AND PURPOSE: PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 µM) or PDE4 inhibitor rolipram (1-10 µM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. EXPERIMENTAL APPROACH: Right and left ventricular trabeculae from freshly explanted hearts of 5 non-ß-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through ß1 adrenoceptors (ß2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through ß2 adrenoceptors (ß1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC50s. KEY RESULTS: Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-ß-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. CONCLUSIONS AND IMPLICATIONS: Metoprolol induces a control by PDE3 of ventricular effects mediated through both ß1 and ß2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through ß2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Ventrículos do Coração/efeitos dos fármacos , Metoprolol/efeitos adversos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Agonistas alfa-Adrenérgicos/química , Agonistas alfa-Adrenérgicos/farmacologia , Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Antagonistas de Receptores Adrenérgicos beta 2/farmacologia , Agonistas Adrenérgicos beta/química , Agonistas Adrenérgicos beta/farmacologia , Antiarrítmicos/efeitos adversos , Antiarrítmicos/uso terapêutico , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Epinefrina/agonistas , Epinefrina/farmacologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Ventrículos do Coração/metabolismo , Ventrículos do Coração/fisiopatologia , Humanos , Técnicas In Vitro , Metoprolol/uso terapêutico , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Norepinefrina/agonistas , Norepinefrina/farmacologia , Inibidores da Fosfodiesterase 3/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Receptores Adrenérgicos beta 1/química , Receptores Adrenérgicos beta 2/química
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