Functionality of beta-adrenergic receptors in patients with cirrhosis treated chronically with non-selective beta-blocke
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ORIGINAL ARTICLE
Functionality of beta‑adrenergic receptors in patients with cirrhosis treated chronically with non‑selective beta‑blockers Susana Almenara1,2,3 · Beatriz Lozano1,3 · Paula Gimenez1 · Ivan Herrera4 · Cayetano Miralles4 · Pablo Bellot4 · María Rodríguez4 · Rubén Francés1,5,6 · Jose M. Gonzalez‑Navajas1,3,6 · Sonia Pascual1,4,6 · Pedro Zapater1,2,3,6,7 Received: 13 June 2020 / Accepted: 17 August 2020 © Asian Pacific Association for the Study of the Liver 2020
Abstract Background In patients with cirrhosis, beta-adrenoceptors expressed on peripheral blood mononuclear cells have a reduced response to catecholamine stimulation. This study aimed to determine if chronic treatment with beta-blockers influences these changes. Methods Blood samples were collected from patients with cirrhosis treated in outpatient clinics. Differences in cyclic AMP production before and after stimulation of mononuclear cells with epinephrine and/or N-Formylmethionine-leucylphenylalanine (fMLP) was used as a marker of beta-adrenoceptors activity in patients treated (N = 19) versus not treated (N = 55) with beta-blockers. In addition, we studied the gene expression of different types of adrenoceptors and possible associations with the activity of beta-adrenoceptors, the serum concentrations of catecholamines and cytokines, and the presence of bacterial antigens such as DNA or gram-negative bacterial endotoxin in patients’ blood. Results The increase in intracellular cAMP concentrations after stimulation of adrenergic receptors with epinephrine was significantly higher in samples from patients treated with beta-blockers. Older patients showed lower responses to epinephrine stimulus, while the response increased linearly with the duration of the beta-blocker treatment. mRNA expression levels of adrenoceptors β1, β2, β3 and α1-A, B and D showed no significant differences according to treatment with beta-blockers. Neither serum cytokines nor catecholamines levels were significantly associated with the intracellular production of cAMP after adrenergic stimulation. Conclusion Chronic treatment with beta-blockers in patients with cirrhosis enables beta-adrenoceptors to respond to catecholamine stimulation irrespective of the degree of systemic adrenergic or immune activations of the patient at the time of sampling.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12072-020-10083-5) contains supplementary material, which is available to authorized users. * Pedro Zapater [email protected] 1
4
Liver Unit, Hospital General Universitario de Alicante, Alicante, Spain
5
Clinical Medicine Department, Universidad Miguel Hernández, Elche, Spain
CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
2
Clinical Pharmacology Unit, Hospital General Universitario de Alicante, Alicante, Spain
6
Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain
3
Instituto de Investigación, Desarrollo e Innovación en Biotecnologia Sanitaria de Elc
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