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Experimental data using candesartan and captopril indicate no double-edged sword effect in COVID-19.
Pedrosa, Maria A; Valenzuela, Rita; Garrido-Gil, Pablo; Labandeira, Carmen M; Navarro, Gemma; Franco, Rafael; Labandeira-Garcia, Jose L; Rodriguez-Perez, Ana I.
Affiliation
  • Pedrosa MA; Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
  • Valenzuela R; Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
  • Garrido-Gil P; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
  • Labandeira CM; Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
  • Navarro G; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
  • Franco R; Research Center for Molecular Medicine and Chronic Diseases (CIMUS), IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain.
  • Labandeira-Garcia JL; Hospital Alvaro Cunqueiro, University Hospital Complex, Vigo, Spain.
  • Rodriguez-Perez AI; Networking Research Center on Neurodegenerative Diseases (CIBERNED), Spain.
Clin Sci (Lond) ; 135(3): 465-481, 2021 02 12.
Article in En | MEDLINE | ID: mdl-33479758
The key link between renin-angiotensin system (RAS) and COVID-19 is ACE2 (angiotensin-converting enzyme 2), which acts as a double-edged sword, because ACE2 increases the tissue anti-inflammatory response but it is also the entry receptor for the virus. There is an important controversy on several drugs that regulate RAS activity and possibly ACE2, and are widely used, particularly by patients most vulnerable to severe COVID-19. In the lung of healthy rats, we observed that candesartan (an angiotensin type-1, AT1, receptor blocker; ARB) and captopril (an ACE inhibitor; ACEI) up-regulated expression of tissue ACE2 and RAS anti-inflammatory axis receptors (AT2 and Mas receptors). This effect was particularly pronounced in rats with metabolic syndrome (obesity, increased blood pressure and hyperglycemia) and aged rats. Treatment of cultures of human type-II pneumocytes with candesartan or captopril induced up-regulation of ACE2 expression in cells. Treatment with viral spike protein induced a decrease in full-length (i.e. transmembrane) ACE2, an increase in levels of a short intracellular ACE2 polypeptide and an increase in ADAM17 activity in cells, together with an increase in levels of soluble ACE2 and major proinflammatory cytokines in the culture medium. Spike protein-induced changes and levels of spike protein internalization in cells were inhibited by pretreatment with the above-mentioned drugs. The results suggest that these drugs increase ACE2 levels and promote the anti-inflammatory RAS axis in the lung. Furthermore, possible up-regulation of viral entry by the drug-induced increase in expression of transmembrane ACE2 is counteracted by additional mechanisms, particularly by drug-induced inhibition of ADAM17 activity.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tetrazoles / Benzimidazoles / Biphenyl Compounds / Captopril / COVID-19 Drug Treatment Limits: Animals / Female / Humans / Male Language: En Journal: Clin Sci (Lond) Year: 2021 Document type: Article Affiliation country: Spain Country of publication: United kingdom

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Tetrazoles / Benzimidazoles / Biphenyl Compounds / Captopril / COVID-19 Drug Treatment Limits: Animals / Female / Humans / Male Language: En Journal: Clin Sci (Lond) Year: 2021 Document type: Article Affiliation country: Spain Country of publication: United kingdom