Simvastatin causes pulmonary artery relaxation by blocking smooth muscle ROCK and calcium channels: Evidence for an endothelium-independent mechanism
| Autor: | Basma G. Eid, Nick Ashton, Mais Absi, Alison M. Gurney, George Hart |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Simvastatin Muscle Physiology Physiology Muscle Relaxation Smooth Muscle Cells 030204 cardiovascular system & hematology Pharmacology Muscle Smooth Vascular Phenylephrine 0302 clinical medicine Animal Cells Medicine and Health Sciences polycyclic compounds Pulmonary Arteries Endothelial dysfunction Musculoskeletal System Rho-associated protein kinase Smooth Muscles Pulmonary Arterial Hypertension rho-Associated Kinases Multidisciplinary Voltage-dependent calcium channel Chemistry Muscles Drugs Heart Arteries Calcium Channel Blockers medicine.anatomical_structure Medicine lipids (amino acids peptides and proteins) Anatomy Cellular Types medicine.symptom Research Article Muscle Contraction Muscle contraction medicine.drug Nitric Oxide Synthase Type III Endothelium Cardiac Ventricles Science Muscle Tissue Pulmonary Artery 03 medical and health sciences Nifedipine medicine Animals Rats Wistar Muscle Cells Statins Biology and Life Sciences Cell Biology medicine.disease Rats Disease Models Animal Biological Tissue 030104 developmental biology 15-Hydroxy-11 alpha 9 alpha-(epoxymethano)prosta-5 13-dienoic Acid Cardiovascular Anatomy Blood Vessels Calcium Channels Endothelium Vascular Hydroxymethylglutaryl-CoA Reductase Inhibitors |
| Zdroj: | PLoS ONE, Vol 14, Iss 8, p e0220473 (2019) PLoS ONE Absi, M, Eid, B G, Ashton, N, Hart, G & Gurney, A M 2019, ' Simvastatin causes pulmonary artery relaxation by blocking smooth muscle ROCK and calcium channels : Evidence for an endothelium-independent mechanism ', PLoS ONE, vol. 14, no. 8, e0220473 . https://doi.org/10.1371/journal.pone.0220473 |
| ISSN: | 1932-6203 |
| Popis: | Simvastatin reduces pulmonary arterial pressure and right ventricular hypertrophy in animal models of pulmonary arterial hypertension (PAH) and is thought to restore endothelial dysfunction. In vivo effects of drugs are complicated by several factors and little is known of the direct effects of statins on pulmonary arteries. This study investigated the direct effects of simvastatin on pulmonary arteries isolated from rats with or without monocrotaline-induced PAH. Simvastatin suppressed contractions evoked by the thromboxane A2 receptor agonist U46619 (30 nM), the α1–adrenergic agonist phenylephrine (5 μM) and KCl (50 mM) by ~50% in healthy and diseased arteries, but did not reduce contraction evoked by sarco/ endoplasmic reticulum ATPase blockers. It relaxed hypertensive arteries in the absence of stimulation. Removing the endothelium or inhibiting eNOS did not prevent the inhibition by simvastatin. Inhibiting RhoA/rho kinase (ROCK) with Y27632 (10 μM) suppressed contractions to U46619 and phenylephrine by ~80% and prevented their inhibition by simvastatin. Y27632 reduced KCl-induced contraction by ~30%, but did not prevent simvastatin inhibition. Simvastatin suppressed Ca2+ entry into smooth muscle cells, as detected by Mn2+ quench of fura-2 fluorescence. The calcium antagonist, nifedipine (1 μM), almost abolished K+-induced contraction with less effect against U46619 and phenylephrine. We conclude that simvastatin relaxes pulmonary arteries by acting on smooth muscle to interfere with signalling through G-protein coupled receptors and voltage-dependent Ca2+ entry. Its actions likely include inhibition of ROCK-dependent Ca2+ sensitisation and voltage-gated Ca2+ channels. These are likely to contribute to the beneficial effects of simvastatin in animal models of PAH. |
| Databáze: | OpenAIRE |
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