Simvastatin causes pulmonary artery relaxation by blocking smooth muscle ROCK and calcium channels: Evidence for an endothelium-independent mechanism.

Abstract

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.

• Authors: Mais Absi, Basma G Eid, Nick Ashton, George Hart, Alison M Gurney
• Journal: PloS one (PLoS One) Vol. 14 Issue 8 Pg. e0220473 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 31369604 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Calcium Channels
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Phenylephrine
• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
• Simvastatin
• Nitric Oxide Synthase Type III
• rho-Associated Kinases

Topics

• 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid (pharmacology)
• Animals
• Calcium Channel Blockers (pharmacology)
• Calcium Channels (drug effects, physiology)
• Disease Models, Animal
• Endothelium, Vascular (drug effects, physiology)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Male
• Muscle Relaxation (drug effects, physiology)
• Muscle, Smooth, Vascular (drug effects, physiology)
• Nitric Oxide Synthase Type III (antagonists & inhibitors, metabolism)
• Phenylephrine (pharmacology)
• Pulmonary Arterial Hypertension (drug therapy, physiopathology)
• Pulmonary Artery (drug effects, physiology)
• Rats
• Rats, Wistar
• Simvastatin (pharmacology)
• rho-Associated Kinases (antagonists & inhibitors)