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Type: Journal article
Title: Acute modulation of vasoconstrictor responses by pravastatin in small vessels
Author: Ghaffari, N.
Smith, C.
Kennedy, J.
Stafford, I.
Beltrame, J.
Citation: Circulation Journal, 2011; 75(6):1506-1514
Publisher: Blackwell Science Asia
Issue Date: 2011
ISSN: 1346-9843
Statement of
Nader Ghaffari, Christine Ball, Jennifer A Kennedy, Irene Stafford and John F Beltrame
Abstract: Background: Statins have been shown to inhibit conduit vessel constrictor responses via the endothelial nitricoxide (NO) pathway. Clinical studies have implicated an effect in microvascular resistance vessels; however, direct effects of therapeutically relevant statin concentrations have not been examined. We examined the effect of acute pravastatin pretreatment on vasoconstrictor responsiveness of isolated rat mesenteric small vessels. Methods and Results: Pravastatin (112 nmol/L) pretreatment for 60 min reduced both the potency and maximal constrictor responses to phenylephrine, thromboxane (U46619) and serotonin in small vessels. This effect was abolished by endothelial denudation, NO synthase (NOS) inhibition with N-ω-nitro-L-arginine methyl ester (L-NAME 300 μmol/L) and Akt inhibition (Akt1/2 kinase inhibitor 500 nmol/L), confirming an endothelium-dependent mechanism and implicating a NO-mediated effect via the Akt pathway. Maximal superoxide scavenging with polyethylene glycolsuperoxide dismutase (PEG-SOD), 150 U/ml did not influence phenylephrine constrictor responses but potentiated pravastatin’s effect, suggesting that the statin did not increase NO bioavailability merely via an antioxidant mechanism. In contrast, pravastatin did not affect endothelin-1 (ET-1) constrictor responses. However, after pre-incubation with a selective endothelin-B (ETB) receptor antagonist (BQ788 3 μmol/L) pravastatin inhibited ET-1 constriction, suggesting that its effect is via the same mechanistic pathway as the ETB receptor. Conclusions: In small vessels, pravastatin inhibits constrictor responses by increasing endothelial NO bioavailability via the Akt pathway. Furthermore, ETB receptor blockade unmasks this effect in ET-1 constrictor responses.
Keywords: Endothelin-1
DOI: 10.1253/circj.CJ-10-0954
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