Document Detail


Mevalonate availability and cardiovascular functions.
MedLine Citation:
PMID:  8265617     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Data delineating the relationship between disorders of cholesterol metabolism and elevated blood pressure (BP) do not exist. We postulated that mevalonate, the metabolic precursor of endogenous cholesterol and the direct product of 3-hydroxy-3-methylglutaryl-CoA reductase, was a contributing factor for the maintenance of vascular tone and systemic BP. We conducted in vivo, ex vivo, and in vitro experiments in normotensive and hypertensive rats, where exogenous mevalonate and lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, were used, respectively, to increase or limit mevalonate availability. Mevalonate decreased BP in the whole animal without significant change in plasma cholesterol. Incubation of aortas with mevalonate attenuated their reactivity to norepinephrine and increased their response to endothelium-dependent and -independent relaxing factors. Lovastatin, in contrast, had the opposite effect in vivo and in vitro: it increased BP, enhanced vascular response to norepinephrine, and impaired endothelium-dependent and -independent relaxations. Neither agent modified cholesterol vascular content. Alteration of vascular reactivity was also observed in resistance vessels from animals pretreated with lovastatin. Our findings suggest that mevalonate availability is an unrecognized metabolic contributor to vascular tone and BP. They imply that (i) metabolites of the mevalonate pathway other than cholesterol could potentially control vascular functions and cardiovascular hemodynamics, (ii) elevated arterial pressure could be in part the consequence of primary disorders of this pathway, and (iii) pharmacological inhibition of mevalonate production as a means to lower plasma cholesterol may have an adverse impact on other cardiovascular risk factors, such as BP.
Authors:
J B Roullet; H Xue; A S Pappu; C Roullet; S Holcomb; D A McCarron
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  90     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  1993 Dec 
Date Detail:
Created Date:  1994-01-21     Completed Date:  1994-01-21     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  11728-32     Citation Subset:  IM    
Affiliation:
Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, Portland 97201.
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MeSH Terms
Descriptor/Qualifier:
Acetylcholine / pharmacology
Analysis of Variance
Animals
Aorta, Thoracic / drug effects,  physiology*
Blood Pressure / drug effects*
Lovastatin / pharmacology*
Male
Mevalonic Acid / analogs & derivatives*,  metabolism,  pharmacology*
Muscle, Smooth, Vascular / drug effects,  physiology*
Nitroprusside / pharmacology
Norepinephrine / pharmacology
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Rats, Wistar
Systole / drug effects
Vascular Resistance / drug effects
Grant Support
ID/Acronym/Agency:
P30 DK 40566-04/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
150-97-0/Mevalonic Acid; 15078-28-1/Nitroprusside; 503-48-0/mevalonolactone; 51-41-2/Norepinephrine; 51-84-3/Acetylcholine; 75330-75-5/Lovastatin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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