Mevalonate availability and cardiovascular functions.
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.
Roullet
J B
JB
Division of Nephrology, Hypertension and Clinical Pharmacology, Oregon Health Sciences University, Portland 97201.
Xue
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H
Pappu
A S
AS
Roullet
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C
Holcomb
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S
McCarron
D A
DA
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects*; D066298:In Vitro Techniques; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*; D009599:Nitroprusside / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D013599:Systole / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D009599:Nitroprusside; C015367:mevalonolactone; D008148:Lovastatin; D000109:Acetylcholine; D008798:Mevalonic Acid; D009638:Norepinephrine