TY - JOUR
T1 - Mevalonate availability affects human and rat resistance vessel function
AU - Roullet, Jean Baptiste
AU - Xue, Hong
AU - Roullet, Chantai M.
AU - Fletcher, William S.
AU - Cipolla, Marilyn J.
AU - Harker, Christian T.
AU - McCarron, David A.
PY - 1995/7
Y1 - 1995/7
N2 - Previous data in rat conductance vessels indicated that cellular mevalonate contributes to vascular tone and systemic blood pressure control. Using exogenous mevalonate (M) or lovastatin, a 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitor (L), we characterized the role of mevalonate availability in resistance artery function, both in experimental animals and humans. Rat mesenteric artery resistance vessels (MARV, n = 9) were incubated for 48 h with either L, M, L + M, or vehicle (V) and tested for reactivity to NE, serotonin, acetylcholine, atrial natriuretic peptide, and sodium nitroprusside (SNP). Lovastatin increased sensitivity to NE (P < 0.03) and serotonin (P < 0.003), and significantly impaired the response to all three vasodilators. These effects were reversed by co-incubation with mevalonate. Mevalonate alone had no effect. In separate experiments, intravascular free Ca2+ concentration ((ivf)Ca2+) was determined in fura- 2AM loaded MARV. Basal (ivf)Ca2+ was increased after a 48-h exposure to L (52.7±4.6 nM, L, vs. 29.7±2.4 nM, V, n = 12, P < 0.003), as were (ivf)Ca2+ levels following stimulation with low (100 nM) NE concentrations. Similar (ivf)Ca2+ concentrations were achieved during maximum contraction with NE (10 mM) in both groups. Human resistance arteries of human adipose tissue were also studied. Lovastatin increased the sensitivity to NE (ED50 = 372±56 nM, V, and 99±33 nM, L, P < 0.001) and significantly decreased the relaxation to acetylcholine and SNP of human vessels. We conclude that mevalonate availability directly contribute to resistance vessel function and vascular signal transduction systems in both experimental animals and humans. The study calls for the identification of non-sterol, mevalonate-derived vasoactive metabolites, and suggests that disorders of the mevalonate pathway can alter vascular tone and cause hypertension.
AB - Previous data in rat conductance vessels indicated that cellular mevalonate contributes to vascular tone and systemic blood pressure control. Using exogenous mevalonate (M) or lovastatin, a 3-hydroxy-3-methyl-glutaryl CoA (HMG-CoA) reductase inhibitor (L), we characterized the role of mevalonate availability in resistance artery function, both in experimental animals and humans. Rat mesenteric artery resistance vessels (MARV, n = 9) were incubated for 48 h with either L, M, L + M, or vehicle (V) and tested for reactivity to NE, serotonin, acetylcholine, atrial natriuretic peptide, and sodium nitroprusside (SNP). Lovastatin increased sensitivity to NE (P < 0.03) and serotonin (P < 0.003), and significantly impaired the response to all three vasodilators. These effects were reversed by co-incubation with mevalonate. Mevalonate alone had no effect. In separate experiments, intravascular free Ca2+ concentration ((ivf)Ca2+) was determined in fura- 2AM loaded MARV. Basal (ivf)Ca2+ was increased after a 48-h exposure to L (52.7±4.6 nM, L, vs. 29.7±2.4 nM, V, n = 12, P < 0.003), as were (ivf)Ca2+ levels following stimulation with low (100 nM) NE concentrations. Similar (ivf)Ca2+ concentrations were achieved during maximum contraction with NE (10 mM) in both groups. Human resistance arteries of human adipose tissue were also studied. Lovastatin increased the sensitivity to NE (ED50 = 372±56 nM, V, and 99±33 nM, L, P < 0.001) and significantly decreased the relaxation to acetylcholine and SNP of human vessels. We conclude that mevalonate availability directly contribute to resistance vessel function and vascular signal transduction systems in both experimental animals and humans. The study calls for the identification of non-sterol, mevalonate-derived vasoactive metabolites, and suggests that disorders of the mevalonate pathway can alter vascular tone and cause hypertension.
KW - HMG-CoA reductase inhibitors
KW - cholesterol
KW - isoprenoids
KW - lovastatin
KW - vascular tone
UR - http://www.scopus.com/inward/record.url?scp=0029086372&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029086372&partnerID=8YFLogxK
U2 - 10.1172/JCI118027
DO - 10.1172/JCI118027
M3 - Article
C2 - 7615793
AN - SCOPUS:0029086372
SN - 0021-9738
VL - 96
SP - 239
EP - 244
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 1
ER -