Alpha1-adrenoreceptor stimulation causes vascular smooth muscle cell hypertrophy: a possible role for isoprenoid intermediates.
We investigated whether contraction-induced agonists such as alpha1-adrenoceptor agonists are important regulators of smooth muscle cell hypertrophy by examining the effects of one potent agonists, phenylephrine, on the hypertrophy. Under the experimental conditions used, we found that phenylephrine was potent in inducing alpha1-adrenoreceptor-dependent hypertrophy of vascular smooth muscle cells as defined by increased incorporation of [14C]leucine in a dose-dependent fashion. Further, we assessed the effect of lovastatin, an 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on hypertrophy of cultured vascular smooth muscle cells as defined by the increased incorporation of [14C]leucine caused by phenylephrine. Lovastatin (5-15 microM) caused a significant dose-dependent reduction in [14C]leucine incorporation which was completely prevented in the presence of exogenous mevalonate (100 microM). Exogenous low density lipoprotein (100 microg/ml) and cholesterol (15 microg/ml) did not prevent lovastatin inhibition of [14C]leucine incorporation. In contrast, the isoprenoid farnesol largely prevented inhibition of [14C]leucine incorporation by the lovastatin. We conclude that mevalonate metabolites are essential for phenylephrine-induced smooth muscle cell hypertrophy, possibly through the production of the isoprenoid farnesol.
Nishio
E
E
Department of Pharmacology, National Defense Medical College, Saitama, Japan.
Kanda
Y
Y
Watanabe
Y
Y
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000473:pathology / Q000648:ultrastructure; D002250:Carbon Radioisotopes; D002452:Cell Count; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004347:Drug Interactions; D005204:Farnesol / Q000378:metabolism* / Q000494:pharmacology; D006984:Hypertrophy; D007930:Leucine / Q000378:metabolism; D008148:Lovastatin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D010656:Phenylephrine / Q000494:pharmacology; D017368:Protein Prenylation; D051381:Rats; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology*; D014166:Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism
D000316:Adrenergic alpha-Agonists; D000924:Anticholesteremic Agents; D002250:Carbon Radioisotopes; D018340:Receptors, Adrenergic, alpha-1; D010656:Phenylephrine; D005204:Farnesol; D002784:Cholesterol; D008148:Lovastatin; D014166:Transferases; D007930:Leucine; D008798:Mevalonic Acid