Lovastatin induces relaxation and inhibits L-type Ca(2+) current in the rat basilar artery.
Statins inhibit cholesterol biosynthesis and protect against ischaemic stroke. It has become increasingly apparent that the beneficial effects of statin therapy may extend beyond lowering of serum cholesterol. The present study was done to explore possible pleiotropic statin effects at the level of the cerebral vascular smooth muscle. Lovastatin, lovastatin acid, simvastatin and pravastatin, were added to segments of the rat basilar artery and effects on contraction and Ca2+ handling were examined. Pravastatin had no effect on contraction. Simvastatin, lovastatin, and, to a lesser degree, lovastatin acid, caused relaxation (IC50=0.8, 1.9 and 22 micromol/l) of both intact and denuded arteries precontracted with 5-HT or high-K+. This effect was not reversed by mevalonate, suggesting that it was not related to cholesterol or isoprenoid metabolism. Relaxation was associated with a reduction of the intracellular Ca2+ concentration measured with Fura 2 and with a reduced Mn2+ quench rate, suggesting a direct effect on ion channels in the smooth muscle cell membrane. Current measurements in isolated and voltage clamped basilar artery muscle cells demonstrated that both lovastatin and lovastatin acid inhibit L-type Ca2+ current. We propose that lipophilicity is an important factor behind the effects of statins on vascular tone and that Ca2+ current inhibition is the likely mechanism of action.
Bergdahl
Andreas
A
Department of Physiological Sciences, Lund University, Biomedical Center, BMC F12, S-22184 Lund, Sweden.
Persson
Erik
E
Hellstrand
Per
P
Swärd
Karl
K
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001488:Basilar Artery / Q000187:drug effects* / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D005260:Female; D066298:In Vitro Techniques; D008148:Lovastatin / Q000494:pharmacology*; D008798:Mevalonic Acid / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D010865:Pilot Projects; D017035:Pravastatin / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology
D000924:Anticholesteremic Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D008148:Lovastatin; D019821:Simvastatin; D017035:Pravastatin; D008798:Mevalonic Acid