Statins Decrease Serotonin-Induced Contractions in Coronary Arteries of Swine in vitro

Abstract

Recent evidence suggests that statins improve the status of patients with coronary artery disease not only by reducing cholesterol levels, but also by acting at the level of the endothelium-smooth muscle unit. Previous results from our laboratory showed that these drugs interact with the vascular wall by partially inhibiting calcium-dependent, agonist-induced contractions in rat aortas. To evaluate whether this effect is also extended to the coronary vasculature, we assessed the effect of statins on serotonin (5-HT) induced contractions of left and right coronary arteries of swine. Concentration-response curves for the 5-HT-induced contractions (from 0.1 nmol/l to 100 µmol/l) were calculated on rings from both coronaries in the presence and absence of either (5 µmol/l) pravastatin, mevastatin, simvastatin, lovastatin, or atorvastatin. After a 45-min incubation period, all statins significantly reduced the E_max for the 5-HT-induced contractions, ranging from 51.9 ± 1.9% (simvastatin) to 15.9 ± 2.0% (pravastatin) in the left coronary artery and from 48.8 ± 2.0% (simvastatin) to 17.8 ± 2.5% (pravastatin) in the right coronary artery. The EC₅₀ values for the 5-HT-induced contractions were 0.150 ± 0.005 µmol/l for the left coronary artery and 0.171 ± 0.010 µmol/l for the right coronary artery. These values significantly changed after incubation with statins, ranging from 1.240 ± 0.101 µmol/l (for simvastatin) to 0.081± 0.008 µmol/l (for pravastatin) in the left coronary artery and from 1.410 ± 0.075 µmol/l (for simvastatin) to 0.084 ± 0.008 µmol/l (for pravastatin) in the right coronary artery. This evidence supports the possibility that, beyond their lipid-lowering properties, statins may provide a beneficial effect in atherosclerotic patients by reducing the tone in the coronary vasculature, facilitating blood flow to the myocardium.

Atorvastatin acutely reduces the reactivity to spasmogens in rat aorta: implication of the inhibition of geranylgeranylation and MYPT‐1 phosphorylation

“…Short‐term incubation (30 min) with atorvastatin (10 −6 –10 −4 m ) significantly decreased the contractions to NA, ET‐1, and KCl in isolated rat aorta. Indeed, these findings are consistent with previous studies which reported that in vitro exposure to statins, including atorvastatin, can modulate vascular contractile reactivity directly and independently from cholesterol lowering effects . Therein, a difference was noticed in relation to the incubation period with statins ranging from short‐ (45 min–2 h) to long‐term (24–48 h) exposure to obtain a remarkable effect.…”

Inhibition of serotonin-induced mitogenesis, migration, and ERK MAPK nuclear translocation in vascular smooth muscle cells by atorvastatin

“…Many studies address the effects of statins on responses induced by serum rather than by particular stimuli, such as here for 5-HT. While Crespo and Quidgley (9) found that statins inhibit serotonininduced contraction of coronary arteries, to our knowledge, our study is the first to report effects of a statin on serotonininduced mitogenesis and migration of any cell type. MartinezGonzalez et al (44) reported that lovastatin inhibits PDGF/ EGF/insulin-induced mitogenesis of human PASMCs at 25 M, while another report (16) found that mevastatin inhibited serum-induced rat PASMC growth at 80 M. The dose range of atorvastatin at which we observed significant inhibition (1-10 M) is lower than the effective doses used in these other studies, and even the small inhibitory effect at 0.1 M atorvastatin ( Fig.…”

Differential Regulation of the Left and Right Coronary Arteries of Swine

“…Response differences to 5-HT are particularly important because this agent plays a predominant role in the events leading to acute ischemic states of the heart [11,12] . Indeed, previous results from our laboratory [13] showed that although different statins decrease the 5-HT-induced contraction in both coronary arteries, the magnitude of the reduction was higher in LCA. That the response of LCA to this calcium-mobilizing agent differs from of the RCA suggests that, in addition to the anatomical differences reported previously [4] , LCA and RCA are subjected to a differential physiological regulation.…”

“…A two-hook chamber was used to study the LCA and RCA at the same time. Before initiation of the experiments, the rings were equilibrated for 1 h under a resting tension of 2.0 g. This tension was chosen because previous experiments in our laboratory indicated that this resting tension yields a maximal contraction in this preparation [13] .…”