Effect of pravastatin on impaired endothelium-dependent relaxation induced by lysophosphatidylcholine in rat aorta1

Abstract

Aim: To investigate the effects of pravastatin, a potent 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on impaired endothelium-dependent relaxation induced by lysophosphatidylcholine (LPC), the major component of oxidized low-density lipoprotein, in rat thoracic aorta. Methods: Both the endothelium-dependent relaxation response to acetylcholine and the endotheliumindependent relaxation response to sodium nitroprusside of aortic rings were measured by recording isometric tension after the rings were exposed to LPC in the absence or presence of pravastatin to estimate the injury effect of LPC and the protective effect of pravastatin on the aortic endothelium, respectively. Results: Exposure of aortic rings to LPC (1-10 µmol/L) for 30 min induced a significant concentration-dependent inhibition of endothelium-dependent relaxation to acetylcholine, but did not affect endothelium-independent relaxation in response to sodium nitroprusside. Pre-incubation of aortic rings with pravastatin (0.3-3 mmol/L) for 15 min and then co-incubation of the rings with LPC (3 µmol/L) for another 30 min significantly attenuated the inhibition of endothelium-dependent relaxation induced by LPC. This protective effect of pravastatin (1 mmol/L) was abolished by N G -nitro-L-arginine methyl ester (30 µmol/L), an inhibitor of nitric oxide synthase, but not by indomethacin (10 µmol/L), an inhibitor of cyclooxygenase. Moreover, protein kinase C inhibitor chelerythrine (1 µmol/L) the superoxide anion scavenger superoxide dismutase (200 kU/L), and the nitric oxide precursor L-arginine (3 mmol/L) also improved the impaired endotheliumdependent relaxation induced by LPC, similar to the effects of pravastatin. Conclusion: Pravastatin can protect the endothelium against functional injury induced by LPC in rat aorta, a fact which is related to increasing nitric oxide bioavailability.

Protective Effects of EPA and Deleterious Effects of DHA on eNOS Activity in Ea hy 926 Cultured with Lysophosphatidylcholine

“…In these conditions, LysoPtdCho induced a decrease in the stimulating effect of histamine on eNOS activity and a concomitant decrease in Ser 1177 eNOS phosphorylation. This result is in agreement with the decreased endothelial release of NO by LysoPtdCho as reported in the literature [26,27]. Several mechanisms have been proposed to explain the effect of LysoPtdCho including a decrease of arginine availability due to an inactivation of the arginine transporter [28], an increased production of asymmetric dimethyl arginine (ADMA), an endogenous eNOS inhibitor [29], or still a decrease in eNOS expression [30].…”

Acute Modulation of Vasoconstrictor Responses by Pravastatin in Small Vessels

“…38 Moreover, the enhancement of relaxation of rat aorta to acetylcholine after atorvastatin treatment was eliminated in the presence of SOD, suggesting that reduction in superoxide was the major mechanism for the enhanced relaxation response to acetylcholine. 38 Similar protective effects against oxidative stress have been suggested for both acute 29 and chronic in-vivo 39 and in-vitro 40 protection by statins against low-density lipoprotein-induced endothelial dysfunction in rat aorta.…”

“…Influence of Superoxide on the Effect of Pravastatin Because pravastatin could potentially limit superoxide levels 28, 29 and thereby inhibit the degradation of NO to peroxynitrite, pravastatin's effect on phenylephrine responses was assessed in the presence of maximal superoxide scavenging with polyethylene glycol-superoxide dismutase (PEG-SOD). The concentration of PEG-SOD required for maximal superoxide scavenging was determined in preliminary experiments in a cell-free system, using superoxide generation by hypoxanthine-xanthine oxidase and measurement via lucigenin-derived chemiluminescence assessed using a Picolite-luminometer (Packard Instruments, CT, USA).…”

Skin Autofluorescence Is Associated with Endothelial Dysfunction in Uremic Subjects on Hemodialysis

“…The patients who used ACEIs/ARBs, or statins had better FMD values than the patients who did not use ACEIs/ARBs or statins ( Table 2 ). Previous studies have suggested that statins can upregulate endothelial nitric oxide synthase, thereby improving endothelial-dependent vasodilatation of rat aorta [ 31 , 32 ]. The interaction between angiotensin II and angiotensin II receptor type I may increase reactive oxygen species production, further attenuating the nitric oxide and bradykinin production.…”