Department of Pharmacy, Banasthali Vidyapith, Banasthali, 304022, Rajasthan, India.
Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Raebareli, Lucknow, Uttar Pradesh, India.
Inflammopharmacology. 2023 Jun;31(3):1279-1288. doi: 10.1007/s10787-023-01219-8. Epub 2023 Apr 10.
Simvastatin is a semisynthetic inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and is used extensively to treat atherosclerotic cardiovascular disease. Apart from the lipid-lowering effect, simvastatin has been documented to offer impressive vasorelaxant activity. However, the mechanism associated with this vasorelaxant activity has yet not been substantially explored. Thus, the present study has aimed to elucidate the mechanism(s) associated with simvastatin-induced vasorelaxation using an established rat aortic ring model. The results from the study depicted that simvastatin caused significant relaxation in aortic rings pre-contracted with phenylephrine and potassium chloride (KCl). The vasorelaxant effect of simvastatin was attenuated by methylene blue (sGC-dependent cyclic guanosine monophosphate (cGMP) inhibitor), N-nitro-L-arginine methyl ester (L-NAME; NO synthase inhibitor), 4-aminopyridine (K blocker), glibenclamide (K blocker), and barium chloride (K blocker). In addition, the vasorelaxant effect of simvastatin was slightly reduced by PD123319 (angiotensin II type 2 receptor (ATR) antagonist). However, indomethacin (COX inhibitor), 1H-[1,2,4]Ox adiazolol [4,3-α]quinoxalin-1-one (ODQ; selective soluble guanylate cyclase (sGC) inhibitor), losartan (angiotensin II type 1 receptor (ATR) antagonist), atropine (muscarinic receptor blocker), and tetraethyl ammonium (TEA; K blocker) did not affect the vasorelaxant effect of simvastatin. Furthermore, simvastatin was found to attenuate the release of calcium (Ca) from intracellular stores in the presence of ruthenium red (ryanodine receptor, RyR inhibitor) and extracellular stores via nifedipine (voltage-operated Ca channels, VOCC blocker) and SK&F96365 (receptor-operated Ca channel, ROCC blocker). Thus, it can be concluded that the vasorelaxant effect of simvastatin involves NO/cGMP pathways, ATR receptors, Ca channels, and K channels.
辛伐他汀是 3-羟基-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶的半合成抑制剂，广泛用于治疗动脉粥样硬化性心血管疾病。除了降脂作用外，辛伐他汀还具有令人印象深刻的血管舒张活性。然而，与这种血管舒张活性相关的机制尚未得到充分探索。因此，本研究旨在使用已建立的大鼠主动脉环模型阐明与辛伐他汀诱导的血管舒张相关的机制。研究结果表明，辛伐他汀可使预先用苯肾上腺素和氯化钾（KCl）收缩的主动脉环显著舒张。辛伐他汀的血管舒张作用被亚甲蓝（sGC 依赖性环鸟苷单磷酸（cGMP）抑制剂）、N-硝基-L-精氨酸甲酯（NOS 抑制剂）、4-氨基吡啶（K 通道阻断剂）、格列本脲（K 通道阻断剂）和氯化钡（K 通道阻断剂）减弱。此外，辛伐他汀的血管舒张作用被 PD123319（血管紧张素 II 型 2 受体（ATR）拮抗剂）轻度减弱。然而，吲哚美辛（COX 抑制剂）、1H-[1,2,4]恶二唑并[4,3-α]喹喔啉-1-酮（ODQ；选择性可溶性鸟苷酸环化酶（sGC）抑制剂）、氯沙坦（血管紧张素 II 型 1 受体（ATR）拮抗剂）、阿托品（毒蕈碱受体阻滞剂）和四乙铵（TEA；K 通道阻断剂）均不影响辛伐他汀的血管舒张作用。此外，辛伐他汀被发现可在钌红（ryanodine 受体，RyR 抑制剂）存在下减轻细胞内储存库中 Ca 的释放，并通过硝苯地平（电压门控 Ca 通道，VOCC 阻断剂）和 SK&F96365（受体操纵性 Ca 通道，ROCC 阻断剂）减轻细胞外储存库中 Ca 的释放。因此，可以得出结论，辛伐他汀的血管舒张作用涉及 NO/cGMP 途径、ATR 受体、Ca 通道和 K 通道。
