Department of Pharmacology, Institute of Pharmaceutical Sciences, Khyber Medical University, Hayatabad, Peshawar 25100, Khyber Pakhtunkhwa, Pakistan.
Department of Pharmacology, College of Medicine, Shaqra University, Shaqra 11961, Saudi Arabia.
Medicina (Kaunas). 2023 Oct 10;59(10):1805. doi: 10.3390/medicina59101805.
: We have recently reported that Fluvastatin, Atorvastatin, Simvastatin and Rosuvastatin have calcium channel antagonistic activities using rabbits' intestinal preparations. The current study is focused on the effects of Pitavastatin and Lovastatin for possible inhibition of vascular L-Type calcium channels, which may have vasorelaxant effect(s). Combined effects of Pitavastatin and Lovastatin in the presence of Amlodipine were also tested for vasorelaxation. : Possible relaxing effects of Pitavastatin and Lovastatin on 80 mM Potassium chloride (KCL)-induced contractions and on 1 µM norepinephrine (N.E)-induced contractions were studied in isolated rabbit's aortic strips preparations. Relaxing effects on 80 mM KCL-induced vascular contractions were further verified by constructing Calcium Concentration Response Curves (CCRCs), in the absence and presence of three different concentrations of Pitavastatin and Lovastatin using CCRCs as negative control. Verapamil was used as a standard drug that has L-Type calcium channel binding activity. In other series of experiments, we studied drug interaction(s) among Pitavastatin, Lovastatin, and amlodipine. : The results of this study imply that Lovastatin is more potent than Pitavastatin for having comparatively lower EC (7.44 × 10 ± 0.16 M) in intact and (4.55 × 10 ± 0.10 M) in denuded aortae for KCL-induced contractions. Lovastatin amplitudes in intact and denuded aortae for KCL-induced contractions were, respectively, 24% and 35.5%; whereas amplitudes for Pitavastatin in intact and denuded aortae for KCL-induced contractions were 34% and 40%, respectively. A left shift in the EC values for the statins was seen when we added amlodipine in EC (Log Ca M). Right shift for CCRCs state that Pitavastatin and Lovastatin have calcium channel antagonistic effects. Lovastatin in test concentration (6.74 × 10 M) produced a right shift in relatively lower EC (-2.5 ± 0.10) Log Ca M as compared to Pitavastatin, which further confirms that lovastatin is relatively more potent. The right shift in EC resembles the right shift of Verapamil. Additive effect of Pitavastatin and Lovastatin was noted in presence of amlodipine ( < 0.05). : KCL (80 mM)-induced vascular contractions were relaxed by Pitavastatin and Lovastatin via inhibitory effects on L-Type voltage-gated calcium channels. Lovastatin and Pitavastatin also relaxed Norepinephrine (1 µM)-induced contractions giving an insight for involvement of dual mode of action of Pitavastatin and Lovastatin.
: 我们最近报道了氟伐他汀、阿托伐他汀、辛伐他汀和罗苏伐他汀在兔肠制剂中具有钙通道拮抗活性。本研究侧重于匹伐他汀和洛伐他汀对血管 L 型钙通道的抑制作用，这可能具有血管舒张作用。还测试了匹伐他汀和洛伐他汀在氨氯地平存在下的联合作用对血管舒张的影响。: 在分离的兔主动脉带制剂中，研究了匹伐他汀和洛伐他汀对 80mM 氯化钾（KCL）诱导的收缩和 1μM 去甲肾上腺素（N.E.）诱导的收缩的可能舒张作用。通过构建钙浓度反应曲线（CCRC），进一步验证了 KCL 诱导的血管收缩对 80mM KCL 诱导的血管收缩的舒张作用，在不存在和存在三种不同浓度的匹伐他汀和洛伐他汀的情况下使用 CCRC 作为阴性对照。维拉帕米被用作具有 L 型钙通道结合活性的标准药物。在另一系列实验中，我们研究了匹伐他汀、洛伐他汀和氨氯地平之间的药物相互作用。: 本研究结果表明，洛伐他汀比匹伐他汀更有效，因为它在完整的和去内皮的主动脉中对 KCL 诱导的收缩具有较低的 EC（7.44×10±0.16M）（4.55×10±0.10M）。洛伐他汀在完整和去内皮的主动脉中对 KCL 诱导的收缩的幅度分别为 24%和 35.5%；而匹伐他汀在完整和去内皮的主动脉中对 KCL 诱导的收缩的幅度分别为 34%和 40%。当我们在 EC（LogCaM）中加入氨氯地平时，他汀类药物的 EC 值向左移位。CCRC 的右移表明匹伐他汀和洛伐他汀具有钙通道拮抗作用。在测试浓度（6.74×10M）下的洛伐他汀产生相对较低的 EC（-2.5±0.10）LogCaM 的右移，与匹伐他汀相比，这进一步证实了洛伐他汀相对更有效。EC 的右移类似于维拉帕米的右移。在氨氯地平存在下，匹伐他汀和洛伐他汀的相加作用明显（<0.05）。: KCL（80mM）诱导的血管收缩通过抑制 L 型电压门控钙通道被匹伐他汀和洛伐他汀松弛。匹伐他汀和洛伐他汀还松弛了去甲肾上腺素（1μM）诱导的收缩，这为匹伐他汀和洛伐他汀的双重作用模式提供了线索。
