Atorvastatin and Fluvastatin Potentiate Blood Pressure Lowering Effect of Amlodipine through Vasorelaxant Phenomenon

Abstract

Background and Objectives: We have recently reported that stains have calcium channel blocking activity in isolated jejunal preparations. In this study, we examined the effects of atorvastatin and fluvastatin on blood vessels for a possible vasorelaxant effect. We also studied the possible additional vasorelaxant effect of atorvastatin and fluvastatin, in the presence of amlodipine, to quantify its effects on the systolic blood pressure of experimental animals. Materials and Methods: Atorvastatin and fluvastatin were tested in isolated rabbits' aortic strip preparations using 80mM Potassium Chloride (KCl) induced contractions and 1 micro molar Norepinephrine (NE) induced contractions. A positive relaxing effect on 80 mM KCl induced contractions were further confirmed in the absence and presence of atorvastatin and fluvastatin by constructing calcium concentration response curves (CCRCs) while using verapamil as a standard calcium channel blocker. In another series of experiments, hypertension was induced in Wistar rats and different test concentrations of atorvastatin and fluvastatin were administered in their respective EC₅₀ values to the test animals. A fall in their systolic blood pressure was noted using amlodipine as a standard vasorelaxant drug. Results: The results show that fluvastatin is more potent than amlodipine as it relaxed NE induced contractions where the amplitude reached 10% of its control in denuded aortae. Atorvastatin relaxed KCL induced contractions with an amplitude reaching 34.4% of control response as compared to the amlodipine response, i.e., 39.1%. A right shift in the EC₅₀ (Log Ca++ M) of Calcium Concentration Response Curves (CCRCs) implies that statins have calcium channel blocking activity. A right shift in the EC₅₀ of fluvastatin with relatively less EC₅₀ value (-2.8 Log Ca++ M) in the presence of test concentration (1.2 × 10^-7 M) of fluvastatin implies that fluvastatin is more potent than atorvastatin. The shift in EC₅₀ resembles the shift of Verapamil, a standard calcium channel blocker (-1.41 Log Ca++ M). Conclusions: Atorvastatin and fluvastatin relax the aortic strip preparations predominantly through the inhibition of voltage gated calcium channels in high molar KCL induced contractions. These statins also inhibit the effects of NE induced contractions. The study also confirms that atorvastatin and fluvastatin potentiate blood pressure lowering effects in hypertensive rats.

Keywords: amlodipine; atorvastatin; calcium channel blocking activity; fluvastatin; statins; verapamil.

Figure 1

Effects of atorvastatin on isolated aortic strip preparations to show relaxant effects in intact and denuded tissues. (A) Effects of atorvastatin on KCL-induced contractions in isolated aortic strip preparations to show relaxant effects in denuded tissues. (B) Effects of atorvastatin on KCL-induced contractions in isolated aortic strip preparations to show relaxant effects in intact tissues. (C) Effects of atorvastatin on Nor-Epinephrine induced contractions in isolated aortic strip preparations to show relaxant effects in denuded tissues (all values are mean ± SD, n = 4). (D) Effects of atorvastatin on Nor-Epinephrine induced in isolated aortic strip preparations to show relaxant effects in intact tissues. All values are mean ± SD, n = 4.

Figure 2

Effects of fluvastatin on isolated aortic strip preparations to show relaxant effects in intact and denuded tissues. (A) Effects of Fluvastatin on KCL-induced contractions in isolated aortic strip preparations to show relaxant effects in denuded tissues. (B) Effects of Fluvastatin on KCL-induced contractions in isolated aortic strip preparations to show relaxant effects in intact tissues. (C) Effects of Fluvastatin on Nor-Epinephrine induced contractions in isolated aortic strip preparations to show relaxant effects in denuded tissues. (D) Effects of Fluvastatin on Nor-Epinephrine induced in isolated aortic strip preparations to show relaxant effects in intact tissues. All values are mean ± SD, n = 4.

Figure 3

Effects of amlodipine on isolated aortic strip preparations to show relaxant effects in intact and denuded tissues. (A) Effects of amlodipine on KCL-induced contractions in isolated aortic strip preparations to show relaxant effects in denuded tissues. (B) Effects of amlodipine on KCL-induced contractions in isolated aortic strip preparations to show relaxant effects in intact tissues. (C) Effects of amlodipine on Nor-Epinephrine induced contractions in isolated aortic strip preparations to show relaxant effects in denuded tissues. (D) Effects of amlodipine on Nor-Epinephrine induced in isolated aortic strip preparations to show relaxant effects in intact tissues. All values are mean ± SD, n = 4.

Figure 4

CCRCs in the absence and presence of statins. (A) To show construction of CCRCs in the absence and presence of different concentrations of atorvastatin in isolated aortic strip preparations (all values are mean ± SD, n = 4). (B) To show construction of CCRCs in the absence and presence of different concentrations of fluvastatin in isolated aortic strip preparations (all values are mean ± SD, n = 4). (C) To show construction of CCRCs in the absence and presence of different concentrations of verapamil in isolated aortic strip preparations (all values are mean ± SD, n = 4).

Figure 5

To show additional effect of atorvastatin and fluvastatin on the blood pressure lowering effect of amlodipine (all values are mean ± SD, n = 4) using Paired t-test at 95% Confidence Interval. (A) To show additional effect of atorvastatin with amlodipine on systolic Blood pressure. (B) To show additional effect with fluvastatin with amlodipine on systolic Blood pressure. (C) To show effect of amlodipine on systolic Blood pressure.