Effects of GS-967, GS-6615 and ranolazine on the responses of the rabbit aorta to adrenergic nerve stimulation

FIGURE 1. Sections of experimental records showing contractile effects of electrical field stimulation on rabbit aortic in the absence and in the presence of tetrodotoxin (10−6 M), guanethidine (10−6 M) or prazosin (10−6 M). Tracings are representative of various aortic rings from different rabbits. In all cases, the differences of the responses before and after treatment were statistically significant (p < 0.05).

FIGURE 2. Adrenergic nervous stimulation. Effects of electrical field stimulation at 2 Hz (A), 4 Hz (B) and 8 Hz (C) on rabbit aorta in the absence (control, n = 7) and in the presence of tetrodotoxin (TTX) (10–6 M, n = 6), guanethidine (GN) (10–6 M, n = 5), or prazosin (PRZ) (10–4 M, n = 6). Values are means ± SEM shown by vertical bars. A paired t-test was used. The level of significance used was 5% (*p < 0.05).

FIGURE 3. Modulatory effect of GS-967 on adrenergic nerve stimulation. Contractile effects of electrical field stimulation at 4 Hz on rabbit aorta in the absence (control, n = 8) and in the presence of GS-967 (10−7–10−4 M, n = 6) (A) or in vessels previously incubated with Charybdotoxin (Chb) (10−6 M) (B). Values are means ± SEM shown by vertical bars. A paired t-test was used. The level of significance used was 5% (*p < 0.05).

FIGURE 4. Modulatory effect of GS-6615 on adrenergic nerve stimulation. Contractile effects of electrical field stimulation at 4 Hz on rabbit aorta in the absence (control, n = 7) and in the presence of GS-6615 (10−7–10−4 M, n = 6) (A) or in vessels previously incubated with Charibdotoxin (Chb) (10−6 M) (B). Values are means ± SEM shown by vertical bars. A paired t-test was used. The level of significance used was 5% (*p < 0.05).

FIGURE 5. Modulatory effect of Ranolazine on adrenergic nerve stimulation. Effects of electrical field stimulation at 4 Hz on rabbit aorta in the absence (control, n = 6) and in the presence of Ranolazine (RAN) (10−7–10−4 M, n = 7). Values are means ± SEM shown by vertical bars. A paired t-test was used. The level of significance used was 5% (*p < 0.05).

FIGURE 6. Intervention of COX-1, COX-2, and NO in the effects of RAN. Contractile effects of electrical field stimulation at 4 Hz on rabbit aorta in the absence (control, n = 7) and in the presence of Ranolazine (RAN) (10−7–10−4 M) and previously incubated with L-NAME (10−4 M, n = 6) (A) Nimesulide (10−6 M, n = 5) (B) or SC-560 (10−6 M, n = 5) (C). Values are means ± SEM shown by vertical bars. A paired t-test was used. The level of significance used was 5% (*p < 0.05).

FIGURE 7. Intervention of calcium and potassium channels in the effects of RAN. Contractile effects of electrical field stimulation at 4 Hz on rabbit aorta in the absence (control, n = 7) and in the presence of Ranolazine (RAN) (10−7–10−4 M, n = 6) and previously incubated with Verapamil (10−6 M, n = 6) (A) Nifedipine (10−6 M, n = 6), (B) Apamin (10−6 M, n = 6) (C) or Charybdotoxin (10−6 M, n = 7) (D). Values are means ± SEM shown by vertical bars. A paired t-test was used. The level of significance used was 5% (*p < 0.05).

FIGURE 8. Effects of RAN on α1 adrenergic receptors. Concentration-response curves for noradrenaline (10−9–10−3 M) in aortic rings in the absence (control) or presence of Ranolazine (RAN) (10−7–10−4 M). Values are mean ± SEM. The data have been obtained from Table 1, where the pD2 values, Emax, and statistical significance are presented. RAN 10−6, 10−5 and 10−4 M with p < 0.05 vs. control.

FIGURE 9. Effects of GS-967 and GS-6615 on α1 adrenergic receptors. Concentration-response curves for noradrenaline (10−9–10−3 M) in aortic rings in the absence (control) and in the presence of GS-967 (10−7–10−4 M) (A) or in the presence of GS-6615 (10−7–10−4 M) (B). Values are means ± SEM. The data have been obtained from Tables 2, 3, where the pD2 values, Emax, and statistical significance are presented.

FIGURE 10. Mechanisms involved in the relaxing effects of RAN. Relaxant effects of Ranolazine (RAN) (10−7–10−4 M) on rabbit aortic rings precontracted with different agonists, noradrenaline (10−5 M, n = 6), endothelin-1 (10–7 M, n = 6) or KCl (60 mM, n = 5) (A). Relaxant actions of Ranolazine (10−7–10−4 M) on aortic rings precontracted with noradrenaline (10−5 M) in the presence of L-NAME (N-omega-nitro-L-arginina metil éster) (10−4 M, n = 6) (B) or Charybdotoxin (ChTX) (10−6 M, n = 7) (C). Values are means ± SEM. A one-way ANOVA was used (*p < 0.05).

FIGURE 11. Mechanisms involved in the relaxing effects of GS-967 and GS-6615. Relaxant actions of GS-967 (10−7–10−4 M) (A) or GS-6615 (10−7–10−4 M) (B) on aortic rings precontracted with noradrenaline (10−5 M, n = 6) or endothelin (10−7 M, n = 5) in the presence of L-NAME (N-omega-nitro-L-arginina metil éster) (10−4 M, n = 5) or Charybdotoxin (ChTX) (10−7 M, n = 6). Values are means ± SEM. *p < 0.05.