Simvastatin prevents KATP channel-mediated vasodilation in pulmonary hypertension

M. Absi1, M. Al-Chawishly2, G. Hart2, A. Gurney2. 1Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9NT, UNITED KINGDOM, 2Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UNITED KINGDOM.

Introduction: simvastatin was reported to attenuate the development of pulmonary arterial hypertension (PAH) in animal models and to enhance the effectiveness of a KATP channel activator1. This contrasts with the finding that statins inhibit KATP channels in arterial smooth muscle cells2. The aim of this study was to determine how acute simvastatin treatment affects pulmonary vasodilation mediated by KATP channel activation in health and in PAH.

Method: Rats received 60 mg/kg monocrotaline (MCT) or saline i.p. PAH progression was monitored by echocardiography. Vessel myography was used to measure the contraction of isolated intra-pulmonary arteries (PAs) to the thromboxane A2 receptor agonist, U46619 (9,11-Dideoxy-9a,11a-methanoepoxy prostaglandin F2α, 30nM), followed by relaxation in response to the KATP channel activator, levcromakalim (100nM - 10µM), the Kv7 channel activator, retigabine (10 nM - 200 µM) or the calcium antagonist, nifedipine (1 nM - 1 µM). Some vessels were incubated with 3 μM simvastatin for 1 hour before applying U46619. Data are given as mean ± SEM and analysis employed one-way ANOVA with Bonferroni’s post hoc test.

Results: Levcromakalim relaxed control PAs with pEC50 = 7.2 ± 0.1 (n=7), which remained unchanged in MCT vessels (pEC50 = 7.0 ± 0.1, n=7). In contrast, the maximal relaxation to levcromakalim increased from 110 ± 3% in control vessels to 198 ± 25% (n=9, P=0.001) in diseased PAs. After simvastatin treatment, levcromakalim relaxed control arteries with a similar pEC50 = 6.9 ± 0.1, but a significantly decreased maximum relaxation (88 ± 8%, n=7, P=0.07). In MCT vessels, simvastatin markedly reduced the maximum relaxation to levcromakalim (48 ± 12%, n=8, P=0.001), without affecting its pEC50 (6.5 ± 0.2, n=8). Retigabine reduced tension by 50% at 2.8 ± 0.1 µM (n=6) and this was unchanged with simvastatin treatment (1.5 ± 4 µM, n=6). Preventing smooth muscle Ca2+ influx with nifedipine also caused concentration-dependent relaxation, tension being reduced by 50% at 20 ± 0.3 nM (n=6) nifedipine. This was unaffected by simvastatin (23.9 ± 0.06 nM, n=6).

Conclusion: Consistent with inhibition of KATP channels, simvastatin suppressed dilation to levcromakalim without affecting dilation to Kv7 channel activation or calcium channel inhibition. In PAH, the maximal dilation to levcromakalim was doubled and the inhibitory effect of simvastatin became much more pronounced. Simvastatin is therefore predicted to reduce the effectiveness of KATP channel activation in vivo.

References: 1. Jiang L et al. (2012). Pharmazie. 67: 547-52. 2. Seto et al. (2013). PLoS One. 8: e66404.