Background Preterm labour is a leading cause of perinatal and neonatal death. Nifedipine is used clinically for tocolysis but has a lack of specificity relative to vascular smooth muscle. We hypothesized that a combination of nifedipine with myometrial specific potassium channel openers will enhance tocolysis without adverse vascular effects.
Methods Myometrial strips were mounted in 10–25 ml organ bath chambers in physiological conditions under 20 mN tension and isometric force measured. Spontaneous contractions were:
(i) pre-treated with nifedipine (0, 3, 10, 30, 100 nM) and exposed to cumulative doses of the K+ channel openers pinacidil, riluzole and linoleic acid at 20 min intervals.
(ii) exposed to simultaneous doses of riluzole and pinacidil combined with 3 nM or 10 nM nifedipine.
Significance (p<0.05) was determined using Wilcoxon sign rank or binomial test.
Results Pinacidil alone reduced activity integral (AI) (IC50 ± SEM 1.85 µM ± 0.03), and when combined with 3 nM nifedipine (1.49 µM ± 0.04), and 10 nM nifedipine (0.52 µM ± 0.12). 10 µM and 30 µM pinacidil in combination with 3 nM and 10 nM nifedipine completely abolished contractions (p≤0.05). Riluzole reduced AI at 30 µM (p=0.007) (IC50 26.4 ± 0.06) and at 3 µM when combined with 3 nM nifedipine (IC50 5.4 µM ± 0.04). Riluzole 30 µM combined with 3 nM nifedipine reduced AI 20 min into the dosing period (p=0.03). Linoleic Acid had no effect.
Conclusion Combining potassium channel openers with nifedipine can significantly increase tocolytic potential in myometrial smooth muscle. This should provide enhanced selectivity versus vascular smooth muscle.