The role of endothelium and calcium and large conductance calcium–activated potassium channels in the effect of fospropofol on vascular smooth muscles

Objective: Regarding the unfavorable properties of propofol we investigated the effects of fospropofol, a water-soluble prodrug of propofol, on human internal mammary artery (IMA) rings, as an alternative. Since desired vascular tonus is crucial during cardiac surgery the effect of agents used for induction and/or sedation is important. To clarify the endothelium dependent and calcium and potassium channel modulated mechanism of action of these drugs will enable us to control the patients during and after surgery in intensive care period. Methods: The arterial rings obtained from the remenants of the IMA used in 19 patients underwent coronary artery bypass grafting were mounted in the organ baths and stabilized under resting tension of 0.5–1 g in physiological Krebs solution at 37°C (gassed with 95%O₂ and 5% CO₂, pH=7.4). The basal and KCl (120mM)-stimulated vascular tonus and the effect of cumulative propofol (n=8) and fospropofol (n=11) (10^-7-10^-5 M) was recorded. In another group of IMA segments same protocol of fospropofol was applied to endothel-intact and denuded vessels to investigate the role of endothelium. Then to understand the involvement of L-type Ca⁺² and BKCa K⁺ channels, the vessels were preincubated by nifedipine (n=8) or iberiotoxin (n=7) followed by the KCl stimulation and fospropofol doses. All the arterial responses were recorded real-time by Biopac data acquisition and analysis system. The results were normalized by tissue weight and given as the percentage of KCl-induced contraction. Results: Fospropofol caused less and later vasodilation compared to propofol (p<0.05). The role of endothelial layer in the vasodilatory role of fospropofol was shown by attenuated effect in endothel-denuded rings. Blocking BKCa potassium channels with iberiotoxin increased contraction and blunted the vasodilatory effect of fospropofol. Conclusion: In conclusion, fospropofol appears to be a better alternative to propofol with potentially reduced risk of vasodilation-induced hypotension and maintaining vascular tone. further studies are required to validate these findings and to better understand its underlying mechanisms.