Objectives: Sildenafil citrate, a specific phosphodiesterase-5 inhibitor, is increasingly used for pulmonary hypertension in pregnancy. Sildenafil is also emerging as a potential candidate for the treatment of intra-uterine growth retardation and for premature labor. Its effects in the fetoplacental circulation are not known. Our objectives were to determine whether phosphodiesterase-5 is present in the human feto-placental circulation, and to characterize the effects and mechanisms of action of sildenafil citrate in this circulation.Study Design: Ex vivo human chorionic plate arterial rings were used in all experiments. The presence of phosphodiesterase-5 in the feto-placental circulation was determined by western blotting and immunohistochemical staining. In a subsequent series of pharmacologic studies, the effects of sildenafil citrate in pre-constricted chorionic plate arterial rings were determined. Additional studies examined the role of cGMP and nitric oxide in mediating the effects of sildenafil.Results: Phosphodiesterase-5 mRNA and protein was demonstrated in human chorionic plate arteries. Immunohistochemistry demonstrated phosphodiesterase-5 within the arterial muscle layer. Sildenafil citrate produced dose dependent vasodilatation at concentrations at and greater than 10 nM. Both the direct cGMP inhibitor methylene blue and the cGMP-dependent protein kinase inhibitor Rp-8-Br-PET-cGMPS significantly attenuated the vasodilation produced by sildenafil citrate. Inhibition of NO production with L-NAME did not attenuate the vasodilator effects of sildenafil. In contrast, sildenafil citrate significantly enhanced the vasodilation produced by the NO donor sodium nitroprusside. Conclusion:Phosphodiesterase-5 is present in the feto-placental circulation. Sildenafil citrate vasodilates the feto-placental circulation via a cGMP dependent mechanism involving increased responsiveness to NO.

BackgroundSevoflurane has been demonstrated to vasodilate the foeto-placental vasculature. We aimed to determine the contribution of modulation of potassium and calcium channel function to the vasodilatory effect of sevoflurane in isolated human chorionic plate arterial rings.MethodsQuadruplicate ex vivo human chorionic plate arterial rings were used in all studies. Series 1 and 2 examined the role of the K+ channel in sevoflurane-mediated vasodilation. Separate experiments examined whether tetraethylammonium, which blocks large conductance calcium activated K+ (KCa++) channels (Series 1A+B) or glibenclamide, which blocks the ATP sensitive K+ (KATP) channel (Series 2), modulated sevoflurane-mediated vasodilation. Series 3 – 5 examined the role of the Ca++ channel in sevoflurane induced vasodilation. Separate experiments examined whether verapamil, which blocks the sarcolemmal voltage-operated Ca++ channel (Series 3), SK&F 96365 an inhibitor of sarcolemmal voltage-independent Ca++ channels (Series 4A+B), or ryanodine an inhibitor of the sarcoplasmic reticulum Ca++ channel (Series 5A+B), modulated sevoflurane-mediated vasodilation.ResultsSevoflurane produced dose dependent vasodilatation of chorionic plate arterial rings in all studies. Prior blockade of the KCa++ and KATP channels augmented the vasodilator effects of sevoflurane. Furthermore, exposure of rings to sevoflurane in advance of TEA occluded the effects of TEA. Taken together, these findings suggest that sevoflurane blocks K+ channels. Blockade of the voltage-operated Ca++channels inhibited the vasodilator effects of sevoflurane. In contrast, blockade of the voltage-independent and sarcoplasmic reticulum Ca++channels did not alter sevoflurane vasodilation.ConclusionSevoflurane appears to block chorionic arterial KCa++ and KATP channels. Sevoflurane also blocks voltage-operated calcium channels, and exerts a net vasodilatory effect in the in vitro foeto-placental circulation.

Tranexamic acid and trauma TO THE EDITOR: Gruen and colleagues 1 have not accurately represented the current safety data on the risk of vascular occlusive events (VOE) with tranexamic acid (TxA), including deep vein thrombosis (DVT) and pulmonary embolism (PE). A systematic review of data for 10 488 surgical patients showed lower mortality with TxA and no difference in DVT (risk ratio [RR], 0.86; 95% CI, 0.53-1.39; P = 0.54) or PE (RR, 0.61; 95% CI, 0.25-1.47; P = 0.27). 2 The CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage 2) 3 trial involving 20 211 patients showed there was a trend to fewer VOE in the tranexamic acid group compared with placebo (168/10 060 [1.7%] v 201/10 067 [2.0%]; P = 0.084). Gruen et al implied that the low rate of PE (0.7%) and DVT (0.4%) in this study renders these findings suspect. Low detection of DVT and PE applied equally to both groups and only affects study power-which is not an issue in this large study. Gruen and colleagues stated that "in contrast" the observational MATTERs (Military Application of Tranexamic Acid in Trauma Emergency Resuscitation) 4 trial showed PE and DVT rates that were, respectively, nine and 12 times the rates for the control group. They neglected to mention that the rates in the control group were 2/603 (0.3%) and 1/603 (0.2%)-lower than the rates in the less severely injured CRASH 2 patients. The MATTERs study was unblinded, so the difference could easily have been due to more investigations in the TxA group. Finally, the MATTERs study reported that the inhospital mortality in the TxA group was 17.4% compared with 23.9% in the group not given TxA (P = 0.03). Unlike nonfatal DVT and PE, death is not a condition that requires investigations to diagnose.