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Sildenafil and an early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets.

Binns-Loveman KM, Kaplowitz MR, Fike CD.

Division of Neonatology, Department of Pediatrics, Wake Forest University School of Medicine, Winston-Salem, North Carolina.

Devising therapies that might prevent the onset or progression of pulmonary hypertension in newborns has received little attention. Our major objective was to determine whether sildenafil, a selective phosphodiesterase inhibitor, prevents the development of an early stage of chronic hypoxia-induced pulmonary hypertension in newborn pigs. Another objective was to determine whether sildenafil causes pulmonary vasodilation without systemic vasodilation in piglets with chronic pulmonary hypertension. Piglets were raised in room air (control, n = 5) or 10-11% O(2) (hypoxic, n = 17) for 3 days. Some piglets (n = 4) received oral sildenafil, 12 mg/kg/day, throughout exposure to hypoxia. All piglets were anesthetized and catheterized, and pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), aortic pressure (Ao), and cardiac output (CO) were measured. Then for some piglets raised in hypoxia for 3 days, a single oral sildenafil dose (3 mg/kg, n = 6) or placebo (n = 5) was given, and hemodynamic measurements were repeated. For piglets raised in hypoxia for 3 days, mean Ppa and calculated PVR were elevated above respective values in control piglets. Mean Ppa and PVR did not differ between piglets that received sildenafil throughout exposure to hypoxia and those that did not. For piglets with chronic hypoxia-induced pulmonary hypertension that received a single oral dose of sildenafil, mean Ppa and PVR decreased, while mean Pw, CO, mean Ao, and systemic vascular resistance remained the same. All hemodynamic measurements were unchanged after placebo. Oral sildenafil did not influence the early stage of chronic hypoxia-induced pulmonary hypertension in newborn piglets. However, a single oral dose of sildenafil caused pulmonary vasodilation, without systemic vasodilation, in piglets with chronic hypoxia-induced pulmonary hypertension, which may have therapeutic implications. (c) 2005 Wiley-Liss, Inc.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15880376&query_hl=1

cGMP-phosphodiesterase antagonists inhibit Ca(2+)-influx in Dictyostelium discoideum and bovine cyclic-nucleotide-gated-channel.

Lusche DF, Kaneko H, Malchow D.

Department of Biology, University of Konstanz, Universitaetstr.10, D-78457 Konstanz, Germany.

We used antagonists of cGMP-phosphodiesterases to examine the role of cGMP for light-scattering oscillations and cAMP-induced Ca(2+)-influx in Dictyostelium discoideum, however, SCH 51866 (cis-5,6a,7,8,9,9a-hexahydro-2-[4-(trifluoromethyl)phenylmethyl]-5-methyl-cyclopent[4,5]imidazo[2,1-b]purin-4(3H)-one) and sildenafil citrate (1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1-H-pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazine citrate) were poor inhibitors of cGMP-hydrolysis. Instead, SCH 51866 (IC(50)=16 muM) and sildenafil, blocked chemoattractant (cAMP)-induced Ca(2+)-influx as determined with a Ca(2+)-specific electrode. SCH 51866 (150 muM) affected neither spontaneous cGMP transients during light-scattering-oscillations nor cAMP-mediated K(+)-efflux. SCH 51866 and sildenafil are competitive inhibitors of cGMP phosphodiesterases. However, the activity of cGMP-dependent protein kinase Ialpha (PKGIalpha) was not altered by SCH 51866 (150 muM). By contrast, patch-clamp measurements of bovine cone cGMP-gated-channels (cyclic-nucleotide-gated-channel, CNGA3), stably expressed in human embryonic kidney cells, HEK 293 cells, revealed reversible, competitive and dose-dependent inhibition of sodium currents by SCH 51866 (IC(50)=25 muM) and sildenafil, but not by another inhibitor of cGMP-phosphodiesterases, UK 114,542. The possibility that D. discoideum cells also express a cGMP-regulated channel is supported by our finding that LY 83583 (6-(phenylamino)-5,8-quinolinedione) (35 muM), known to inhibit cyclic-nucleotide-gated-channels as well as guanylyl-cyclases, reduced cAMP-induced Ca(2+)-influx in D. discoideum, but did not affect cAMP-induced cGMP accumulation. Utilizing a PDED null strain that exhibits a prolonged and elevated cGMP transient following receptor activation, we found that the inhibition of Ca(2+)-influx by SCH 51866 in the wildtype was absent in the mutant. Our results show that SCH 51866 and sildenafil are antagonists of a Ca(2+)-permeable channel (CNGA3) and that both compete with cGMP for a regulatory site of Ca(2+)-influx in D. discoideum.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15878705&query_hl=1

Embryo transfer: factors involved in optimizing the success.

Sallam HN.

Department of Obstetrics and Gynaecology, University of Alexandria and Alexandria Fertility Center, Alexandria, Egypt.

PURPOSE OF REVIEW: Embryo transfer is arguably the most critical step in assisted reproduction. The purpose of this article is to review the different aspects of the procedure in the light of recent evidence. RECENT FINDINGS: Randomized trials have shown that significantly higher pregnancy rates are obtained when embryo transfer is performed under ultrasound guidance, the embryos are deposited in the middle part of the uterine cavity, an atraumatic technique is used and when low-dose aspirin is routinely administered following the procedure. Blood in the catheter and leaving the embryos inside it for more than 120 s diminish the pregnancy rate significantly. Air in the catheter, immediate removal of the catheter, performing two transfers in the same cycle, prolonged bed rest, sexual intercourse after embryo transfer or the use of sildenafil do not affect the results. Based on currently available evidence, Cochrane reviews have concluded that the live birth rate is not increased by delaying embryo transfer from day two to three or to the blastocyst stage, and that single embryo transfer leads to lower live birth rates than the transfer of two embryos. The value of a mock transfer a few days before the actual procedure has been challenged as the position of the uterus may change. The effect of holding the cervix with a volsellum, routinely administering antibiotics and the superiority of one catheter over the others is still to be determined. SUMMARY: Recent studies confirm the importance of the various aspects of embryo transfer. More randomized studies are needed to further evaluate them.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15870564&query_hl=1

Oral Sildenafil for Treatment of Severe Pulmonary Hypertension in an Infant.

Hon KL, Cheung KL, Siu KL, Leung TF, Yam MC, Fok TF, Ng PC.

Department of Paediatrics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, China.

We report the use of oral sildenafil in a 5-month-old preterm infant with severe bronchopulmonary dysplasia and pulmonary arterial hypertension refractory to inhaled nitric oxide treatment, maximal ventilatory support and conventional vasodilator therapy. Sildenafil was prepared as a liquid suspension by the method of trituration and administered via an orogastric tube to the patient. Forty-eight hours after sildenafil treatment, echocardiography revealed that the tricuspid incompetence was substantially diminished and the contractility of both ventricles improved, indicating a marked reduction in pulmonary arterial pressure. Oral sildenafil treatment was continued for 6 months until complete resolution of pulmonary arterial hypertension, and oxygen supplement was weaned off. There was no adverse effect during the treatment period. Oral sildenafil may be useful in reducing pulmonary vascular resistance and can be considered for treatment of severe pulmonary arterial hypertension secondary to bronchopulmonary dysplasia. Copyright (c) 2005 S. Karger AG, Basel. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15870496&query_hl=1

Use of oral sildenafil in patients with irreversible pulmonary hypertension not eligible for heart transplantation.

Gomez-Moreno S, Lage E, Hernandez A, Campos A, Cabezon S, Ordonez A, Hinojosa R.

University Hospital Virgen del Rocio, Seville, Spain. silviagmoreno@hotmail.com

Heart transplantation is contraindicated in patients with acute irreversible pulmonary hypertension (PH), but new drugs are opening up therapeutic possibilities. Sildenafil citrate is a nonselective pulmonary vasodilator that is being used in our hospital to treat several patients with PH and which has allowed the inclusion of 1 patient on the waiting list for heart transplantation. A 20-year-old man with Becker muscular dystrophy was diagnosed at the age of 19 years with dilated cardiomyopathy with severe pulmonary artery systolic pressure (PH = 60 mm Hg). A pretransplantation study, including a right hemodynamic analysis with an acute vasodilator test using intravenous epoprostenol, revealed the irreversible character of the PH. Inasmuch as the administration of dobutamine did not achieve an adequate reduction of PH, oral sildenafil was started (25 mg every 12 hours) as salvage therapy. An echocardiogram obtained 2 months after starting sildenafil therapy showed normal right cavities, previously dilated, as well as minimal protosystolic tricuspid regurgitation without PH. A new right hemodynamic study performed after 4 months showed a reduction in pulmonary vascular resistance, from 8 U to 3.5 U Woods. As a result, the patient has now been included on the waiting list for heart transplantation. The promising example of this patient confirms the necessity to carry out controlled trials to establish definitively the indications for the use of sildenafil in patients with irreversible PH.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15866670&query_hl=1