Pulmonary vascular effects of sildenafil on the development of chronic pulmonary hypertension in the ovine fetus.

We investigated the pulmonary vascular effects of prophylactic use of sildenafil, a specific phosphodiesterase-5 inhibitor, in late-gestation fetal lambs with chronic pulmonary hypertension. Fetal lambs were operated on at 129 +/- 1 days gestation (term = 147 days). Ductus arteriosus (DA) was compressed for 8 days to cause chronic pulmonary hypertension. Fetuses were treated with sildenafil (24 mg/day) or saline. Pulmonary vascular responses to increase in shear stress and in fetal PaO2 were studied at, respectively, day 4 and 6. Percent wall thickness of small pulmonary arteries (%WT) and the right ventricle-to-left ventricle plus septum ratio (RVH) were measured after completion of the study. In the control group, DA compression increased PA pressure (48 +/- 5 to 72 +/- 8 mmHg, P < 0.01) and pulmonary vascular resistance (PVR) (0.62 +/- 0.08 to 1.15 +/- 0.11 mmHg x ml(-1) x min(-1), P < 0.05). Similar increase in PAP was observed in the sildenafil group, but PVR did not change significantly (0.54 +/- 0.06 to 0.64 +/- 0.09 mmHg x ml(-1) x min(-1)). Acute DA compression, after brief decompression, elevated PVR 25% in controls and decreased PVR 35% in the sildenafil group. Increased fetal PaO2 did not change PVR in controls but decreased PVR 60% in the sildenafil group. %WT and RVH were not different between groups. Prophylactic sildenafil treatment prevents the rise in pulmonary vascular tone and altered vasoreactivity caused by DA compression in fetal lambs. These results support the hypothesis that elevated PDE5 activity is involved in the consequences of chronic pulmonary hypertension in the perinatal lung.

Effects of nociceptive stimuli on the pulmonary circulation in the ovine fetus.

The fetus is able to exhibit a stress response to painful events, and stress hormones have been shown to modulate pulmonary vascular tone. At birth, the increased level of stress hormones plays a significant role in the adaptation to postnatal life. We therefore hypothesized that pain may alter pulmonary circulation in the perinatal period. The hemodynamic response to subcutaneous injection of formalin, which is used in experimental studies as nociceptive stimulus, was evaluated in chronically prepared, fetal lambs. Fetal lambs were operated on at 128 days gestation. Catheters were placed into the ascending aorta, superior vena cava, and main pulmonary artery. An ultrasonic flow transducer was placed around the left pulmonary artery. Three subcutaneous catheters were placed in the lambs' limb. The hemodynamic responses to subcutaneous injection of formalin, to formalin after fetal analgesia by sufentanil, and to sufentanil alone were recorded. Cortisol and catecholamine concentrations were also measured. Pulmonary vascular resistances (PVR) increased by 42% (P < 0.0001) after formalin injection. Cortisol increased by 54% (P = 0.05). During sufentanil infusion, PVR did not change significantly after formalin. Cortisol increased by 56% (P < 0.05). PVR did not change during sufentanil infusion. Norepinephrine levels did not change during any of the protocols. Our results indicate that nociceptive stimuli may increase the pulmonary vascular tone. This response is not mediated by an increase in circulating catecholamine levels. Analgesia prevents this effect. We speculate that this pulmonary vascular response to nociceptive stimulation may explain some hypoxemic events observed in newborn infants during painful intensive care procedures.

Pulmonary vasodilator effects of norepinephrine during the development of chronic pulmonary hypertension in neonatal lambs.

BACKGROUND: This experimental study was performed to determine the effects of norepinephrine on: (i) the pulmonary vascular tone during the development of pulmonary hypertension (PH) in the fetus and (ii) the circulatory adaptation at birth after chronic intrauterine PH. METHODS: Chronically instrumented fetal lambs were randomized into two groups: (i) a group with PH obtained by antenatal partial ligation of the ductus arteriosus (DA) (n=9) and (ii) a control group without DA ligation (n=6). Pulmonary vascular responses to norepinephrine (1.5 microg min(-1)) were measured in utero 7 days after surgery. At day 8 post-surgery, after delivery, animals were ventilated for 3 h with oxygen 100%. The group with PH was randomly assigned to receive norepinephrine or saline. RESULTS: Mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR) were higher in the PH group (P<0.01). Norepinephrine-induced decrease in PVR was more pronounced in the PH group than in the control group (63 vs 35%, respectively; P<0.01). In the PH group, the decrease in PVR during mechanical ventilation was greater in the animals receiving norepinephrine than in the animal receiving saline (from 1.05 (0.12) to 0.1 (0.02) vs from 1.04 (0.1) to 0.2 (0.04) mm Hg ml(-1) min(-1), respectively; P<0.01). After 3 h of ventilation, mean PVR in the PH lambs treated by norepinephrine was similar to those measured in the control lambs. Aortic pressure was higher in the group treated with norepinephrine. CONCLUSION: The data suggest that norepinephrine may improve post-natal pulmonary adaptation in the newborn with persistent PH both by increasing systemic vascular pressure and by increasing pulmonary blood flow.

Accessibility of abciximab to megakaryocytes and endothelial cells in the bone marrow compartment: studies on a patient receiving antithrombotic therapy.

Abciximab, chimaeric Fab fragments of the monoclonal antibody 7E3 (c7E3 Fab), has achieved widespread use as an anti-platelet agent for blocking GP IIb-IIIa (alphaIIbbeta3) function and preventing ischaemic complications after coronary artery angioplasty. However, its accessibility to the bone marrow compartment during therapy is unknown, as is its ability to bind alphavbeta3 in vivo. Using electron microscopy and immunogold labelling, we have looked for abciximab in the bone marrow of a patient who became thrombocytopenic during treatment. The presence of abciximab was assessed on ultrathin frozen sections of a marrow aspirate, the drug being revealed by a rabbit antibody to c7E3 Fab. Labelling was maximal on fragmenting megakaryocytes (MK) and proplatelets in the vascular sinus and in direct access to the blood compartment. Not only the plasma membrane but also the demarcation membrane system (DMS) and the membranes of alpha-granules were labelled. Abciximab was also revealed on the luminal surface of endothelial cells lining the marrow sinuses, thereby confirming for the first time its ability to bind to alphavbeta3 in vivo. The study revealed no signs that abciximab had accumulated in the marrow.