Effects of prostaglandin E1 on pulmonary circulation in patients with pulmonary hypertension.

The effects of prostaglandin E1 on pulmonary circulation and left ventricular performance have been studied in 20 patients with mitral valve disease and pulmonary hypertension. Prostaglandin E1 was administered intravenously over a period of 30 minutes. The dose used was 0.01 microgram/kg per min during the first 15 minutes and 0.02 microgram/kg per min subsequently. The first dose led only to an insignificant fall in left ventricular end-diastolic pressure. Infusion of prostaglandin E1 in a dose of 0.02 microgram/kg per min resulted in a significant fall in the pulmonary arterial pressure (P less than 0.001), total pulmonary resistance (P less than 0.001), left ventricular end-diastolic pressure (P less than 0.001), and aortic pressure (P less than 0.01), and an increase in the pulmonary blood volume (P less than 0.01), cardiac index (P less than 0.01), and heart rate (P less than 0.05). No significant differences were noted in stroke volume index or left ventricular dP/dt at 50 mmHg after prostaglandin E1. These results indicate that exogenously administered prostaglandin E1 causes active vasodilatation of the pulmonary vascular bed and has no inotropic action on the cardiac muscle.     

Effect of prostaglandin E1 on pulmonary circulation in pulmonary atresia. A quantitative morphometric study.

The structural effect of prostaglandin E1 on the pulmonary circulation in pulmonary atresia has been studied by applying quantitative morphometric techniques to the injected and inflated lungs of eight babies who had received prostaglandin E1 for between 30 hours and 12 days. The most striking effect was on the pulmonary arterial smooth muscle. Relative arterial medial thickness was reduced and muscle did not extend as far along the arterial pathway as compared with the normal and with untreated cases of pulmonary atresia, dying at a similar age. The reduction in muscularity tended to increase the longer the duration of infusion. In all cases the thin arterial media was less compact than normal, and localised aneurysmal dilatations occurred, varying in extent and severity between cases. The preacinar arteries were dilated in comparison with the untreated cases, but, by contrast, the intra-acinar arteries remained abnormally small. The number of intra-acinar arteries per unit area of lung was greater in prostaglandin E1 treated than in untreated cases. Infusion of prostaglandin E1 is now the ideal emergency treatment for pulmonary atresia, but the findings in the present study suggest that it should be given for as short a time as possible before the pulmonary blood flow is increased by surgical treatment.     

Renal prostaglandin E2 biosynthesis: Dependence on angiotensin II

To study the interaction of the prohypertensive renin-angiotensin axis with the antihypertensive renal prostaglandins, angiotensin-converting enzyme inhibition (captopril and teprotide) and angiotensin blockade (Sar¹-lle⁸-All) were produced in rabbits in vivo and renal slice prostaglandin E₂ was measured in vitro after 30 minutes of incubation in Krebs-Ringer HCO^?₃ buffer. In rabbits with angiotensin-converting enzyme inhibition, de novo prostaglandin E₂ synthesis decreased in cortical, outer medullary and papillary slices by 85, 52 and 47 percent, respectively. Similar degrees of inhibition were observed with angiotensin blockade. It is concluded that renal prostaglandin E₂ synthesis is angiotensin II dependent under these conditions. This finding suggests that any increase in the prohypertensive antinatriuretic renin-angiotensin axis may be associated with a secondary increase in renal prostaglandin E₂ which may be acting in an antihypertensive natriuretic compensatory fashion.     

Pulmonary arterial structure in pulmonary atresia after prostaglandin E2 administration.

Administration of long-term, oral prostaglandin E2 in two babies with pulmonary atresia did not appear to influence pulmonary arterial smooth muscle development, nor was there evidence of damage to the vessel walls, as has previously been reported after treatment of the same condition with prostaglandin E1.     

Measurement of splanchnic circulation in dogs: changes induced by prostaglandin E1

In seven anesthetized dogs the effects of intravenously administered prostaglandin E1 on mesenteric arterial and portal venous blood flows and pancreatic capillary blood flow were measured with a transit-time ultrasonic volume flowmeter and a laser Doppler flowmeter. Basal blood flow of the superior mesenteric artery and of the portal vein were 5.7 +/- 0.6 and 11.2 +/- 1.0 ml/min/kg, respectively. Prostaglandin E1 caused a dose-dependent increase in these blood flows. The maximal effect was observed at a dose of 1.0 microgram/kg, when the superior mesenteric arterial blood flow increased 117.9 +/- 3.2% and the portal venous blood flow increased 99.4 +/- 1.7%. Prostaglandin E1 produced an initial rapid increase, followed by a decrease in pancreatic capillary blood flow. The results indicate that the flowmeters used in the present study are widely available for the study of splanchnic circulation and may have a possibility for clinical application.     

前列腺素E1对先心病重度肺动脉高压患者肺组织结构的影响

选择 2 8例先心病重度肺动脉高压患者 ,在应用前列腺素 E1 (PGE1 )前后行肺组织活检术 ,光镜下观察肺小动脉组织结构及其变化特点。用法 :PGE1 15～ 2 5 ng/ (kg·min)持续静滴 ,每天用药 10～ 12 h,14 d为 1疗程。结果示有 2 6例患者的肺组织结构明显改善 ,病理损害减轻 ,其他 2例无变化。认为应用 PGE1 治疗能够改善肺组织结构 ,使病情减轻 ,且能提高手术治愈率     

Epidermal growth factor augments reactivity to angiotensin II in the rat pulmonary circulation

To determine if epidermal growth factor (EGF), a vascular smooth muscle mitogen exhibiting systemic vasoactivity, causes constriction or dilation of the pulmonary vascular bed, this study evaluated the actions of EGF in isolated, buffer-perfused rat lungs and in isolated rat pulmonary arteries. In perfused rat lungs with baseline vasomotor tone, EGF administered at bolus doses of 10(-9) to 3 x 10(-7) M failed to exert either constrictor or dilator actions or to promote edema formation as evidenced by a constant lung wet-to-dry-weight ratio. Elevation of baseline tone with either prostaglandin (PG)F2 alpha or angiotensin II also failed to unmask an effect of EGF on pulmonary vascular resistance. In contrast to these negative observations, pretreatment with 5 x 10(-8) M EGF consistently augmented pressor responses evoked by angiotensin II. Constrictor responses to potassium chloride and to PGF2 alpha were unaffected by EGF pretreatment. In isolated rat extrapulmonary arteries, EGF provoked contraction in 40% of the preparations studied. Responsive vessels exhibited maximal EGF-induced contractions that were approximately 25% of that associated with angiotensin II and were characterized by an ED50 of 7 x 10(-8) M. Relaxant activity of EGF could not be demonstrated in isolated arterial preparations with normal resting tone or with tone elevated by addition of norepinephrine to the tissue bath. Endothelial denudation also failed to unmask contractile or relaxant effects of EGF. Similar to its actions in isolated, perfused rat lungs, EGF potentiated contractions of isolated pulmonary arteries induced by angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of angiotensin II in renal prostaglandin E2 production after furosemide administration

The role of plasma angiotensin II (Ang II) in furosemide-stimulated renal prostaglandin E2 (PGE2) production was evaluated in eight healthy subjects. Urine was collected for 60 minutes after furosemide administration (20 mg i.v.) with or without captopril pretreatment, and urinary excretion of PGE2, sodium, and furosemide was determined. Plasma renin activity (PRA) and Ang II were also measured before and 60 minutes after furosemide administration. Urinary PGE2 excretion, PRA, and Ang II increased after furosemide administration without captopril pretreatment, and there was a significant correlation between the increment in Ang II and that in urinary PGE2 excretion. Urinary PGE2 excretion and Ang II did not increase after furosemide administration with captopril pretreatment. Urine volume and urinary excretion of sodium and furosemide were not influenced by captopril pretreatment. These results suggest that Ang II may play an important role in furosemide-stimulated PGE2 production.     

The pulmonary circulation and its systemic arterial supply in pulmonary atresia

The pulmonary circulation and its systemic arterial supply in cases of pulmonary atresia were studied angiocardiographically. In 69% of the cases the pulmonary arteries were hypoplastic and supplied by a patent ductus arteriosus or a few large systemic arteries. A classification into four groups is suggested, and a developmental paradox represented by this classification is discussed.     

Comparison of effects of aspirin and indomethacin on human platelet prostaglandin synthetase.

Human platelets were incubated in vitro with either aspirin or indomethacin and the prostaglandin synthetase activity of the resultant microsomal fraction from each incubation measured using a radiometric technique. Whereas aspirin produced a dose-related inhibition of the enzyme, indomethacin produced little or no inhibition over the same concentration range (10(-6) mol/l--10(-3) mol/l). Furthermore, administration of aspirin (600 mg) to volunteers produced a highly significant, prolonged inhibition of platelet microsomal prostaglandin synthetase whereas no inhibition was found with indomethacin (50 mg). As indomethacin is considerably more potent than aspirin as an inhibitor of human platelet prostaglandin synthetase in vitro, the results suggest a fundamental difference in the nature of the inhibition produced by each drug, aspirin being an essentially irreversible inhibitor whereas the inhibition produced by indomethacin is reversible. Studies with [3H-acetyl] aspirin have confirmed previous findings (Roth and Majerus, 1975) that aspirin produces an irreversible acetylation of a particulate fraction protein from human platelets.     

Cyclooxygenase inhibition and effects of hypoxia on pulmonary circulation and gas exchange in anesthetized dogs

To investigate whether endogenously produced prostanoids are involved in hypoxic pulmonary vasoconstriction, pulmonary hemodynamic and gas exchange parameters and eicosanoid metabolites were measured in 5 anesthetized, artificially ventilated dogs (mean body weight 27 kg). Hypoxia elicited pulmonary vasoconstriction, but blood plasma levels of thromboxane B₂ (TXB₂) and 6-keto-prostaglandin F_1α (6kPGF_1α) (stable metabolites of TXA₂ and prostaglandin I₂, respectively) remained unchanged. Administration of the cyclooxygenase inhibitor indomethacin blocked the synthesis of prostanoids, so that 6kPGF_1α and TXB₂ levels decreased to values below the detection level (10 pg·ml⁻¹) both during normoxia or hypoxia, but did not affect pulmonary vascular resistance or the alveolar-arterial P_O2 difference (Pai - Pa)_O2. The pulmonary vascular bed remained, however, responsive to TXA₂ as evidenced by infusion of the TXA₂ mimetic, U 46619, which significantly increased the pulmonary vascular resistance and (Pai - Pa)_O2. Our data suggest that prostanoids are not involved in eliciting the effects of hypoxia on pulmonary hemodynamics and gas exchange efficiency.     

The cGMP-specific phosphodiesterase inhibitor E4021 dilates the pulmonary circulation.

We investigated the pulmonary vascular effects of E4021, a potent inhibitor of cGMP-specific phosphodiesterase, in control late-gestation fetal lambs, and in newborn lambs with persistent pulmonary hypertension (PPHN) after prenatal ligation of the ductus arteriosus. E4021 alone significantly relaxed fifth-generation pulmonary arteries isolated from control fetal lambs, an effect completely blocked after inhibition of nitric oxide synthase (NOS). In contrast, E4021 did not relax pulmonary arteries isolated from hypertensive lambs. Pretreatment with E4021 (10(-7) M) significantly enhanced relaxations to the NO donor S-nitrosyl-acetyl-penicilamine (SNAP) in arteries from both control and hypertensive lambs. In control, fully instrumented fetal lambs, infusions of E4021 (31 microgram/min) selectively dilated the pulmonary circulation, an effect again blocked after inhibition of NO synthase. Further studies were performed in newborn lambs with PPHN to study the vascular effects of E4021 alone, and in combination with inhaled NO. E4021 alone (1 to 100 microgram/kg/min) decreased pulmonary artery pressure (Ppa) in a dose-dependent fashion, and had minimal effect on systemic pressure. At the highest dose (100 microgram/kg/min), the dilation was selective for the pulmonary circulation. In subsequent protocols, E4021 (10 microgram/kg/min) significantly decreased Ppa and pulmonary vascular resistance (PVR), but these pulmonary vascular effects were not enhanced after NO inhalation at 0.5 or 5 ppm. We speculate that the lack of enhancement was due to the dramatic effects of E4021 alone. Potent, specific phosphodiesterase inhibitors such as E4021 may prove to be useful in the treatment of PPHN.