Prostacyclin and thromboxane in gynecology and obstetrics

Ylikorkala, Olavi; Mäkilä, U.-M.

doi:10.1016/s0002-9378(85)80221-0

Cited by 160 publications

(39 citation statements)

References 127 publications

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“…22 The data available at this point, however, are discordant. 23 A marked alteration occurred in urinary excretion of vasodilator compounds in PIH. Renal kallikrein, PGEj, and 6-keto-PGF Ia were significantly reduced as compared with levels in normotensive pregnancy, though urinary 6-keto-PGF la was still higher than in nonpregnant women.…”

Section: Discussionmentioning

confidence: 99%

Altered excretion of prostaglandin and thromboxane metabolites in pregnancy-induced hypertension.

et al. 1988

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SUMMARY The renal and systemic metabolites (the latter as 2,3-dinor derivatives) of prostacyclin and thromboxane A 2 were measured, along with renal prostaglandin E 2 and kallikrein, in the urine of 15 patients with pregnancy-induced hypertension, 15 normotensive pregnant women matched for both age and gestational age, and 15 normotensive nonpregnant control women. Urinary excretion of all prostaglandin and thromboxane metabolites studied proved significantly higher in normotensive pregnant women than in controls. Prostaglandin E 2 , 6-keto-prostaglandin F lcr , and 2,3-dinor-6-ketoprostaglandin F, a were significantly lower in pregnancy-induced hypertensive women than in normotensive pregnant women, whereas thromboxane B 2 and 2,3-dinor-thromboxane B 2 showed no significant differences in the two groups. A significant negative correlation (r = -0.636, p< 0.01) was found between urinary 2,3-dinor-6-keto-prostaglandin F, a and mean blood pressure in the two groups of pregnant women taken as a whole. These data indicate that, in pregnancy-induced hypertension, there is an imbalance between vasodilator and vasoconstrictor factors, not only in the kidneys, but also at the systemic vascular level. This imbalance, which may in itself produce vasoconstriction, may also potentiate the hypertensive effect of catecholamines and angiotensin II. is defined as systemic arterial hypertension (diastolic blood pressure > 85 mm Hg or mean blood pressure > 9 5 mm Hg) appearing in the third trimester of pregnancy, often associated with edema and proteinuria.' A number of hypotheses have been advanced regarding the pathogenesis of PIH, but the ultimate mechanism responsible for blood pressure elevation is still unknown. PIH has been attributed to one or more of the following factors: impaired renal function, 2 inappropriate activation of the renin-angiotensin-aldosterone system, 3 and decreased production of progestational compounds. 4 By acting as vasodilators and natriuretic factors, prostaglandin E 2 (PGE 2 ) and kinins might in some way be involved in the regulation of plasma volume. 9 -l0 Vasodilator prostaglandins, particularly prostacyclin (PGI 2 ), appear to play an important role in the control of vascular reactivity, platelet aggregability, and renal and uteroplacental blood flow during normal pregnancy, whereas thromboxane A 2 (TXA 2 ) is known to have the opposite effect." An imbalance between these two compounds might account for some of the phenomena characterizing PIH. On the basis of these observations, then, the renal prostaglandin system appears to be somehow involved in the sequence of events leading to the full clinical development of PIH. Since renal involvement in PIH is not enough in itself to account for systemic hypertension, the aim of our study was to evaluate not only the urinary excretion of PGE 2 , kallikrein, and the renal metabolites of PGI 2 and TXA 2 , but also the 2,3-dinor metabolites of PGI 2 and TXA 2 deriving from the systemic production

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Section: Discussionmentioning

confidence: 99%

Altered excretion of prostaglandin and thromboxane metabolites in pregnancy-induced hypertension.

et al. 1988

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“…They could be understood causally by similar mechanisms. Sulotroban is a selective antagonist of TXA2, but also of prostaglandin F2a (Stegmeier et al, 1984), which controls the perfusion of the uterine mucosa in equilibrium with prostaglandin E2 (Chan 1983;Ylikorkala & Makila, 1985). An excess of prostaglandin E2 caused by sulotroban could lead to diapedetic haemorrhages if the platelet function dependent on TXA2 is simultaneously blocked.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of the thromboxane A2 receptor antagonist sulotroban (BM 13.177) in renal failure.

Piper¹,

Staiger²,

Jumeau-Ziemendorff³

et al. 1989

Brit J Clinical Pharma

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1 Ten healthy volunteers and 26 hospital in-patients with endogenous creatinine clearances of 98 to 4 ml min-' received an oral dose of 800 mg sulotroban (BM 13.177). The plasma and urine concentrations of sulotroban were measured by gas-chromatography over 72 h and the pharmacokinetic parameters were calculated. 2 The AUC rose from 28.5 mg 1-1 h in healthy volunteers to 631.4 mg 1-1 h in preterminal renal failure (medians). The CLR decreased from 317.0 ml min-' to 6.5 ml min'1 at the lowest renal capacity.3 According to the AUC values, reduction of the dose is not necessary at CLCr > 50 ml min-', a dose of 20-40% of normal is appropriate at CLCr of 20-50 ml min-'. At CLCr ' 20 ml min-' the normal dose should be reduced to < 20% of normal.4 Vaginal spotting was noted in three female patients and a gastro-intestinal haemorrhage that did not require transfusion in one male patient. These may be associated with the action of sulotroban.

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“…The discovery that thromboxane A2 (TXA2) has physiologic effects opposite those of PG12 has led to the hypothesis that the concentration of PGI2 relative to the concentration of TXA2 is lower in preeclamptic than in normal pregnancies (15)(16)(17)(18). This hypothesis has received some indirect support from studies that have sought to increase the ratio of PG12 to TXA2 by PGI2 infusion (19)(20)(21) or preferential inhibition (22,23) of TXA2 synthesis by aspirin (16) or by other nonsteroidal antiinflammatory agents (23). In both a retrospective study (24) and randomized, double-blind trial (16), investigators observed that pregnant individuals who took aspirin developed hypertension and proteinuria less frequently than those who did not.…”

Section: Introductionmentioning

confidence: 99%

In vitro activity of nicotinamide adenine dinucleotide- and nicotinamide adenine dinucleotide phosphate-linked 15-hydroxyprostaglandin dehydrogenases in placentas from normotensive and preeclamptic/eclamptic pregnancies.

Jarabak¹,

Watkins²,

Lindheimer³

1987

J. Clin. Invest.

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Concentrations of prostaglandins E2 and I2 may be decreased in preeclamptic and eclamptic pregnancies. Because these prostaglandins produce vasodilation and inhibit platelet aggregation it has been suggested that a reduction in their biosynthesis might play an important role in the pathogenesis of the hypertension and coagulation abnormalities associated with preeclampsia. Placental tissue is an extremely rich source of several enzymes that catalyze the catabolism of prostaglandins. The present study was initiated to determine whether one of these catabolic enzymes might be increased in preeclamptic/ eclamptic pregnancies. The activities of the NAD-and the NADP-linked 15-hydroxyprostaglandin dehydrogenases were measured in 16 preeclamptics (mean diastolic pressure, 108±13 mmHg) and compared with 16 normotensive controls matched for age (20.8±5.43 vs. 20.6±5.16) and gestational week of delivery (34.6±5.40 vs. 35.0±5.06). These results indicate that the activity of the placental NAD-linked 15-hydroxyprostaglandin dehydrogenase is elevated in preeclampsia (40.1±31.3 vs. 14.9±8.30 mU/g tissue, P < 0.01). If this increase were also expressed in vivo, its effect on prostaglandin metabolism could be mistaken for impaired prostacyclin biosynthesis unless both the 6-keto-and 6,15-diketo-metabolites of prostacyclin were measured.

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Prostacyclin and thromboxane in gynecology and obstetrics

Cited by 160 publications

References 127 publications

Altered excretion of prostaglandin and thromboxane metabolites in pregnancy-induced hypertension.

Altered excretion of prostaglandin and thromboxane metabolites in pregnancy-induced hypertension.

Pharmacokinetics of the thromboxane A2 receptor antagonist sulotroban (BM 13.177) in renal failure.

In vitro activity of nicotinamide adenine dinucleotide- and nicotinamide adenine dinucleotide phosphate-linked 15-hydroxyprostaglandin dehydrogenases in placentas from normotensive and preeclamptic/eclamptic pregnancies.

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