Urinary prostaglandins and renal function in chronic liver diseases

Changes in urinary PGE2 and PGF2 alpha excretion in chronic liver diseases were observed in relation to renal hemodynamics and sodium balance. After equilibration on a 110-170-meq sodium diet, daily urine collections were analyzed for PGE2 and PGF2 alpha by a new extraction and radioimmunoassay method. PGE2 was significantly greater in cirrhotics than in healthy subjects and in chronic hepatitis. The value was greater in cirrhotics with ascites than in those without ascites (p less than 0.05). PGF2 alpha did not differ among the groups. In cirrhotics PGE2 was correlated negatively with creatinine clearance (Ccr)(r = -0.76, p less than 0.001). After administration of 200 mg indomethacin, a significant fall in Ccr was seen only in cirrhotics with ascites. The percentage fall in PGE2 after indomethacin correlated with that in Ccr (r = 0.89, p less than 0.05) and with that in urinary sodium excretion (r = 0.68, p less than 0.02). These results suggest that PGE2 is essential in the maintenance of renal function in liver cirrhosis with ascites.     

Regulation of eicosanoid production in rabbit colon by interleukin-1

Prostaglandins and thromboxanes are increased in human and experimental colitis, but the factors that regulate this enhanced production are unclear. The present studies evaluate the effects of the monokines, interleukin-1 alpha and beta on eicosanoid production in rabbit colon. In tissue incubations the peak dose response of eicosanoid release to human recombinant interleukin-1 is 50 ng/ml. Interleukin-1 alpha increases prostaglandin E2 (PGE2) by 4.5 +/- 1.9 ng/g tissue, 6-keto PGF1 alpha by 6.2 +/- 2.7 ng/g, and thromboxane B2 by 2.1 +/- 0.3 ng/g compared to placebo. In isolated rabbit colons perfused with Krebs' solution, 10-h infusion of interleukin-1 alpha (50 ng/ml) progressively increases production of PGE2, 6-keto PGF1 alpha, and thromboxane B2. Bolus injections of bradykinin increase production of PGE2, but not 6-keto PGF1 alpha and thromboxane B2, and these responses are markedly augmented by interleukin-1 alpha: at 10 h bradykinin-stimulated PGE2 production is 518 +/- 104 vs. 95 +/- 18 ng/5 min (p less than 0.005), 6-keto PGF1 alpha is 172 +/- 88 vs. 8 +/- 2 ng/5 min (p less than 0.02), and thromboxane B2 is 60 +/- 14 vs. 13 +/- 4 ng/5 min (p less than 0.02) for interleukin-treated colons vs. placebo-treated colons, respectively. The response is greater with interleukin-1 alpha than interleukin-1 beta. This study demonstrates that interleukin-1 stimulates prostaglandin and thromboxane production in normal colon tissue. These data are consistent with the concept that interleukin-1 production by inflammatory cells may augment prostaglandin and thromboxane production in colitis.     

Liposyn infusion increases plasma prostaglandin concentrations

To determine whether Liposyn infusion results in increased plasma prostaglandin (PG) concentrations, the following study was performed in 33 adult rabbits with chronically implanted arterial and venous catheters. Plasma PG concentrations were determined by radioimmunoassay for two vasodilators, PGE2 and PGI2 (as measured by its metabolite 6-keto-PGF1 alpha), and two vasoconstrictors, thromboxane (TX) A2 and PGF2 alpha, as measured by their metabolites TXB2 and PGF2 alpha-M, respectively. A 1-hour infusion of Liposyn at 4 ml per kg resulted in statistically significant increases in arterial and venous concentrations of PGE2 and 6-keto-PGF1 alpha (p less than 0.001) and of TXB2 (p less than 0.04). There were no significant changes in PGF2 alpha-M plasma concentrations. Liposyn infusion also resulted in a small but statistically significant increase in PaO2 of 4.7 +/- 1.5 torr (p less than 0.01). It is concluded that Liposyn infusion results in statistically significant increases in plasma concentrations of PGE2, 6-keto-PGF1 alpha, and TXB2.     

The effects of hog pancreatic kallikrein on the plasma kinins-prostaglandins and renin-angiotensin-aldosterone systems

Recently several reports have been presented stating that glandular kallikrein is present in human and animal blood, and that the oral administration of hog pancreatic kallikrein (HPK) normalises decreased urinary kallikrein and prostaglandin E2 (PGE2) excretions and elevated blood pressure in hypertensive patients. In this study, HPK (2,000 KU/kg body weight) was intramuscularly injected into male rabbits, and several hormones (plasma kinins, plasma PGE, plasma 6-keto PGF1 alpha, plasma thromboxane B2 (TXB2), plasma renin activity (PRA), plasma aldosterone, plasma ACTH) were measured before and after HPK administration in order to clarify the role of glandular kallikrein in the blood. Plasma kinins concentrations were significantly increased (the mean baseline level: 1 +/- 1 pg/ml (mean +/- S.E.), 30 min: 230 +/- 22 (p less than 0.001), 60 min: 288 +/- 36 (p less than 0.001), and 120 min: 130 +/- 9 (p less than 0.001] after HPK administration. Plasma levels of PGE were slightly increased after HPK administration, but the change was not significant as compared with the mean baseline level. Plasma levels of 6-keto PGF1 alpha were significantly increased from the mean baseline level of 229 +/- 38 pg/ml to 594 +/- 131 (p less than 0.05) at 30 min and to 378 +/- 67 (p less than 0.01) at 60 min but were decreased to 278 +/- 37 at 120 min after HPK administration. On the other hand, the changes in plasma TXB2, aldosterone and ACTH concentrations, and PRA were not significant before and after HPK administration. From the present study, it was clarified that the exogenous intramuscular administration of HPK increased plasma levels of kinins and PGI2, but induced no elevation in plasma levels of other hormones including PRA. Therefore, it was concluded in this acute experiment that there was a close relationship between the kallikrein-kinin system and PGs.     

Thromboxane B2, 6-keto-PGF1 alpha, PGE2, PGF2 alpha, and PGA1 plasma levels in arteriosclerosis obliterans: relationship to clinical manifestations, risk factors, and arterial pathoanatomy

Current concepts of atherogenesis based on animal and human investigations indicate prostaglandins as a key factor in atherosclerotic lesions. The plasma profiles of thromboxane B2 (TXB2), 6-keto-PGF1 alpha, PGE2, PGF2 alpha, and PGA1 were investigated by means of a sensitive radioimmunoassay technique in 40 patients with arteriosclerosis obliterans and in 30 healthy control subjects. Abnormally high levels of TXB2 and PGE2 (222.97 +/- 320.86 pg/ml, mean +/- SD, vs 20 +/- 2.1 and 352.66 +/- 235.54 vs 24.4 +/- 3, p less than 0.01) were detected in arteriosclerosis obliterans patients. The ratio between TXB2 and 6-keto-PGF1 alpha was increased from 1.2 in control subjects to 6.0 in patients. In arteriosclerosis obliterans TXB2 increased in relation to clinical manifestations and to the extension of the vascular damage. In addition, TXB2 was positively related to serum triglyceride content (r = 0.562, p less than 0.05) and inversely related to platelet count (r = 0.727, p less than 0.001). The marked imbalance between the stable metabolites of thromboxane and prostacyclin in arteriosclerosis obliterans patients provides biologic evidence which fits well with the thrombogenic theory of atherosclerosis. These results further support the theory that prostaglandins may be heavily involved in atherosclerosis.     

Endogenous prostaglandin E2 metabolite levels, renin-angiotensin system and catecholamines versus acute hemodynamic response to captopril in chronic congestive heart failure

Hemodynamic and hormonal responses to captopril were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25-mg dose, stroke volume (SV) increased from 53 +/- 7 to 63 +/- 9 ml (p less than 0.05), while pulmonary wedge pressure (PWP) decreased from 20 +/- 2 to 14 +/- 2 mm Hg (p less than 0.01). The hemodynamic changes were associated with increases in plasma renin activity (PRA; p less than 0.05) and in plasma levels of a novel bicyclo-prostaglandin E2 metabolite (bicyclo-PGE-m; p less than 0.01), whereas norepinephrine (NE) showed a falling tendency. In general, basal hemodynamic and basal hormonal levels did not correlate. Captopril-induced changes in mean artery pressure (MAP) and mean pulmonary artery pressure (mPAP) were positively correlated to pre-captopril PRA (r = 0.74, p less than 0.01; r = 0.64, p less than 0.05) and to changes in PRA (r = 0.85, p less than 0.01; r = 0.80, p less than 0.01) with a similar trend for angiotensin II (AII); decreases of systemic vascular resistance were more pronounced in patients with higher control NE levels (r = 0.62, p less than 0.05), the reduction of NE levels being highest in patients with higher basal concentrations (p less than 0.001); the captopril-induced decreases of mPAP and PWP were inversely related to basal bicyclo-PGE-m levels (r = 0.60, p less than 0.05; r = 0.61, p less than 0.05), and changes in mPAP were closely related to basal ratios of AII/bicyclo-PGE-m (r = 0.67, p less than 0.01). Thus, captopril exerts its acute beneficial hemodynamic effect by inhibiting the generation of AII, associated with toning down of sympathetic stimulation and increased production of vasodilating prostaglandins, such as PGE2. The relation between AII and PGE2-counteracting substances-might determine the hemodynamic response to captopril in the patients.     

Absence of prostacyclin involvement in angiotensin-induced aldosterone secretion in rat adrenal cells

The role of prostaglandins (PGs) in aldosterone secretion was studied in isolated rat adrenal glomerulosa cells. [14C]Arachidonic acid was metabolized to [14C]6-keto-PGF1 alpha, [14C]PGF2 alpha, [14C]PGE2, and [14C]PGD2. Pretreatment with indomethacin (5 X 10(-5) M) or U-51605 (5 micrograms/ml) inhibited the synthesis of these metabolites. Angiotensin II (AII) stimulated a concentration-related release of aldosterone and 6-keto-PGF1 alpha, but not PGE2. Significant increases in aldosterone and 6-keto-PGF1 alpha occurred at AII concentrations of 0.2 and 2 nM. The increases in 6-keto PGF1 alpha concentrations after AII treatment were small, however (278 +/- 33 pg/10(6) cells X h for control vs. 581 +/- 90 after 2 nM AII). At higher concentrations, AII further stimulated aldosterone, but 6-keto PGF1 alpha levels declined. AII stimulated the synthesis of aldosterone and 6-keto PGF1 alpha in parallel with time of incubation. Indomethacin (3 microM) decrease basal and AII-stimulated aldosterone release by 40% and 23%, respectively, and inhibited the synthesis of PGs. U-51605 (5 micrograms/ml) failed to alter aldosterone release. Arachidonic acid increased the synthesis of PGE2 and 6-keto-PGF1 alpha in a concentration-related manner without altering the synthesis of aldosterone. In contrast, PGH2 stimulated the release of PGE2, 6-keto-PGF1 alpha, and aldosterone. PGI2 and PGE2 stimulated aldosterone secretion, which was concentration related. Threshold stimulation by PGI2 and PGE2 occurred at 0.5 and 5 nM, respectively. Maximal stimulation occurred at 5 nM for PGI2 and at 5000 nM for PGE2, with PGE2 producing the greater maximal response. Treatment of the cells with trypsin eliminated the steroidogenic response to PGE2. These findings indicate that PGI2 and PGE2 are produced by the adrenal glomerulosa cells, and the synthesis of PGI2 may be stimulated by AII. However, the concentrations of PGI2 synthesized are not adequate to stimulate aldosterone secretion. Thus, PGI2 does not appear to mediate angiotensin-induced aldosterone secretion.     

Changes in cerebrovascular prostaglandins and thromboxane as a function of systemic blood pressure. Cerebral blood flow autoregulation of the newborn

Cerebrovascular concentrations of prostaglandin E (PGE), prostaglandin F2 alpha (PGF2 alpha), 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), and thromboxane B2 (TXB2) were determined over a blood pressure range of 17-117 mm Hg (induced by inflation of balloon-tipped catheters placed in the thoracic descending aorta and at the aortic root) in eight newborn piglets to access the role of prostanoids in cerebral blood flow (CBF; measured using radioactive microspheres) autoregulation. Basal systemic blood pressure, heart rate, blood gases, total CBF, and prostanoid concentrations were stable. CBF was constant between 50 and 90 mm Hg, but beyond this range CBF varied directly with blood pressure (tau = 0.48; p less than 0.05). Sagittal sinus concentrations of PGE, PGF2 alpha, and 6-keto-PGF1 alpha varied with blood pressure according to a quadratic function (R2 = 0.92 to 0.96; p less than 0.0001), exhibiting lowest values between mean blood pressures of 60 and 90 mm Hg. During hypotension (17-49 mm Hg), there was a greater relative increase in sagittal sinus concentrations of TXB2 than of PGE, PGF2 alpha, and 6-keto-PGF1 alpha; at the lowest blood pressures, TXB2 increased by 658 +/- 44%, and prostaglandins increased on the average by 331 +/- 49% (p less than 0.01) from their values during normotension (50-90 mm Hg). During hypertension (91-117 mm Hg), cerebrovascular production and concentrations of prostaglandins increased by 142 +/- 31% and 45 +/- 10%, respectively, but did not change for TXB2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sequential alterations in glomerular prostaglandin and thromboxane synthesis in diabetic rats: relationship to the hyperfiltration of early diabetes

The present study examined the role of enhanced production of prostaglandin (PG) E2 and 6-keto-PGF1a, the stable metabolite of PGI2, by glomeruli from streptozotocin diabetic rats in the mediation of hyperfiltration. Correlative measurements of insulin clearance (CIn) and glomerular production of PGE2, 6-keto PGF1a and thromboxane (TX) B2 (the stable metabolite of TXA2) were made at two time points, nine to 15 days and 25 to 28 days after streptozotocin. CIn was elevated by 40% to 50% in diabetic rats studied at nine to 15 or 25 to 28 days compared to values in age-matched controls. Basal production of PGE2, 6-keto PGF1a and TXA2 (as reflected by TXB2) and increases in response to A23187 were elevated in glomeruli from nine to 15-day diabetic rats compared to values in control glomeruli. Exogenous arachidonate abolished these differences. Treatment of nine-day diabetic rats with indomethacin (3 mg/kg/d) rapidly (within 24 hours) and reversibly suppressed CIn without altering CIn in control rats. Indomethacin had no effect on plasma glucose in control or diabetic rats. Treatment of nine to 15-day diabetic rats with insulin (10 U/kg/d by osmotic minipump) beginning 24 hours after streptozotocin lowered plasma glucose to values that were not significantly different from control and prevented the rise in CIn. Treatment of diabetic rats with insulin or incubation of glomeruli from untreated diabetic rats with insulin (0.3 mU/mL) for two hours in vitro reduced basal and A23187 induced increases in PGE2, 6-keto PGF1a, and TXB2 to values that were not different from those in control glomeruli.(ABSTRACT TRUNCATED AT 250 WORDS)     

Prostanoid concentrations in maternal/fetal plasma and amniotic fluid and intrauterine tissue prostanoid output in relation to myometrial contractility during the onset of adrenocorticotropin-induced preterm labor in sheep

Prostanoid [prostaglandin (PG)] concentrations were measured in ovine maternal and fetal plasma and amniotic fluid during the onset of preterm labor induced by the administration of a pulsatile infusion of ACTH-(1-24) (P-ACTH; 66.7 ng/min for 15 min every 2 h) to the fetus and in saline-infused controls. P-ACTH administration stimulated a change in intra-uterine pressure from type A-activity, characterized by sustained increases of low amplitude, to type B labor-like activity of short duration, high amplitude (greater than or equal to 10 mm Hg) increases which occurred between 12 and 8 h before the onset of labor. PGF2 alpha and/or PGFM (13,14-dihydro-15-keto PGF2 alpha) concentrations increased consistently in all fluids 16 h or earlier before labor. All PGs increased in fetal carotid arterial plasma (PGE2 greater than PGF2 alpha) and amniotic fluid, and the relative increases in each PG were similar. However, PGF2 alpha and PGFM selectively increased in maternal vena caval and aortic plasma, whereas smaller or negligible increases in the prostacyclin hydrolysis metabolite 6-keto PGF1 alpha (6KF) and PGE2 were noted. The output of PGs E2 and F2 alpha (picograms per 10(5) cells/8 h) increased 1.6- and 1.7-fold, respectively, by cells dispersed from the chorioallantois of P-ACTH-treated animals compared to that in control animals infused with saline for 100 h. From fetal cotyledons, these increases were 2.4-fold (P less than 0.05) and 3.6-fold, respectively. No significant changes occurred in 6-keto PGF1 alpha output from any tissue or PGE2 or PGF2 alpha output from amnion or maternal cotyledons. We conclude 1) that PGs increase in all fluids before the increase in uterine mechanical activity during induced preterm labor, implying that PGs mediate this event and are not a result thereof; 2) that syntheses of PGs E2 and F2 alpha increase similarly in intrauterine tissues with the onset of labor; and 3) that a selective increase in PGF2 alpha, a myometrial stimulatory PG, occurs exclusively in maternal plasma, suggesting that endoperoxide conversion to PGF2 alpha is specifically enhanced during parturition or suggesting the existence of an intrauterine tissue source of 9-keto PG reductase.     

Plasma norepinephrine and age as determinants of systemic hemodynamics in men with established essential hypertension

Two primary predictor variables, age and supine plasma norepinephrine, were studied with respect to their influences on supine hemodynamic variables in 52 white men with essential hypertension who were 23 to 67 years of age and had been off active therapy for at least 4 weeks. Plasma norepinephrine was related to age (r = 0.39, p less than 0.01), correlated closely with mean arterial pressure (MAP; r = 0.54, p less than 0.0002) and systemic vascular resistance (r = 0.49, p less than 0.0005), and was related inversely to cardiac output (r = -0.26, p less than 0.06) and stroke volume (r = -0.31, p less than 0.05). Age correlated weakly with MAP (r = 0.31, p less than 0.05) and more strongly with systemic vascular resistance (r = 0.46, p less than 0.005) but was negatively related to cardiac output (r = -0.41, p less than 0.005) and heart rate (r = -0.33, p less than 0.05). Weight did not correlate with any of the hemodynamic variables. Partial regression techniques yielded significant residual correlations between age-adjusted plasma norepinephrine and MAP (r = 0.42, p less than 0.005) or systemic vascular resistance (r = 0.38, p less than 0.005). Residual correlations with cardiac output (r = -0.34, p less than 0.05), heart rate (r = -0.36, p less than 0.02), and systemic vascular resistance (r = 0.33, p less than 0.05) remained after adjusting age for the corresponding plasma norepinephrine values. These correlations demonstrate the independent effects of sympathetic nervous activity and the aging process on the systemic vasoconstriction and decreased cardiac function observed in essential hypertension.     

Effect of single-dose aspirin on TXA2 and PGI2 cyclooxygenases in vivo

The present study investigated the sensitivities of the thromboxane A2 (TXA2) cyclooxygenase and the prostacyclin (PGI2) cyclooxygenase to aspirin using an in vivo animal model. In this model, arachidonic acid (AA) was administered to mice via cardiac puncture, and plasma levels of thromboxane B2 (TXB2) and 6-keto prostaglandin F1 alpha (6-keto PGF1 alpha) were determined. Infusion of AA (5, 10, 25 and 50 mg/kg) resulted in a dose-dependent increase in both TXB2 and 6-keto PGF1 alpha. Pretreatment with aspirin resulted in a dose-dependent and parallel decrease in TXB2 and 6-keto PGF1 alpha production. This nonselective inhibition occurred at all doses of aspirin (1, 10 and 50 mg/kg) and at all levels of cyclooxygenase activity (5-50 mg/kg AA). These results indicate that the TXA2 and PGI2 cyclooxygenase enzymes are equally sensitive to inhibition by a single dose of aspirin.     

尿中前列腺素变化在肾移植排异反应中的诊断价值

为了探讨肾移植术后尿中前列腺素的变化及其临床意义，我们测定了３４例肾移植术后患者、１６例尿毒症患者尿中前列腺素的变化。结果表明，尿中前列腺素的变化，尤其是ＴＸＢ２的变化是监测肾移植早期排异反应的较好指标。     

Coronary spasm, prostaglandin and HLA factors

To elucidate the contribution of prostanoids in coronary spasm, plasma levels of thromboxane B2 (TXB2) and 6-keto PGF1 alpha at the coronary sinus and ascending aorta in 21 patients with variant angina were measured, as compared with findings in 20 with effort angina and 13 subjects with normal coronaries. In the coronary sinus blood, plasma TXB2 in patients with effort angina exhibited statistically significant high levels, as compared with data in the controls. On the contrary, the data obtained from patients with variant angina were not statistically significant. However, eight patients whose coronary angiogram revealed more than 50% of coronary stenoses had statistically significant high levels of TXB2 and other patients with normal coronaries or less than 50% of narrowing showed almost the same levels of TXB2 as the controls. In contrast to TXB2, the plasma levels of 6-keto PGF1 alpha in patients with variant angina were very low in both groups with variant angina. These data suggest that high levels of TXB2 observed in patients with atherosclerotic coronaries may be an accelerating factor while low levels of prostacyclin may be an essential factor leading to spasm. HLA analysis of 23 patients with variant angina was performed to search for genetic factors, under the hypothesis that such may contribute to the low levels in prostacyclin. This preliminary study revealed statistically significant high frequencies of Bw52 and B-40 in the patients, as compared with frequencies among 152 normal Japanese. Genetic studies are ongoing in our clinic.     

Effect of the leukotriene receptor antagonist LY-171883 on endotoxemia in awake sheep

The effect of the leukotriene D4, leukotriene E4 (LTD4/E4) receptor antagonist LY-171883 was studied in endotoxemia. Eighteen awake sheep were divided into three groups. In Group (n = 4) 4 mg/kg LY-171883 was twice injected intravenously. In Group II (n = 9) 1 microgram/kg E. coli endotoxin was administered intravenously. In Group III (n = 5) 4 mg/kg LY-171883 was given 15 min before, and 30 min after endotoxin. Infusion of LY-171883 in Group I did not alter baseline hemodynamic and pulmonary measurements. Infusion of endotoxin in Group II was followed by an initial rise of pulmonary artery pressure (PAP) to 51 torr (P less than 0.001), pulmonary microvascular pressure (Pmv) to 25 torr (P less than 0.005), pulmonary vascular resistance (PVR) to 1,019 dynes sec. cm-5 (P less than 0.001), systemic vascular resistance (SVR) to 2,830 dynes sec. cm-5 (P less than 0.001), plasma thromboxane B2 (TXB2) to 4,971 pg/ml (P less than 0.001), lymph TXB2 to 5,500 pg/ml (P less than 0.001), plasma 6-Keto PGF1 alpha to 1,469 pg/ml (P less than 0.005), and lymph 6-Keto PGF1 alpha to 2,518 pg/ml (P less than 0.005). The cardiac index (CI) fell to 100 ml/min. kg (P less than 0.01), PaO2 to 61 torr (P less than 0.01), and circulating WBC to 2,800 microliter (P less than 0.001). This was followed by a rise in pulmonary lymph flow (QL) to 35 ml/h (P less than 0.01) and lymph protein clearance (L/P.QL) to 23 ml/h (P less than 0.01). Pretreatment with LY-171883 in Group III resulted in rise of PAP to 35 torr (P less than 0.005), PmV to 18 torr (P less than 0.05), PVR to 398 dynes sec. cm-5 (P less than 0.01), SVR to 1,732 dynes sec. cm-5 (P less than 0.05), and CI increased to 170 ml/min.kg (P less than 0.005). L/P.QL, QL, Hgb, WBC, PaO2, PaCO2, Qs/QT, plasma and lymph TXB2, and plasma and lymph 6-Keto PGF1 alpha were not significantly changed by LY-171883. It is concluded that LY-171883 inhibited the smooth muscle effects of endotoxin, namely reduced PAP, Pmv, PVR, and SVR and increased cardiac output. Hypoxemia and increased pulmonary vascular permeability were unaffected by this leukotriene receptor antagonist.     

Concentrations of prostaglandins in plasma, seminal vesicles, and ovaries of aging C57BL/6NNia mice

Concentrations of prostaglandin E1 (PGE1), and prostaglandin E2 (PGE2) (combined in the same radioimmunoassay) and prostaglandin F2 alpha (PGF2 alpha) were analyzed in circulating plasma and seminal vesicles of 3- and 26 to 27-month-old males and in circulating plasma and ovaries of 3-, 6-, 14 to 18- and 26 to 30-month-old female C57BL/6NNia mice. The amount of PGE declined in the plasma (P less than 0.05) and seminal vesicles (P less than 0.02) of aged male mice, whereas PGF2 alpha concentrations remained unchanged. There were no statistical differences in plasma or ovarian concentrations of PGE or PGF2 alpha when comparing the various age groups of female mice. It does not appear as if age-related changes in prostaglandins play a significant role in reproductive senescence.     

Lipoprotein and hepatic lipase activity and high-density lipoprotein subclasses after cardiac transplantation

Atherosclerosis is the leading obstacle to long-term survival in cardiac transplant patients. Increases in plasma triglycerides and lipoprotein cholesterol levels occur after transplantation that may contribute to transplant atherosclerosis. The etiology of this increase is unclear. We investigated the interaction of immunosuppressive medications with plasma triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, the HDL subclasses HDL2 and HDL3 cholesterol, and hepatic and lipoprotein lipase activity in 72 consecutive cardiac transplant patients compared to 51 healthy control subjects. In the transplantation group, greater concentrations of plasma triglyceride (80%, p less than 0.001), LDL cholesterol (16%, p less than 0.005) and hepatic lipase activity (100%, p less than 0.001) were noted, whereas lipoprotein lipase activity was noted to be significantly lower (124%, p less than 0.001). No difference was detected in HDL, HDL2, or HDL3 cholesterol. Cyclosporine dose was significantly associated with hepatic lipase activity (r = 0.33, p less than 0.02) and inversely associated with lipoprotein lipase activity (r = -0.28, p less than 0.05). Lipoprotein lipase activity after transplantation correlated inversely with triglycerides (r = -0.36, p less than 0.002) and positively with HDL cholesterol (r = 0.23, p less than 0.05) and HDL2 cholesterol (r = 0.29, p less than 0.05). Hepatic lipase activity correlated inversely with LDL cholesterol (r = -0.21, p less than 0.08). In multiple regression analysis, cyclosporine dose was the major source of variation in hepatic lipase activity.     

Contribution of vasopressin to vasoconstriction in patients with congestive heart failure: comparison with the renin-angiotensin system and the sympathetic nervous system

Ten patients with advanced congestive heart failure were treated with an arginine vasopressin V1 antagonist during hemodynamic monitoring to determine the contribution of vasopressin to vasoconstriction in this disorder. The vasopressin antagonist caused a decrease in systemic vascular resistance in the three patients whose plasma vasopressin was greater than 4.0 pg/ml (average for the group was 2.4 +/- 0.6). Plasma vasopressin concentration correlated with the percent decrease of systemic vascular resistance (r = 0.70, p less than 0.025), serum sodium (r = 0.72, p less than 0.02) and serum creatinine (r = 0.85, p less than 0.005). To compare the relative roles of vasopressin, the renin-angiotensin system and the sympathetic nervous system, these patients also received captopril and phentolamine. Captopril decreased systemic vascular resistance by 20% (p less than 0.05), mostly in patients with high plasma renin activity. Levels of plasma renin activity ranged between 1 and 46 ng/ml per h (average 14.7 +/- 5.7) and correlated with serum sodium (r = 0.77, p less than 0.025), serum creatinine (r = 0.73, p less than 0.025) and right atrial pressure (r = 0.67, p less than 0.05). Phentolamine decreased systemic vascular resistance in all patients (average 34%, p less than 0.01), but the decrease did not correlate with the pretreatment norepinephrine concentration. Norepinephrine levels were elevated in all patients (694 +/- 110 pg/ml) and correlated with baseline stroke volume index (r = 0.75, p less than 0.025) and plasma renin activity (r = 0.67, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute effects of captopril on cardiopulmonary hemodynamics and renin-angiotensin-aldosterone and bradykinin profile in hypertension

Hemodynamic variables were measured and plasma renin activity (PRA), angiotensin II (AII), aldosterone, and bradykinin assays performed in 21 hypertensive men on regular diet and thiazide diuretics before and 60 to 90 minutes after 25 mg oral captopril. Heart rate, right and left ventricular filling pressures, mean cardiac index (CI), and pulmonary vascular resistance (PVR) remained unchanged. The mean intra-arterial pressure (MAP) fell from 140 +/- 5 to 116 +/- 6 mm Hg (p less than 0.001) correlating with reduction of systemic vascular resistance (SVR) (r = 0.87, p less than 0.001), control PRA (r = 0.59, p less than 0.01), and All levels (r = 0.72, p less than 0.005) but not with control bradykinin or its postcaptopril rise (p less than 0.01). The fall in SVR correlated with reduction in plasma All (r = 0.80, p less than 0.001) and aldosterone concentrations (r = 0.53, p less than 0.05). Of four patients (19%) with precipitous fall in MAP after captopril, three needed volume expansion for circulatory support. We conclude: (1) All reduction by captpril and not bradykinin potentiation explains most of the agent's hemodynamic response in hypertensive circulation, (2) endogenous All may have a supportive role for SVR and possibly for CI but not for PVR, and (3) extra precaution is warranted while captopril is being started in patients taking diuretics.     

Antipyrine elimination as a dynamic test of hepatic functional integrity in obstructive jaundice.

Antipyrine elimination was studied in 29 patients with obstructive jaundice Antipyrine half-lives calculated using plasma concentrations at four and 24 hours ('short antipyrine test') were significantly correlated with those calculated using six time points (p less than 0.001). Mean antipyrine half-life was 28.3 +/- 8 hours (standard error) and was significantly longer than in normal subjects (p less than 0.001). Antipyrine half-life did not correlate with standard biochemical liver function tests, but correlated positively with the postoperative half-time for clearance of endogenous bilirubin (p less than 0.05), and negatively with hepatic cytochrome P-450 content measured in peroperative liver biopsies (p less than 0.05). Of six patients with antipyrine half-life greater than 20 hours, four died, one preoperatively of gastrointestinal haemorrhage and three postoperatively of sepsis. Serial short antipyrine tests were performed in 13 patients before and after biliary drainage. Those with an initial antipyrine half-life greater than 15 hours showed significant changes after drainage, while those with an antipyrine half-life less than 15 hours did not. The test of antipyrine half-life may aid in selecting high risk patients with obstructive jaundice for percutaneous biliary drainage before definitive surgery, and in determining the optimal time for such preliminary biliary decompression.