Arginine vasopressin response to hypertonicity in hypertension studied by arginine vasopressin assay in unextracted plasma.

OBJECTIVE: To investigate whether plasma osmolality (Posm)-plasma arginine vasopressin (PAVP) response relationships with particular characteristics of sensitivity, gain or response pattern (linear/non-linear) occur more frequently in hypertensive than normotensive subjects. DESIGN: Analysis of Posm-PAVP curves observed in individual normotensive and hypertensive subjects rather than whole groups was considered appropriate for the described objective. METHODS: A sensitive and precise radioimmunoassay of PAVP in unextracted plasma was developed. Posm was raised in 11 normotensive and 19 hypertensive subjects by infusion of NaCl solution (0.86 mol/l, i.v.), and PAVP assayed at intervals. Best-fitting linear and non-linear equations for the Posm-PAVP relationship were established by computer. RESULTS: The mean rise in osmolality, blood pressure and blood volume was similar in the two groups. Hypertensive subjects showed a tendency towards higher rates of response (pmol AVP/l per mosm per kg) at Posm greater than 290 mosm/kg, leading to a non-linear response pattern compared with the normotensive subjects. CONCLUSIONS: The enhanced PAVP responses found in the hypertensive subjects at Posm greater than 290 mosm/kg may reinforce vascular and central nervous pathogenetic mechanisms.

The pathogenesis of the ovarian hyperstimulation syndrome (OHS): a possible role for ovarian renin.

Two patients with severe ovarian hyperstimulation syndrome are described. Increased plasma concentrations of immunoradiometrically determined total renin are shown, together with greatly increased plasma levels of active renin and aldosterone. These very high values for total renin, renin activity and aldosterone were not suppressed when extracellular compartments were greatly expanded; the values subsequently declined to normal levels, despite the use of diuretics. This suggested that the renin was of non-renal origin since its production was apparently unaffected by influences which control juxtaglomerular secretion. The high concentrations of the renin-angiotensin-aldosterone system suggest that it contributes to the genesis of the ovarian hyperstimulation syndrome.

Effects of angiotensin I converting enzyme inhibition and calcium channel blockade on plasma levels of active and inactive renin in conscious rabbits.

The interplay of juxtaglomerular (jg) calcium fluxes and exposure to AII in the regulation of jg renin secretion, was examined in vivo. An inhibitor of angiotensin I converting enzyme (captopril), a blocker of calcium channels (verapamil) and AII amide were infused, singly or in combination, into the ear vein of conscious rabbits. The effects on arterial pressure, and on levels of active and inactive plasma renin were monitored. Captopril (50 micrograms X min-1 X kg-1) produced a greater percentage increase in renin secretion than did verapamil (20 micrograms X min-1 X kg-1), whilst the percentage fall in arterial pressure was similar. AII amide counteracted more effectively the actions of captopril than those of verapamil. When captopril was infused first, addition of verapamil did not enhance renin secretion (P greater than 0.2). When verapamil was infused first, addition of captopril greatly enhance renin secretion (P less than 0.01). However, when captopril was infused first, and its actions then suppressed by AII amide, addition of verapamil led to extremely high rates of renin secretion. The findings suggest the following: the short loop negative feedback plays in vivo an important role in the rapid modulation of jg renin secretion and the action of AII may involve up- and down-regulation at the receptor and/or post-receptor level; infused agents have rapid access to the critical sites of jg cells; exposure to raised concentrations to AII not only reduces the effectiveness of AII, but also enhances jg secretory responses to lack of AII, as well as to calcium channel blockade. Thus, at least some of the jg calcium channels appear to respond both to AII and to blockers; extreme changes in the levels of active renin are possible without changes of inactive renin levels. Secretion of the latter may be under separate control, or its secretion rate parallelled by the rate of its activation.

The renin-angiotensinogen reaction during pregnancy and oral contraception: estimation of kinetic parameters by an autologous plasma renin assay.

A method has been developed which allows estimation of the kinetic parameters of the plasma renin-angiotensinogen reaction from data obtained by autologous renin assays at several plasma dilutions. The quantitative aspects of the renin-angiotensin system were examined in 28 plasma samples from 23 healthy, normotensive pregnant women. They were compared with 20 women who were not pregnant, of whom 12 were taking oral contraceptives and eight were not. In the first 3 months of pregnancy, there was a sharp increase in plasma renin activity and concentration. Plasma angiotensinogen rose steadily throughout pregnancy. The higher concentrations of renin and angiotensinogen would lead to an increase in angiotensin formation with potentially adverse consequences. However, this increase may be reduced by the fall in the affinity between renin and angiotensinogen which is suggested by the present observation that the Michaelis-Menten constant (Km) attained values five to six times higher than those seen in women not taking oral contraceptives. The smaller increases in plasma renin and angiotensinogen induced by oral contraceptives were less effectively compensated by lower affinity. Circumstantial evidence is provided which suggests that the observed high Km values may be due to oestrogen/pregnancy-induced synthesis of an angiotensinogen with a lower affinity for renin.

Reduced activation and affinity of renin during pregnancy and oral contraception: determination of kinetic parameters by a fully autologous plasma renin assay.

In healthy normotensive pregnancy, a complex functional network develops between the cardiovascular system, the volume and composition of the extracellular fluid and the renin-angiotensin system (RAS). Cardiac output and heart rate increase, but blood pressure is reduced. The kidneys increase in size and both the glomerular filtration rate and renal blood flow increase early. Renal tubular water and sodium reabsorption is even more enhanced, so that the total body water of mother and foetus rises in the course of pregnancy by 6-8 litres. Plasma osmolality falls by about 10 mosm/kg. yet total body sodium increases by about 1 mol. Understandably, in the face of such complex fluid and pressure adjustments, data on the changes of the RAS in normal pregnancy are often contradictory. However, there is general agreement that the angiotensinogen and inactive renin in plasma are greatly raised. Most groups have also found a considerable increase in active renin. These changes could lead to higher rates of angiotensin I (AI) formation (and hence high circulating angiotensin II levels), with adverse consequences for mother and foetus. The high proportion of inactive renin may reflect a reduction in the rate of activation of prorenin in order to avoid these consequences. This reduction may involve kallikreins which have been listed amongst the putative in vivo activators of prorenin. Excessive AI formation in pregnancy could also be avoided by the production of functionally different renins or angiotensinogens. Such changes will be difficult to detect with assays which require addition of extraneous renin or angiotensinogen.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of gold salts and penicillamine on serum complement.

The effects of the gold salt sodium aurothiomalate and of d-penicillamine on complement were studied in vitro. Total haemolytic complement was inhibited by 0.05-1mM gold. The inhibitory potency of gold was inversely correlated to the concentration of complement in the system, but was not diminished by albumin or decomplemented serum protein in concentrations approaching those circulating in blood. Penicillamine which itself slightly inhibited complement, prevented or reversed the action of gold. Conversion of C1s to C1esterase was not inhibited. Gold inhibited the action of C1esterase on component C4, but not the action on small-molecular synthetic ester substrates. Only very high gold concentrations (375-560 microM) inhibited the conversion of C3 to C3b. No inhibition of the alternative pathway was detected.

Effect of ionizing radiation on 15-hydroxy prostaglandin dehydrogenase (PGDH) activity in tissues.

Whole body irradiation of mice with 200-1000 R of unfiltered X-radiation (230 kV, 15 mA, 140 R/min) produced extensive falls of 15-hydroxy prostaglandin dehydrogenase (PGDH) activity in the spleen within 4 hours. A transient recovery between 4 and 72 hours was followed by a second reduction in PGDH levels which was still evident 7 days after exposure. In the jejunum and kidney, the falls were smaller. High doses (1000 R) increased PGDH activity in the lung. Effects of radiation on the other cellular enzymes, including other dehydrogenases in the cytosol, were less pronounced, and in some cases the opposite of the effects on PGDH. The loss of PGDH may contribute to the increase in prostaglandin concentrations in the spleen and jejumun, and thereby to some features in radiation sickness.

Prostaglandins and complement changes in some conditions related to inflammation.

Exposure to ionizing radiation produces several systemic and local reactions which could be mediated by prostaglandins. Prostaglandin levels were therefore studied in blood and tissues of mice which had been exposed to x-rays. Significant increases were found in spleens after 200 to 700 R, and in lungs after 600 to 700 R. These changes were most pronounced 4-7 days after irradiation. Ionizing radiation promptly and potently reduced the activity of prostaglandin dehydrogenase in the spleen, whereas prostaglandin synthesis was less affected. Evidence was obtained for the activation and consumption of haemolytic complement in serum in the course of heart-lung operations involving extracorporeal circulation. Activation involved primarily the classical pathway, and only slightly the alternate pathway.

Effect of ionizing radiation on prostaglandin-like activity in tissues.

One to 7 days after whole body exposure of mice to a single dose of 700 R of x-rays, little or no change was detected in prostaglandin-like activity in the brain, blood and seminal vesicles. Slight increases in intestinal and renal tissue were not significant. In the lung, mean activity rose from 62 ng/g to a transient peak of 145 ng/g wet weight on the fourth day (P less than 0.05). In the spleen, mean levels rose steadily from 13.2 ng/g to 259 ng/g on the fourth day (P less than 0.01), and were still 184.4 ng/g on the seventh day. 2 Prostaglandin-like activity was measured 4 days after single doses of 200-700 R. In the lung, a significant rise was produced by 600 and 700 R, and in the spleen by 200-700 R. 3 Thin layer chromatography showed that part of the prostaglandin-like activity in spleen extracts had RF similar to that of [3H]-prostaglandin E1, and part to that of [3H]-prostaglandin F2alpha. 4 Splenic tissue from mice exposed to 700 R four days earlier, inactivated prostaglandin E1 less potently than did tissue from non-irradiated mice.

Effects on serum complement of normal and pre-eclamptic pregnancy and of oral contraceptives.

The complement system was studied in normal gestation and puerperium, in pre-eclampsia and in women taking oral contraceptives. In 12 normal pregnancies, CH50 titres, C4, C3, C6 and C7 were increased throughout pregnancy; the serum concentration of C1 inhibitor was decreased in the last 2 quarters but greatly raised after delivery. Oral oestrogen-progestogen contraceptives also raised C3 but in contrast to pregnancy lowered CH50, C6 and C7. The different effects of pregnancy and of oral contraceptives may be due to materno-foetal immune reactions. In 9 patients with pre-eclamplsia, complement levels showed a wider scatter and a significantly higher C3 level than in normal pregnancy. Conversion of C3 to C3i was found in 2 of these patients.

Effects of suramin on complement, blood clotting, fibrinolysis and kinin formation.

1. The inhibition by suramin of complement components, and of blood clotting, fibrinolytic, and plasma kinin forming factors depended on the conditions of the assay and on the substrates used.2. Haemolysis by complement was more effectively inhibited in red blood cell suspensions, than in agarose gel plates. In esterolytic tests, the activation of component 1 (C1) to C1 esterase was significantly inhibited by 0.1-0.3 mM suramin, and the activity of C1 esterase by 0.5 mM suramin.3. Part of the anticoagulant effect of suramin is due to inhibition of the action of thrombin on fibrinogen.4. Suramin did not inhibit fibrin degradation by the fibrinolytic system in plasma. In esterolytic tests, the activation of plasminogen was more potently inhibited than the activity of plasmin.5. Activation of plasma kallikrein, measured either by kinin formation or by esterolysis, was inhibited by 0.1-0.3 mM suramin. Active plasma kallikrein was inhibited by 0.3-0.5 mM suramin. Pancreatic kallikrein was weakly inhibited, and urinary kallikrein not at all.

Blood changes in experimental arthritis in two types of genetically different rats.

1. Rats genetically resistant to dextran and other agents producing the anaphylactoid reaction (NR rats), have a higher polymorph count than do rats which react to these agents (R rats).2. NR rats do not develop polyarthritis when a hind paw is injected intradermally with Freund's adjuvant.3. The polyarthritis produced by an intravenous injection of Mycoplasma arthritidis culture develops more slowly in NR rats than in R rats.4. It is not clear whether the higher polymorph count in NR rats is a main factor in determining their resistance to adjuvant-induced arthritis.