The extent of the destruction, during passage through the lungs, of a substance secreted by the heart.

1. In vitro, the lungs of male Wistar rats, 220-230 g, removed heart substance (HS) from saline perfusates. HS could not be recovered by subsequent perfusion with HS free solution.2. A maximum rate of HS-uptake, 8.5 ng biological equivalents of 18-monoacetate of D-aldosterone (18 MA)/min, was reached at a concentration of HS equivalent to 3.5 ng 18 MA/ml. at a flow of 6 ml./min.3. Uptake was not significantly affected by a fall in temperature from 38 to 18-20 degrees C or by reduction in P(CO) (2) to zero. Uptake was reduced by anoxia and was enhanced by decrease of pH from 7.4 to 6.6.4. 30% of the HS taken up by the lungs at 20 degrees C was recoverable: none of the HS taken up at 38 degrees C was recovered.5. Uptake of HS by binding is considered rate-limiting to the destruction of HS in the lungs.6. The concentrations of HS found in the pulmonary and carotid arterial blood of cats under chloralose anaesthesia, during haemorrhage, were biologically equivalent to 1098 +/- 38.7 and 169 +/- 13.4 ng 18 MA/100 ml. (means +/- S.E.) respectively, in four experiments.

The formation of a renally active peptide by cat lungs from gamma-globulin in vitro and the plasma concentrations of this peptide, in vivo.

1. A substance (LS), extracted in aqueous acetone and separated by partition and thin-layer chromatography, has been obtained from lung perfusates and from the systemic blood of cats.2. LS is assayed biologically in rats during sustained saline diuresis by measurement of the muequiv Na retained. This parameter is linearly related to the log concentration of LS infused.3. Lungs perfused with Tyrode fluid neither contain nor produce LS. Production of LS begins when gamma-globulins (in cat plasma, mixed ox globulins or equine Cohn II) are present in the perfusing fluid.4. The proteinase inhibitor trasylol does not prevent the formation of LS by lung; trasylol protects LS from break-down during re-perfusion and during isolation from perfusates or from blood.5. In cats under chloralose anaesthesia LS is present during haemorrhage in systemic arterial and mixed venous blood, the arterial concentration of LS is approximately four times the venous.

The isolation of a renally active substance from arterial blood.

1. A substance (Art. HS) which resembles the 18-monoacetate of D-aldosterone (18 MA) in its biological actions is found in arterial blood of cats and sheep: Art. HS is assayed in terms of antidiuretic activity equivalent to synthetic 18 MA.2. In cats under chloralose anaesthesia, dialysis of arterial blood (2-3 ml./min) in a small external circuit (8-15 ml.) without disturbance of heart rate, blood pressure or respiration, predicts a physiological concentration of Art. HS equivalent to 31.5-51.9 ng 18 MA/100 ml. Efficiency of dialysis assumed in this calculation is 100%.3. Art. HS is almost evenly distributed throughout the plasma and formed elements of blood.4. Concentrations of Art. HS found during severe arterial haemorrhage are equivalent to 188 +/- 6.7 and 151 +/- 9.2 ng 18 MA/100 ml. in cats and sheep respectively.5. Art. HS has been isolated from 27.6 l. sheep arterial blood by ethyl acetate: chloroform 1:1 extraction, defatting by partitioning between methanol and petroleum ether and purifying by seven-stage thin layer chromatography on MN Kieselgel UV(254). Final yield was equivalent in activity to 21.6 mug 18 MA. Synthetic 18 MA was used as R(F) marker. Spots of 2 mug 18 MA are visible on MN Kieselgel UV under U.V. Art. HS activity equivalent to 21.6 mug 18 MA cannot be seen.6. Art. HS was not detectable in IVC blood of cats under chloralose anaesthesia during haemorrhage. The threshold for detection was the equivalent of 15-20 ng 18 MA/100 ml.7. Art. HS resembles a substance liberated by the heart (Lockett & Retallack, 1970a, b, 1971) in chromatographic properties, biological properties and stability in aqueous solution. Art. HS is very much more stable in aqueous solution than 18 MA.

The separation of renal activity from lung and from the venous effluent from perfused lungs.

1. Antidiuretic and salt-retaining activity has been separated from cat and ox lung, and from the venous effluent of blood-perfused cat lungs, by acetone extraction, gel filtration, partition and thin-layer chromatography.2. The chromatographic properties of the renally active substance from lung and from pulmonary venous blood are similar.3. The renal actions of these substances, demonstrable in vivo and in the isolated organ, are characterized by reduction in the excretion of water and Na. Renal blood flow, glomerular filtration rate and the urinary Na/K are not significantly affected.4. Concentrations of the lung substance which equate with angiotensin II-val(5)-amide in reduction of urinary Na in rats during water diuresis and under alcohol sedation do not raise the mean arterial pressure of the anaesthetized rat nor contract the superfused rat colon. At these dose levels angiotensin II is markedly vasopressor and contracts the superfused rat colon.

The release of a renally active substance by perfused rat hearts.

1. A substance (HS) which resembles the 18-monoacetate of D-aldosterone (18-MA) in its biological actions is released by perfused rat hearts, HS is assayed in terms of activity equivalent to synthetic 18-MA.2. Isolated rat hearts perfused with modified Krebs bicarbonate Ringer without recirculation secrete progressively less and less HS.3. Addition of D-aldosterone to recirculating perfusate supplying a heart no longer secreting measurable quantities of HS causes a rapid and very marked increase in the output of HS from the heart. If radioactively labelled D-aldosterone is supplied the HS synthesized is radioactively labelled. No measurable amounts of HS are formed from 18-hydroxycorticosterone.4. Chromatographic differentiation between 18-MA and HS, initially difficult, has been achieved.5. The rate of secretion of HS from the hearts of adrenalectomized animals is markedly reduced: synthesis of HS is immediately resumed when these hearts are supplied with D-aldosterone, but at a subnormal rate.

Factors controlling the secretion of a substance biologically resembling the 18-monoacetate of D-aldosterone by heart muscle.

1. Previous work has demonstrated that the cat heart secretes a substance which resembles the 18-monoacetate of D-aldosterone (18 MA) in chromatographic properties and biological actions. This substance (HS) releases ADH from the neurohypophysis and, in higher concentration, causes renal retention of salt and water. HS is extracted from blood, separated chromatographically and assayed in terms of equivalent 18 MA activity either by inhibition of water diuresis in rats or by reduction of the excretion of Na by the isolated kidney. Positive correlation has been demonstrated between heart rate and HS secretion.2. Heart-lung preparations from cats have been used to disclose additional factors controlling the rate of secretion of HS from heart muscle.3. Positive inotropic effects produced by administration of digoxin or adrenaline or by increase in peripheral resistance are associated with increases in the secretion of HS.4. Negative inotropic effects produced by high concentrations of procaine hydrochloride or by increase in venous return without change in external work are associated with decrease in HS secretion.

The diuretic actions of prostaglandin E1 and of noradrenaline, and the occurrence of a prostaglandin E1-like substance in the renal lymph of cats.

1. The actions of noradrenaline, prostaglandin E(1) and angiotensin II-amide on various parameters of renal function and on the flow of renal lymph and its equivalent content of prostaglandin E(1)-like activity have been compared in cats under chloralose anaesthesia.2. All three compounds produced diuresis and natriuresis. Noradrenaline (0.1-0.3 mug/kg.min) and angiotensin II (0.1-0.2 mug/kg.min) with rise of the filtration fraction (FF) and GFR; prostaglandin E(1) (0.13-0.19mug kg.min) with increase in GFR but without change in FF. Noradrenaline and angiotensin markedly raised renal perfusion pressure, prostaglandin E(1) lowered it by approximately 10 mm Hg.3. All three compounds increased the renal lymph flow. Only PGE(1) and noradrenaline markedly raised the equivalent concentration of PGE(1) in the renal lymph.4. Complete block of alpha and beta adrenergic receptors prevented the vasopressor effect and the rise in FF caused by noradrenaline but did not markedly reduce the diuretic and natriuretic effects nor the influence on renal lymph.5. Effects of PGE(1) and of angiotensin were unaffected by alpha and beta adrenergic block and atropinization did not prevent the release of PGE(1)-like material or the diuresis caused by noradrenaline.6. It is suggested that the diuretic and natriutetic actions of noradrenaline are in large part attributable to the intrarenal action of this PGE(1)-like substance of unknown origin.