Publisher Summary This chapter discusses prostaglandins and thromboxanes. The prostaglandins are C 20 acids formed from polyunsaturated fatty acids by oxygenation and cyclization. The thromboxanes, which were originally found in platelets, have now been identified in a variety of tissues. Rapid progress is being made in understanding their biological roles. Earlier studies on vascular and airway smooth muscle demonstrated that endoperoxides had unique effects that could not be attributed to conversion into the stable prostaglandins. Because aspirin, an inhibitor of endoperoxide formation, inhibits the second wave of aggregation, it was suggested that the endoperoxides play a role in the release reaction. The potency of the endoperoxides in causing contractions of the isolated rabbit aorta was of particular interest. However, the occurrence of thromboxanes is not limited to platelets. The transformation of arachidonic acid into thromboxane B 2 has also been observed in lung tissue, spleen, kidney, leukocytes, umbilical artery, and brain.

Prostaglandins and thromboxanes.

Angiotensins are peptide hormones derived from the protein precursor angiotensinogen by the sequential actions of proteolytic enzymes (Figure 1). The classic pathway of angiotensin synthesis includes a reaction catalyzed by angiotensin-converting enzyme (ACE), which occurs not only in plasma but also in the kidneys, brain, adrenal glands, ovaries, and possibly other tissues.1 The intrarenal renin–angiotensin system affects glomerular filtration, as discussed below, but the importance of angiotensin synthesis in other tissues is not known. Angiotensin II, the principal effector of the renin–angiotensin cascade, can also be synthesized by a pathway that does not require ACE.2 Angiotensin II stimulates a variety . . .

Angiotensin Receptors and Their Antagonists

Prostaglandins E1, E2, F2α and A2 are enzymically inactivated to different extents during passage through the pulmonary circulation The enzyme responsible is probably 15-hydroxyprostaglandin dehydrogenase

Inactivation of Prostaglandins by the Lungs

The details of a radioimmunoassay capable of measuring as 5 pg of prostaglandin A, E, and F (PGA, PGE, and PGF) in human and rat plasma are described. Plasma samples are extracted (with 4000 cpm [3H] PGE1 added for calculation of recovery) with an organic solvent system at an apparent pH of 5.8 and then chromatographed on silicic acid columns with increasing concentrations of methanol to separate PGA, PGE, and PGF. Each chromatographed sample is measured by radioimmunoassay, using the homologous antibody and tritiated marker. 40 normal individuals had mean plasma concentrations of PGA, PGE, and PGF of 1062±107 pg/ml, 385±30 pg/ml, and 141±15 pg/ml, respectively. Elevated PGE levels were measured in the plasma of patients with medullary carcinoma of the thyroid, carcinoid, and neuroblastoma. Treatment of rats with indomethacin decreased serum PGE levels by 67%. The radioimmunoassay appears to be of considerable experimental as well as clinical interest.

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Radioimmunoassay measurement of prostaglandins E, A, and F in human plasma.

Functions of the renal nerves.

STIMULATION of the splenic nerves releases prostaglandins from the spleen to give concentrations of as much as 0.2 µg/ml. in splenic venous blood1. The release of prostaglandins might influence organs remote from the site of release, for prostaglandins can exert potent actions on smooth muscle2. The lung has recently been shown to determine the fate of many vasoactive substances; some are activated—conversion of angiotensin I to angiotensin II (ref. 3)—and some inactivated. The degree of inactivation seems to be specific for a given substance, ranging from almost complete (bradykinin4, 5-hydroxytryptamine5, prostaglandins E1 E2 and F2α (ref. 1)), to minor (noradrenaline6), to allowance of their free passage (adrenaline6 and angiotensin II (ref. 7)). The removal of prostaglandins by the lung restricts their activities to the organs from which they are released and between their organ of origin and the site in the pulmonary circulation where they are inactivated1. A prostaglandin which passed through the lungs after its release from an organ could be considered a circulating hormone, as long as it is not rapidly degraded in the blood. Ferreira and Vane1 reported that prostaglandins E1 E2 and F2α were stable in blood, though rapidly inactivated by the lung. Removal of prostaglandins A1 and A2 by the lung was not determined because the assay organs are insensitive to them. Vascular smooth muscle, however, unlike other smooth muscle, is reactive to low concentrations of prostaglandins A1 and A2 (refs. 8–10) and the renal vasculature is probably most sensitive to prostaglandins A1 and A2 (refs. 10 and 11). Because the renal vasculature is also sensitive to prostaglandins E1 and E2 (ref. 12), it has been used as an index of the fate of prostaglandins infused into the venous and arterial circulations.

Selective Passage of Prostaglandins across the Lung

Renal prostaglandins (PCs) might mediate an antihypertensive function of the kidney. The blood-superfused organ technique possesses the sensitivity (threshold < 0.4 ng/ml blood) and specificity required for identification of PGs in blood. Induction of unilateral renal ischemia in 14 chloraloseanesthetized dogs reduced renal blood flows from a mean value of 257 to 109 ml/min on the ischemic side and from 250 to 209 ml/min on the contralateral side. Concomitantly, PG-like substances were detected by assay organs in the venous blood of ischemic (13 experiments) and contralateral (11 experiments) kidneys. In one experiment, in a spontaneously hypertensive dog, PGs were not detected during renal ischemia.

Renal venous blood and renal medullary tissue were extracted for acidic lipids and assayed for PG-like substances. Extracts of venous blood collected during renal ischemia and extracts of renal medulla yielded substances with biological activity indistinguishable from PG-like substances or PG standards. Chromatographic characterization of PG-like substances suggests that they are predominantly a mixture of PGE2 and PGF2α.

Prostaglandin-Like Substances Appearing in Canine Renal Venous Blood During Renal Ischemia

Prostaglandin A1: Antihypertensive and Renal Effects: Studies in Patients with Essential Hypertension

THE plasma of dogs loaded with saline seems to contain a “natriuretic hormone” which inhibits the reabsorption of sodium by the proximal renal tubule in the rat1. It also seems that plasma from dogs infused with saline will inhibit the uptake of para-aminohippurate (PAH) by slices of rabbit kidney cortex2. We have tried to determine the relationship between these two factors. One class of compounds which has properties common to “natriuretic hormone” and the factor inhibiting PAH uptake is the prostaglandins. Both “natriuretic hormone” and prostaglandins are dialysable and produce an increase in sodium excretion1,3ndash;5. In addition, prostaglandins are capable of exhibiting a 280 mmicron chromophore which is the absorption peak at which Bricker et al. observed inhibition of PAH by saline expanded plasma2. In order to relate prostaglandins, “natriuretic hormone” and the PAH inhibiting factor, we have studied the effect of prostaglandins on PAH accumulation by rabbit kidney cortex in vitro.

Prostaglandins and Natriuresis: the Effect of Renal Prostaglandins on PAH Uptake by Kidney Cortex

Findings in a case of neonatal tetany in a child whose mother had elevated blood parathyroid hormone levels because of a parathyroid adenoma are given. The child was found to have hypocalcemia, hypomagnesemia, and hyperphosphatemia. Parathyroid hormone in the infant was found to be elevated. It has been postulated that the pathophysiologic mechanism of the hypocalcemia in this syndrome is transient hypoparathyroidism. The present case suggests a different mechanism: hypomagnesemia and end-organ refractoriness to parathyroid hormone, a state analogous to pseudohypoparathyroidism.

James B. Lee

Papers

Selective Passage of Prostaglandins across the Lung

Prostaglandin-Like Substances Appearing in Canine Renal Venous Blood During Renal Ischemia

Prostaglandin A1: Antihypertensive and Renal Effects: Studies in Patients with Essential Hypertension

Prostaglandins and Natriuresis: the Effect of Renal Prostaglandins on PAH Uptake by Kidney Cortex

Transient Neonatal Hypocalcemia, Hypomagnesemia, and High Serum Parathyroid Hormone with Maternal Hyperparathyroidism