Diabetes insipidus with renal resistance to vasopressin in the desoxycorticosterone-treated dog: a possible role for prostaglandins.

We examined the release of vasopressin and the renal response to exogenous vasopressin before and during desoxycorticosterone acetate (DOCA) administration in the dog. As treatment with DOCA produced potassium loss, urine volume increased, urinary osmolality decreased, and urinary PGE2 tended to increase. The increase in urine volume was accompanied by increases in serum sodium, in plasma osmolality and in plasma arginine vasopressin. The threshold for vasopressin release measured during polyuria was higher than control but the rate of vasopressin release was unchanged. The DOCA-induced polyuria was not affected by treatment with vasopressin which further increased plasma vasopressin. Treatment with indomethacin which corrected the increase in urinary PGE2 excretion but not the hypokalemia, restored the renal responsiveness to vasopressin, decreased the secretion of vasopressin, and corrected the polyuria and the hypernatremia. These findings suggest that DOCA-induced polyuria is attributable to a decrease in renal responsiveness to vasopressin which may be mediated in part by an increase in the renal synthesis of prostaglandins.

Demonstration and distribution of kassinin-like material (substance K) in the rat central nervous system.

Antiserum was raised against kassinin in rabbits. Cross-reactivity with other tachykinins was determined; these included substance K (100%) and substance P (0.1%). Peptides extracted from rat brain and synthetic tachykinins were chromatographed by reverse-phase HPLC. The major peak of kassinin-like material eluted at a time different from that of synthetic kassinin, eledoisin, physalaemin, neurokinin beta, and substance P but coeluted with substance K. Measurement of kassinin-like material in macrodissected and microdissected brain regions indicated that the distribution of kassinin-like material was similar to that of substance P.

Hylambatin, a structurally unique tachykinin: effects on insulin and glucagon secretion.

Hylambatin is the first example of a tachykinin which possesses a methionyl methionine residue at the C-terminus, rather than the C-terminal tripeptide -Gly-Leu-Met-NH2 which hitherto has been a characteristic feature of all members of the tachykinin family. The effect of hylambatin on the secretion of glucoregulatory hormones was examined in the rat. Hylambatin, injected intravenously in graded doses 10 and 30 min before blood collection, significantly increased both plasma glucose and plasma insulin, whereas the secretion of glucagon was not affected. This profile of action is different from that of kassinin or substance P. Should hylambatin, like other neuropeptides, be present in mammalian tissue, it may have a role in the regulation of carbohydrate metabolism.

Correction of polyuria by activation of adenylate cyclase in Brattleboro rats.

The diterpene forskolin has been demonstrated to activate adenylate cyclase in many tissues, independently of receptors, guanyl nucleotides or the guanine nucleotide regulatory protein. Rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain) have a defect in the synthesis of vasopressin. This absence of vasopressin is reflected by polyuria and a decrease in the urinary excretion of cyclic AMP, which mediates the action of vasopressin in the epithelial cells of the collecting ducts. Treatment of Brattleboro rats or of control Long-Evans rats with forskolin in doses as low as 7 micrograms/animal produced a significant decrease in urine volume. The reduction in urinary volume was associated with a significant increase in the cyclic AMP content of renal medullary tissue. Thus, systemic activation of adenylate cyclase can correct the pathophysiological consequences of the absence of vasopressin.

Defective leukocyte adenylate cyclase function in hypokalemia.

Patients with hypokalemia due to Bartter's syndrome show an increase in adrenergic nervous system function with significantly elevated plasma norepinephrine excretion. Prolonged exposure to neurotransmitters or hormones is known to lead to a down-regulation of target-cell responsiveness. We measured cyclic AMP generation by leukocytes in response to the beta-adrenergic agonist isoproterenol and to prostaglandin E1 (PGE1) in six patients with Bartter's syndrome. As compared to normal controls, the response of cyclic AMP production by leukocytes to stimulation by 1-isoproterenol or PGE1 was significantly decreased. These results indicate that in Bartter's syndrome and probably in other diseases involving hypokalemia isoproterenol- and PGE1-sensitive adenylate cyclase activities of leukocytes are reduced. Because the effect of PGE1 on adenylate cyclase is not mediated through the specific beta-adrenoceptor, it is possible that a defect in receptor-adenylate cyclase coupling or a more distal post-receptor defect is responsible for the reduction in cyclic AMP production.

PGE2 and 6-keto-PGF1 alpha excretion in Brattleboro rats with hereditary hypothalamic diabetes insipidus.

Brattleboro rats, a strain with hereditary hypothalamic diabetes insipidus, were found to excrete significantly higher amounts of both renal (PGE2) and vascular (6-keto-PGF1 alpha) prostaglandins than control Long-Evans rats. The increased prostaglandin synthesis was reversed by vasopressin treatment. These results suggest that in the intact organism prostaglandin synthesis in the kidneys and in the endothelial cells of blood vessels may be under tonic inhibitory control by vasopressin. The findings further support the view that prostaglandins play an important role in the regulation of water excretion and in the pathogenesis of polyuric conditions.

The role of the adrenergic nervous system in sodium and water excretion.

There is considerable evidence that the renal nerves contribute to the regulation of salt and water excretion by a direct effect on tubular reabsorption, independent of changes in renal hemodynamics. Whereas the effect of the adrenergic nervous system on sodium reabsorption appears to be established in anesthetised animals, it has been suggested that the basal activity of the renal sympathetic nerves in conscious dogs is too low to have a significant effect on sodium reabsorption by the proximal tubules. However, denervation natriuresis and diuresis has recently been demonstrated in conscious euvolemic and conscious volume expanded rats. The effects of renal nerve stimulation on the handling of sodium and water by the proximal tubule can be mimicked by infusion of the alpha-adrenergic agonist norepinephrine and prevented by infusion of an alpha-adrenergic antagonist. This confirms that it is mediated by alpha-receptors. The adrenergic nervous system may have an independent role in the control of sodium excretion or may be complementary to other systems such as the renin-angiotensin-aldosterone system.

Dermorphin: an opioid peptide from amphibian skin which affects endocrine pancreatic function.

We examined the effect of intravenous injection of the amphibian skin opioid heptapeptide dermorphin on plasma glucose, insulin, glucagon and somatostatin in the rat. Dermorphin in doses ranging from 0.1 to 10 micrograms per animal did not affect plasma insulin or somatostatin-like immunoreactivity (SLI). In contrast, the opiate peptide significantly stimulated plasma glucagon and decreased plasma glucose, both 10 and 30 min following injection. The results suggest an effect of dermorphin on the endocrine pancreas. Since dermorphin has been shown to be present in rat and porcine tissues, it may have a role in the regulation of glucose metabolism.

Renal thromboxane excretion in Brattleboro rats with hereditary hypothalamic diabetes insipidus. Effect of vasopressin treatment.

Rats with hereditary hypothalamic diabetes insipidus (Brattleboro strain) which are devoid of vasopressin, excrete significantly increased amounts of immunoreactive thromboxane B2 in urine. The increase was corrected by treatment with vasopressin. These results suggest that, in the intact organism, thromboxane synthesis may be under tonic inhibitory control by vasopressin although other renal mechanisms explaining the increase in thromboxane cannot be excluded. Our observations further support an involvement of prostaglandins and thromboxanes in the regulation of water metabolism.

A sibship with hypokalemic alkalosis and renal proximal tubulopathy.

A new syndrome, characterized by hypokalemic alkalosis, hyperreninemia, aldosterone, high urinary prostaglandin E2 excretion, normal BP, and resistance of BP to angiotensin II is described in three of four siblings. Histologic examination of tissue obtained by biopsy from the kidneys showed an intense staining of the proximal tubular cells, as well as an extreme hypertrophy of the proximal tubular basement membranes, features that previously have not been observed. On electron microscopic examination, the characteristic changes of the tubular cells consisted of very dense cytoplasm, compact mitochondria, and pyknotic nuclei. In contrast to Bartter's syndrome, the juxtaglomerular apparatus were of normal appearance. Glomerular filtration rate and renal plasma flow were within normal limits. Fractional distal delivery of proximal tubular solute and fractional chloride reabsorption in the thick ascending limb of the loop of Henle were normal. The findings of a genetic linkage between the syndrome and the major histocompatibility system suggests that this familial tubulopathy is an inherited disorder.

Hypokalaemia stimulates prostacyclin synthesis in the rat.

1. To examine the hypothesis that the normalcy of blood pressure, despite an increase in circulating angiotensin II, and the blood pressor hyporesponsiveness to infusion of pressor agents which are associated with hypokalaemia, are due to overproduction of prostacyclin, the principal prostaglandin (PG) synthesized by the vascular endothelium, we studied the effect of experimental hypokalaemia on the urinary excretion of immunoreactive 6-keto-prostaglandin F1 alpha, a stable metabolite of prostacyclin, in the rat. 2. The animals were fed on a potassium-deficient diet for 9 days. Twenty-four hour urine samples were collected daily for measurement of urinary excretion of immunoreactive 6-keto-PGF1 alpha, PGE2 and 13,14-dihydro-15-keto-PGF2 alpha (PGFM). 3. Hypokalaemia caused significant increases of the three prostaglandins measured. 4. We conclude that hypokalaemia is a potent stimulus of both renal and vascular prostaglandins. The results suggest that an increase in prostacyclin synthesis in peripheral blood vessel walls may be responsible for the resistance of blood pressure to infusion of pressor substances as well as for the normalcy of blood pressure, despite the presence of high circulating angiotensin II concentrations, in conditions associated with hypokalaemia.

The interactions of prostaglandins with the sympathetic nervous system--a review.

In most isolated tissues, prostaglandins, particularly of the E-series, inhibit stimulated norepinephrine release from prejunctional nerve endings and inhibit sympathetic neurotransmission. They may also modulate the response of target organs to the neurotransmitter. In some tissues PGE enhances the response to norepinephrine. It appears that the effect of PGE on norepinephrine release is mediated by restriction of calcium availability at the nerve ending, although this mechanism is incompletely understood. Prostaglandins other than PGE do not appear to play a major role in the modulation of norepinephrine release. In the intact organism, prostaglandins facilitate norepinephrine release. Inhibition of prostaglandin synthesis causes a decrease in norepinephrine release. It is not clear if the effects in vivo are mediated by a direct action of prostaglandins or through baroreceptor reflex mechanisms.