Hans-Georg Güllner

PROSTACYCLIN OVERPRODUCTION IN BARTTER'S SYNDROME

Urinary excretion of 6-keto-prostaglandin F1alpha and thromboxane B2, the major metabolites of prostacyclin and of thromboxane A2, respectively, was measured by specific radioimmunoassays in five female patients with Bartters syndrome and in five normal female controls. The patients with Bartters syndrome excreted about four times as much 6-keto-PGF1alpha as the controls; their excretion of thromboxane B2 was no different from that of the controls. These data suggest that overproduction of prostacyclin mediates both the hyper-reninaemia and the hyporesponsiveness of blood-pressure to pressor agents in Bartters syndrome.

Adrenergic Receptor Function is Different in Male and Female Patients with Essential Hypertension

As plasma norepinephrine (NE) levels may be similar in hypertensive and normotensive subjects, the sensitivity of adrenergic receptors was investigated in patients with essential hypertension and normotensive subjects of similar age and sex. Alpha-adrenergic receptor sensitivity was measured in platelets by the specific binding of [3H]dihydroergocryptine and the NE inhibition of prostaglandin E1 (PGE1)-stimulated cyclic AMP (cAMP) production. The number of alpha-adrenergic receptors in platelets from hypertensive women was 1.5 times that in the platelets from normotensive ones, with no differences between hypertensive and normotensive women or between men and women in the affinity of the alpha-adrenergic receptor for [3H]dihydroergocryptine. PGE1-stimulated cAMP production was half as great in hypertensive as in normotensive men, while NE inhibition of PGE1-stimulated cAMP production was similar in hypertensive and normotensive men and women. [3H]Dihydroergoeryptine binding in female hypertensives, and PGE1-stimulated cAMP in male hypertensives did not differ from that in sex-matched controls. The sensitivity of the beta-adrenergic receptor, measured by [3H]dihydroalprenolol binding and cAMP production was similar in hypertensive and normotensive subjects.

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.

Correction of hypokalemia by magnesium repletion in familial hypokalemic alkalosis with tubulopathy

The effect of magnesium treatment on serum potassium and potassium balance was examined in three siblings with a recently described syndrome of hypokalemic alkalosis with renal tubulopathy. Oral magnesium supplementation for 11 days in the three siblings increased mean serum potassium from 2.7 +/- 0.1 meq/liter to 3.3 +/- 0.2 meq/liter (p less than 0.05). In addition, urinary and fecal potassium excretion decreased by about 11 meq/day. Magnesium chloride did not affect plasma renin activity while the patients were supine or upright. In contrast, mean supine plasma aldosterone concentration increased from 5.3 +/- 1.5 ng/dl to 13.2 +/- 4.1 ng/dl (p greater than 0.1) and mean upright plasma aldosterone concentration increased from 17.4 +/- 3.8 ng/dl to 66.1 +/- 7.3 ng/dl (p less than 0.01). These findings suggest that hypokalemia and potassium loss in this disorder may be caused by abnormal magnesium metabolism. The increase in plasma aldosterone concentration may have been caused by the positive potassium balance or a direct effect of magnesium on aldosterone secretion from the adrenal gland.

Timing antihypertensive medication.

the aminoglycoside administered unless another cause, such as septic shock, was obvious. Most of the patients were older adults with infections complicating serious medical disorders. The groups receiving gentamicin or tobramycin did not differ in age, sex, weight, initial serum-creatinine, total dose given, tvpe of infection, duration of therapy, or concurrent use of diuretic or cephalosporin drugs.

Regulation of sodium and water excretion by catecholamines

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 anesthetized 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 have 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 they are 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.

Correction of increased prostacyclin synthesis in Bartter's syndrome by indometracin treatment

The role of prostacyclin and thromboxane A2 in the pathogenesis of Bartters syndrome was investigated by measurement of the urinary excretion of 6-keto-PGF1 alpha and thromboxane B2, respectively, in five patients. The prostaglandin metabolites were extracted from urine by a reproducible method and measured by specific radioimmunoassays. The patients with Bartters syndrome excreted about four-times as much 6-keto-PGF1 alpha as the normal controls. In contrast, there was no significant difference in the urinary excretion of thromboxane B2 between the patients and the controls. In a second part of the study, three patients were treated with indomethacin (150 mg/day for four days), an inhibitor of prostaglandin synthesis. This regimen suppressed urinary excretion of 6-keto-PGF1 alpha by 43% and that of thromboxane B2 by 46%. It is suggested that the increase in prostacyclin production is responsible for both the hyperreninemia and and the other endocrine derangements as well as the hyporesponsiveness of blood pressure to intravenous infusion of vasopressors in patients with Bartters syndrome.

Effect of Prostacyclin (PGI2) on Renal Function and Renin Secretion in Hypophysectomized Dogs

The effect of PGI2, the principal metabolite of arachidonic acid in mammalian arterial and venous tissues, on renal function and renin secretion was investigated in anesthetized, hypophysectomized dogs undergoing a maximal water diuresis. PGI2 in a concentration of 0.04 microgram/kg/min significantly increased urine flow and urinary sodium and potassium excretion in the absence of changes in glomerular filtration rate or blood pressure. The fact that PCI2 significantly increased free water clearance and distal delivery of sodium and inhibited distal fractional rea0sorption of glomerular filtrate is suggestive of an effect on proximal as well as distal sites of the nephron. PGI2 increased renin secretion rates threefold. This promotion of renin release may have been caused by an increase of ion flux across the macula densa or by an increase in renal blood flow. On a molar basis, PGI2 is about 10 times more potent than PGE2 with regard to natriuresis, diuresis and renin release when studied under identical conditions. Thus, PCI2 may be the major prostaglandin involved in the regulation of salt and water excretion.

Gastrin releasing peptide: Endocrine functions in the rat

The effect of porcine gastrin releasing peptide (GRP), a heptacosapeptide with potent gastrin releasing activity which has recently been isolated from porcine non-antral gastric tissue, on pituitary function was investigated in the rat. Graded doses of synthetic porcine GRP were injected intravenously and the animals were killed at various intervals after injection. Prolactin, growth hormone, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) were measured in serum by specific radioimmunoassays. GRP had no significant effect on prolactin, growth hormone or FSH serum concentrations at any dose or sampling time studied. In contrast, the heptacosapeptide significantly stimulated LH release and suppressed TSH secretion with injection of low doses. There are striking structural and some functional similarities between GRP and bombesin, an amphibian skin tetradecapeptide which shows amino acid homology with the C-terminal region of GRP. This suggests that the endocrine effects of GRP may be mediated by its bombesin-like residue.

Effect of porcine gastrin releasing peptide on anterior pituitary hormone release.

Abstract The effect of porcine gastrin releasing peptide (GRP), a heptacosapeptide with potent gastrin releasing activity which has recently been isolated from porcine non-antral gastric tissue, on pituitary function was investigated in the rat. Graded doses of synthetic porcine GRP were injected intravenously and the animals were killed at various intervals after injection. Growth hormones, LH, FSH, and TSH were measured in serum by specific radioimmunoassays. GRP had no significant effect on growth hormone or FSH serum concentrations at any dose or sampling time studied. In contrast, the heptacosapeptide significantly stimulated LH and suppressed TSH secretion in a dose-related fashion. Since there are striking structural similarities between GRP and bombesin, a tetradecapeptide from amphibian skin which shows amino acid homology with the C-terminal region of GRP, GRP may be the mammalian counterpart of bombesin.