Addison A. Taylor

Bartter's syndrome: A disorder characterized by high urinary prostaglandins and a dependence of hyperreninemia on prostaglandin synthesis

Urinary prostaglandins E2 and F2alpha were measured by gas chromatography-mass spectrometry in three adult women and an adolescent girl with Bartters syndrome. On a constant metabolic diet prostaglandin E2 ranged from 293 to 1,221 ng/day (mean, 640 ng/day) and exceeded the normal range for adults of 76 to 281 ng/day in all patients. Prostaglandins F2alpha ranged from 291 to 1,061 ng/day (mean, 747 ng/day) in the adult women. Only in a young girl did prostaglandins F2alpha (1,677 ng/day) clearly exceed the normal range for adults of 422 to 871 ng/day. Treatment with indomethacin, which decreased urinary prostaglandin E-like material by 69 per cent or more, did not affect blood pressure. Plasma renin activity, which ranged from 5.2 to 22.2 ng/ml/hour (patients supine) and from 23.3 to 30.4 ng/ml/hour (patients upright), and urinary aldosterone, which ranged from 14.0 to 45.6 ng/day, decreased by 79, 65 and 52 per cent, respectively. The clearance of creatinine was lower for the eight or nine days of treatment, the balances of sodium and potassium were positive, and serum potassium was higher than in control. Ibuprofen, an inhibitor of prostaglandin synthetase which differs in structure from indomethacin, produced metabolic effects which were qualitatively similar to those of indomethacin. The results indicate that the renal synthesis of prostaglandins is increased in Bartters syndrome and that prostaglandins mediate the hyperreninemia and hyperaldosteronism which characterize the disorder. The over-production of prostaglandins by the kidney could be proximal cause of the syndrome, or secondary to intrarenal changes of an unknown nature. This study provides additional evidence for an important role for prostaglandins in the release of renin.

Endothelium-dependent hyperpolarization caused by bradykinin in human coronary arteries.

The present study was designed to determine whether bradykinin induces endothelium-dependent hyperpolarization of vascular smooth muscle in human coronary arteries, and if so, to define the contribution of this hyperpolarization to endothelium-dependent relaxations. The membrane potential of arterial smooth muscle cells (measured by glass microelectrodes) and changes in isometric force were recorded in tissues from six patients undergoing heart transplantation. In the presence of indomethacin and NG-nitro-L-arginine (NLA), the membrane potential was -48.3 +/- 0.6 and -46.9 +/- 0.6 mV, in preparations with and without endothelium, respectively, and was not affected by treatment with perindoprilat, an angiotensin-converting enzyme inhibitor. In the presence of both indomethacin and NLA, bradykinin evoked transient and concentration-dependent hyperpolarizations only in tissues with endothelium, which were augmented by perindoprilat and mimicked by the calcium ionophore A23187. Glibenclamide did not inhibit membrane hyperpolarization to bradykinin. In rings contracted with prostaglandin F2 alpha, the cumulative addition of bradykinin caused a concentration-dependent relaxation during contractions evoked by prostaglandin F2 alpha, which was not abolished by NLA and indomethacin. The present findings demonstrate the occurrence of endothelium-dependent hyperpolarization, and its contribution to endothelium-dependent relaxations, in the human coronary artery.

Differentiated vascular myocytes: are they involved in neointimal formation?

The role of differentiated vascular myocytes are neointimal formation in canine carotid artery was investigated. Using antibodies and cDNA probes, cells were characterized in situ and after isolation. In situ characterization indicated the majority of medial cells expressed both smooth muscle myosin and alpha actin but many cells were negative to these markers. All adventitial cells were negative for these proteins. The muscle protein-positive cells were designated differentiated, vascular myocytes (VSMC). The others were designated type 2 cells. Sequential enzyme digestion from lumenal surface yielded VSMC ( > 90%) while digestions from the adventitial surface yielded type 2 cells ( > 90%). VSMC were viable in culture but did not spread, proliferate, or alter expression of muscle proteins. Type 2 cells proliferated and increased their expression of muscle actin but did not express muscle myosin. Characterization of neointimal cells from injured carotid arteries indicated they were morphologically and immunologically identical to cultured type 2 cells. We concluded that: (a) canine carotid artery media consists of a heterogeneous cell population: (b) serum does not stimulate isolated VSMC to undergo phenotypic modulation or proliferate: and (c) type 2 cells may be responsible for neointimal formation because they proliferate and acquire a phenotype identical to in situ neointimal cells.

Spironolactone and Endocrine Dysfunction

Therapy with spironolactone is often associated with estrogenlike side-effects, including impotence and gynecomastia in men and menstrual irregularity in women. Several possible mechanisms by which spironolactone could cause these side-effects have been identified. Spironolactone has been shown to affect both gonadal and adrenal steroidogenesis, to elevate plasma gonadotrophin levels in children, and to act as an antiandrogen at the target tissue level. This conference presents a discussion of how these effects might interact to produce the endocrine side effects associated with spironolactone therapy.

The Kallikrein-Kinin System in Bartter's Syndrome and Its Response to Prostaglandin Synthetase Inhibition

The kallikrein-kinin system was characterized in seven patients with Bartters syndrome on constant metabolic regimens before, during, and after treatment with prostaglandin synthetase inhibitors. Patients with Bartters syndrome had high values for plasma bradykinin, plasma renin activity (PRA), urinary kallikrein, urinary immunoreactive prostaglandin E excretion, and urinary aldosterone; urinary kinins were subnormal and plasma prekallikrein was normal. Treatment with indomethacin or ibuprofen which decreased urinary immunoreactive prostaglandin E excretion by 67%, decreased mean PRA (patients recumbent) from 17.3+/-5.3 (S.E.M.) ng/ml per h to 3.3+/-1.1 ng/ml per h, mean plasma bradykinin (patients recumbent) from 15.4+/-4.4 ng/ml to 3.9+/-0.9 ng/ml, mean urinary kallikrein excretion from 24.8+/-3.2 tosyl-arginine-methyl ester units (TU)/day to 12.4+/-2.0 TU/day, but increased mean urinary kinin excretion from 3.8+/-1.3 mug/day to 8.5+/-2.5 mug/day. Plasma prekallikrein remained unchanged at 1.4 TU/ml. Thus, with prostaglandin synthetase inhibition, values for urinary kallikrein and kinin and plasma bradykinin returned to normal pari passu with changes in PRA, in aldosterone, and in prostaglandin E. The results suggest that, in Bartters syndrome, prostaglandins mediate the low urinary kinins and the high plasma bradykinin, and that urinary kallikrein, which is aldosterone dependent, does not control kinin excretion. The high plasma bradykinin may be a cause of the pressor hyporesponsiveness to angiotensin II which characterizes the syndrome.

Hypokalemia, in Bartter's Syndrome and Other Disorders, Produces Resistance to Vasopressors via Prostaglandin Overproduction:

Summary The role of hypokalemia and increased synthesis of prostaglandins in the decreased response of blood pressure to intravenous angiotensin II was studied in patients with Bartters syndrome and in patients with psychogenic vomiting. In patients with Bartters syndrome with high urinary prostaglandin E, treatment with an inhibitor of prostaglandin synthesis corrected the hyperreninemia and restored the pressor response to angiotensin II to normal but only partially corrected the hypokalemia. In patients with psychogenic vomiting with high urinary prostaglandin E, correction of the hypokalemia corrected the hyperreninemia and restored the pressor response to angiotensin II and to norepinephrine to normal. The findings suggest that hypokalemia, by stimulation of the synthesis of prostaglandin E in the kidney, produces hyperreninemia. An increase in synthesis of prostaglandin E in vascular tissue, stimulated by hypokalemia per se or by angiotensin II (produced by the hyperreninemia) or by both, increases the vascular resistance to angiotensin II and to norepinephrine.

Plasma concentrations of propranolol and 4-hydroxypropranolol in man measured by high pressure liquid chromatography.

Abstract A quantitative method for the simultaneous determination of propranolol and its major active metabolite, 4-hydroxypropranolol, in human plasma is described using high pressure liquid chromatography. As little as 1.5 ng/ml of propranolol and 5 ng/ml of 4-hydroxypropranolol can be measured with good precision by a fluorometric detector. Triamterene and quinidine are the only commonly used cardiovascular drugs that interfere with the assay. The pharmacokinetics of propranolol and 4-hydroxypropranolol were studied in three patients following oral administration of various dosages of propranolol. High pressure liquid chromatography allows more rapid analysis of plasma propranolol and 4-hydroxypropranolol concentrations than gas chromatographic-mass spectrometric methods, without sacrificing specificity or sensitivity.

Plasma norepinephrine concentrations: No differences among normal volunteers and low, high or normal renin hypertensive patients

Abstract Plasma norepinephrine concentrations were measured by a sensitive radioenzymatic method in 51 patients with essential hypertension and 26 age-matched normal volunteers under conditions of ad libitum sodium intake, after volume expansion by infusion of saline intravenously, and after volume contraction by administration of furosemide orally. The hypertensive patients were classified into low, normal and high renin groups both by renin-sodium indexing and by their renin response to furosemide and saline administration. Plasma norepinephrine concentrations were similar among normal volunteers and patients with low, normal or high renin hypertension while the people were either recumbent or after they stood for 5 min. These and other results do not support the hypothesis that abnormal activity of the sympathetic nervous system accounts for the low or high renin values seen in many hypertensive patients.

The syndrome of inappropriate antidiuretic hormone secretion as a cause of hyponatremia in cystic fibrosis

The syndrome of inappropriate secretion of antidiuretic hormone was observed in two patients with cystic fibrosis during acute exacerbation of chronic pulmonary disease. It was diagnosed by the accepted clinical and laboratory criteria and confirmed in one case by values for immunoreactive vasopressin that were inappropriately high for plasma osmolality. The severe hyponatremia was corrected by fluid restriction, alone or combined with intravenous treatment with diuretic and hypertonic saline solution. In addition, there was simultaneous therapy of the pulmonary disease. SIADH thus must be added to salt loss as a cause of hyponatremia in CF, and may be more common than realized in patients with CF and severe pulmonary disease.

Renal function following cortical necrosis in childhood

Renal disease rarely spares juxtamedullary nephrons. To identify unique characteristicsof these nephrons, renal function was assessed over 19 months in a 17-month-old child following cortical necrosis and 25 days of anuria. Open renal biopsies (ages 17 and 23 months) showed cortical destruction with selective sparing of juxtamedullary nephrons. C inulin (7.2±1.0) and renal plasma flow (C PAH ) (34±6.6/0.6 M. 2 ) were very low. Plasma renin and erythropoietin values were normal. High TmPAH/GFR, maximum Uosm, C H 2 O /GFR, and NH 4+ excretion, low minimum Uosm, C PO 4 /GFR, C urea /GFR, and the range of Uosm and C Na /GFR are consistent with preservation of relatively more tubular function per glomerular filtration rate than usual in severe renal failure.