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Biomedical subjects

H R Keiser

Publications and source records attributed to H R Keiser.

At least 181 records · Page 10Linked to original sources
PubMed1977

Inhibition of vasopressin-stimulated prostaglandin E biosynthesis by chlorpropamide in the toad urinary bladder. Mechanism of enhancement of vasopressin-stimulated water flow.

Chlorpropamide is known to enhance the water permeability response of the toad urinary bladder to vasopressin and to theophylline. In other studies, we have shown that prostaglandin E synthesis by the toad bladder inhibits the water permeability response to arginine vasopressin and to theophylline. In this study, the effect of chlorpropamide on vasopressin-, theophylline-, and cyclic AMP-stimulated water flow and on prostaglandin E biosynthesis was investigated in the toad urinary bladder in vitro. Chlorpropamide inhibited prostaglandin E biosynthesis during vasopressin-, theophylline- and cyclic AMP-stimulated water flow. Tolbutamide and glyburide, two other sulfonylurea compounds, also enhanced vasopressin-stimulated water flow and inhibited vasopressin-stimulated prostaglandin E biosynthesis. We conclude that the mechanism of enhancement on vasopressin-stimulated water flow by the sulfonylureas is the inhibition of prostaglandin E biosynthesis.

Animals↗
PubMed1976

Interference with histamine and imidazole acetic acid metabolism by salicylates: a possible contribution to salicylate analgesic activity?

In man, rats and mice, the urinary excretion of the histamine and L-histidine metabolite, imidazole acetic acid, is increased and that of the conjugated metabolite, ribosylimidazole acetic acid, decreased by small doses of salicylates. In contrast to salicylates, other non-salicylate anti-inflammatory drugs, indomethacin, phenylbutazone, phenacetin and acetaminophen do not influence the excretion of the urinary metabolites of histamine and L-histidine. Since imidazole acetic acid is reported to have analgesic and narcotic activity, there is the inference that the analgesic properties of salicylate might be due in part to interference in imidazole acetic acid metabolism.

Adolescent↗
PubMed1976

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 Bartter's 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 Bartter's 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.

Adolescent↗
PubMed1976

Familial aggregation of urinary kallikrein concentration in childhood: relation to blood pressure, race and urinary electrolytes.

Biochemical alterations that have been correlated with elevated blood pressure have not received extensive epidemiologic study because of the technical difficulties involved. Because the excretion of urinary kallikrein is reduced significantly in adult hypertensives, we have studied urinary kallikrein in a cohort of children in whom familial aggregation of blood pressure has been demonstrated. Casual specimens of urine were obtained in household surveys, and urinary concentration of kallikrein was determined in 601 children aged 5-18 years. The children were from 163 families, whose members also had their blood pressures measured. Familial aggregation of urinary kallikrein concentration was found by analysis of variance (F=3.45, p less than 0.001) even in these casual specimens and was demonstrable for black and white children analyzed separately. Urinary kallikrein concentration was significantly lower in black children than in white children (p less than 0.001) and was positively correlated with urinary creatinine and urinary potassium and inversely related to urinary sodium concentrations. Urinary kallikrein concentration also was being altered by season (being lowest in the summer) and by time of day (being highest in the morning). Families with the lowest mean kallikrein concentrations tended to have higher blood pressures than did families with the highest mean kallikrein concentrations, although the effect is small and subject to many variables.

Adolescent↗
PubMed1976

Urinary kallikrein in hypertensive animal models.

Urinary kallikrein excretion was studied in a number of animal models of hypertension. Kallikrein excretion was subnormal in spontaneously hypertensive rats as compared to Wistar/Kyoto rats and in rats made hypertensive by a clip on one renal artery. Kallikrein excretion was supranormal in rats made hypertensive by desoxycorticosterone and salt and in rats receiving desoxycorticosterone alone. It was subnormal after bilateral adrenalectomy. Kallikrein excretion increased in normotensive rats fed a low-sodium diet but was unchanged by a high-sodium diet. Thus, kallikrein excretion responded to changes in activity of sodium-retaining steroids and was not correlated with excretion of salt or water. In studies in dogs with stenosis of one renal artery kallikrein excretion was decreased on the stenoic side and the decrease correlated highly with the reduction in renal blood flow. While the role of the kallikrein-kinin system is still unclear the data indicate that the kidney may modify the initiation or maintenance of hypertension via this potent vasodilator system.

Adrenalectomy↗
PubMed1976

Relationships among urinary kallikrein, mineralocorticoids and human hypertensive disease.

Urinary kallikrein excretion is reduced in patients with hypertension of unknown etiology. In addition, the excretion of this renal, kinin-forming enzyme was found to be elevated in hypertensive patients with primary aldosteronism. Aldosterone regulates kallikrein excretion, as normal subjects show increased kallikrein excretion in response to a low sodium intake, high potassium intake, or the synthetic mineralocorticoid, fludrocortisone, whereas kallikrein excretion falls during treatment with spironolactone. The relationship between kallikrein excretion and aldosterone activity may directly reflect the intrarenal activity of the kallikrein-kinin system, as determined by studies of kallikrein levels from isolated renal cells or of plasma kinin levels in man in response to postural changes or saline loads. Some patients with essential hypertension do not show a normal increase in kallikrein excretion in response to low dietary sodium intake despite an apparently normal aldosterone response, suggesting that there may be a defect in the renal kallikrein-kinin system in these patients. Whether these findings are of pathogenetic significance in human hypertensive disease remains to be determined.

Fludrocortisone↗
PubMed1976

17 alpha estradiol: separation of estrogen effect on collagen from other clinical and biochemical effects in man.

In rodents the effect of 17alpha estradiol upon collagen is identical to that of 17beta estradiol, but the 17alpha estradiol effect upon uterine lining is 1/1000 that of 17beta estradiol. Both steroids reverse the effect of D-penicillamine on rodent skin collagen. Five human beings with the skin collagen changes associated with D-penicillamine were treated with 17alpha estradiol for three to six weeks. 17alpha estradiol caused no detectable changes in blood pressure, breast development, menstrual periods, serum liver enzymes, serum proteins, plasma growth hormone, insulin, serum clotting factors, serum triglycerides, serum copper or serum ceruloplasma. In contrast, 17alpha estradiol increased skin prolyl hydroxylase activity, increased soluble collagen content in the skin and increased urinary hydroxyproline excretion. These studies with 17alpha estradiol, point out a specificity difference between the various sites of estrogen action in human beings.

Collagen↗
PubMed1976

Prostaglandins are overproduced by the kidneys and mediate hyperreninemia in Bartter's syndrome.

In summary, the cardinal features of the syndrome of renal juxtaglomerular hyperplasia include overproduction of plasma renin activity, elevation of plasma angiotensin II concentration, elevation of aldosterone secretion and of plasma aldosterone concentration, hypokalemic alkalosis, and a resistance of arterioles to the pressor action of angiotensin II and norepinephrine. In the present studies, elevation of urinary PGE2 but not of PGF2alpha has been demonstrated. Inhibition of prostaglandin synthetase with indomethacin or ibuprofen has been shown to decrease plasma renin activity, and plasma aldosterone concentration and secretion rate, leading to a positive potassium balance and restoration of normal plasma potassium. The inhibitors decreased and glomerular filtration rate, and induced sodium retention. The results indicate that overproduction of PGE by the kidneys is a cardinal feature, but not necessary the primary one, in the pathogenesis of this syndrome.

Adolescent↗
PubMed1975

Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites.

Approximately 10% to 20% of isoniazid recipients manifest biochemical evidence of liver injury. A smaller number of patients develop clinically overt hepatitis. Isoniazid is metabolized in man at extremely variable rates, and the rate is under genetic control. Two separate clinical studies have noted a possible relation between susceptibility of patients to isoniazid liver injury and rapid metabolism (acetylation) of the drug. For this reason, 21 patients who had recovered from probable isoniazid hepatitis and 5 patients who previously had manifested biochemical evidence of mild isoniazid liver injury were genetically phenotyped as rapid or slow isoniazid acetylators by the sulfamethazine method. The rapid phenotype was found in 86% of patients with probable hepatitis and in 60% of the possible ones, whereas the expected frequency was 45%. Eximination of isoniazid metabolites revealed that rapid acetylators hydrolze much more isoniazid to isonic otinic hydrazine moiety than do slow acetylators. The hydrazine moiety liberated from isoniazed is primarily acetylhydrazine, and studies in animals show this metabolite to be converted to a potent acylating agent that produces liver necrosis. We suggest that release of the hepatotoxic hydrazino moiety of isoniazid in man is responsible for isoniazid liver injury.

Acetylation↗
PubMed1975

Bradykinin and human airways.

This work explored the effects of bradykinin (BK) on human airways. Bradykinin (1 mug/kg body weight) was rapidly injected intravenously and respiratory system resistance (Rrs), closing volume (CV), forced vital capacity (FVC), expiratory volume in the first second (FEV1) maximal midexpiratory flow (MMF), and peak flow (PF) were measured. Bradykinin in normals produced no changes in Rrs or CV, but reduced the FVC. This suggests alveolar duct constriction, since no constriction of either large or small airways occurred with the decreased FVC. Bradykinin in asthmatics decreased the Rrs and CV, and increased the FEV1, MMF and PF, while the FVC did not change significantly. The absence of a significant increase in the FVC in the presence of concomitant bronchodilation, suggests that asthmatics also had alveolar duct construction. These data are consistent with animal studies which show that BK may release adrenalin (or other agents) with secondary effects, such as bronchodilation. The secondary bronchodilation seen in asthmatics but not in normals, is probably a result of the initial higher intrinsic bronchial tone of the asthmatics.

Adolescent↗
PubMed1975

Peripheral resistance to thyroxine: a cause of short stature in a boy without goitre.

A euthyroid pubertal boy was investigated for short stature and was found to have an elevated serum thyroxine and delayed bone age. In spite of high thyroxine levels, there were no clinical signs of hyperthyroidism and kinetic studies revealed a normal rate of thyroxine metabolism. Plasma TSH levels were elevated but there was no goitre. Administration of up to 900 mug of thyroxine or 225 mug of triiodothyronine led to minimal changes in urinary hydroxyproline excretion, pulse rate and body weight. These observations indicate that this boy has a target organ insensitivity to thyroid hormones. When compared with other patients with this disorder, the studies further emphasize that this condition may have a variable clinical presentation. In addition, the extent of the target organ defect may not be evident from routine clinical and laboratory observations. The possible molecular basis of the defect is discussed.

Adolescent↗
PubMed1975

Urinary kallikrein excretion in spontaneously hypertensive rats.

Urinary kallikrein was similar in 16-week-old Wistar/Kyoto (W/Ky) and spontaneously hypertensive (SH) rats, but at 23 weeks the SH rats excreted significantly less kallikrein. When dietary sodium was restricted, kallikrein excretion increased in the W/Ky but not in the SH rats. On high dietary sodium the opposite occurred: kallidrein excretion increased in the SH but not in the W/Ky rats. The pattern of urinary kallikrein excretion has some similarity to that seen in human hypertensive disease, i.e., the SH rat excretes less kallikrein than the normotensive control at 23 weeks of age and does not show an increased excretion when fed a low sodium diet. However, the rise in kallikrein shown by the SH rat on a high sodium diet is unique for this hypertensive model.

Animals↗
PubMed1975

Regulation of postocclusive hyperemia by endogenously synthesized prostaglandins in the dog heart.

Experiments were performed to evaluate the role of prostaglandin synthesis in the regulation of coronary blood flow in dog hearts. The left main coronary artery was cannulated and flow measured both in otherwise intact animals and in canine heart-lung preparations. Prostaglandin E was measured by radioimmunoassay. Reactive hyperemia (flow after occlusion release) was induced by coronary occlusion for 10, 15, and 20 s and was 39 plus or minus 13 (mean plus or minus SEM), 66 plus or minus 21, and 82 plus or minus 24 ml, respectively. Indomethacin, an inhibitor of prostaglandin synthetase, reduced reactive hyperemia at 10, 15, and 20 s to 15 plus or minus 5, 33 plus or minus 11, and 47 plus or minus 17 ml, respectively (P smaller than 0.05). Meclofenamate, a different prostaglandin synthetase inhibitor, gave similar results. In a second group of five dogs, prostaglandin production of the heart was examined in response to 20-s occlusions. There was a significant increase in prostaglandin production from a basal level of 18.6 plus or minus 4.9 mg/min to 35.3 plus or minus 5.8 ng/min after occlusion of the coronary artery for 20 s (P smaller than 0.05). After indomethacin, this increase in prostaglandin production was not observed and reactive hyperemia was significantly reduced. Thus, prostaglandin synthesis appears to be important to modulating canine coronary blood flow in response to brief periods of coronary occlusion.

Adenosine↗
PubMed1975

Changes in preference for NaCl following administration of 6-azauridine and 6-azauridine triacetate.

Preliminary evidence in man has suggested that 6-azauridine triacetate (6-AzUrdTA) might adversely affect taste acuity. The production of measurable serum concentrations of homocysteine in rabbits treated with 6-AzUrdTA further suggested a mechanism for the possible adverse effects of this drug on taste, since administration of other thiol-containing drugs in man and animals had been shown to decrease taste acuity. Since changes in preferences for NaCl solutions have been shown to reflect changes in taste acuity in the rat, preference for NaCl solutions in rats treated with 6-AzUrdTA were measured in a two-bottle test. Detection and recognition thresholds were also measured in patients with scleroderma before and after the administration of 6-AzUrdTA. Serum copper and zinc concentrations were measured in both rats and man. Rats given 6-AzUrdTA exhibited a significantly greater intake of 0.30-M NaCl than control rats, who avoided this solution. This change was accompanied by a significant decrease in serum zinc concentrations. No significant changes in taste acuity occurred in the patients. These data suggest that administration of 6-AzUrdTA affects taste acuity in rats either through the addition of thiols or the depletion of zinc.

Administration, Oral↗