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Biomedical subjects

L Axelrod

Publications and source records attributed to L Axelrod.

At least 37 records · Page 2Linked to original sources
PubMed1986

Plasma eicosanoid levels in rats with nonketotic diabetes mellitus: effect of severity.

Nonketotic diabetes mellitus (DM) is associated with increased platelet production of thromboxane (TX) A2 and decreased endothelial production of prostacyclin (prostaglandin [PG]I2), but measurements of stable derivatives of these substances in the circulation have yielded discordant results. We studied the relationship between the severity of nonketotic DM and the plasma levels of 13,14-dihydro-15-keto-PGE2, 6-keto-PGF1 alpha, and TXB2 (stable derivatives of PGE2, PGI2, and TXA2, respectively) in rats, using three commonly employed doses of streptozotocin (40, 50, and 60 mg/kg body weight) to induce nonketotic DM of varying severity. Small differences in the severity of DM were associated with considerable differences in the plasma levels of 13,14-dihydro-15-keto-PGE2 and 6-keto-PGF1 alpha but not TXB2. Each eicosanoid responded differently to variations in the severity of DM. The plasma 13,14-dihydro-15-keto-PGE2 level was significantly lower than normal in the rats given 40 mg/kg streptozotocin, was unchanged from normal in the rats given 50 mg/kg and was significantly higher than normal in the rats given 60 mg/kg. The plasma 6-keto-PGF1 alpha level was significantly increased in rats given 40 mg/kg and 60 mg/kg, but was unchanged in those given 50 mg/kg. The plasma TXB2 level was not significantly different from normal in any one of the three groups of rats with nonketotic DM. The effect of severity on the plasma levels of the PGE2 and PGI2 derivatives is unexplained, but may reflect the origin of these derivatives from diverse organs and tissues, and the differing effects of abnormal metabolic factors (eg, fatty acids, glucose, insulin, pH) on the synthesis of these derivatives.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Prostacyclin production by isolated rat adipocytes: evidence for cyclic adenosine 3',5'-monophosphate-dependent and independent mechanisms and for a selective effect of insulin.

The rat adipocyte contains two separate mechanisms for prostaglandin (PG) production. Norepinephrine stimulates prostacyclin (PGI2) and PGE2 production and triglyceride lipolysis in isolated rat adipocytes. In contrast, the vasoactive peptides angiotensin II, vasopressin, and bradykinin stimulate PGI2 production, but not PGE2 production or triglyceride lipolysis, in these cells. In this study, we characterized the two separate mechanisms of PG production with respect to the time course, the role of cAMP, the identity of the adrenergic receptor, and the effects of insulin and glucocorticoids. Angiotensin II stimulated PGI2 production rapidly (at 5 min) and independently of cAMP. beta-Adrenergic stimulation with isoproterenol produced a rapid 11-fold increase in the cAMP concentration and stimulated PGI2 production more slowly (at 120 min). The phosphodiesterase inhibitor 1-methyl-3-isobutylxanthine (0.2 and 0.5 mM) and the adenylate cyclase activator forskolin (10 microM) also stimulated cAMP production rapidly and PGI2 production more slowly. 1-Methyl-3-isobutylxanthine (5.0 mM) further stimulated cAMP levels, but prevented the increase in PGI2 production and blunted the increase in glycerol release seen at lower concentrations. beta-Adrenergic blockade with propranolol or timolol completely inhibited the norepinephrine- or isoproterenol-stimulated production of PGI2 and triglyceride lipolysis, respectively. Insulin selectively inhibited isoproterenol-stimulated PGI2 production and triglyceride lipolysis at physiological concentrations, but had no effect on angiotensin II-stimulated PGI2 production. In contrast, dexamethasone inhibited PGI2 production induced by both isoproterenol and angiotensin II. We conclude that: angiotensin II stimulates PGI2 production rapidly and independently of cAMP, but isoproterenol stimulates PGI2 production more slowly, an effect that is cAMP dependent; insulin inhibits the cAMP-dependent beta-adrenergic stimulation of PGI2 production (and triglyceride lipolysis), but not the cAMP-independent angiotensin II-induced stimulation of PGI2 production (this suggests that the former effect is mediated by a decrease in cAMP levels in the adipocyte); and dexamethasone inhibits both mechanisms of PGI2 production. Both mechanisms of PGI2 production by rat adipocytes are exquisitely sensitive to hormonal regulation.

1-Methyl-3-isobutylxanthine↗
PubMed1986

Plasma level of 13,14-dihydro-15-keto-PGE2 in patients with diabetic ketoacidosis and in normal fasting subjects.

Plasma levels of 13,14-dihydro-15-keto-PGE2, a stable derivative of PGE2, are elevated in rats with diabetic ketoacidosis (DKA) and decrease in response to insulin therapy. In patients with insulin-dependent diabetes mellitus type I (IDDM) the plasma levels of this derivative also rise in response to insulin withdrawal and then fall in response to insulin replacement. We wished to determine whether the level of this substance is elevated acutely when patients present with DKA and to determine whether the levels fall during treatment. We also wished to identify the origin of the circulating 13,14-dihydro-15-keto-PGE2 in patients with DKA and in normal fasting subjects. We measured the plasma level of 13,14-dihydro-15-keto-PGE2 in five patients with DKA and in six normal subjects during a 24-h fast. In the patients with DKA before treatment, the plasma 13,14-dihydro-15-keto-PGE2 level was threefold above normal. During therapy, the 13,14-dihydro-15-keto-PGE2 level fell toward normal. There was a significant direct correlation between the plasma free fatty acid (FFA) level and the plasma 13,14-dihydro-15-keto-PGE2 level before and during treatment. In addition, the inverse correlation between the plasma free-insulin level and the plasma 13,14-dihydro-15-keto-PGE2 level approached significance (P = .06). In contrast, in the normal fasting subjects the plasma FFA level rose to values comparable to those observed in the patients with DKA, but there was no significant increase in the plasma 13,14-dihydro-15-keto-PGE2 level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1985

Depression of serum calcium by increased plasma free fatty acids in the rat: a mechanism for hypocalcemia in acute pancreatitis.

Some patients with hypertriglyceridemia and acute pancreatitis have marked hypocalcemia and high levels of plasma free fatty acids (FFAs). This study tests the hypothesis that increased plasma FFAs can significantly reduce the calcium level in vivo, a phenomenon which is different from local formation of calcium soaps due to lipolysis of adipose tissue lipids. Free fatty acid elevation was induced in rats by the administration of heparin and by the infusion of triglycerides. The results show that, compared with controls, induction of elevated FFA (from 1.57 +/- 0.08 mEq/L to 5.64 +/- 0.35, mean +/- SEM) causes the concentration of calcium to fall rapidly (from 9.04 +/- 0.06 mg/dl to 8.42 +/- 0.10, p less than 0.001). There is a significant (p less than 0.001) positive correlation between spontaneous baseline concentration of FFA and the responsiveness of calcium concentration to FFA challenge. At near-normal levels of FFA there is a significant (p less than 0.001) correlation between the magnitude of increased FFA concentration and decreased calcium concentration. Additional studies in vivo and in vitro show that elevated plasma triglycerides per se did not interfere with measurement of calcium concentration; however, FFA-albumin complexes bind calcium and lower its measured value. These findings suggest that (a) changes in the concentration of FFA occurring spontaneously may affect measured serum calcium concentration; (b) the observed depression of serum calcium concentration may be due in part to intravascular sequestration of calcium by FFA, but increased flux of circulating calcium-FFA complexes into extravascular and intracellular sites may also be important; (c) the markedly increased FFA concentration in some patients with acute pancreatitis may contribute significantly to hypocalcemia and calcium flux in these patients. As parathyroid hormone secretion, function, or integrity may be impaired in pancreatitis, the depressant effect of FFA could be even greater in that disease than in this model.

Animals↗
PubMed1985

Stimulation of prostacyclin production in isolated rat adipocytes by angiotensin II, vasopressin, and bradykinin: evidence for two separate mechanisms of prostaglandin synthesis.

We compared the effects of three vasoactive peptides (angiotensin II, vasopressin, and bradykinin) and norepinephrine on the production of prostaglandin I2 [prostacyclin (PGI2)] and PGE2 by isolated rat adipocytes. Angiotensin II, vasopressin, and bradykinin stimulated PGI2 production but had minimal or no effect on PGE2 production or triglyceride lipolysis in isolated rat adipocytes, while norepinephrine stimulated PGI2 production, PGE2 production, and triglyceride lipolysis. The arachidonic acid that serves as substrate for PGI2 production in adipocytes in response to the vasoactive peptides appears to be derived from the cellular phospholipids rather than the triglycerides in these triglyceride-laden cells. The adipocyte contains two separate mechanisms for PG production: 1) a catecholamine-stimulated mechanism for the production of PGI2 and PGE2 that is activated concomitantly with triglyceride lipolysis, and 2) a mechanism activated by vasoactive peptides for the stimulation of PGI2 production independent of triglyceride lipolysis and PGE2 production. These mechanisms may have distinct functions.

Adipose Tissue↗
PubMed1985

Effect of carbohydrate supplementation on reproductive hormones during fasting in men.

We previously demonstrated that during a 10-day fast in mildly obese men, urinary gonadotropin excretion significantly increased, and serum testosterone concentrations significantly decreased. The mechanisms by which these changes occur are unknown. We postulated that the mechanism of the gonadotropinuria might involve decreased proximal renal tubular reabsorption of gonadotropins during fasting and might be related to renal tubular reabsorption of ketones during fasting, a process that is enhanced by carbohydrate (CHO) administration. We studied the effects of CHO supplementation on ketosis, ketonuria, and reproductive hormone secretion and excretion in 14 mildly obese men, 24-54 yr old, who were 14-69% above ideal body weight. Group I (n = 6) received no CHO supplementation, group II (n = 4) received 15 g CHO, and group III (n = 4) received 45 g CHO daily during the 10-day fast (F). During the control (C) and refeeding (R) periods, all subjects received a 1500-cal diet. Daily 24-h urine collections were made for the measurement of total ketones (millimolar concentrations) and LH and FSH (expressed as international units of the Second International Reference Preparation of human menopausal gonadotropin). Values (mean +/- SE) for 3 representative days (control day 3, fasting day 8, and refeeding day 3) for all subjects are shown below: (table; see text) We also studied the effects of CHO supplementation on serum levels of pituitary gonadotropins, LH and FSH responses to exogenous LHRH stimulation, biological activity of LH, and circulating total and free testosterone levels. Neither dose of CHO prevented the decline in total and free testosterone levels. Serum LH concentrations, as measured by both the RIA and in vitro bioassay did not change significantly with fasting. Serum FSH concentrations in daily samples did not change significantly. The previously reported decline in the FSH response to LHRH stimulation with fasting was not prevented by CHO. We conclude that CHO supplementation prevents the gonadotropinuria of fasting in men. The effect appears to occur in the kidney. The mechanisms may be related to that by which CHO promotes the renal tubular reabsorption of ketones. The reduced serum testosterone level cannot be explained by a lack of biologically active LH. It appears that fasting has a direct effect on the testis, possibly by reducing its responsiveness to gonadotropic stimulation or by inhibiting steroidogenesis.

Adult↗
PubMed1984

Plasma prostaglandin levels and circulating fuel levels in rats with diabetic ketoacidosis: effects of cyclooxygenase inhibitors and of alpha and beta adrenergic blockade.

We studied the effects of two structurally unrelated inhibitors of the fatty acid cyclooxygenase and of alpha and beta adrenergic blockade on the elevated plasma levels of 13,14-dihydro-15-keto-prostaglandin (PG)E2, 6-keto-PGF1 alpha and thromboxane (TX)B2, the stable derivatives of PGE2, PGI2 (prostacyclin) and TXA2, respectively, in rats with streptozotocin-induced diabetic ketoacidosis (DKA). Meclofenamic acid and indomethacin each produced a significant decrease in the elevated plasma levels of 13,14-dihydro-15-keto-PGE2, 6-keto-PGF1 alpha and TXB2. Phentolamine significantly reduced the plasma level of TXB2 but had no effect on the elevated circulating levels of glucose, free fatty acids, total ketones, 13,14-dihydro-15-keto-PGE2 or 6-keto-PGF1 alpha. Propranolol significantly reduced the elevated circulating levels of glucose, free fatty acids and total ketones but had no effect on the levels of the three prostaglandin derivatives. The ability of meclofenamic acid and indomethacin to reduce the plasma levels of 13,14-dihydro-15-keto-PGE2, 6-keto-PGF1 alpha and TXB2 confirms that the plasma levels of these three derivatives are elevated in rats with DKA. Since abnormalities in the production of PGI2 and perhaps other cyclooxygenase derivatives may contribute to the pathogenesis of certain important hemodynamic and gastrointestinal features of DKA, cyclooxygenase inhibitors may play a role in the management of selected patients with this disorder. Alpha adrenergic activity is essential for the maintenance of the elevated plasma TXB2 level in rats with DKA. The fall in the plasma TXB2 level during alpha adrenergic blockade appears to reflect inhibition of platelet aggregation and platelet TXA2 production, but other sources of the elevated plasma TXB2 level in DKA are not excluded. Beta adrenergic activity contributes to the maintenance of elevated circulating levels of glucose, free fatty acids and total ketones in experimental DKA but not to the elevated plasma levels of the prostaglandin derivatives.

6-Ketoprostaglandin F1 alpha↗
PubMed1983

Inhibition of prostacyclin production mediates permissive effect of glucocorticoids on vascular tone. Perturbations of this mechanism contribute to pathogenesis of Cushing's syndrome and Addison's disease.

Glucocorticoids have a permissive effect on vascular tone and blood pressure; they enhance vascular responsiveness to vasopressors such as catecholamines without necessarily having an effect when administered alone. This effect does not require central or systemic mediation. Prostacyclin (prostaglandin I2; PGI2), a potent vasodilator, is produced by the vascular endothelium, vascular smooth muscle cells, adipocytes, and other cells. PGI2 production by vascular endothelium and other cells is decreased by glucocorticoids. The hypothesis is proposed that the effect of glucocorticoids on vascular tone is mediated by inhibition of PGI2 production by vascular endothelium (possibly other cells also). The inhibition of PGI2 production by glucocorticoids may contribute to the hypertension of Cushing's syndrome. Loss of this inhibitory effect in glucocorticoid deficiency states (eg, Addison's disease) may cause enhanced PGI2 production, which may contribute to the haemodynamic and gastrointestinal manifestations of these disorders.

Addison Disease↗
PubMed1983

Inhibitory effect of insulin on prostacyclin production by isolated rat adipocytes.

Physiologic concentrations of insulin completely inhibited the norepinephrine-induced increment in the production of 6-keto-prostaglandin (PG) F1 alpha, the stable derivative of prostacyclin (PGI2), by isolated rat adipocytes. The inhibition of PGI2 production by insulin in isolated rat adipocytes supports the view that the elevated plasma level of 6-keto-PGF1 alpha in rats with non-ketotic diabetes mellitus and diabetic ketoacidosis is derived at least in part from production of PGI2 by the adipocyte cell mass.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Invasive external otitis. Report of 21 cases and review of the literature.

We report 21 cases of invasive external otitis and review 130 cases from the English literature. Invasive external otitis is the term that most appropriately describes the locally invasive Pseudomonas infections that begins in the external ear canal, breaches the epithelial barrier and results in signs of local subcutaneous tissue invasion. Nineteen patients were diabetic. FIfteen of these 19 had preexistent, long-standing diabetes (average 15.8 years) and 10 had microvascular disease. Studies of the skin of the temporal bone in two patients provided evidence of diabetic microangiopathy of the dermal capillaries. Pseudomonas aeruginosa was isolated from the involved area in all cases. All patients without neurologic deficits survived, compared with six of nine with deficits of the central nervous system. All 13 patients in whom initial therapy was successful received a combination of an aminoglycoside and a semisynthetic penicillin, whereas all six episodes of recurrent disease occurred when only one antibiotic was used. The overall mortality was 15 percent (three of 20 in whom the long-term outcome is known). We propose that diabetic microangiopathy of the skin of the temporal bone results in poor local perfusion and creates an environment well suited for invasion by Pseudomonas aeruginosa. There is a good correlation between the extent of disease clinically and prognosis. Effective treatment requires early diagnosis and combination therapy with an aminoglycoside and a semisynthetic penicillin.

Adolescent↗
PubMed1981

Enhancement of ketosis by 16,16 dimethylprostaglandin E2 during the genesis of diabetic ketoacidosis in rats.

We examined the effects of 16,16 dimethylprostaglandin E2 (DMPGE2) on the development of diabetic ketoacidosis (DKA) in rats. Animals received DMPGE2, 200 or 300 microgram/kg body weight subcutaneously in 0.5 ml saline, or the saline carrier alone at 0, 12, 24 and 36 hours after administration of streptozotocin. At 40 hours, blood was obtained for measurement of plasma free fatty acids (FFAs) and ketone bodies. DMPGE2 produced a dose-related decrease in plasma FFA levels at 40 hours. FFA levels were 2.76 +/- 0.39 meg/L (mean +/- SEM) with saline, 1.72 +/- 0.22 meg/L with 200 microgram/kg DMPGE2 (p less than 0.05 vs saline) and 1.19 +/- 0.17 meg/L with 300 microgram/kg DMPGE2 (p less than 0.025 vs saline) consistent with the previously demonstrated antilipolytic effect of DMPGE2 in vivo and in vitro. Despite suppression of lipolysis, DMPGE2 enhanced the development of ketosis during the genesis of DKA. The beta-hydroxybutyrate level was 5.89 +/- 0.06 mM with saline, 8.15 +/- 1.02 mM with 200 microgram/kg DMPGE2 and 11.17 +/- 0.60 mM with 300 microgram/kg DMPGE2 (p less than 0.001 vs saline). This study demonstrates that this analog of prostaglandin E2 promotes the development of ketosis during the genesis of DKA despite decreased substrate availability. This may be due to enhancement of hepatic ketogenesis, impairment of ketone disposal, or both.

Animals↗
PubMed1981

Congenital goiter and the development of metastatic follicular carcinoma with evidence for a leak of nonhormonal iodide: clinical, pathological, kinetic, and biochemical studies and a review of the literature.

We report a large kindred of patients with congenital goiter, followed for 15 yr, in which two siblings (one male and one female) developed metastatic follicular thyroid carcinoma. These two patients were evaluated by iodine kinetic analysis. None of the classical defects of T4 biosynthesis was present in either patient. Rather, both patients had extremely rapid rates of iodine turnover, with elevated 131I uptake and excessive spillage of iodide in the urine. Serum iodoalbumin was present, probably as a nonspecific result of glandular hyperplasia. Iodine kinetic analysis after the ingestion of potassium perchlorate and methimazole was compatible with a leak of nonhormonal iodide from the thyroid. It is not possible to determine whether this iodide leak is the primary pathogenetic defect or is secondary to another unidentified abnormality. The unprecedented development of metastatic thyroid cancer in patients with congenital goiter occurred, in both instances years after subtotal thyroidectomy without thyroid hormone replacement therapy, suggesting a role for TSH in the genesis of human thyroid cancer. On the basis of our study of these patients and a review of the literature, we conclude that TSH is likely to be a factor in the induction of human follicular thyroid carcinoma.

Adenocarcinoma↗