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Biomedical subjects

J R Gill

Publications and source records attributed to J R Gill.

At least 19 recordsLinked to original sources
PubMed1992

Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Alleles↗
PubMed1992

Distinction between hyperaldosteronism due to bilateral hyperplasia and unilateral aldosteronoma: reliability of CT.

Hyperaldosteronism due to a unilateral adenoma must be distinguished from hyperaldosteronism due to bilateral hyperplasia to enable the proper choice between surgical treatment (for adenoma) or medical treatment (for hyperplasia). To compare the efficacy of computed tomography (CT) and adrenal venous sampling, both examinations were performed in 24 patients with primary aldosteronism. All patients with a diagnosis of adenoma based on findings at venous sampling underwent adrenalectomy. The CT-based diagnosis was unilateral aldosteronoma in 17 patients and hyperplasia in seven patients. On the basis of venous sampling, unilateral adenoma was diagnosed in 22 patients; this diagnosis was confirmed by means of unilateral adrenalectomy in 21 patients. The most common error was diagnosis of hyperplasia based on the presence of bilateral nodules on CT scans: In six of seven patients with such a diagnosis, venous sampling and subsequent surgery revealed a unilateral adenoma. In hyperaldosteronism with multiple bilateral nodules, CT cannot reliably permit distinction between hyperplasia and adenoma.

Adenoma↗
PubMed1991

Effects of prostaglandins, cAMP, and changes in cytosolic calcium on platelet aggregation induced by a thromboxane A2 mimic (U46619).

The effects of U46619, a thromboxane mimic, on cytosolic Ca2+ concentration and platelet aggregation were determined in human platelets. Cytosolic Ca2+ concentration was determined by Quin-2 fluorescence and platelet aggregation quantitated with an aggregometer. Addition of U46619 (1 x 10(-7) M) to the platelet suspension produced a rapid increase in cytosolic Ca2+ and platelet aggregation. Pretreatment of platelets with EGTA (3 x 10(-3) M), verapamil (5 x 10(-4) M), a calcium entry blocker, or 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride (1 x 10(-3) M), an inhibitor of intracellular Ca2+ release, either blunted or markedly delayed the rate, but not the magnitude, of increase in cytosolic Ca2+ and prevented platelet aggregation by U46619. Pretreatment of platelets with prostaglandin I2 (PGI2) (5 x 10(-8) M), PGD2 (5 x 10(-8) M), PGE1 (5 x 10(-8) M), PGF2 alpha (1 x 10(-5) M), dibutyryl cAMP (5 x 10(-3) M), or forskolin (1 x 10(-6) M) prevented both the increase in cytosolic Ca2+ and the associated platelet aggregation induced by U46619. These data suggest that U46619 may induce platelet aggregation through an increase in cytosolic Ca2+, and that both Ca2+ entry and its release from intracellular storage sites probably contribute to the increase in cytosolic Ca2+. Furthermore, the rate of the increase in cytosolic Ca2+ concentration, as well as the magnitude of the increase, appear to be critical for platelet aggregation induced by U46619. Our data are consistent with the hypothesis that PGs inhibit U46619-induced platelet aggregation by preventing the increase in cytosolic Ca2+, and that these effects may be mediated via an increase in cAMP, since they were induced by PGs and cAMP.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

High urinary dopa and low urinary dopamine-to-dopa ratio in salt-sensitive hypertension.

Dopamine in urine is derived substantially from renal uptake and decarboxylation of 3,4-dihydroxyphenylalanine (dopa), and increases in excretion of dopa normally parallel increases in excretion of dopamine during salt loading. Since patients with salt-sensitive hypertension may have decreased urinary excretion of dopamine during dietary salt loading, the present study was designed to evaluate the response of dopa to salt loading. Sixteen inpatients with normal-renin essential hypertension ate a constant metabolic diet containing 9 mmol/day sodium for 7 days, followed by the same diet but containing 249 mmol/day sodium for 7 days. Salt sensitivity was defined as an increase in mean arterial pressure of 8 mm Hg between the diets; on this basis, nine patients were salt-sensitive and seven, salt-resistant. The rate of urinary dopa excretion was significantly higher in the salt-sensitive patients throughout the study (mean rates 132 +/- 13 nmol/day in the salt-sensitive group and 78 +/- 9 nmol/day in the salt-resistant group for the 14 days of observation, p less than 0.01). When dietary sodium intake was increased to 249 mmol/day, urinary dopa excretion increased significantly more in salt-sensitive patients than salt-resistant patients. At the end of the high salt diet, dopamine excretion was significantly attenuated in the salt-sensitive patients, despite higher rates of dopa excretion. Thus, the urinary ratio of dopamine to dopa was decreased in salt-sensitive patients, regardless of salt intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Defective fasciculata zone function as the mechanism of glucocorticoid-remediable aldosteronism.

Glucocorticoid-remediable aldosteronism is characterized by unusual sensitivity of aldosterone secretion to ACTH. Suppressibility by glucocorticoid and continued stimulability by exogenous ACTH has provided the basis for diagnosis and treatment of the disorder. A qualitative biochemical abnormality consisting of marked overproduction of the products of the cortisol C-18 oxidation pathway, 18-hydroxycortisol and 18-oxocortisol, has been examined in 10 patients with the disorder and compared to the normal C-18 oxidation products of corticosterone, aldosterone, and 18-hydroxycorticosterone. The technique, based on stable isotope dilution mass fragmentography, measured the tetrahydro urinary metabolites of aldosterone, 18-hydroxycorticosterone, and 18-oxocortisol and unmetabolized 18-hydroxycortisol. All 4 C-18 oxygenated corticosteroids were markedly elevated in the untreated state and showed rapid parallel suppression with low doses of glucocorticoid. The proportional changes in C-18 oxygenated cortisols together with aldosterone and 18-hydroxycorticosterone suggested the mechanism of a common catalytic site of a cytochrome P450 methyl oxidase serving both cortisol and corticosterone substrates. The ACTH-dependent secretion of the C-18 oxidation products of both corticosterone and cortisol in the disorder is attributed to the acquisition of methyl oxidase activity by the fasciculata zone, where there are abundant pools of these precursors.

Adolescent↗
PubMed1989

Urinary excretion of dihydroxyphenylalanine and dopamine during alterations of dietary salt intake in humans.

1. Urinary excretion of dopamine (DA) increases during dietary salt loading. The majority of urinary DA is derived from circulating dihydroxyphenylalanine (dopa). Whether the increase in urinary DA excretion during salt loading results from increased efficiency of uptake of dopa by proximal tubular cells of the kidney, facilitation of intracellular conversion of dopa to DA, or increased delivery of dopa to tubular uptake sites, has been unknown. 2. In 10 inpatient normal volunteers on a constant diet, daily excretion of dopa and DA was assessed during normal sodium intake (109 mmol/day) for 1 week, low sodium intake (9 mmol/day) for 1 week and high sodium intake (249 mmol/day) for 1 week. 3. Urinary DA excretion exceeded urinary dopa excretion by about tenfold, and the excretion of both DA and dopa increased by about twofold between the low and high salt diets, with similar proportionate changes. Plasma dopa was unchanged by dietary salt manipulation. 4. The results indicate that increases in urinary DA excretion during dietary salt loading can be accounted for by increased delivery of dopa to sites of uptake by proximal tubular cells. Since dopa is released into the bloodstream by sympathetic nerve endings and by the brain, and since interference with decarboxylation of dopa attenuates natriuretic responses, dopa may function indirectly as a neurohormone involved in homoeostatic regulation of sodium balance.

Adult↗
PubMed1988

Plasma and urinary catecholamines in salt-sensitive idiopathic hypertension.

Nineteen patients with normal renin idiopathic hypertension were arbitrarily classified as salt-sensitive or salt-resistant depending on whether their mean arterial pressure did or did not increase by 8% or more when sodium intake was increased. The responses of the two subsets and of five normal subjects to sodium intakes of 9, 109, and 249 mEq/day given for 7 days were as follows: The salt-sensitive subjects retained more sodium than normal and plasma or urinary norepinephrine did not decrease when they were given a high sodium intake; urinary dopamine was normal but did not increase normally when sodium intake was increased. The salt-resistant subjects excreted sodium normally and plasma and urinary norepinephrine was decreased by 30 and 37%, respectively, when they were given a high sodium intake; urinary dopamine was supernormal and did not increase further when sodium intake was increased. Cumulative sodium retention during the high sodium intake was directly related to the percentage of change in plasma norepinephrine in the hypertensive subjects, suggesting that renal adrenergic activity was a factor in the impaired sodium excretion in the salt-sensitive patients. Cumulative sodium retention and the percentage of change in plasma norepinephrine were inversely related to urinary dopamine in the hypertensive subjects, suggesting that increased formation of dopamine in renal and neural tissue in the salt-resistant subjects may have been responsible for the differences between the subsets in renal and adrenergic responses to a high sodium intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Glucocorticoid-suppressible aldosteronism: a disorder of the adrenal transitional zone.

Glucocorticoid-suppressible aldosteronism (GSA) is a rare form of hyperaldosteronism in which the increased secretion of aldosterone and the elevation of blood pressure are corrected when ACTH secretion is suppressed. Two 17-hydroxylated analogs of 18-hydroxycorticosterone and aldosterone, 18-hydroxycortisol and 18-oxocortisol, which had been identified in the urine of patients with hyperaldosteronism due to an adrenal adenoma and in bullfrog adrenal tissue incubated with cortisol, are produced in greater than normal quantities in patients with GSA. The excretion of 18-hydroxycortisol and 18-oxocortisol in nine patients with GSA was 2914 +/- 923 (+/- SD) nmol/day [1108 +/- 351 micrograms/day; normal, 165 +/- 94 nmol/day (63 +/- 36 micrograms/day)] and 141 +/- 77 nmol/day [53 +/- 29 micrograms/day; normal, 3.2 +/- 2.4 nmol/day (1.2 +/- 0.9 micrograms/day)], respectively. The excretion of aldosterone 18-oxoglucuronide was 53 +/- 18 nmold/day [19.4 +/- 6.8 micrograms/day; normal, 16.9 +/- 7.5 nmol/day (6.1 +/- 2.7 micrograms/day)]. Aldosterone excretion was elevated in six patients and within the normal range in three patients. The degree of abnormality in 18-hydroxycortisol and 18-oxocortisol excretion was significantly greater than that in aldosterone. Dexamethasone administration decreased excretion of the three steroids to the normal range. ACTH administration for 3 days resulted in an exaggerated increase in the excretion of these steroids, suggesting ACTH dependence of these steroids in patients with GSA. The excessive production of these steroids, which are 17- and 18-hydroxylated, indicate that they are produced by hybrid-type cells which we have called transitional cells, which are also capable of producing aldosterone. These findings are consistent with the postulate that cytochrome P-450-corticosterone methyl oxidase fails to disappear normally in the zona glomerulosa cells as they migrate to the zona fasciculata and acquire 17-hydroxylase activity. This abnormality explains the supernormal conversion of cortisol to 18-hydroxycortisol and 18-oxocortisol and the ACTH dependence of aldosterone secretion in GSA.

Adolescent↗
PubMed1987

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.

Animals↗
PubMed1985

On the mechanism of renal vasoconstriction induced by acetylcholine in indomethacin-treated dogs.

Renal arterial infusion of acetylcholine (ACh) in control dogs produced a natriuresis and diuresis and an increase in renal plasma flow (RPF) without a change in glomerular filtration rate (GFR) or in renin secretory rate (RSR). In dogs pretreated with indomethacin (Indo), an inhibitor of prostaglandin synthetase, renal arterial infusion of ACh first produced a rise, then a decline in urine flow, sodium excretion (UNaV) and GFR that was accompanied by a progressive fall in RPF and a progressive rise in RSR. The rise in RSR was potentiated by renal arterial infusion of an alpha-adrenergic receptor blocker, phenoxybenzamine (Phenoxy), and attenuated, but not completely abolished, by beta-adrenergic receptor blockade with propranolol (Prop). Chemical denervation with reserpine alone, or in combination with chronic surgical renal denervation, failed to prevent the fall in RPF, GFR and UNaV and the rise in RSR produced by ACh in Indo-treated dogs. Renal arterial infusion of Phenoxy and intravenous infusion of Prop, alone or in combination with renal arterial infusion of an angiotensin II antagonist, saralasin, failed to maintain the vasodilatory, diuretic and natriuretic effects of ACh in Indo-treated dogs. Elimination of endogenous vasopressin by hypophysectomy also failed to prevent the vasoconstriction induced by ACh in Indo-treated dogs. The results suggest that ACh produced renal vasoconstriction in Indo-treated dogs by mechanism(s) other than an increase in renal adrenergetic activity or an increase in the activity of the renin-angiotensin system. The results also suggest that the vasoconstriction was independent of vasopresin.

Acetylcholine↗
PubMed1985

Endocrine, renal, and hemodynamic responses to graded dopamine infusions in normal men.

The present study was performed to determine the hemodynamic, hormonal, and natriuretic responses to infusions of dopamine (DA) that reflect physiological as well as pharmacological levels in blood or tissue. In six normal men, DA was infused for 2 h at three fixed dosages (0.03 or 0.1, 0.3, and 3.0 micrograms/kg X min) on three separate occasions, which resulted in increases in mean plasma DA concentrations from basal levels of less than 0.03 ng/ml to 0.69 +/- 0.12, 3.73 +/- 0.40, and 38.4 +/- 3.80 (+/- SE) ng/ml. Mean plasma PRL decreased and DA excretion increased significantly from basal levels during all three DA infusions. Plasma LH decreased and norepinephrine (NE) excretion increased during both the middle and high dose infusions, while sodium excretion, plasma NE, and heart rate increased only during the high dose DA infusion. Basal plasma aldosterone values were low and did not change with DA treatment. PRA, TSH, and FSH also did not change. GH responses were difficult to assess because of the frequency of episodic secretions. Since DA concentrations in hypophysial-portal blood may equal or exceed 1 ng/ml, these results support a role for DA in the acute regulation of PRL, and possibly LH, in normal men. As a natriuretic response occurred only at supraphysiological concentrations of circulating DA, if DA has a physiological role in modulating sodium excretion during normal sodium intake, it must be released from dopaminergic neurons or otherwise locally produced in very high concentrations in the kidney.

Adult↗
PubMed1984

Prostaglandin E2 but not F2 alpha restores the natriuretic response to acetylcholine in indomethacin-treated dogs.

Renal arterial infusion of acetylcholine (ACh) (40 micrograms/min) produces a natriuresis, diuresis, and an increase in renal plasma flow (RPF) without a change in glomerular filtration rate (GFR) or renin secretory rate (RSR). The present study was designed to examine the role of prostaglandins in this natriuretic response to ACh. In dogs pretreated with indomethacin (Indo) (5 mg/kg, i.v.), an inhibitor of prostaglandin synthesis, renal arterial infusion of ACh produced an increase and then a decline in urinary flow and sodium excretion accompanied by a progressive fall in GFR and RPF and a progressive increase in RSR. Renal arterial infusion of PGE2 (1.9 micrograms/min) but not PGF2 alpha (1.9 micrograms/min) before and during the infusion of ACh restored the diuretic and natriuretic response to ACh in Indo-treated dogs. Renal arterial infusion of bradykinin (BK) (3 micrograms/min) in Indo-treated dogs produced a diuresis and natriuresis similar to that produced by PGE2; renal arterial infusion of BK, however, did not restore the diuretic and natriuretic response to ACh in Indo-treated dogs. The data suggest that Indo shortens the diuretic and natriuretic response to ACh by inhibiting synthesis of prostaglandins, possibly PGE but not PGF. The data further suggest that PGE2 restores the diuretic and natriuretic response to ACh in Indo-treated dogs through a specific action rather than by its action as a renal vasodilator.

Acetylcholine↗
PubMed1984

Correction of hypokalemia corrects the abnormalities in erythrocyte sodium transport in Bartter's syndrome.

In Bartter's syndrome, the defective renal tubular transport has been postulated to be a manifestation of a more generalized membrane abnormality. To explore this possibility, sodium concentration, ouabain-sensitive (pump transport), ouabain-resistant but furosemide-sensitive (Na-K-Cl cotransport), and ouabain- and furosemide-resistant (passive transport) 22Na effluxes were measured in erythrocytes obtained from nine patients with Bartter's syndrome before and during correction of hypokalemia. Intracellular [Na+] in erythrocytes obtained from nine patients with Bartter's syndrome was significantly (P less than 0.001) higher than that in 30 normal controls (11.8 +/- 1.8 vs. 7.3 +/- 1.4 mmol/liter cells). Pump transport and Na-K-Cl cotransport 22Na effluxes were significantly (P less than 0.01) increased, whereas the rate constant for these effluxes as well as for passive 22Na efflux did not differ from normal. Correction of hypokalemia and maintenance of a normal serum potassium decreased intracellular [Na+] to 8.2 +/- 1.8 mmol/liter cells, a normal value, and corrected the ouabain-sensitive and furosemide-sensitive 22Na effluxes. The results indicate that exposure of erythrocytes to a low potassium environment is responsible for the high intracellular [Na+] and, in turn, the high sodium efflux in Bartter's syndrome. The normal sodium efflux observed during correction of hypokalemia and the consistently normal rate constants for all three efflux parameters measured suggest that intrinsic sodium transport processes in erythrocytes are normal in Bartter's syndrome.

Bartter Syndrome↗
PubMed1984

Endogenous prostacyclin synthesis is decreased during activation of the renin-angiotensin system in man.

Prostacyclin has been implicated as a mediator of renin release, whereas angiotensin II evokes prostaglandin I2 (PGI2) release from both vascular and nonvascular tissues in vitro. The physiological significance of these observations was assessed by measurement of an index of endogenous prostacyclin biosynthesis in human volunteers during varied activation of the renin-angiotensin system secondary to manipulation of dietary sodium. Excretion of the major urinary metabolite of prostacyclin in man, 2,3-dinor-6-keto-PGF1 alpha (PGI-M), fell from 295 +/- 51 to 176 +/- 35 (+/- SEM) ng g creatinine-1 (P less than 0.01) in 10 normal subjects when sodium intake was decreased from 150 to 10 meq/day. In five patients with primary hyperaldosteronism, PGI-M fell from 199 +/- 34 ng g creatinine-1 preoperatively to 120 +/- 26 pg/mg creatinine-1 after removal of the adenoma. In such patients, the reduction in PGI-M was associated with a significant increase in PRA. Thus, in both normal subjects and patients with hyperaldosteronism, PGI-M excretion fell rather than increased with activation of the renin-angiotensin system. This suggests that systemic biosynthesis of PGI2 is unrelated to renin release and that angiotensin II is unlikely to stimulate endogenous prostacyclin biosynthesis under these conditions in man.

Adenoma↗