PubMed Health⌕ Search

Biomedical subjects

G T Griffing

Publications and source records attributed to G T Griffing.

At least 37 records · Page 2Linked to original sources
PubMed1988

Identification of 19-hydroxy-progesterone in human placenta.

We have tentatively demonstrated the presence of a 19-hydroxylated C21 steroid, 19-hydroxy-progesterone, in normal human placenta. A 19-hydroxylated steroid such as 19-hydroxy-progesterone, if produced by the placenta, could serve as a precursor for such hypertensinogenic 19-nor-steroids as 19-nor-deoxycorticosterone and 19-nor-progesterone. Freshly delivered, homogenized placental tissue was extracted and subjected to thin layer chromatography. A steroid corresponding to standard 19-hydroxy-progesterone was subsequently purified in HPLC, where authentic 19-hydroxy-progesterone and the sample had the same retention time. The identity of the sample was further confirmed by repeat HPLC after acetylation and mass spectrometry. Our experiment indicates that 19-hydroxy-progesterone is present in term placental tissue, where it appears to be synthesized.

Acetylation↗
PubMed1988

Selective 19-hydroxylase inhibition by an aromatase inhibitor, 4-hydroxyandrostenedione.

19-Nor-deoxycorticosterone is a newly recognized mineralocorticoid which has been associated with some forms of genetic, experimental, and human hypertension. To further examine this relationship, specific inhibitors of 19-nor-deoxycorticosterone biosynthesis must be developed. Since 19-hydroxylation is the pivotal step in both 19-nor-deoxycorticosterone biosynthesis and aromatization of androgens to estrogens, we evaluated an aromatase inhibitor, 4-hydroxyandrost-4-ene-3,17-dione on the inhibition of 19-hydroxylation in both rat and human adrenal mitochondria in vitro and 19-nor-deoxycorticosterone production and blood pressure in spontaneously hypertensive rats in vivo. Adrenal mitochondria from 48 male Sprague-Dawley rats and 1 patient with an aldosterone-producing adenoma were incubated in the presence of deoxycorticosterone substrate both with and without 4-hydroxyandrost-4-ene-3,17-dione. 4-Hydroxyandrost-4-ene-3,17-dione produced significant inhibition of 19-hydroxy-deoxycorticosterone production in both rat and human adrenal mitochondria, with a smaller and not significant inhibition of corticosterone and 18-hydroxy-corticosterone. 4-Hydroxyandrost-4-ene-3,17-dione given subcutaneously to spontaneously hypertensive rats lowered 19-nor-deoxycorticosterone by 69% and completely abolished hypertension compared to Wistar-Kyoto controls. These data demonstrate that 4-hydroxyandrost-4-ene-3,17-dione is a specific inhibitor of 19-hydroxylase, that it lowers 19-nor-deoxycorticosterone production and prevents hypertension in the spontaneously hypertensive rat. These studies reinforce the possible pathogenic significance of 19-nor-deoxycorticosterone in hypertension in spontaneously hypertensive rats.

Androstenedione↗
PubMed1987

Antihypertensive effects of an aromatase inhibitor in the spontaneously hypertensive rat.

Recent studies from this laboratory have demonstrated that 19-nor-deoxycorticosterone, a potent mineralocorticoid, has been excreted in excess in the urine of young spontaneously hypertensive rats (SHR). Although urinary 19-nor-deoxycorticosterone levels decline before the onset of hypertension, preliminary evidence suggests that 19-nor-deoxycorticosterone is further oxygenated to other steroid products in older SHR. Since 19-hydroxylation is the essential first step in the formation of 19-nor-deoxycorticosterone from deoxycorticosterone and since the mechanism-based aromatase inhibitor 10-propargyl-androst-4-ene,3,17-dione preferentially inhibits 19-hydroxylation, this agent was administered to weanling SHR to determine whether inhibition of 19-nor-deoxycorticosterone formation could modify or prevent hypertension. Accordingly, either 10 mg of 10-propargyl-androst-4-ene,3,17-dione or vehicle (control) was injected daily for several weeks in 4.5 week-old SHR. Injection of 10-propargyl-androst-4-ene,3,17-dione reduced urinary free 19-nor-deoxycorticosterone and retarded the development of hypertension compared with the effect of vehicle injection (p less than 0.05). Mean blood pressure levels in SHR receiving 10-propargyl-androst-4-ene,3,17-dione were lower than those in SHR receiving vehicle for each of the first 8 weeks of treatment (p less than 0.05). These data support the importance of 10-nor-corticosteroids in the pathogenesis of hypertension in SHR.

Aging↗
PubMed1987

Biphasic 19-nor-deoxycorticosterone excretion after adrenal enucleation is associated with altered adrenal mitochondrial cytochrome P450 11 beta-, 18-, and 19-hydroxylase activities.

After adrenal enucleation (AE) rats avidly retain sodium (early phase), but after 7-10 days they lose this sodium avidity (late phase). Although increased production of a mineralocorticoid, 19-nor-deoxycorticosterone (19-Nor-DOC), has been implicated, 19-Nor-DOC levels during the early and late phases of AE have not been systematically measured. Furthermore it is not known why 19-Nor-DOC production should increase during a time when production of 11 beta- and 18-hydroxylated corticosteroids are decreased in AE. The purpose of this study was to examine the 11 beta, 18-, and 19-hydroxylase pathways in the early and late phases of AE. The results demonstrate increased urinary 19-Nor-DOC and decreased 18-OH-DOC and corticosterone excretion in the early phase of AE at a time when adrenal mitochondrial 11 beta- and 18-hydroxylase activities were decreased but 19-hydroxylase activity was unchanged. During the late phase of AE, urinary 19-Nor-DOC had decreased and 18-OH-DOC and corticosterone had increased to levels indistinguishable from those in sham controls. This reduction in 19-Nor-DOC was associated with a decrease in 19-hydroxylase activity in AE. Since the 11 beta, 18-, and 19-hydroxylases have a common substrate (DOC), it is possible that differential flux of DOC through these pathways could account for the changes in steroid production in AE. These data suggest that the increased 19-Nor-DOC excretion in AE may be due to alterations in enzyme activity leading to a shunting of DOC into the 19-Nor-DOC pathway. In addition, the synchronicity of 19-Nor-DOC with sodium excretion suggests that it has an important role in the pathogenesis of the sodium retention in AE.

Adrenal Glands↗
PubMed1987

Elevated urinary 19-Nor-deoxycorticosterone glucuronide in Cushing's syndrome.

Hypertension is a common finding in patients with Cushing's syndrome (CS), but the cause is unknown. One possibility is excess production of nonaldosterone mineralocorticoids, such as 19-nor-deoxycorticosterone (19-Nor-DOC). To evaluate this possibility we measured urinary 19-Nor-DOC glucuronide in normal subjects (n = 14) and patients with essential hypertension (n = 10), pituitary-dependent CS (n = 8), and adrenal tumors producing CS (n = 6). The subjects were admitted to a metabolic unit where 24-h urine samples were collected while they ate an isocaloric diet (128 meq Na+ 80 meq K+/day). 19-Nor-DOC glucuronide was purified by extraction and chromatography and measured by RIA. Urinary 19-Nor-DOC glucuronide excretion was significantly higher in patients with both pituitary CS and adrenal CS compared to that in normal subjects, while the values in the two CS groups were similar. The patients with essential hypertension also had elevated urinary 19-Nor-DOC glucuronide excretion, although the values were lower than those in either CS group. These results demonstrate that a nonaldosterone mineralocorticoid, 19-Nor-DOC, is produced in excess in patients with either pituitary or adrenal CS and, thus, suggest a possible role for 19-Nor-DOC in the pathogenesis of some hypertensive disorders.

Adenoma↗
PubMed1985

Intranasal aerosolized insulin. Mixed-meal studies and long-term use in type I diabetes.

We assessed the efficacy of intranasal aerosolized insulin containing laureth-9 as a surfactant in patients with Type I diabetes by fasting studies in 8 patients, mixed-meal studies in 15, and long-term home use in 8. The intranasal insulin (1 U per kilogram of body weight in 1 per cent laureth-9) was rapidly absorbed (in 15 minutes); it lowered the plasma glucose level by 50 per cent in 45 minutes in fasting normal controls and by 50 per cent in 120 minutes in fasting diabetics. The glucose-lowering potency depended on the insulin dose and surfactant concentration. Nasal irritation was proportional to surfactant concentration, with great variability among subjects. After intranasal insulin used before meals (1 U per kilogram in 1 per cent laureth-9), the two-hour postprandial glucose level increased above before-meal levels by 38 mg per deciliter, as compared with 191 mg per deciliter after intranasal placebo in patients with Type I diabetes (P less than 0.05). An outpatient feasibility study examining three months of use of intranasal aerosolized insulin before meals as a supplement to Ultralente insulin revealed that the aerosol was well tolerated, with glycemic control (as indicated by the percentage of glycohemoglobin, home glucose measurements, and hypoglycemic reactions) comparable to that during a subsequent three-month period of conventional subcutaneous insulin treatment. The results suggest that intranasal insulin has potential as an adjunct to subcutaneous insulin in the therapy of Type I diabetes.

Absorption↗
PubMed1985

Discordance of plasma DHEA-S, DHEA, and cortisol responses with various ACTH regimens.

The origin and time course of ACTH-stimulated adrenal androgens are controversial. Since previous protocols have used differing ACTH preparations and routes of administration, we sought to compare plasma DHEA and DHEA-S responses to four ACTH regimens. Fourteen young men underwent the following five three-day study periods: (1) placebo, (2) alpha 1-24 ACTH, 400 micrograms intravenously (IV); (3) alpha 1-39 ACTH, 400 micrograms intramuscularly (IM); (4) alpha 1-18 (D-Ser1, Lys17, Lys18) ACTH, 400 micrograms IM; and (5) alpha 1-18 ACTH, 400 micrograms IV. alpha 1-18 ACTH IV had the most potent and prolonged corticotropic effect, listing more than 24 hours, as measured by plasma cortisol, 17-OHCS, and cortisol secretion rates. alpha 1-39 ACTH and alpha 1-18 ACTH IM were corticotropic up to 12 hours, and alpha 1-24 ACTH IV was corticotropic only up to one hour. Plasma DHEA rose acutely at one hour with all of the ACTH regimens (P less than 0.05). This response was correlated with cortisol (r = 0.62, P less than 0.01) and reflected the relative corticotropic potency of each of the ACTH regimens. Plasma DHEA-S, on the other hand, did not rise acutely at one hour with any of the regimens. DHEA-S did rise at 12 hours with three of the ACTH regimens (alpha-1-24, alpha 1-39, alpha 1-18 IM), but this response was not synchronous with cortisol (r = 0.14, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1985

Plasma immunoreactive gamma melanotropin in patients with idiopathic hyperaldosteronism, aldosterone-producing adenomas, and essential hypertension.

A non-ACTH aldosterone-stimulating factor(s) has been implicated in the pathogenesis of idiopathic hyperaldosteronism (IHA). Although this factor has not been fully characterized, some evidence suggests that it may be related to a pro-gamma-melanotropin (pro-gamma-MSH), derived from the NH2-terminal region of pro-opiomelanocortin. In the present study, plasma immunoreactive (IR-) gamma-MSH levels at 0800 h in patients with IHA were evaluated (90 +/- 17 fmol/ml; range: 13-173 fmol/ml) and found to be significantly higher (P less than 0.05) than those in subjects with aldosterone-producing adenomas (33 +/- 8 fmol/ml), essential hypertension (33 +/- 6 fmol/ml), and normotensive controls (19 +/- 2 fmol/ml). Seven of nine IHA subjects had circulating IR-gamma-MSH levels above the normal range (greater than 35 fmol/ml). In plasmas sampled at 1200 h, IR-gamma-MSH was significantly higher in patients with IHA (95 +/- 26 fmol/ml) and adenomas (63 +/- 23 fmol/ml), as compared with essential hypertensives (31 +/- 6 fmol/ml) and normotensives (19 +/- 3 fmol/ml). Mean plasma IR-ACTH, plasma cortisol, and urinary cortisol levels did not differ significantly between any of these groups. In order to evaluate the effect of a pro-gamma-MSH in vitro, adrenal adenoma tissue was obtained from two patients, one with elevated IR-gamma-MSH (61 fmol/ml) and a second with low IR-gamma-MSH (12 fmol/ml). Aldosterone secretion by dispersed adenoma cells from the former, but not the latter, underwent a fourfold dose-dependent (10(-14)-10(-9) M) increase in response to human Lys-gamma 3-MSH. These data suggest that a pro-gamma-MSH may be implicated as a pathogenic factor in a subset of patients with primary aldosteronism, particularly among those differentially diagnosed as having IHA.

Adenoma↗
PubMed1985

Plasma beta-endorphin levels in primary aldosteronism.

Excessive production of an as yet unidentified aldosterone-stimulating factor may cause idiopathic hyperaldosteronism (IHA). This putative factor may be related to proopiomelanocortin-derived peptides, some of which have aldosterone-stimulating properties. The present study evaluated plasma beta-endorphin, ACTH, cortisol, and aldosterone levels in patients with IHA (n = 10), aldosterone-producing adenomas (n = 4), essential hypertension (n = 11), and normal subjects (n = 10). Plasma and urinary hormone measurements were obtained at timed intervals during an isocaloric, fixed electrolyte intake (Na+, 128 meq/day; K+, 80 meq/day) in a metabolic unit. Plasma for beta-endorphin assay was preincubated with sepharose-bound anti-beta-lipotropin to remove beta-lipotropin that cross-reacted with the beta-endorphin RIA. Mean +/- SE plasma beta-endorphin levels at 0800 h were elevated in IHA patients (47 +/- 13 fmol/ml) compared to those in aldosterone-producing adenoma (25 +/- 9), essential hypertension (16 +/- 1), and normal control (20 +/- 2; P less than 0.05) subjects. Plasma ACTH, plasma cortisol, and urinary cortisol levels were not different in these four groups. These data support the hypothesis that excess production of either beta-endorphin or related proopiomelanocortin-derived peptides may function as aldosterone secretogogue(s) in IHA.

18-Hydroxycorticosterone↗
PubMed1985

The therapeutic effect of a new angiotensin-converting enzyme inhibitor, enalapril maleate, in idiopathic hyperaldosteronism.

Patients with idiopathic hyperaldosteronism (IHA) manifest hypertension, hypokalemia, and renin suppression. IHA is thought to have one of three possible etiologies: zona glomerulosa autonomy, an aldosterone secretory factor, or angiotensin-II (A-II) adrenal hypersensitivity. To determine the contribution of A-II adrenal hypersensitivity in IHA, four patients with IHA were treated with a new angiotensin-converting enzyme inhibitor, enalapril, on a controlled diet (sodium [128 mEq/day] and potassium [80 mEq/day]) in a metabolic unit. The results of this study demonstrate that enalapril therapy in three of four patients normalized blood pressure, improved potassium balance, elevated PRA, reversed the postural increment in plasma aldosterone concentration (PAC), and reduced aldosterone secretion to normal. The fourth patient with bilateral macronodular disease, on the other hand, had no improvement in any of the above indices, despite maximal doses of enalapril (80 mg/day). This patient, however, may have had bilateral adrenal adenomas, based on extremely elevated 18-OH-corticosterone levels (greater than 100 ng/dl), and because of a lack of adrenal A-II hypersensitivity, demonstrated by a fall in pre-enalapril, postural-, and lasix-induced PAC. In conclusion, enalapril improved the hypertension, hypokalemia, renin suppression, and hyperaldosteronism in three patients with IHA over 28 days of therapy. The results of this study suggest an etiologic role of A-II adrenal hypersensitivity in IHA.

Adult↗
PubMed1984

Plasma and urinary 19-nor-deoxycorticosterone in 17 alpha-hydroxylase deficiency syndrome.

17 alpha-hydroxylase deficiency syndrome (17-OHDS) is associated with hypogonadism, hypertension, and hypokalemia. Aldosterone production, however, is not elevated, and therefore, other known or unknown mineralocorticoids must account for the excess in mineralocorticoid activity. This study sought to determine whether 19-nor-deoxycorticosterone (19-nor-DOC), a potent hypertensinogenic mineralocorticoid, was elevated in this syndrome. Plasma and urine from a young woman with 17-OHDS were examined from various corticosteroids before and after ACTH, dexamethasone, and cortisol administration. In the basal state, urinary and plasma 17-hydroxycorticosteroids were decreased, but 17-deoxycorticosteroids were extremely elevated, including corticosterone (B), 18-hydroxy-B (18-OH-B), tetrahydro-B (TH-B), TH-DOC, and 18-OH-TH-DOC. Basal urinary (UF) 19-nor-DOC measured by both high pressure liquid chromatography (4255 ng/day) and RIA [3800 ng/day; normal, 102 +/- 27 (+/- SD), was markedly elevated. UF 19-nor-DOC did not increase further after ACTH administration (4255 ng/day), but it decreased after both dexamethasone (less than 100 ng/day) and cortisol therapy (612 and 218 ng/day). Basal plasma 19-nor-DOC was elevated and increased after ACTH stimulation (366 pg/ml) and decreased during dexamethasone suppression (6 pg/ml). A plasma 19-nor-DOC precursor that converted to nor-DOC upon acidification (perhaps 19-oic-DOC) also was detectable (172 pg/ml). This study, therefore, demonstrates a marked elevation in UF 19-nor-DOC in 17-OHDS, which could account for some of the excess mineralocorticoid activity in this syndrome.

Adolescent↗
PubMed1984

Transitory increment in urinary free 19-nor-deoxycorticosterone after diuretic-induced renin stimulation.

19-Nor-deoxycorticosterone (19-nor-DOC) is a potent mineralocorticoid recently identified in human urine. The factors regulating 19-nor-DOC production are unknown; short term dietary sodium depletion or excess has little effect on 19-nor-DOC excretion in human subjects. This study sought to determine if more prolonged renin stimulation could increase 19-nor-DOC production. Six normal subjects were admitted to a metabolic unit. After a 5-day electrolyte balance period, hydrochlorothiazide (50 mg/day) was administered for 28 days. This treatment resulted in acute natriuresis, a more sustained hypokalemia, and secondary hyperaldosteronism lasting throughout the remainder of the study. Despite the sustained secondary hyperaldosteronism, however, urinary 19-nor-DOC extraction, measured by RIA, increased only slightly on day 3 and subsequently decreased to normal values throughout the remainder of the study (19-nor-DOC, 103 +/- 27 ng/day 0, 175 +/- 26 on day 3, 127 +/- 27 on day 28). The results of this study demonstrate only a minor and transient effect on diuretic-induced renin stimulation on 19-nor-DOC production. Therefore, the physiological regulation of 19-nor-DOC is largely independent of the renin-angiotensin system.

Adult↗
PubMed1983

The superiority of the metyrapone test versus the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome.

Differentiating the cause of Cushing's syndrome traditionally has depended upon measuring the response of 24-hour urine samples of cortisol or glucocorticoid metabolites to the high-dose (8 mg per day) dexamethasone test. The metyrapone test, however, is more convenient because it is a shorter test and requires the obtainment of serum samples, which can be collected more simply and more reliably than 24-hour urine samples. The usefulness of these two tests has not been adequately evaluated in a large series of patients with Cushing's syndrome. This study prospectively evaluated the accuracy of the dexamethasone and metyrapone tests in determining the cause of Cushing's syndrome in a series of 25 unselected patients. The diagnostic accuracy of these tests was calculated as follows: diagnostic accuracy = true positives and true negatives/study population X 100. Results of this study demonstrated that the metyrapone test was more accurate than the dexamethasone test in differentiating Cushing's disease from adrenocortical neoplasm (diagnostic accuracy, 100 percent versus 81 percent). All patients with Cushing's disease had a normal postmetyrapone 11-deoxycortisol concentration (greater than 10 micrograms/dl), while all patients with adrenocortical neoplasm had a suppressed 11-deoxycortisol concentration (less than 10 micrograms/dl). Thus, this study demonstrates that the metyrapone test is superior to the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome.

Adolescent↗
PubMed1983

Reversal of diuretic-induced secondary hyperaldosteronism and hypokalemia by enalapril (MK-421): a new angiotensin-converting enzyme inhibitor.

The study reported here prospectively evaluated the prevention of diuretic-induced secondary hyperaldosteronism and hypokalemia by a converting enzyme inhibitor, enalapril (MK 421). Eighteen normal subjects were randomized into three groups: (1) a HCTZ group (hydrochlorothiazide (HCTZ) 50 mg/day); (2) a MK-421 group (MK-421 10 mg/day); and (3) a HCTZ + MK-421 group [HCTZ 50 mg/day plus MK-421 10 mg/day]. Following a five-day control and a 28-day treatment period, the HCTZ group demonstrated an attenuated but persistent secondary hyperaldosteronism and hypokalemia, the MK-421 group manifested a gradual decline in aldosterone secretion, and the HCTZ + MK-421 group had a delayed but effective correction of secondary hyperaldosteronism and hypokalemia at 28 days but not before. In conclusion, MK-421 reversed diuretic-induced secondary hyperaldosteronism and hypokalemia after 28 days of hydrochlorothiazide therapy. Therefore, converting enzyme inhibitors, such as enalapril, provide useful adjunctive therapy in diuretic-treated patients, but potassium supplementation may be required before the start of four weeks of combined therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

The regulation of urinary free 19-nor-deoxycorticosterone and its relation to systemic arterial blood pressure in normotensive and hypertensive subjects.

19-Nor-deoxycorticosterone (19-nor-DOC) is a naturally occurring, potent mineralocorticoid present in hypertensive animal models as well as man. To investigate 19-nor-DOC's regulation and possible pathogenesis in hypertension, urinary free (UF) 19-nor-DOC was measured in 14 hypertensives, correlated with other corticosteroids and systemic arterial blood pressure (BP), and compared to basal and ACTH-stimulated values in 8 normotensive subjects. Seven of the 14 hypertensives had low-renin hypertension, 2 had primary aldosteronism, 1 had an adrenal carcinoma, and another had acromegaly. These studies determined that: 1) although the mean UF 19-nor-DOC was not increased in hypertensives (588 +/- 180 vs. 428 +/- 122 ng/day), 2 low-renin hypertensives had quite elevated levels (2186 and 2018); 2) the UF 19-nor-DOC in hypertensives was correlated with BP but not with PRA, aldosterone secretion, plasma potassium, basal plasma cortisol, or 17-hydroxycorticosteroids; 3) likewise, in normotensives, UF 19-nor-DOC did not correlate with basal plasma cortisol, cortisol secretion, or 17-hydroxycorticosteroids excretion but did correlate after ACTH stimulation. Therefore, although 19-nor-DOC is activated by ACTH administration, it is not correlated with basal parameters of cortisol production, suggesting that factors other than ACTH regulate basal 19-nor-DOC secretion. Furthermore 19-nor-DOC is elevated in some hypertensive patients, and it is directly related to the elevation of mean systemic BP. This suggests that, although 19-nor-DOC could contribute to hypertensive disease in some individuals, it does not appear to be due to excess ACTH.

17-Hydroxycorticosteroids↗