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Biomedical subjects

G H Williams

Publications and source records attributed to G H Williams.

At least 91 records · Page 5Linked to original sources
PubMed1995

Study of the rat adrenal renin-angiotensin system at a cellular level.

To address the question as to how zona glomerulosa (ZG) cell angiotensin II (Ang II) secretion is regulated, we developed an immuno-cell blot assay to measure its secretion from single cells. We compared these results with those obtained from population studies using a superfusion system. Modulation of Ang II secretion was investigated acutely (by administrating potassium [K+] or captopril) and chronically (by feeding the animals low or high sodium diets). The area of secretory cells, halo areas, and halo intensities varied widely but were highly significantly correlated (P < 0.001) with each other. A disproportionate amount of Ang II was secreted by a small number of large cells. When K+ concentration was increased from 3.6 to 0 mM, superfused ZG cells increased their Ang II secretion 2.32 +/- 0.59-fold. Administration of captopril reduced the K(+)-stimulated Ang II secretion 1.24 +/- 0.07 fold. These findings were reflected in the cell blot assay as a change in the frequency distribution of halo area by K+ and captopril in the same direction as in the population study. In both conditions, the percentage of secretory cells did not change significantly from control. Superfused ZG cells from rats on a low sodium diet secreted 1.85 +/- 0.58-fold more Ang II than cells from sodium-loaded rats (p < 0.05, n = 6). The cell blot assay confirmed these findings with sodium restriction significantly increasing (P < 0.001) both the halo area and its frequency distribution to a larger portion of high secreting cells. However, in contrast to acute treatment with K+ or captopril, the number of secretory cells also doubled. Thus, the individual ZG cell uses two mechanisms to modify Ang II production. In response to acute stimulation and suppression, the amount of Ang II secreted per cell is modified without changing the number of secretary cells. With chronic stimulation, both the amount of Ang II secreted per cell and the number of secretary cells increase.

Angiotensin II↗
PubMed1995

CT of postmeningitic deafness: observations and predictive value for cochlear implants in children.

PURPOSE: To demonstrate CT abnormalities encountered in children with postmeningitic deafness and to assess the value of CT in the prediction of cochlear implantation difficulties. METHODS: Thirteen children with postmeningitic deafness were evaluated with high-resolution, thin-section CT. CT findings were correlated with surgical anatomy at the time of cochlear implantation, with particular regard to the prediction of implant success. RESULTS: CT findings included normal scans (3 of 13, 23.1%), cochlear stenosis (5 of 13, 37.7%), cochlear fibroossific change (1 of 13, 7.7%), cochlear ossification (4 of 13, 30.8%), and osseous hypertrophy at the round window niche (4 of 13, 30.8%). Nine of 10 patients with abnormal findings had incomplete or difficult implantations (90%); 7 (88.8%) of these 9 received limited electrode insertions. CONCLUSION: Attention to subtle otological abnormalities on thin-section CT is helpful in the prediction of early success or failure of implantation in children with postmeningitic deafness. Those with CT abnormalities had a 90% risk of incomplete or difficult insertions with a 70% chance of limited electrode insertion.

Adolescent↗
PubMed1994

Acute and delayed effects of corticotropin-releasing hormone on dopamine activity in man.

Interactions between the hypothalamic-pituitary-adrenal (HPA) axis and central dopamine systems have been hypothesized to play a role in the pathophysiology of psychosis, but the normal physiology of HPA axis-dopamine interactions has not been fully defined. We report results from two uncontrolled pilot studies which explored the effects of ovine corticotropin-releasing hormone (CRH) on dopamine activity in healthy human subjects. Administration of CRH did not produce changes in plasma levels of homovanillic acid (HVA), the major dopamine metabolite, over the subsequent 3.5 hours. However, when the effects of CRH were followed over a longer period in a small subgroup, we found that CRH administration produced a two-fold rise in plasma HVA levels 20 hours later, without affecting plasma levels of 3-methoxy-4-hydroxyphenylglycol (MHPG), a major metabolite of norepinephrine. Thus, the findings of these pilot studies suggest that CRH may exert delayed but not acute effects on dopamine activity in man.

Adrenocorticotropic Hormone↗
PubMed1994

Responsiveness and calibration of the General Well-Being Adjustment Scale in patients with hypertension.

We examined the discriminant ability and responsiveness of the General Well-Being Adjustment Scale in patients enrolled in a randomized clinical trial of antihypertensive therapy. We also tried to translate the effects of physical symptoms on general well-being. This secondary analysis used demographic, clinical, physical symptom, and general well-being data for 545 white, male hypertensive patients. General well-being was measured by the General Well-Being Adjustment Scale (GWB) collected on 2 occasions over 8 weeks of treatment. Patients with any one of 14 physical symptoms or problems, compared to those without symptoms, had lower GWB scores (p < 0.003 to p < 0.0001). Decreases of 2.83-8.76 points in GWB scores were observed in patients developing physical symptoms over the 8 week study period (p < 0.05 to p < 0.0001). These effects were demonstrated in patients developing cold sensitivity, sexual problems, chest pain, shortness of breath, loss of taste, nausea, hot or cold spells, numbness and tingling, dry mouth, blurred vision, and dizziness. We conclude that the GWB is responsive to clinically meaningful changes in symptoms and may provide a more complete evaluation of the effects of medical treatment. The GWB is a valid and responsive measure of health status outcomes in the evaluation of antihypertensive treatment.

Adult↗
PubMed1994

Genetic approaches to understanding the pathophysiology of complex human traits.

Genetic approaches to understanding the pathophysiology of complex human traits, for example, hypertension, can complement physiologic analyses and are likely to improve our ability to treat or prevent the disease. A particularly useful approach is to perform linkage analysis with candidate genes using intermediate phenotypes. This has proven successful so far in identifying two genes involved in hypertension. The first was a fusion gene mutation which linked the regulatory region of the 11B-hydroxylase gene to the coding sequence for the protein of aldosterone synthetase. This mutant gene is responsible for the condition glucocorticoid-remediable aldosteronism (GRA). The intermediate phenotype used was increased levels of the adrenal steroids 18-oxo and hydroxycortisol. The gene for GRA was identified using a pedigree approach. It is likely, to identify other genes in hypertension, that the most appropriate population to be affected would be sib pairs, that is, sibling pairs who both have hypertension. In a recent study the angiotensinogen gene also was linked to hypertension in individuals who had severe or early onset hypertension. In addition, a variant of the angiotensinogen gene, substitution of threonine rather than methionine at codon 235, was specifically associated with hypertension. In a separate study, the T235 homozygote of the angiotensinogen gene was associated with the non-modulating intermediate phenotype of essential hypertension. Since converting enzyme inhibitors appear to correct the specific defect underlying the elevated blood pressure in non-modulators, identification of the gene potentially associated with non-modulation raises the strong possibility that genetic screening will allow for more specific therapy.

Alleles↗
PubMed1994

Sustained volume expansion and [Na,K]ATPase inhibition in chronic renal failure.

Hypotheses regarding the pathogenesis of volume-dependent hypertension have invoked an endogenous sodium pump inhibitor or digitalis-like factor (DLF) to link altered sodium homeostasis to the rise in blood pressure. Our goal was to develop a clinical protocol that achieved predictable, sustained volume expansion, with the premise that renal failure patients on peritoneal dialysis would increase intravascular volume, gain weight, and raise blood pressure (BP) in relation to measured increases in DLF. In a 5-day protocol, dialysis was kept constant but dietary NaCl and fluids were modified in 7 patients. DLF was measured as inhibition of [Na,K]ATPase. Likewise, the first 2 L of daily peritoneal dialysate (PD) was processed on HPLC and the eluate analyzed for DLF. The group achieved significant weight gain (WT) by day 3 (delta WT = 4.1 +/- 1.2 kg, P < .05). Likewise, mean arterial pressure (MAP) and plasma DLF activity increased significantly. All variables were highly correlated (DLF v WT: R = 0.88, P = .004; MAP v DLF: R = 0.82, P = .01; MAP v WT: R = 0.90, P = .003). Although a number of HPLC fractions contained agents that interacted with the assay, only one PD HPLC fraction (at 19.5 min) contained DLF activity that correlated with changes in MAP (R = 0.60, P = .002), and body weight (R = 0.67, P = .0003). We conclude that candidate DLF responds to sustained volume expansion and the relationship suggests that it could influence blood pressure. Moreover, the application of stringent criteria to the confusing array of factors in plasma that may affect assays for DLF appears to reduce the field dramatically, to a single candidate in this setting.

Adult↗
PubMed1994

Nonmodulating trait may precede the development of hypertension.

The nonmodulating trait thought to explain development of hypertension in 25 to 35% of patients, is characterized by abnormal angiotensin II (AII)-mediated control of aldosterone release and renal blood flow (RBF). Some data support the possibility that nonmodulation is an inherited trait, but others argue that it is an acquired epiphenomenon of the hypertensive state. We report the first case of a normotensive patient with nonmodulation who subsequently developed frank hypertension. Patient RR was studied on six occasions over a 5-year period, two while normotensive, four while hypertensive. This patient consistently demonstrated an abnormally low plasma aldosterone response to AII (3 ng/kg/min) on a low salt (10 mEq sodium) diet while both normotensive and hypertensive. A consistently abnormally depressed RBF response to AII on a high salt (150 to 200 mEq sodium) diet as well as a depressed RBF increment when the diet was changed from low salt to high salt were also noted. Thus, RR demonstrated nonmodulation by multiple criteria while both normotensive and hypertensive. We conclude that the nonmodulating trait may be a heritable defect that leads to the development of hypertension and is not an epiphenomenon.

Aldosterone↗
PubMed1994

Responses to converting enzyme and renin inhibition. Role of angiotensin II in humans.

We compared the renal vascular responses to angiotensin converting enzyme inhibition and renin inhibition to assess the influence of angiotensin II (Ang II). We examined the renal and endocrine responses to the renin inhibitor enalkiren, to captopril, and to placebo in nine healthy and nine hypertensive men on a 10-mmol sodium diet. Ang II was infused to assess effects of the agents on renal and adrenal responsiveness to Ang II. Plasma Ang II concentration was suppressed similarly with enalkiren and captopril--an identical level of blockade was achieved. Although renal plasma flow was stable during placebo, a substantial rise was seen with both enalkiren (+133 +/- 26 mL/min per 1.73 m2) and captopril (+99.4 +/- 22.6). There was remarkable intrasubject concordance between the renal plasma flow responses to renin inhibition and converting enzyme inhibition (r = .90, P < .004). The vasodilator response to both agents correlated inversely with the fall in renal plasma flow induced by Ang II alone (r = -.66, P < .05). Both agents significantly enhanced the renal vascular response to Ang II (P = .01), and, furthermore, the renal vasodilator response to captopril predicted the potentiation of the renal plasma flow response to Ang II after either agent (enalkiren: r = .91, P < .001; captopril: r = .56, P < .05). Concordance of the maximal renal plasma flow response to the two agents appeared in the hypertensive men as well. Our results indicate that the acute renal response to captopril largely reflects a reduction in Ang II formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Regulation of aldosterone secretion in hypertensive blacks.

Hypertension in blacks is common, often severe, and largely unexplained. Recent studies have suggested that aldosterone secretion in blacks may be reduced, whereas older data demonstrate no racial differences in aldosterone excretion. We performed this study to examine adrenal responsiveness in black hypertensive patients under controlled metabolic conditions. Thirty-one black hypertensive patients and 7 black normotensive subjects were studied on intakes of 10 mmol/d sodium and 100 mmol/d potassium, with the renin-angiotensin-aldosterone system further stimulated by upright posture or infusion of angiotensin II (Ang II). Forty-six hypertensive and 14 normotensive whites underwent the same protocol as a comparison group. Hypertensive blacks and whites had similar mean basal plasma aldosterone levels on a low salt diet, lower in both groups than in normotensive subjects. In the black patients, however, plasma aldosterone responses were significantly lower than responses in white hypertensive patients when further stimulated by either posture (1451 +/- 216 versus 2571 +/- 225 pmol/L [52.3 +/- 7.8 versus 92.7 +/- 8.1 ng/dL], P < .002) or Ang II infusion (843 +/- 122 versus 1617 +/- 189 pmol/L [30.4 +/- 4.4 versus 58.3 +/- 6.8 ng/dL], P < .001). Renin status did not account for the difference. Basal and stimulated plasma aldosterone concentrations, on the other hand, were similar in normotensive white and black subjects. Blunted adrenal responses to upright posture and Ang II infusion are common among black hypertensive patients. These abnormalities may be part of a larger constellation of abnormalities in blacks, reflecting perhaps a greater, more frequent underlying disturbance in salt handling than in whites.

Adrenocorticotropic Hormone↗
PubMed1994

Relation of pressor responsiveness to angiotensin II and insulin resistance in hypertension.

To test the hypothesis that the hypertension associated with insulin resistance is secondary to an altered responsiveness of the vasculature to pressor agents, we evaluated the relationship between insulin resistance and pressor responses to angiotensin II (AII) in 21 hypertensive (HT) and 8 normotensive (NT) subjects on both a high (200 meq) and a low (10 meq) sodium diet. When sodium balance was achieved, each supine fasting subject underwent an AII infusion at a rate of 3 ng/kg per min for 60 min, with blood pressure monitored every 2 min. On the next day under similar conditions, a euglycemic hyperinsulinemic clamp was performed, with plasma glucose clamped at 90 mg/dl for 120 min. There was no significant relationship between the glucose disposal rate (M) or the insulin sensitivity index (M divided by the mean insulin level [M/I]) and blood pressure response to AII in the NTs, but a highly significant (P < 0.019) negative correlation (r = -0.55) in the HTs. Furthermore, in eight lean HTs whose body mass index was identical to that observed in the NTs, the relationship was even more striking (P < 0.008; r = -0.85). The results on high and low salt diets were similar; however, the M and M/I were significantly increased (P < 0.05) in the NTs but not HTs with sodium restriction. In conclusion, HTs but not NTs display a striking correlation between pressor response to AII and insulin resistance. This relationship is independent of the level of sodium intake. Furthermore, sodium intake modifies insulin sensitivity in NTs but not HTs. These results strongly suggest that a primary change in pressor response to vasoactive agents in insulin-resistant subjects can contribute to their elevated blood pressure.

Adult↗
PubMed1994

The effect of losartan on potassium-stimulated aldosterone secretion in vitro.

Potassium (K+) and angiotensin-II (Ang-II) are two distinct secretagogues for aldosterone release. However, a local adrenal renin-angiotensin system is present, and several studies suggest a complex interaction between K+ and locally produced Ang-II. First, superfusing zona glomerulosa (ZG) cells with K+ stimulates the secretion of both Ang-II and aldosterone. Second, K(+)-stimulated aldosterone secretion can be reduced in the presence of angiotensin-converting enzyme inhibitors. Because angiotensin-converting enzyme inhibitors are not specific inhibitors of the adrenal renin-angiotensin system, we further tested the hypothesis that locally produced Ang-II participates in K(+)-stimulated aldosterone release from rat ZG cells by using a specific Ang-II antagonist. Although type 1 (AT1) and type 2 (AT2) Ang-II receptors are present in ZG cells, only AT1 antagonist has been shown to mediate Ang-II-induced aldosterone secretion. Losartan, a specific AT1 antagonist, was used in this study. In the presence of losartan (10 microM for 9 mM K+ and 100 microM for 5 mM K+), the average aldosterone secretion during 2 h of superfusion with 9 mM K+ and 5 mM K+ was 70.1 +/- 5.4% (n = 5) and 58.5 +/- 2.2% (n = 3), respectively, of that in its absence. Losartan did not alter the amount of Ang-II secreted. The inhibitory effect of losartan lasted longer than 60 min after it was terminated. In summary, our results support the hypothesis that locally produced Ang-II contributes to the aldosterone secretory response to K+ stimulation at both physiological and supraphysiological levels.

Aldosterone↗
PubMed1994

Essential hypertension as an endocrine disease.

Several lines of evidence strongly suggest that the majority of patients with essential hypertension have an endocrine basis for their elevated blood pressure. Abnormalities in vascular tone, circulating hormone levels, and the responsiveness of target tissues to these hormones all contribute to the pathogenesis of the increased blood pressure. The actual frequency of each of these subsets of patients is unknown, but it is likely to be substantial. Intriguingly, most of these abnormalities are not associated with hormonal overproduction per se but, rather, a change in the response of target tissues to specific hormones, with compensatory mechanisms actually responsible for the increased blood pressure. There is evidence that each of these endocrine abnormalities may be inherited, so there is a high likelihood that a genetic marker can be found to identify each subgroup. Already there is the intriguing possibility that if subgroups of patients can be identified easily, specific therapy will be possible.

Endocrine System Diseases↗
PubMed1993

Effect of sodium intake on insulin sensitivity.

To examine the effects of sodium intake on insulin sensitivity, we performed euglycemic insulin clamp studies (40 mU.m-2.min-1) in eight healthy normotensive nondiabetic white males (age = 36 +/- 5 yr; wt = 66 +/- 3 kg) after 5 days on high (200 meq/day)- and low (10 meq/day)-sodium diets administered in random order. High sodium intake was associated with significantly greater urinary sodium excretion (160 +/- 7 vs. 8 +/- 2 meq/day; P < 0.0001), suppression of plasma aldosterone (7 +/- 3 vs. 38 +/- 6 ng/dl; P < 0.001) and renin (1.5 +/- 0.2 vs. 6.0 +/- 0.9 ng.ml-1.h-1; P < 0.005) levels, but no change in blood pressure (116 +/- 3/63 +/- 2 vs. 114 +/- 3/64 +/- 2 mmHg; P = not significant). The rate of glucose infusion during the clamp was significantly reduced during the high- vs. low-sodium diet (279 +/- 19 vs. 334 +/- 24 mg.m-2.min-1; P < 0.01). This impairment in insulin sensitivity was not related to changes in serum potassium, epinephrine, norepinephrine, cortisol, or growth hormone but was highly correlated with an increment in circulating free fatty acid levels during high sodium intake (r = 0.82, P < 0.05). These data suggest that 1) high sodium intake may exacerbate insulin resistance by increasing circulating free fatty acids, and 2) differences in sodium intake may influence measures of insulin sensitivity in other disease states.

Adult↗
PubMed1993

Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function.

BACKGROUND: Recent clinical trial data indicate that the use of angiotensin converting enzyme (ACE) inhibitors among patients with left ventricular dysfunction results in reduced rates of coronary thrombosis, a provocative finding that suggests a potential interaction between the renin-angiotensin system and fibrinolytic function. METHODS AND RESULTS: In four normotensive subjects and six hypertensive patients, we investigated whether infusion of angiotensin II (Ang II) affected circulating levels of plasminogen activator inhibitor-1 (PAI-1), the most important physiological inhibitor of tissue-type plasminogen activator (t-PA). Overall, mean levels of PAI-1 antigen increased significantly from 20.1 ng/mL before Ang II infusion to 36.0 ng/mL at the end of Ang II infusion (p = 0.008), whereas no change in PAI-1 was observed for control subjects infused with 5% dextrose (p = 0.46). Among the normotensive subjects for whom graded doses of Ang II were infused at 0, 1, 3, and 10 ng.kg-1.min-1, mean PAI-1 levels increased sequentially from 14.7 ng/mL to 23.0, 26.8, and 33.5 ng/mL, a dose-response relation that, compared with controls, was highly significant (p < 0.001). Among the hypertensive patients for whom a single 45-minute infusion of Ang II was given at a dose of 3 ng.kg-1.min-1, PAI-1 levels increased from 23.7 to 37.7 ng/mL, whereas PAI-1 levels among control subjects infused with 5% dextrose decreased from 16.9 to 10.8 ng/mL (p = 0.04). Finally, when compared with infusion of 5% dextrose solution, infusion of Ang II appeared to have little effect on circulating levels of t-PA antigen. CONCLUSIONS: These in vivo data suggest that infusion of Ang II results in a rapid increase in circulating levels of PAI-1, a finding that may help to explain clinical observations linking the renin-angiotensin system and thrombotic risk.

Angiotensin II↗