The phenomenon of resistance to a thiazide diuretic in acute kidney failure

The resistance to hypothiazid (hydrochlorothiazide) during the development of acute renal insufficiency (ARI) induced by glycerin injection was studied in rat experiments. Natriuretic, kaliuretic, and hydrouretic activity of the diuretic decreased two days after injection of a glycerin solution. In this period hypothiazid excretion with the urine was least. Ten days later, despite the restoration of the water- and electrolyte-excretion function of the kidneys and normalization of hypothiazid excretion with the urine, the natriuretic effect of the drug was still very poor. This is indirect evidence of the long-term affection of the receptors for the thiazid diuretics during the development of ARI. The affection remains even after the excretory function of the kidneys is restored. The high correlation between the cumulative excretion of hypothiazid with the urine and natriuresis encountered in intact animals was weaker in rats with acute renal insufficiency.     

Impact of gender on the renal response to angiotensin II

BACKGROUND: It is clear that women with renal disease progress to end stage at a slower rate than do men. We hypothesized that this protection may result from gender-mediated differences in responses to angiotensin II (Ang II), which has known hemodynamic effects that are thought to promote renal disease progression. We examined sex differences in renin-angiotensin system (RAS) function by measuring renal hemodynamic function and circulating plasma components of the RAS at baseline and in response to graded infusions of Ang II. METHODS: We studied two groups of normal healthy subjects, 24 men and 24 women, mean age 28 +/- 1 years, ingesting a controlled sodium and protein diet. We examined baseline concentrations of angiotensin converting enzyme, plasma renin activity, Ang II, and aldosterone. Inulin and paraaminohippurate clearance techniques were used to estimate effective renal plasma flow (ERPF) and glomerular filtration rate (GFR) at baseline and in response to graded Ang II infusion (0.5, 1.5, and 2.5 ng/kg/min). RESULTS: Mean baseline values for mean arterial pressure and aldosterone were lower in women, whereas values for plasma Ang II, GFR, ERPF, and filtration fraction (FF) did not differ. In response to Ang II, both groups exhibited a similar increase in mean arterial pressure and a decline in ERPF. GFR was maintained during Ang II infusion only in men, resulting in an augmentation of FF. In women, GFR declined in parallel with ERPF, and the FF response was significantly blunted. 17beta-Estradiol plasma concentrations influenced the ERPF response to Ang II infusion, with higher levels predicting a blunting of the decrease. The GFR response was not affected. CONCLUSIONS: The renal microcirculation in sodium-replete women may respond differently to Ang II than that of men, with the female sex predicting a lesser augmentation of FF and possibly a blunted increase in intraglomerular pressure. The mechanism remains obscure, but these contrasting responses may help to explain gender-mediated differences in renal disease progression.     

Long-term evaluation of combined antihypertensive therapy with lisinopril and a thiazide diuretic in patients with essential hypertension

For the treatment of hypertension, the combination of an angiotensin-converting enzyme (ACE) inhibitor and a thiazide diuretic is supported by multiple lines of evidence, because these drugs have synergistic action and are expected to cancel out each other's adverse side effects. However, the long-term outcome of this combination antihypertensive therapy is not entirely clear. In the present multicenter open trial, we investigated the long-term efficacy and safety of combined antihypertensive therapy with an ACE inhibitor, lisinopril, and a thiazide diuretic, trichlormethiazide. A total of 466 patients with essential hypertension were treated with lisinopril alone (monotherapy group, n = 360) or with a combination of lisinopril with trichlormethiazide (combination therapy group, n = 106) for 1 year. The average blood pressure was effectively lowered to below 150/90 mmHg in both the monotherapy and the combination therapy groups throughout the study period. The average maintenance dose of lisinopril was lower when combined with thiazide than when given alone (9.8 vs. 11.5 mg/day, p < 0.001). Dry cough was the major side effect of lisinopril; no severe adverse effects were observed. The incidence of cough was not significantly different between the monotherapy group (13.1%) and the combination therapy group (11.3%). The increase in serum potassium observed in the monotherapy group was reversed by the concurrent use of the thiazide diuretic in the combination therapy group. Fasting blood glucose was significantly reduced in the monotherapy group; the reduction observed in the combination therapy group was not significant. Thus, the present results provide useful information as to the effectiveness and safety of combined antihypertensive therapy with lisinopril and a thiazide in comparison with monotherapy with lisinopril.     

Influence of hypophysectomy on renal proteoglycans and their modulation by insulin-like growth factor-I and its receptor

Hypophysectomy leads to growth retardation of the animals, which is believed to be related to the deficiency of certain growth factors influencing the metabolism and synthesis of glycoproteins. Conceivably, the extracellular matrix proteins (ECM) are also affected, in particular the sulfated proteoglycans (PGs). In this study, we investigated the status of the ECM proteins and sulfated PGs, and the expression and de novo synthesis of insulin-like growth factor-I (IGF-I) receptor (IGF-IR) in hypophysectomized (Hx) rats. The studies were extended to ascertain the effect of IGF-I on the de novo synthesis of glomerular ECM glycoproteins in Hx rats. An organ perfusion system was used in which isolated rat kidneys were radiolabeled with either [35S]sulfate or [35S]methionine, after which IGF-IR and ECM macromolecules were isolated and characterized by biochemical and tissue autoradiographic procedures. Hypophysectomy resulted in a fall in IGF-I levels in serum and isolated renal glomeruli. Reduced synthesis of ECM proteins, i.e. type IV collagen, laminin, and sulfated PGs, and reduced synthesis and mRNA expression of IGF-IR were observed in the glomeruli of the Hx rats. Tissue autoradiographic studies revealed a reduced grain density (concentration of radiation) over various cell types of the glomerulus. After inclusion of IGF-I in the perfusion medium not only was synthesis restored to normal in Hx rats, but it far exceeded the control basal values in the intact animals. Under the influence of IGF-I, the magnitude of increased synthesis of the ECM proteins, in particular the sulfated PGs, was highly accentuated in the kidneys of the Hx group compared to the controls. Also, a remarkably increased [35S]sulfate incorporation was observed in the glomerular mesangial cells. The analysis of IGF-IR by specific binding studies revealed a decreased concentration of the receptors, but an increased IGF-I-binding affinity, the latter of which probably contributed to the IGF-I-induced accentuated synthesis of renal glomerular PGs in the Hx group.     

Influence of gender on the pharmacokinetics and pharmacodynamics of drugs

Historically, women, the elderly, and minorities were underrepresented in clinical drug trials. Information on possible gender-related differences in the pharmacokinetics of drugs is often lacking, although for some drugs significant differences could be demonstrated. In women, absorption, protein binding, volume of distribution, and metabolism of drugs may differ due to hormonal influences on physiological functions. Sex-related differences could be shown for phase I (cytochrome P450) as well as phase II (especially glucuronidation) reactions. Since many women world-wide take oral contraceptives, data should be provided to determine to what extent other drugs are influenced by estrogens and progestogens or to what extent the other drugs may attenuate the contraceptive efficacy. Moreover, estrogens interact with various enzymes and receptors, e.g. at the endothelial function as well as dopaminergic receptor sites, and may therefore attenuate or enhance drug effects or even drug side-effects. For a number of drugs it is well recognized, that women suffer more frequently from side-effects, however, it is often not clear, if this is due to gender differences in the pharmacokinetics or pharmacodynamics of the responsible drug. Very little is known about these gender-related differences and the possibility that women may show a different pattern of treatment response than men. As a result, drug approval authorities now require more data on the pharmacokinetics of novel drugs in women as well as a sufficient accrual of women in efficacy and outcome trials.     

Disparate patterns of aldosterone response during diuretic treatment of hypertension

In 50 patients with essential hypertension treated with chlorthalidone, 100 mg daily for 6 weeks, treatment responders (fall in mean pressure, greater than or equal to 10%) and nonresponders experienced similar weight and electrolyte changes. Although induced increments and post-treatment values of plasma renin were higher in nonresponders than responders, there was a far more striking difference in aldosterone reactivity. Aldosterone excretion rose by less than 10% in the responders but almost doubled in the nonresponders. Again, within the normal renin subgroup alone (n = 28), nonresponders exhibited control renin values and treatment-induced changes in plasma renin closely similar to those in responders, but experienced a significantly greater increase in aldosterone excretion. Possibly this increase in aldosterone produced subtle volume retention or a direct pressor effect in nonresponding patients. Although changes in aldosterone and in renin correlated with each other in both responders and nonresponders, the slopes of the regression lines in the two groups differed significantly. Thus, cofactors governing sensitivity of the aldosterone response to renin stimulation ultimately may determine the antihypertensive effectiveness of diuretics.     

Influence of age and gender on quantitative sacroiliac joint scintigraphy

The value of quantitative sacroiliac joint scintigraphy for detecting sacroiliitis is controversial. Age and gender may contribute to this discordance. In previous reports, the number of control groups has been small and might not exactly reflect the change of sacroiliac/sacral (SI/S) ratios related to different age. In addition, the selection of control subjects was not strict. In most studies, care was not taken to ensure that control subjects did not have a history of back pain or any other relevant conditions. In addition, there was no requirement for a normal radiograph as a condition of inclusion. The aim of our study was to evaluate the consequent changes in SI/S ratios, according to age (in 10-yr intervals) and gender. METHODS: Over a period of 5 yr, 413 control subjects without a history of back pain, scoliosis, kyphosis, joint pain, arthritis, lesions within the pelvis, chemotherapy or systemic disease such as diabetes or systemic lupus erythematosus were included in this study. A posterior planar film of the pelvis was obtained to calculate SI/S ratio 3 hr after injection of 740 MBq 99mTc-methylenediphosphonate. Our data showed that: (a) the change in SI/S ratios related to age was significant in both females and males; (b) the SI/S ratios were higher in males younger than 30 yr and higher in men in the 41-50-yr age group and in females in other groups; (c) the SI/S ratios declined steadily with increasing age in females, whereas there were two plateaus in men aged 21-40 yr and 41-70 yr; (d) there were significant differences of SI/S ratios between the genders in certain age groups; and (e) no differences were found between left SI/S ratios and right SI/S ratios. CONCLUSION: The influence of age and gender on SI/S ratios are substantial, and it is essential for each department to establish its own values for SI/S ratios based on gender and age (in 10-yr intervals).     

Effect of indomethacin on the renal response to angiotensin II receptor blockade in healthy subjects

BACKGROUND: Non-steroidal anti-inflammatory drugs are known to promote sodium retention and to blunt the blood pressure lowering effects of several classes of antihypertensive agents including beta-blockers, diuretics and angiotensin converting enzyme (ACE) inhibitors. The purpose of the present study was to investigate the acute and sustained effects of indomethacin on the renal response to the angiotensin II receptor antagonist valsartan and to the ACE inhibitor enalapril. METHODS: Twenty normotensive subjects maintained on fixed sodium intake (100 mmol sodium/day) were randomized to receive for one week: valsartan 80 mg o.d., enalapril 20 mg o.d., valsartan 80 mg o.d. + indomethacin 50 mg bid and enalapril 20 mg o.d. + indomethacin 50 mg bid. This single-blind study was designed as a parallel (valsartan vs. enalapril) and cross-over trial (valsartan or enalapril vs. valsartan + indomethacin or enalapril + indomethacin). Renal hemodynamics and urinary electrolyte excretion were measured for six hours after the first and seventh administration of each treatment regimen. RESULTS: The results show that valsartan and enalapril have comparable renal effects characterized by no change in glomerular filtration rate and significant increases in renal plasma flow and sodium excretion. The valsartan- and enalapril-induced renal vasodilation is not significantly blunted by indomethacin. However, indomethacin similarly abolishes the natriuresis induced by the angiotensin II antagonist and the ACE inhibitor. CONCLUSIONS: This observation suggests that although angiotensin receptor antagonists do not affect prostaglandin metabolism, the administration of a non-steroidal anti-inflammatory drug blunts the natriuretic response to angiotensin receptor blockade.     

Comparison of the water diuretic activity of kappa receptor agonists and a vasopressin receptor antagonist in dogs

Strategies for developing selective water diuretic agents have involved development of kappa opioid receptor agonists and vasopressin V2 receptor antagonists; however, these two classes of compounds have not been compared directly. We have investigated the activity of three kappa receptor agonists and one nonpeptide vasopressin receptor antagonist in conscious dogs. SB 215520, SB 215519 and niravoline are selective kappa agonists with variable abilities to cause a water diuresis and ataxia in rats. When administered to conscious hydropenic dogs, the kappa agonists resulted in an increase in free water clearance; however, these effects were associated with an antinatriuresis, an increase in heart rate and, at the higher doses, central nervous system side effects. Conversely, the vasopressin receptor antagonist, OPC 31260, resulted in a significant water diuresis without any accompanying changes in sodium excretion and heart rate, and with no apparent central nervous system effects. These studies suggest that, at least in dogs, a vasopressin receptor antagonist is a more selective water diuretic than a kappa receptor agonist.     

Influence of counselor gender on reactivity to clients.

Explored the responses of 40 experienced counselors to videotaped clients. Five female and 5 male counselors saw 1 of 4 clients: angry female or male or depressed female or male. During 4 vignette stops, counselors explored their immediate subjective reaction to the clients. Their verbal material was taperecorded and rated by 2 judges on sympathy, identification, defensiveness, and anger. Counselors themselves rated 4 variables: liking, attractiveness for counseling, empathy, and comfort. Multivariate ANOVA produced 2 significant counselor/gender effects. Female counselors rated themselves as more empathic than did males, and females were rated as angrier than were males. Results are discussed in terms of the method developed for the study. (24 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of gender constancy and social power on sex-linked modeling.

In cognitive-developmental theory, gender constancy is considered a necessary prerequisite for the emulation of same-sex models, whereas according to social learning theory, sex-role development is promoted through a vast system of social influences with modeling serving as a major conveyor of sex role information. The present 2 experiments, with 68 29–70 mo old children, tested these predictions. In accord with social learning theory, even Ss at a lower level of gender conception emulated same-sex models in preference to opposite-sex ones in Exp I. Level of gender constancy was associated with higher emulation of both male and female models rather than operating as a selective determinant of modeling. This finding corroborates modeling as a basic mechanism in the sex-typing process. Exp II explored the limits of same-sex modeling by pitting social power against the force of collective modeling of different patterns of behavior by male and female models. Social power over activities and rewarding resources produced cross-sex modeling in boys but not girls. This unexpected pattern of cross-sex modeling is explained by the differential sex-typing pressures that exist for boys and girls and socialization experiences that heighten the attractiveness of social power for boys. (34 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Male therapists' clinical bias: Influence of client gender roles and therapist gender role conflict.

This study examined male therapists' gender role conflict, client sexual orientation, and client emotional expression as they interrelated with clinical judgments about male clients. Using a series of written clinical vignettes to manipulate the client variables of sexual orientation and emotional expression, 196 experienced male therapists completed a measure of male gender role conflict, read a clinical vignette varying the client's sexual orientation and emotional expression, and rated the client on several clinical dimensions. Canonical analysis revealed 2 roots indicating that therapist gender role conflict factors, in combination with client sexual orientation and emotional expression, were associated with therapists' ratings of the male client's prognosis and how much therapists liked, had empathy for, had comfort with, and had willingness to see the male client. Implications for counseling practice, limitations, and future research are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of onset density on spoken-word recognition.

Previous research has suggested that the initial portion of a word activates similar sounding words that compete for recognition. Other research has shown that the number of similar sounding words that are activated influences the speed and accuracy of recognition. Words with few neighbors are processed more quickly and accurately than words with many neighbors. The influences of the number of lexical competitors in the initial part of the word were examined in a shadowing and a lexical-decision task. Target words with few neighbors that share the initial phoneme were responded to more quickly than target words with many neighbors that share the initial phoneme. The implications of onset-density effects for models of spoken-word recognition are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Influence of potassium on renal ammonia production

The influence of potassium homeostasis on ammonia production was investigated with both cortical and medullary slices from rat kidney. Renal cortical slices from rats depleted of potassium by dietary restriction produced 31% more NH3 than slices from pair-fed controls. A high-potassium diet for 1 wk diminished ammonia production in cortical slices by 5% in comparison with rats pair fed a normal diet (161 vs. 169 mumol/90 min per g wet wt; P less than 0.05). Pair feeding did not introduce an experimental artifact, since animals ingesting similar K+ diets showed no difference in NH3 production. In contrast to cortex, NH3 production by outer medullary slices from K+-depleted animals was similar to pair-fed controls. Medulla from potassium-loaded rats exhibited an impressive inhibition in NH3 production averaging 36%. These striking differences between cortex and medulla suggest that specific alterations in potassium homeostasis may influence NH3 production selectively at different tubular sites. In vitro manipulation of K+ homeostasis produced by varying bathing media K+ from 0 to 144 mM, with concomitant changes in intracellular K+ from 30 to 130 mM, had no detectable influence on NH3 production by cortical slices. Hence altered cortical ammoniagenesis is not the direct result of acute changes in extracellular or intracellular cortical fluid K+ or in the transcellular gradient for K+. Although the specific cellular mechanisms whereby K+ alters ammoniagenesis remains undefined, the observation that K+ loading diminishes while K+ depletion enhances NH3 production supports the supposition that K+ and NH3 are linked in a physiologic control system.     

Differentiation of the effect of diuretic urine extracts on the renal medullary blood flow (author''s transl)]

1. The isolation of transferrin from rat serum by means of affinity chromatography on CNBr-activated Sepharose 4 B is described. -2. Subfractionation by isoelectric focusing yielded two transferrin fractions with identical biological behaviour but with small differences in isoelectric point (6.0 and 5.8) and sialic acid contents.