How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure? (41/2815)

OBJECTIVE: Angiotensin II (AII) and aldosterone are not always fully suppressed during chronic angiotensin converting enzyme (ACE) inhibitor treatment. In congestive heart failure (CHF) such failure of hormonal suppression is associated with increased mortality. This study examined how common AII and aldosterone increases are observed during routine clinical practice. PATIENTS AND METHODS: 91 patients with symptomatic (mean New York Heart Association class 2.7) CHF (mean (SD) left ventricular ejection fraction 29.9 (8)%, range 9-46%) were studied 4-6 hours after ACE inhibitor dosing. A representative range of ACE inhibitors (enalapril, lisinopril, captopril, perindopril, and fosinopril) was examined. RESULTS: Supine measurements showed a wide range of AII (10.5 (25.5) pg/ml), aldosterone (130.8 (136) pg/ml), and serum ACE (12.1 (13.3) EU/l; excludes captopril data) concentrations on diuretics. AII concentrations > 10 pg/ml were seen in 15% of patients, and aldosterone concentrations > 144 pg/ml were seen in 38% of patients. AII concentrations were significantly correlated (p < 0.001) with ACE but not with aldosterone concentrations. Aldosterone concentrations were not significantly correlated with ACE concentrations. CONCLUSIONS: AII "reactivation" occurred in 15% and failure of aldosterone suppression in 38% of routine CHF patients taking ACE inhibitor treatment. AII "reactivation" was associated with both low and high levels of ACE activity, which suggests that multiple different mechanisms are at play. In patients with high plasma ACE concentrations, non-compliance should be considered along with inadequate dose titration. In patients with low plasma ACE and high AII concentrations, non-ACE mediated production of AII may be operative. Raised aldosterone concentrations appear to be more common than AII "reactivation". It is important to establish the cause of detectable or increased AII concentrations in a heart failure patient treated with an ACE inhibitor. The measurement of serum ACE may help to identify the likely cause as poor compliance or inadequate dose.  (+info)

Angiotensin II negatively modulates L-type calcium channels through a pertussis toxin-sensitive G protein in adrenal glomerulosa cells. (42/2815)

In bovine adrenal glomerulosa cells, angiotensin II and extracellular K+ stimulate aldosterone secretion in a calcium-dependent manner. In these cells, physiological concentrations of extracellular potassium activate both T-type (low threshold) and L-type (high threshold) voltage-operated calcium channels. Paradoxically, the cytosolic calcium response to 9 mM K+ is inhibited by angiotensin II. Because K+-induced calcium changes observed in the cytosol are almost exclusively due to L-type channel activity, we therefore studied the mechanisms of L-type channel regulation by angiotensin II. Using the patch-clamp method in its perforated patch configuration, we observed a marked inhibition (by 63%) of L-type barium currents in response to angiotensin II. This effect of the hormone was completely prevented by losartan, a specific antagonist of the AT1 receptor subtype. Moreover, this inhibition was strongly reduced when the cells were previously treated for 1 night with pertussis toxin. An effect of pertussis toxin was also observed on the modulation by angiotensin II of the K+ (9 mM)-induced cytosolic calcium response in fura-2-loaded cells, as well as on the angiotensin II-induced aldosterone secretion, at both low (3 mM) and high (9 mM) K+ concentrations. Finally, the expression of both Go and Gi proteins in bovine glomerulosa cells was detected by immunoblotting. Altogether, these results strongly suggest that in bovine glomerulosa cells, a pertussis toxin-sensitive G protein is involved in the inhibition of L-type channel activity induced by angiotensin II.  (+info)

Quantification and distribution of Ca(2+)-activated maxi K(+) channels in rabbit distal colon. (43/2815)

The Ca(2+)-activated maxi K(+) channel is an abundant channel type in the distal colon epithelium, but nothing is known regarding the actual number and precise localization of these channels. The aim of this study has therefore been to quantify the maxi K(+) channels in colon epithelium by binding of iberiotoxin (IbTX), a selective peptidyl ligand for maxi K(+) channels. In isotope flux measurements 75% of the total K(+) channel activity in plasma membranes from distal colon epithelium is inhibited by IbTX (K(0.5) = 4.5 pM), indicating that the maxi K(+) channel is the predominant channel type in this epithelium. Consistent with the functional studies, the radiolabeled double mutant (125)I-IbTX-D19Y/Y36F binds to the colon epithelium membranes with an equilibrium dissociation constant of approximately 10 pM. The maximum receptor concentration values (in fmol/mg protein) for (125)I-IbTX-D19Y/Y36F binding to colon epithelium are 78 for surface membranes and 8 for crypt membranes, suggesting that the maxi K(+) channels are predominantly expressed in the Na(+)-absorbing surface cells, as compared with the Cl(-)-secreting crypt cells. However, aldosterone stimulation of this tissue induced by a low-Na(+) diet does not change the total number of maxi K(+) channels.  (+info)

Dexamethasone in resting and exercising men. II. Effects on adrenocortical hormones. (44/2815)

This study presents the reactions of adrenocorticosteroids (cortisol and aldosterone) and sex steroids [testosterone, androstenedione, and dehydroepiandrosterone and its sulfate (DHAS)] 1) to a dexamethasone (Dex) treatment, which is expected to lower steroid levels via the ACTH blockade, and 2) to an exercise bout at maximal O(2) consumption, which is expected to increase steroid production via ACTH stimulation. Consistent with the decrease in ACTH, all steroids except testosterone reacted negatively to Dex, independently of the dose (0.5 and 1.5 mg administered twice daily for 4.5 days). After exercise, plasma ACTH rose to 600% of basal value, resulting in a significant increase in aldosterone and adrenal androgens, but cortisol and DHAS were unaffected. This apparently surprising result can be explained by differences in peripheral metabolism: a theoretical calculation predicted that after 15 min the increase in hormone concentration may only reach 12% for cortisol and 2% for DHAS. For cortisol and adrenal androgens, assays were carried out using plasma and saliva. The consistent results obtained from the two matrices allow us to consider salivary assays as a useful tool for steroid abuse detection.  (+info)

Interaction of CYP11B1 (cytochrome P-45011 beta) with CYP11A1 (cytochrome P-450scc) in COS-1 cells. (45/2815)

The interactions of CYP11B1 (cytochrome P-45011beta), CYP11B2 (cytochrome P-450aldo) and CYP11A1 (cytochrome P-450scc) were investigated by cotransfection of their cDNA into COS-1 cells. The effect of CYP11A1 on CYP11B isozymes was examined by studying the conversion of 11-deoxycorticosterone to corticosterone, 18-hydroxycorticosterone and aldosterone. It was shown that when human or bovine CYP11B1 and CYP11A1 were cotransfected they competed for the reducing equivalents from the limiting source contained in COS-1 cells; this resulted in a decrease of the CYP11B activities without changes in the product formation patterns. The competition of human CYP11A1 with human CYP11B1 and CYP11B2 could be diminished with excess expression of bovine adrenodoxin. However, the coexpression of bovine CYP11B1 and CYP11A1 in the presence of adrenodoxin resulted in a stimulation of 11beta-hydroxylation activity of CYP11B1 and in a decrease of the 18-hydroxycorticosterone and aldosterone formation. These results suggest that the interactions of CYP11A1 with CYP11B1 and CYP11B2 do not have an identical regulatory function in human and in bovine adrenal tissue.  (+info)

Hyperkalemia in patients infected with the human immunodeficiency virus: involvement of a systemic mechanism. (46/2815)

BACKGROUND: The appearance of hyperkalemia has been described in human immunodeficiency virus (HIV)-positive patients treated with drugs with amiloride-like properties. Recent in vitro data suggest that individuals infected with HIV have alterations in transcellular K+ transport. METHODS: With the objective of examining the presence of alterations in transmembrane K+ equilibrium in HIV-positive patients, we designed a prospective, interventional study involving 10 HIV-positive individuals and 10 healthy controls, all with normal renal function. An infusion of L-arginine (6%, intravenously, in four 30-min periods at 50, 100, 200, and 300 ml/hr) was administered, and plasma and urine electrolytes, creatinine, pH and osmolality, total and fractional sodium and potassium excretion, transtubular potassium gradient, plasma insulin, renin, aldosterone, and cortisol were measured. RESULTS: A primary disturbance consisting of a significant rise in plasma [K+] induced by L-arginine was detected in only the HIV patients but not in the controls (P < 0.001 between groups). A K+ redistribution origin of the hyperkalemia was supported by its rapid development (within 60 min) and the lack of significant differences between HIV-positive individuals and controls in the amount of K+ excreted in the urine. The fact that the HIV-positive individuals had an inhibited aldosterone response to the increase in plasma K+ suggested a putative mechanism for the deranged K+ response. CONCLUSIONS: These results reveal that HIV-infected individuals have a significant abnormality in systemic K+ equilibrium. This abnormality, which leads to the development of hyperkalemia after the L-arginine challenge, may be related, in part, to a failure in the aldosterone response to hyperkalemia. These results provide a new basis for understanding the pathogenesis of hyperkalemia in HIV individuals, and demonstrate that the risk of HIV-associated hyperkalemia exists even in the absence of amiloride-mimicking drugs or overt hyporeninemic hypoaldosteronism.  (+info)

Renal excretion of monovalent cations during functional adrenalectomy in conscious sheep. (47/2815)

In sheep with both adrenals removed and one re-implanted in the neck, functional adrenalectomy was produced in conscious undisturbed animals by occluding the blood supply to the transplanted gland. Functional adrenalectomy caused a fall in potassium excretion and a very large increase in sodium excretion and was reversed by aldosterone. Hydrocortisone infusions slightly increased potassium excretion and reduced solute-free water reabsorption. Preliminary evidence suggests that potassium secretion into urine was still occurring during the 8 hr period of adrenal occlusion and functional adrenalectomy.  (+info)

GH-receptor distribution in the ovine foetal adrenal gland: ontogenic and functional studies. (48/2815)

In order to examine the role of GH in the regulation of foetal adrenal development and function, we have localized GH-receptor mRNA and protein in adrenal glands of ovine foetuses at specific stages of gestation. Adrenals from 60-75 day (n=4), 100-110 day (n=4) and 140-145 day (n=3) foetal sheep (term is 145-150 days) and non-pregnant adult animals (n=3) were dissected and fixed. GH-receptor mRNA localization was studied by in situ hybridization using a (35)S-labelled antisense cRNA probe, and protein by immunohistochemistry using a specific monoclonal antibody to the GH-receptor. At all ages studied, GH-receptor mRNA and immunoreactivity could be detected throughout the adrenocortical region. In adult adrenals, GH-receptor mRNA and immunoreactivity were also evident throughout the adrenocortical zone, with the strongest expression confined to a defined region of cells at the interface between the zona glomerulosa and zona fasciculata. Northern blot analysis of 100 day and 140 day foetal adrenals confirmed the presence of a 4.4 kb GH-receptor mRNA transcript, while immunoblotting of foetal adrenals at approximately 110 days of gestation revealed a 55 kDa GH-receptor species. To study the effect of GH on the function and growth of the immature foetal adrenal gland in vivo, chronically catheterized ovine foetuses (n=4), between 100 and 110 days of gestation, were given a pulsatile infusion of recombinant bovine GH (125 microgram/15 min, 24 pulses/24 h) for 72 h. Plasma cortisol and aldosterone levels were compared with age-matched controls receiving saline infusion alone (n=4). It was found that there was no difference in the basal plasma level of cortisol or aldosterone, and that infusion of GH did not alter steroid levels or gross adrenal size and morphology. These studies demonstrate strong expression of the GH-receptor in the developing ovine foetal adrenal cortex. However, in the immature foetus GH infusion is without effect on plasma steroid levels, suggesting that the steroidogenic action of GH in the ovine foetus may be gestationally dependent.  (+info)