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  • 1
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 15 (1988), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The effect of renal arterial infusion of synthetic human atrial natriuretic factor (ANF(99–126)) on renal function in the conscious euvolaemic sheep was characterized. ANF (99–126) was infused for 2 h at 5 and 50 μg/h into the renal artery of crossbred Merino ewes with chronically indwelling cannulae inserted in the renal artery. The effect on absolute and fractional excretion of Na, K, Ca, Cl and HCO3, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and free water clearance (CH2O) were measured.2. Infusion at 50 μg/h produced a fourfold increase in Na and Cl excretion. Ca excretion increased eightfold, while K and HCO3 increased by small amounts. At the lower dose only Na, Cl and Ca excretion increased significantly. The changes in absolute excretion of each ion were closely mirrored by changes in fractional excretion. CH2O became more negative at both levels of infusion. Small changes in GFR were measured at both rates of infusion. No changes in ERPF or renin secretion were observed.3. ANF (99–126) infusion at 50 μg/h for 1 h increased the excretion of Li, such that more than 70% of the change in Na excretion was associated with the changes in Li clearance. Changes in GFR accounted for less than 10% of change in Na excretion.4. Following either long-term (50 μg/h for 6 h) or repeated short-term (20 μg/h for 30 min) infusions of ANF (99–126), the response of Na excretion was not sustained. The mechanisms of the tachyphylaxis remains undetermined.5. ANF (99–126) is a powerful stimulus to the absolute and fractional excretion of Na, K, Ca, Cl and HCO3. The mechanism of action is not known, but appears to be related to changes in tubular function and/or a change in glomerulotubular balance.
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 15 (1988), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The effect of potassium (K) loading for 10 days on bone sodium (Na) and total exchangeable Na in sheep was examined.2. There were no significant changes in Na space or exchangeable Na after K loading.3. Bone Na concentration decreased by approximately 20% after K loading.4. The degree of mobilization of Na from both the non-exchangeable and exchangeable pools in bone is sufficient to account to a large degree for the observed increase in extracellular fluid volume and the net negative sodium balance which is observed during K loading.
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 25 (1998), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The last three steps of aldosterone biosynthesis, 11β-hydroxylation, 18-hydroxylation and 18-oxidation, have been demonstrated to be catalysed by one enzyme, which is the cytochrome P450np (CYP11B) in cow, pig, sheep and bullfrog or cytochrome P450aldo (CYP11B2) in rat, human, mouse and hamster.2. The related enzyme P45011β (CYP11B1) from rat, human, mouse and hamster adrenals displays 11β-hydroxylation and 18-hydroxylation activities, but not 18-oxidation activity in vitro. No such enzyme has been reported in the cow, pig or sheep to date.3. Data showing the dissociation of aldosterone secretion from plasma angiotensin II (Angll) levels indicate the presence of other factor(s) that regulate aldosterone biosynthesis in response to changes in body sodium status. Thus, we propose the existence of a ‘sodium status factor’ that regulates aldosterone biosynthesis in addition to Angll, K,+ adrenocorticotropic hormone and atrial natriuretic peptide.4. We propose that during severe sodium deficiency there is a switch in the aldosterone pathway to a pathway using 18-hydroxy-deoxycorticosterone (18-OH-DOC) rather than corti-costerone as an intermediate. This switch may be mediated via the putative ‘sodium status factor’.5. Two models of the hypothesis will be discussed in this paper: (i) a ‘one-enzyme’ model; and (ii) a ‘two-enzyme’ model.6. The one-enzyme model proposes that P450aldo (P45011β as in the case of the cow, sheep and pig) changes its enzymatic activity during severe sodium deficiency (i.e. switching to the alternative aldosterone biosynthesis pathway).7. The two-enzyme model proposes that, under normal circumstances, P450aldo synthesizes aldosterone from deoxycorticosterone, while during severe sodium deficiency the P450up provides the substrate (i.e 18-OH-DOC) for the P450aldo.
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 25 (1998), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The last three steps of aldosterone biosynthesis have been demonstrated to be catalysed by a single enzyme, referred to as CYP11B (or P45011β) in cow, pig, sheep and bullfrog and as CYP11B2 (or P450aldo) in rat, human, mouse and hamster.2. The related enzyme CYP11B1 (also referred to as P45011β) in rat, human, mouse and hamster does not have aldosterone synthesis activity, but no such enzyme has been reported in the cow, pig or sheep to date.3. Exclusive aldosterone secretion in the zona glomerulosa (ZG) of the adrenal cortex in species such as rat, human, mouse and hamster could be ascribed to the restricted distribution of CYP11B2 to the same region in the adrenal cortex.4. In other species, such as cow, pig and sheep, the CYP11B enzyme is expressed throughout the adrenal cortex and, thus, the exclusive aldosterone biosynthesis in the ZG could not be explained simply by the distribution of the enzyme.5. We have shown in the sheep that potassium loading and acute sodium depletion stimulate the CYP11B transcript levels, which are not further increased by chronic sodium depletion.6. The predominant CYP11B in the sheep adrenal cortex catalyses the synthesis of aldosterone from deoxycorticosterone (DOC) in vitro, is expressed throughout the adrenal cortex and the corresponding transcript levels are increased by K+ loading or sodium depletion. In short, as far as the last step of aldosterone biosynthesis is concerned, sheep are different from rats. In the rat, the CYP11B2 transcript or protein is elevated by K+ loading or sodium depletion, but not the CYP11B1 transcript or protein.7. We propose that during severe sodium deficiency there is a switch in the aldosterone pathway to one preferentially involving 18-OH-DOC and not corticosterone.
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 25 (1998), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. There is considerable evidence for the existence of an endogenous inhibitor of Na+/K+-ATPase. The exact physiological nature and role of this postulated agent remains unclear although it would be predicted that one of its actions would bi stimulation of renal sodium excretion.2. The natriuretic effect of renal arterial infusion of ouabain is relatively slow in onset and is sustained.3. The natriuresis is not modified by changes in sodium status unlike the natriuretic effect of atrial natriuretic peptide.4. The natriuretic action of ouabain is enhanced dramatically by acute volume expansion or chronic mineralocorticoid treatment, which both result in hypokalemia, hypertension am hypervolemia.5. The natriuretic response to small increments in blood pressure is markedly enhanced by treatment with ouabain.6. We hypothesize that the interaction between the inhibition of Na+/K+-ATPase and elevated blood pressure could result in the shedding of sodium in conditions where there are increased levels of circulating endogenous digitalis-like factors.
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 16 (1989), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. In chronically cannulated ovine fetuses (100–130 days of gestation) the infusion of cortisol (86.7 ± 15 μg/h for 4 h) or human atrial natriuretic factor (ANF; 4.4 μg for 2 h) resulted in highly significant increases in the excretion of sodium, chloride, potassium and water.2. Cortisol had no significant effect on fetal plasma ANF concentrations. All values are mean and s.e.m. Plasma immunoreactive ANF was 53 ± 5 and 67.3 ± 13 pmol/L in the 4 h saline infused fetuses, and 51.3 ± 14.3 and 74 ± 13.3 pmol/L in cortisol-infused fetuses (n= 7). A separate group of fetuses received 2 h infusions of saline or hANF (4.4 ug/h), and plasma IR-ANF values were measured (n= 3). The values, at 0, 60, 90 and 120 min were, respectively, 19.7 ± 3, 17.3 ± 0.7, 18.7 ± 3.7 and 20.7 ± 3.7 pmol/L in the saline infused group, and 25.3 ± 5.3, 80.7 ± 32.3, 123.3 ± 4.3 and 100 ± 15 pmol/L in the ANF-infused fetuses.3. Blood cortisol concentrations, in fetuses infused for 4 h with 0.9% NaCl, were 3.1 ± 0.8 nmol/L (n= 7); in fetuses infused with 0.9% NaCl for 2 h were 3.6 ± 1 nmol/L (n= 3); in fetuses infused for 4 h with cortisol were 19.9 ± 1.9 nmol/L (n= 7); and in fetuses infused with hANF for 2 h were 6.0 ± 3.0 nmol/L (n= 5).4. There was no effect of fetal hANF infusion on maternal or fetal blood aldosterone concentrations.5. The conclusion of this study was that cortisol and ANF cause natriuresis and diuresis in the immature ovine kidneys by independent mechanisms.
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  • 7
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 15 (1988), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. The haemodynamic and renal effects of short-term infusion of human atrial natriuretic peptide (ANP) (1–28) were examined in sheep treated with ACTH and compared with the responses previously observed in normotensive sheep.2. Infusion of ANP at 100 μg/h for 60 min in ACTH-treated sheep (5 μg/kg per day for 5 days) decreased blood pressure and produced a fall in both cardiac output and stroke volume. No changes were seen in heart rate and total peripheral resistance.3. ANP produced large increases in urine volume, urinary sodium and chloride excretion, and further decreased plasma potassium concentration in the ACTH-treated sheep. Compared with normal sheep studied previously under the same conditions, the ACTH-treated sheep showed a much greater diuretic and natriuretic response to ANP, although the blood pressure response to ANP was similar in both states.4. The change in renal responsiveness to ANP in sheep may be related to the increased blood volume of the ACTH-treated animals because volume expansion is known to enhance the renal effects of ANP.
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  • 8
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. In conscious ewes pregnancy was associated with a significantly increased heart rate and cardiac output, while mean arterial pressure (MAP) and stroke volume were unchanged.2. The present study examines the effect of arginine vasopressin (AVP) infused at 0.3, 1, 3.0, and 10 μg/h, into water-loaded and sodium-depleted ewes, either non-pregnant or during the last third of gestation.3. In the water-loaded state, MAP rose significantly at the lowest rate of infusion in both pregnant and non-pregnant ewes. Bradycardia occurred first at 0.3 μg/h in the pregnant ewes but not until 3.0 μg/h in the non-pregnant animals.4. In sodium deficiency there was no increase in MAP at any rate of infusion in either group. Bradycardia occurred in both groups at 1 μg/h.5. This study shows that the pressor effects of AVP are unchanged by pregnancy. However, pregnant ewes are more sensitive to AVP-induced bradycardia when the ewes are water-loaded.
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  • 9
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 14 (1987), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: 1. To investigate a role for peptides derived from the precursor molecule pro- opiomelanocortin (POMC) on the control of aldosterone secretion (ASR), α-, β-, γ1, and γ2-melanocyte stimulating hormone (MSH), corticotropin-like intermediate lobe peptide (CLIP) or β-endorphin were infused into the adrenal arterial supply of sheep with an adrenal cervical autotransplant.2. None of the peptides had any significant effect on aldosterone secretion rate in Na replete, unstressed, conscious animals. In contrast, ACTH-stimulated ASR approximately twofold.3. POMC-derived peptides other than ACTH appear to have little or no effect on the short-term control of aldosterone secretion in vivo, although a role in control and modulation of adrenal function over the longer term cannot be discounted.
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  • 10
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Clinical and experimental pharmacology and physiology 14 (1987), S. 0 
    ISSN: 1440-1681
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: SUMMARY1. Cyclosporin A (CyA; 12 mg/kg/day) was infused into six conscious sheep over 5 days to examine the haemodynamic effects of the drug in normal animals.2. Mean arterial pressure was increased from 73(1) mmHg to 90(4) mmHg (P 〈 0.001). There was no change in cardiac output but calculated total peripheral resistance was elevated from 16(1) to 21(2) mmHg min/1 (P 〈 0.001) on day 4.3. There was no change in plasma [Na], but a fall in plasma [K]. Urinary Na excretion decreased. Glomerular filtration rate, filtration fraction, renal blood flow, renal vascular resistance, body weight, plasma renin and blood aldosterone concentration were unchanged.4. CyA produces an increase in blood pressure in sheep associated with an increase in total peripheral resistance on days 1, 3, and 4, in the absence of changes in renal function. This suggests that CyA hypertension is not simply a consequence of nephrotoxicity.
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