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1.
Comp Biochem Physiol B Biochem Mol Biol ; 130(3): 385-91, 2001 Oct.
Article in English | MEDLINE | ID: mdl-11567901

ABSTRACT

The retinoblastoma (Rb) gene represents the first tumor suppressor gene characterized. The encoded protein, pRb, plays a crucial role in cell cycle control, preventing malignant cell proliferation. Recently, homologues of the Rb gene have been isolated in fish and the pocket domain, which is central to Rb function, was conserved. In our studies, using coelocanth (Latimeria chalumnae), rainbow trout (Oncorhynchus mykiss), medaka (Oryzias latipes) and English sole (Parophrys vetulus), we have developed a simple protocol for the isolation of the Rb tumor suppressor protein and determined its' tissue and cellular localization. Fish Rb proteins display apparent molecular weights in the range of 100-110 kDa, similar to the human pRb. The protein was detected in all tissues examined, consistent with the proteins' universal role in cellular signalling. An interesting pattern of immunoreactive bands was detected in each of the cells' two main compartments, suggesting differential proteolysis. Immuno-analysis of the pRb in trout liver tumor material revealed an additional Rb reactive product that was absent in normal liver cell extracts.


Subject(s)
Fish Proteins/isolation & purification , Fishes , Retinoblastoma Protein/isolation & purification , Animals , Blotting, Western , Chromatography, Affinity , Electrophoresis, Polyacrylamide Gel , Fish Proteins/chemistry , Hepatocytes/chemistry , Humans , Molecular Weight , Oryzias , Retinoblastoma Protein/chemistry , Trout
2.
N Z Med J ; 112(1096): 351-4, 1999 Sep 24.
Article in English | MEDLINE | ID: mdl-10587052

ABSTRACT

AIM: To document changes in the rate and impact of publications resulting from Health Research Council of New Zealand (HRC) biomedical grants since its inception and to relate the number of publications to Health Priority Areas, fields of research and specific types of grant. METHODS: All original papers or reviews and editorials published by HRC-supported investigators in peer-refereed journals, from 1990 to 1994, were entered into a bibliographic database. RESULTS: In this five-year period, researchers receiving HRC biomedical grants published a total of 2094 articles in 623 peer-reviewed journals, of which 1190 (57%) derived from HRC support. Of the publications, 90.2% were original papers; the remainder were reviews or editorials. From 1990 to 1994, there was an increase in the number of HRC-supported publications (p<0.04) but not of those deriving from other support. There was no change in the quality of publications over this period, as reflected by the impact factor (a measure of the number of times that publications in a journal are cited). The majority (62.6%) of publications derived from project grants, however, the average cost per publication was 8.4% higher for project than for programme (multi-investigator) grants. Finally, nearly 40% of HRC publications directly addressed designated health priority areas. CONCLUSIONS: The present study has examined one aspect of the value for money obtained from the public investment in biomedical research. As the HRC is the major provider of contestable biomedical research funding in New Zealand, bibliometric analysis may be of ongoing value to monitor the effects of changes to the organisation of biomedical research funding in New Zealand.


Subject(s)
Bibliometrics , Publications/statistics & numerical data , Research Support as Topic , Costs and Cost Analysis , New Zealand , Publications/economics
6.
Life Sci ; 57(6): 599-608, 1995.
Article in English | MEDLINE | ID: mdl-7623627

ABSTRACT

Increased arterial blood pressure following a pyrogenic reaction has been reported in previous studies, however the mechanism of this hypertension has not been examined in detail. The present study investigated the effects of both intravenous (IV) and intracerebroventricular (ICV) injection of lipopolysaccharide (LPS) from E. coli on body temperature (Tb), mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), calculated total peripheral resistance (CTPR), stroke volume (SV) and plasma levels of adrenocorticotropin (ACTH) and arginine vasopressin (AVP) in conscious, chronically instrumented sheep. IV injection of LPS (1 microgram) increased Tb in a biphasic manner from 38.7 +/- 0.1 to 39.5 +/- 0.2 degrees C after 50 min and to 39.9 +/- 0.2 degrees C after 130 min, and MAP increased biphasically from 64 +/- 1 to 70 +/- 4 mmHg after 40 min and to 78 +/- 3 mmHg after 130 min. CO initially decreased from 4.4 +/- 0.1 to 3.5 +/- 0.1 after 40 min followed by a secondary rise to 4.8 +/- 0.1 l/min after 100 min. This occurred together with a large, biphasic increase in CTPR from 14.5 +/- 1.0 to 22.0 +/- 2.0 mmHg/l/min at 40 min, and to 18.1 +/- 0.1 mmHg/l/min at 120 min. HR increased from 68 +/- 4 to 97 +/- 4 b/min and SV decreased from 65 +/- 2 to 41 +/- 4 ml/beat during the first phase of activation. Plasma ACTH increased from 22 +/- 9 to 1043 +/- 175 pg/ml after 80 min, and plasma AVP increased from 0.7 +/- 0.2 to 12 +/- 4.0 pg/ml after 60 min. ICV injection of LPS produced a long-lasting increase in Tb and MAP, but had no effect on HR or plasma AVP. Plasma ACTH increased from 30 +/- 12 to 427 +/- 110 pg/ml. These changes suggest that intravenous pyrogenic infection produces a potent vasoconstrictor action in sheep to increase blood pressure, possibly mediated by the actions of AVP within the CNS, or other pyrogenically released vasoconstrictor factors. Furthermore, the duration of activation of the cardiovascular system following peripheral and central LPS administration is different, which together with the contrasting effects on ACTH and AVP, indicate the involvement of several hypertensive mechanisms.


Subject(s)
Endotoxins/pharmacology , Hemodynamics/drug effects , Hypertension/physiopathology , Lipopolysaccharides/pharmacology , Adrenocorticotropic Hormone/blood , Animals , Arginine Vasopressin/blood , Cerebral Ventricles , Endotoxins/administration & dosage , Escherichia coli , Female , Hypertension/blood , Hypertension/chemically induced , Injections , Injections, Intravenous , Lipopolysaccharides/administration & dosage , Sheep , Vascular Resistance/drug effects
7.
Am J Hypertens ; 7(10 Pt 1): 905-12, 1994 Oct.
Article in English | MEDLINE | ID: mdl-7826554

ABSTRACT

The present study examines in detail the short-term cardiovascular actions of atrial natriuretic factor (ANF) in sheep with experimental low-output cardiac failure. Five conscious sheep, surgically implanted with a ventricular pacing wire, were paced at 220 beats/min for 14 days. Most clinical symptoms of congestive heart failure (CHF) were apparent after the 14 days, characterized by low cardiac output, high venous pressure, increased total peripheral resistance, increased plasma levels of ANF, noradrenaline, arginine vasopressin and renin, and marked fluid retention. On day 14 of pacing, intravenous infusion of ANF at 100 micrograms/h for 60 min restored cardiac output to prepacing values and reduced both total peripheral resistance and right atrial pressure. These effects were sustained throughout the infusion period. No change was seen in blood pressure, plasma renin, or noradrenaline levels. These hemodynamic changes, produced by short-term infusion of ANF, contrasted with those seen in normal sheep, where there was a fall in cardiac output with increased total peripheral resistance. These changes reflect a return toward normal of the left ventricular function curve. This is the first study to report that ANF improves cardiac function in conscious sheep with CHF, primarily by a vasodilator action to reduce cardiac preload, and suggests that ANF may be useful in treating the hemodynamic effects associated with cardiac failure.


Subject(s)
Atrial Natriuretic Factor/pharmacology , Cardiac Output/drug effects , Heart Failure/physiopathology , Animals , Atrial Natriuretic Factor/blood , Cardiac Output, Low/drug therapy , Cardiac Output, Low/physiopathology , Electrophysiology , Heart Failure/drug therapy , Hemodynamics , Norepinephrine/blood , Renin/blood , Sheep
8.
Calcif Tissue Int ; 53(2): 117-21, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8402319

ABSTRACT

Glucocorticoids adversely affect bone and mineral metabolism through a number of mechanisms, including inhibition of bone formation. Deflazacort is a glucocorticoid which has been reported to be relatively "bone-sparing." We compared the effects in oophorectomized sheep of deflazacort and prednisolone on the metabolism of osteocalcin (OC), a marker of osteoblast function. An [125]OC infusion method was used to measure the OC plasma clearance rate (PCR) and OC plasma production rate (PPR). Six-day intravenous infusion of deflazacort and prednisolone (in the dose range 0.007-1.00 mg/hour) induced dose-dependent decreases in OC PPR which were of a similar pattern but significantly different magnitude (P < 0.02); deflazacort demonstrated a potency about 150% that of prednisolone. Both steroids decreased plasma OC levels on a dose-related basis but at the lower doses 0.05 mg/hour (P < 0.05) and 0.013 mg/hour (P < 0.0005), deflazacort caused greater decrements. OC PCR was significantly increased only by higher doses of deflazacort (1.00 mg/hour, 0.25 mg/hour; P < 0.05). Deflazacort and prednisolone increased both postabsorptive plasma glucose and plasma calcium levels, but there were no significant differences between their effects. We conclude that plasma OC levels and OC PPR in sheep were more sensitive to the effects of deflazacort than to prednisolone. At high doses, the depressive effect of deflazacort on plasma OC levels may have been due in part to an increased OC PCR which was not evident with prednisolone treatment. However, the agents appeared to have a similar dose-dependent hyperglycemic effect, and both caused a small dose-dependent increase in plasma calcium.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Anti-Inflammatory Agents/pharmacology , Osteocalcin/metabolism , Prednisolone/pharmacology , Pregnenediones/pharmacology , Sheep/metabolism , Animals , Anti-Inflammatory Agents/administration & dosage , Blood Glucose/analysis , Calcium/blood , Dose-Response Relationship, Drug , Female , Infusions, Intravenous , Iodine Radioisotopes , Metabolic Clearance Rate , Osteoblasts/physiology , Osteocalcin/blood , Ovariectomy , Prednisolone/administration & dosage , Pregnenediones/administration & dosage
9.
Life Sci ; 50(24): 1905-12, 1992.
Article in English | MEDLINE | ID: mdl-1534598

ABSTRACT

The renal and cardiovascular effects of ANF infusion have been examined in separate series of experiments; in conscious instrumented sheep following either hemorrhage (10 mL/kg body weight) or removal of 500 mL of plasma by ultrafiltration. Renal arterial infusion of hANF (99-126) at 50 micrograms/h increased sodium excretion from 99 +/- 30 to 334 +/- 102 (p less than 0.05) in normal animals, and from 77 +/- 31 to 354 +/- 118 mumol/min in hemorrhaged animals. Similarly in sheep following ultrafiltration, cardiac output and stroke volume were reduced by intravenous infusion of ANF (100 micrograms/h), although these effects were less marked than those observed in normal animals. The rapid modulation of natriuretic responses to ANF observed in volume expanded animals is not seen in this model of acute volume depletion suggesting that the mechanism through which the renal response to ANF is modulated in low sodium or volume states is not simply the reverse of that which produces rapid enhancement of response following blood volume expansion.


Subject(s)
Atrial Natriuretic Factor/pharmacology , Blood Volume/physiology , Cardiovascular System/drug effects , Kidney/drug effects , Animals , Cardiovascular Physiological Phenomena , Consciousness , Hemodynamics/drug effects , Hemodynamics/physiology , Hemofiltration , Infusions, Intravenous , Kidney/physiology , Renin , Sheep , Ultrafiltration
10.
Clin Exp Hypertens A ; 14(5): 905-22, 1992.
Article in English | MEDLINE | ID: mdl-1395077

ABSTRACT

Synthetic sex steroid administration is a major cause of iatrogenic hypertension but little is known of the haemodynamic or metabolic consequences of these steroids. This study examined the short term blood pressure, volume and metabolic consequences of 5 day administration of synthetic androgen to normal men and synthetic oestrogen or progestogen to normal women. Healthy subjects (8 women, 6 men) on a constant diet took part in each of 3 studies. Males received testosterone undecanoate 120 mg/day (n = 6) and females either ethinyloestradiol 0.3 mg/day (n = 5) or norethisterone 15 mg/day (n = 6) for 5 days in the last week of the cycle. Norethisterone increased lying (+7 mmHg) and standing (+8 mmHg) systolic pressure but the other steroids did not alter blood pressure. All 3 treatments increased body weight. There were no consistent changes in plasma electrolytes or glucose with any steroid, and no urinary sodium retention or changes in urine Na:K ratio. Haematocrit fell on ethinyloestradiol but no steroid significantly increased plasma volume (measured as volume of distribution of 125I human serum albumin). Renin substrate and cortisol rose and renin concentration fell on ethinyloestradiol. These studies suggest that the progestogen component may contribute to the blood pressure raising effects of oral contraceptives.


Subject(s)
Ethinyl Estradiol/pharmacology , Gonadal Steroid Hormones/pharmacology , Hemodynamics/drug effects , Hormones/pharmacology , Metabolism/drug effects , Norethindrone/pharmacology , Testosterone/analogs & derivatives , Adult , Female , Humans , Male , Plasma Volume/drug effects , Testosterone/pharmacology
11.
J Endocrinol ; 130(2): 213-21, 1991 Aug.
Article in English | MEDLINE | ID: mdl-1919393

ABSTRACT

Indirect evidence has suggested that the kidney is a major organ of clearance for osteocalcin, a circulating marker of osteoblast function. The objectives of the present study were (1) to confirm the role of the kidney in osteocalcin clearance (2) to quantify the contribution of extrarenal sites and (3) to investigate the renal mechanism(s) of osteocalcin clearance. Plasma osteocalcin levels, osteocalcin plasma clearance rate (PCR) and plasma production rate (PPR) were determined in oophorectomized (OX) and uninephrectomized oophorectomized (UOX) sheep. The osteocalcin renal extraction efficiency (REE) and the effective renal plasma flow (ERPF) were measured, and the osteocalcin renal clearance rate (RCR) was calculated. The osteocalcin PCR was reduced significantly in UOX compared with OX sheep (2.0 +/- 0.1 (n = 9) vs 2.5 +/- 0.1 litres/h (n = 44); P less than 0.0005). In UOX sheep with plasma creatinine levels less than or equal to 130 mumol/l, the osteocalcin REE was 9 +/- 1.3% and the osteocalcin RCR was 50-91% of osteocalcin PCR (n = 4). In UOX sheep with plasma creatinine levels in the range 100-440 mumol/l, there was a linear relationship between osteocalcin PCR and ERPF; the osteocalcin RCR was related to the osteocalcin PCR (RCR = 0.9 x PCR - 0.50). Intravenous infusion of the synthetic glucocorticoid triamcinolone acetonide (TA) in UOX sheep led to marked decrements in plasma osteocalcin levels and the osteocalcin PPR, and a significant increase in the osteocalcin PCR. These changes were accompanied by a 44% increase in ERPF.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Kidney/metabolism , Osteocalcin/metabolism , Sheep/metabolism , Animals , Female , Iodine Radioisotopes , Kidney/blood supply , Kidney/drug effects , Kidney/surgery , Metabolic Clearance Rate , Osteocalcin/blood , Osteocalcin/pharmacokinetics , Osteocalcin/urine , Regional Blood Flow/drug effects , Triamcinolone Acetonide/pharmacology
12.
Am J Hypertens ; 4(8): 719-22, 1991 Aug.
Article in English | MEDLINE | ID: mdl-1930855

ABSTRACT

The hemodynamic responses to bolus injection of endothelin I (ET) at 5, 15, and 50 micrograms were examined in conscious sheep (n = 5) before and after infusion of nisoldipine at 25 micrograms/kg/h. Endothelin produced dose-dependent increases in mean arterial pressure (MAP + 87 +/- 6 mm Hg at 50 micrograms) and calculated total peripheral resistance (CTPR + 54 +/- 15 mm Hg/L/min at 50 micrograms) and decreases in heart rate (HR - 34 +/- 6 beats/min at 50 micrograms) and cardiac output (CO - 2.6 +/- 0.3 L/min at 50 micrograms) but no change in stroke volume (SV). Nisoldipine attenuated (P less than .05) the endothelin-induced changes in MAP (+26 +/- 3 mm Hg at 5 micrograms) and CTPR (+13.0 +/- 2.1 mm Hg/L/min at 50 micrograms), but not the fall in heart rate or cardiac output. These data are compatible with the hypothesis that vasoconstrictor effects of ET in sheep are in part dependent on influx of calcium through L-type channels.


Subject(s)
Calcium Channel Blockers/pharmacology , Consciousness/physiology , Endothelins/pharmacology , Hemodynamics/physiology , Animals , Cardiac Output/drug effects , Cardiac Output/physiology , Cardiovascular System/drug effects , Dose-Response Relationship, Drug , Endothelins/administration & dosage , Female , Heart/drug effects , Heart/physiology , Hemodynamics/drug effects , Infusions, Intravenous , Nisoldipine/pharmacology , Sheep , Stroke Volume/drug effects , Stroke Volume/physiology
13.
Am J Hypertens ; 3(11): 829-32, 1990 Nov.
Article in English | MEDLINE | ID: mdl-2175624

ABSTRACT

The present study examined the hemodynamic actions of a non-guanylate cyclase linked or "clearance" atrial natriuretic factor (ANF) receptor ligand--des[Gln116Ser117Gly118Leu119Gly120] ANF 102-121 (C-ANF 4-23)--in conscious sheep. The effect of this peptide on the duration and potency of the hypotensive action of ANF (99-126) was also studied. C-ANF (4-23), infused at 400 micrograms/h for 2 h, reduced blood pressure, cardiac output and stroke volume, and increased total peripheral resistance slightly. These changes were similar to those previously observed with infusion of 20 micrograms/h ANF (99-126) in sheep. Endogenous ANF concentration increased from 28 +/- 13 to 85 +/- 18 pg/mL after 80 min infusion of C-ANF (4-23). The duration of hypotensive action from injection of ANF (99-126) was increased almost two-fold during infusion of C-ANF (4-23), however the hypotensive potency of ANF (99-126) was similar both prior to and during infusion of C-ANF (4-23). These studies support the concept of the metabolism of ANF via clearance receptors, suggesting that long-term hemodynamic actions of endogenous ANF may be achieved via prolonged blockade of these clearance receptors.


Subject(s)
Atrial Natriuretic Factor/metabolism , Atrial Natriuretic Factor/pharmacology , Hemodynamics/drug effects , Peptide Fragments/pharmacology , Receptors, Cell Surface/pharmacology , Animals , Atrial Natriuretic Factor/blood , Blood Pressure/drug effects , Cardiac Output/drug effects , Heart Rate/drug effects , Infusions, Intravenous , Receptors, Atrial Natriuretic Factor , Receptors, Cell Surface/blood , Sheep , Stroke Volume/drug effects
14.
J Hypertens ; 8(11): 1007-13, 1990 Nov.
Article in English | MEDLINE | ID: mdl-1963182

ABSTRACT

Hypertension and nephrotoxicity are major clinical problems associated with cyclosporine A administration. Sheep rapidly develop hypertension after intravenous administration of cyclosporine A at 6 mg/kg per day over 5 days, and this is associated with a rise in peripheral resistance. Nephrotoxicity is not a feature of cyclosporine A-induced hypertension in this species. This study reports the use of nisoldipine to investigate the role of Ca2(+)-induced smooth muscle contraction in cyclosporine A-induced hypertension in conscious sheep. After 3 control days, nisoldipine at 24 mg/day was infused intravenously alone for 24h (E1), followed by 5 days of nisoldipine plus cyclosporine A (6 mg/kg per day; E2-E6). After 24 h of nisoldipine alone, mean arterial pressure (MAP) was unchanged, heart rate rose from a control value of 60 +/- 2 beats/min to 102 +/- 9 beats/min (P less than or equal to 0.001), calculated total peripheral resistance (CTPR) fell from 15.8 +/- 0.5 to 11.7 +/- 0.5 mmHg/l per min (P less than or equal to 0.001) and stroke volume fell from 73 +/- 4 ml/beat to 60 +/- 5 ml/beat (P less than or equal to 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Cyclosporins/pharmacology , Hemodynamics/drug effects , Hypertension/prevention & control , Nisoldipine/pharmacology , Animals , Calcium/physiology , Cyclosporins/blood , Drinking/drug effects , Eating/drug effects , Female , Glomerular Filtration Rate/drug effects , Hypertension/chemically induced , Hypertension/physiopathology , Potassium/blood , Renin/blood , Sheep , Sodium/urine
15.
Am J Hypertens ; 3(10): 775-81, 1990 Oct.
Article in English | MEDLINE | ID: mdl-2171563

ABSTRACT

This study investigated the ability of two diuretics, amiloride and frusemide, to prevent the development of ACTH induced hypertension in conscious sheep. Infusion of amiloride (20 mg/day) or frusemide (50 mg/day) for three days into normotensive sheep did not have any significant effects on blood pressure. Amiloride blocked ACTH-induced hypertension and the sodium retention and hypokalemia which is usually associated with ACTH administration. Frusemide failed to completely block the hypertension and potassium loss, however it blocked the transient initial urinary sodium retention associated with ACTH-induced hypertension. As frusemide failed to completely block the hypertension it is unlikely that the amiloride effect is due primarily to effects on urinary Na excretion. It is possible that amiloride is exerting its antihypertensive effects by blocking sodium channels.


Subject(s)
Adrenocorticotropic Hormone/antagonists & inhibitors , Amiloride/pharmacology , Furosemide/pharmacology , Hypertension/prevention & control , Adrenocorticotropic Hormone/adverse effects , Aldosterone/administration & dosage , Aldosterone/pharmacology , Amiloride/administration & dosage , Animals , Blood Pressure/drug effects , Drug Administration Schedule , Drug Combinations , Drug Evaluation, Preclinical , Female , Furosemide/administration & dosage , Hypertension/chemically induced , Hypertension/urine , Infusions, Intravenous , Potassium/analysis , Potassium/blood , Potassium/urine , Saliva/chemistry , Saliva/drug effects , Sheep , Sodium/analysis , Sodium/blood , Sodium/urine
17.
Clin Exp Pharmacol Physiol ; 17(5): 377-80, 1990 May.
Article in English | MEDLINE | ID: mdl-2354554

ABSTRACT

1. Studies in the rat and the dog have shown that infusion of aldosterone for several weeks into the cerebral ventricles (ICV) can produce hypertension at doses that do not have an effect when infused systemically. We have previously shown that a high physiological dose of aldosterone infused intravenously at 10 micrograms/h in sheep produces an increase in blood pressure of 7 mmHg within 2 days. 2. In this paper we report the effects of ICV infusion of aldosterone at 2 micrograms/h for 6 days in conscious sheep. 3. Neither blood pressure nor heart rate were altered, and there were no consistent changes in any of the metabolic parameters measured. 4. These results do not support a role for central effects of aldosterone in the hypertension produced by systemic infusion of the steroid in sheep.


Subject(s)
Aldosterone/pharmacology , Aldosterone/administration & dosage , Animals , Blood Pressure/drug effects , Female , Heart Rate/drug effects , Injections, Intraventricular , Sheep , Sodium/blood
18.
Clin Exp Pharmacol Physiol ; 17(3): 241-5, 1990 Mar.
Article in English | MEDLINE | ID: mdl-2187636

ABSTRACT

1. Synthetic human endothelin-1 was infused intravenously at 15 micrograms/h for 24 h to examine its cardiovascular actions in five conscious sheep. 2. Endothelin produced a maximum increase in mean arterial pressure (MAP) of +8 mmHg at 8 h, with an increase in calculated total peripheral resistance (CTPR) of +2.6 mmHg/L per min, whilst cardiac output (CO) was unchanged. At 24 h MAP was not significantly elevated, however CTPR had increased by +2.8 mmHg/L per min and CO had decreased by 0.9 L/min. 3. This study shows that long-term administration of endothelin produces sustained arterial vasoconstriction in sheep.


Subject(s)
Hemodynamics/drug effects , Peptides/pharmacology , Animals , Blood Pressure/drug effects , Cardiac Output/drug effects , Endothelins , Female , Infusions, Intravenous , Kinetics , Sheep , Time Factors , Vascular Resistance/drug effects
19.
Am J Physiol ; 258(3 Pt 2): F684-9, 1990 Mar.
Article in English | MEDLINE | ID: mdl-2138423

ABSTRACT

To examine the effect of changes in Na status on the renal response to atrial natriuretic factor (ANF), human ANF-(99-126) was infused into the renal artery of conscious sheep while Na replete, Na depleted, or Na loaded. The natriuretic response to ANF was attenuated during Na depletion and enhanced in Na-loaded animals. To demonstrate that the enhancement or attenuation of response was related to Na status rather than to the initial level of Na excretion, aldosterone was infused into the renal artery for 2 h to decrease Na excretion to a level inappropriately low for the animal's Na status (and not different from Na-depleted animals), and they were again challenged with ANF. Their response to ANF, however, was not significantly different from that in normal Na-replete animals but was significantly greater than that observed in Na-depleted animals. Similarly, Na-loaded animals treated with aldosterone had control Na excretion in the Na-replete range; however, their response to ANF was not significantly different from that of Na-loaded animals. The response to ANF was enhanced in sheep treated with aldosterone for 48 h, consistent with Na retention and hypervolemia, secondary to aldosterone treatment. The study demonstrates that Na status or some associated physiological parameter is an important determinant of the natriuretic response to ANF. The present series of experiments demonstrate that changes in aldosterone levels per se are not a determinant of the natriuretic response to ANF.


Subject(s)
Aldosterone/metabolism , Atrial Natriuretic Factor/pharmacology , Kidney/drug effects , Sodium/metabolism , Aldosterone/pharmacology , Animals , Female , Glomerular Filtration Rate/drug effects , Natriuresis , Potassium/urine , Renal Circulation/drug effects , Sheep , Sodium/deficiency , Time Factors
20.
Clin Exp Pharmacol Physiol ; 17(3): 163-6, 1990 Mar.
Article in English | MEDLINE | ID: mdl-2160339

ABSTRACT

1. Studies in sheep have led to the concept of a 'hypertensinogenic' (HT) steroid hormone activity, whereby the blood pressure (BP) raising effects of adrenocortical steroids can be separated from their in vivo glucocorticoid (GC) or mineralocorticoid (MC) activities. 2. The three main lines of evidence are as follows: (i) BP raising effects of ACTH cannot be reproduced by appropriate rates of infusion of steroids with GC and MC activities; (ii) certain steroids e.g. 9 alpha-fluorocortisol can increase BP at rates of infusion below threshold for in vivo GC or MC actions and for many steroids there is no correlation between GC, MC and HT effects; (iii) demonstration of differential antagonism of HT, MC and GC effects. 3. Studies in man show that the BP effects of ACTH are due to cortisol (F) at levels which have both MC and GC activity. However, BP effects of ACTH cannot be blocked by MC and GC antagonists. 4. Although complete separation of in vivo GC, MC and HT activities has not been possible in man, our own studies show a degree of dissociation. Taken together, these data suggest that steroids may raise BP by a HT mechanism distinct from classical in vivo MC or GC activities in man as well as sheep.


Subject(s)
Adrenocorticotropic Hormone/pharmacology , Blood Pressure/drug effects , Hydrocortisone/pharmacology , Administration, Oral , Adrenocorticotropic Hormone/administration & dosage , Desoxycorticosterone/administration & dosage , Drug Administration Schedule , Glucocorticoids/pharmacology , Humans , Hydrocortisone/administration & dosage , Hydrocortisone/blood , Hypertension/etiology , Injections, Intravenous , Mineralocorticoids/pharmacology
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