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ABSTRACT: Levels of thirst and ad libitum drinking decrease with advancing age, making older people vulnerable to dehydration. This study investigated age-related changes in brain responses to thirst and drinking in healthy men. Thirst was induced with hypertonic infusions (3.1 ml/kg 0.51M NaCl) in young (Y) and older (O) subjects. Regional cerebral blood flow (rCBF) was measured with positron emission tomography (PET). Thirst activations were identified by correlating rCBF with thirst ratings. Average rCBF was measured from regions of interest (ROI) corresponding to activation clusters in each group. The effects of drinking were examined by correlating volume of water drunk with changes in ROI rCBF from maximum thirst to postdrinking. There were increases in blood osmolality (Y, 2.8 +/- 1.8%; O, 2.2 +/- 1.4%) and thirst ratings (Y, 3.1 +/- 2.1; O, 3.7 +/- 2.8) from baseline to the end of the hypertonic infusion. Older subjects drank less water (1.9 +/- 1.6 ml/kg) than younger subjects (3.9 +/- 1.9 ml/kg). Thirst-related activation was evident in S1/M1, prefrontal cortex, anterior midcingulate cortex (aMCC), premotor cortex, and superior temporal gyrus in both groups. Postdrinking changes of rCBF in the aMCC correlated with drinking volumes in both groups. There was a greater reduction in aMCC rCBF relative to water drunk in the older group. Aging is associated with changes in satiation that militate against adequate hydration in response to hyperosmolarity, although it is unclear whether these alterations are due to changes in primary afferent inflow or higher cortical functioning.
Proceedings of the National Academy of Sciences 02/2008; 105(1):382-7. · 9.68 Impact Factor
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Annals of the New York Academy of Sciences 12/2006; 689(1):651 - 654. · 3.15 Impact Factor
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ABSTRACT: Impaired regulation of salt and water balance in left ventricular dysfunction and heart failure can lead to pulmonary and peripheral edema and hyponatremia. Previous studies of disordered water regulation in heart failure have used models of low cardiac output with normal cardiac function (e.g., inferior vena cava ligation). We investigated thirst and vasopressin (AVP) secretion in a rat myocardial infarction model of chronic left ventricular dysfunction/heart failure in response to a 24-h water deprivation period. Thirst (implied from water drunk), hematocrit, plasma renin activity, and plasma AVP concentrations increased with water deprivation vs. ad libitum water access. Thirst and plasma AVP concentrations were significantly positively correlated with infarct size after 24-h water deprivation but not under ad libitum water access conditions. The mechanism by which this occurs is unclear but could involve increased osmoreceptor sensitivity, altered stimulation of baroreceptors, the renin-angiotensin system, or altered central neural control.
AJP Regulatory Integrative and Comparative Physiology 12/2003; 285(5):R1203-11. · 3.34 Impact Factor
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ABSTRACT: 1. Angiotensin (Ang) II causes cardiac hypertrophy in vitro and in vivo. It also stimulates the release of endothelin (ET)-1. Endothelin-1 induces hypertrophy of cardiomyocytes in vitro. 2. In the present study, we examined whether the cardiac hypertrophic action of AngII in vivo was mediated by ET-1 via ETA receptors. We also determined whether arginine vasopressin (AVP), another ET-1 stimulator, could cause cardiac hypertrophy in vivo through an ET-1-dependent pathway. 3. In Sprague-Dawley rats (n = 8 per group), we determined whether the orally administered ETA receptor antagonist BMS 193884 could attenuate the cardiac hypertrophic effect of: (i) i.v. AngII infusion at either 100 or 200 ng/kg per min, i.v., for 1 week; (ii) AngII infusion at 100 ng/kg per min, i.v., for 2 weeks; and (iii) AVP infusion at either 2 or 10 ng/kg per min, i.v., for 1 week. Mean arterial pressure and heart rate were also measured. 4. Infusion with AngII for both 1 and 2 weeks increased left ventricular weight. Only AngII infusion at 200 ng/kg per min for 1 week increased blood pressure. Endothelin ETA receptor blockade did not attenuate the left ventricular hypertrophy, even though it reduced the hypertensive effect of AngII. Arginine vasopressin increased blood pressure, but did not cause cardiac hypertrophy. 5. We showed that AngII can cause cardiac hypertrophy through a direct, blood pressure-independent effect on the heart. Endothelin-1 did not mediate the cardiac hypertrophic effect of AngII through ETA receptors. This may indicate the involvement of ETB receptors in this model of cardiac hypertrophy. Arginine vasopressin did not cause cardiac hypertrophy in vivo.
Clinical and Experimental Pharmacology and Physiology 05/2003; 30(4):278-83. · 1.85 Impact Factor
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ABSTRACT: 1. Drinking behaviour after water deprivation is one of the standard tests used to study thirst in humans and animals. Diurnal cycle and food availability are known to influence water intake, but have not been considered in previous studies of thirst after water deprivation. In the present study, we examined the effects of diurnal variation and food availability on water intake after 24 h water deprivation in rats. 2. All rats cycled through four treatments in varying order. These treatments were: (i) 24 h water deprivation with free access to food from 1900 h one day to 1900 h the next day, followed by free access to both food and water (Night-with-Food); (ii) 24 h water deprivation with free access to food from from 1900 h one day to 1900 h the next day, followed by free access to water but not food (Night-without-Food); (iii) 24 h water deprivation with free access to food from 0700 h one day to 0700 h the next day, followed by free access to both food and water (Day-with-Food); or (iv) 24 h water deprivation with free access to food from 0700 h one day to 0700 h the next day, followed by free access to water but not food (Day-without-Food). The amount of water consumed during the first 6 h, post-24 h water deprivation, was examined under each condition. 3. There was a significant diurnal effect (P < 0.001) and a significant food availability effect (P = 0.007) on the water consumed in the 6 h period after water deprivation. Most water was consumed by the Night-with-Food group and the least amount of water was consumed by the Day-without-Food group. These effects persisted after correction for water intake during 6 h periods from 0700 and 1900 h with and without food but without previous water deprivation. The diurnal and food availability effects on water consumption were independent (P = 0.5). 4. The coefficient of variability for each group suggests that the most sensitive measurements of water intake are obtained during the day in the absence of food. 5. We conclude that both the time of day and access to food independently alter water intake in rats subjected to a previous 24 h water deprivation. Our study also supports the validity of performing water intake measurements in thirst studies in rats during the day.
Clinical and Experimental Pharmacology and Physiology 09/2001; 28(9):764-7. · 1.85 Impact Factor
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P A Phillips
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ABSTRACT: Specialists in internal medicine have a strong research and evidence culture, and there is a large evidence base, particularly for diagnostic tests and therapeutics. Deficiencies in evidence exist in the area of clinical diagnosis, including the sensitivity, specificity and positive and negative predictive values of clinical signs. The practice of evidence-based medicine (EBM) by internal medicine specialists is hindered by lack of clinical information support systems for ongoing practice evaluation, benchmarking and improvement. Many internal medicine practitioners are moving towards the use of clinical practice guidelines to aid the EBM process. A greater acceptance of EBM processes, including evaluation and guidelines, and resolving issues of distrust of bureaucracies, practitioner protection and consumer privacy, would increase the use of EBM in internal medicine.
The Medical journal of Australia 05/2001; 174(8):401-2. · 2.81 Impact Factor
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The Medical journal of Australia 04/2000; 172(6):259-60. · 2.81 Impact Factor
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ABSTRACT: The rate of transfer of the knowledge gained from health and medical research into evidence-based practice is determined by many factors. Preconditions for the uptake of new evidence are the availability of good evidence, ready access to the evidence, a supportive organisational environment, and effective mechanisms for promoting knowledge uptake. Evidence-based medicine is being promoted in Australia by a body of enthusiastic clinicians, public health practitioners and consumer advocates, supported by initiatives from national, State and local healthcare services and professional bodies. The short to medium term future of evidence-based medicine in Australia is likely to be shaped by three major factors: a reduction in cost and technical barriers which limit access to computerised databases; a trend towards shared decision-making between clinicians and patients; and increased demand for information to fill the gaps in research-based evidence on specific problems.
The Medical journal of Australia 03/2000; 172(4):180-3. · 2.81 Impact Factor
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P A Phillips
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ABSTRACT: 1. Angiotensin II (AngII) and endothelin (ET) stimulate cardiac hypertrophy in vitro and in vivo. Also AngII stimulates ET production. 2. In order to investigate whether AngII produces its cardiac hypertrophic effects through stimulating ET production which acts on the ETA receptor, male Sprague-Dawley rats (6-8 weeks of age) received an intravenous infusion of AngII at 0, 100 or 200 ng/kg per min via Alzet osmotic minipumps and jugular venous catheters for 7 days (n = 12 per dose). Half of the rats in each group received the selective ETA receptor antagonist BMS 193884 25 mg/kg per orally and the other half received the vehicle daily. 3. Telemetrically measured mean arterial pressure (MAP) rose with the 200 ng/kg per min dose of AngII (P = 0.0001). The ETA receptor blockade lowered MAP in all groups (P = 0.011). Left ventricular weights increased only in the 200 ng/kg per min AngII infusion rats (P = 0.04). There was no effect of ETA receptor blockade on left ventricular weights. 4. These results suggest that AngII causes left ventricular hypertrophy not only in association with a pressor response but also when MAP was lowered with ETA blockade to control levels, suggesting a non-pressor effect of AngII on cardiac hypertrophy. Also, ET, acting via ETA receptors, does not mediate the hypertrophic effect of AngII in this model.
Clinical and Experimental Pharmacology and Physiology 08/1999; 26(7):517-8. · 1.85 Impact Factor
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ABSTRACT: Evidence-based medicine is a process by which clinicians translate clinical information needs into answerable questions, track down answers to those needs as efficiently and effectively as possible using the best evidence available, apply the information to patients and evaluate their performance. Implementing evidence-based medicine is fragmented and variable. The National Health and Medical Research Council of Australia has implemented a research program to determine successful strategies for implementation and sustaining of evidence-based clinical practice. In addition this research program will help to answer whether evidence-based practice improves patient outcomes. This paper describes this program and other strategies that improve the application of evidence-based practice in clinical settings.
Journal of Evaluation in Clinical Practice 06/1999; 5(2):163-8. · 1.23 Impact Factor
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ABSTRACT: Cyclosporin-induced hypertension is a major complication of immunosuppression in transplant recipients but its pathophysiology is only partly understood. Cyclosporin reduces endothelium-dependent vasodilation and increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of: (1) nitric oxide enhancement with L-arginine administration and antagonism with N-nitro-L-arginine; and (2) chronic endothelin receptor blockade with the non-peptide endothelin receptor antagonist, bosentan, in two animal models of cyclosporin-induced hypertension. Cyclosporin, administered daily to female Wistar rats (10 mg/kg per day for 30 days, s.c.) and to marmosets (30 mg/kg per day for 20 days, p.o.) significantly elevated tail cuff systolic blood pressure (BP). L-arginine (250 mg/kg, in saline, i.p.), N-nitro-L-arginine (25 mg/kg, in saline, i.p.), bosentan (100 mg/kg, in arabic gum, p.o.) or vehicle were given daily to the rats during the last week of cyclosporin treatment. Marmosets received L-arginine (300 mg/kg, in water, p.o.), bosentan (100 mg/kg/day in arabic gum, p.o.) or vehicle for the last 7 days of cyclosporin treatment. L-arginine, but not saline alone significantly lowered BP in the cyclosporin-hypertensive rats from 129 +/- 2 mm Hg to 122 +/- 3 mm Hg (P < 0.05), and cyclosporin-hypertensive marmosets from 156 +/- 2 mm Hg to 139 +/- 4 mm Hg (P < 0.01). NOLA significantly increased systolic BP in cyclosporin-treated (from 133 +/- 2 mm Hg at week 3 to 142 +/- 3 mm Hg, P < 0.05) and control rats (from 124.0 +/- 2 mm Hg to 134 +/- 2 mm Hg, P < 0.05) indicating that nitric oxide synthesis in cyclosporin-hypertensive rats could be further antagonised. Bosentan, but not arabic gum alone, also lowered BP in the cyclosporin-hypertensive rats from 134 +/- 1 mm Hg to 122 +/- 3 mm Hg (P < 0.01), and cyclosporin-hypertensive marmosets from 156 +/- 2 mm Hg to 139 +/- 4 mm Hg (P < 0.01). These results support the roles of both increased endothelin synthesis and decreased nitric oxide activity in the pathogenesis of cyclosporin A-induced hypertension.
Journal of Human Hypertension 12/1998; 12(12):839-44. · 2.80 Impact Factor
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P A Phillips
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ABSTRACT: Teaching and research are not funded directly under a casemix funding system, and individual Australian State and Territory governments have provided teaching and research grants to teaching hospitals to defray these costs. Biomedical research funding in Australia lags far behind that of other countries. The declining per capita expenditure on the health system generally, as well as on universities, is jeopardising teaching and research activities, which are not seen as "core" hospital services. Studies in the United States have shown that healthcare services associated with teaching and research are more costly but result in better patient outcomes. It may be time to promote outcome-based funding of teaching and research in the Australian healthcare system.
The Medical journal of Australia 11/1998; 169 Suppl:S53-5. · 2.81 Impact Factor
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ABSTRACT: The hormone arginine vasopressin (AVP) contributes to water retention and vasoconstriction in congestive heart failure (CHF) through effects at the V2 and V1a receptors, respectively. The effect of long-term V2 receptor (V2R) blockade using OPC-31260 was assessed in a rat model of postinfarction-induced CHF. Rats underwent coronary artery ligation or sham operation and were treated for 6 mo with oral OPC-31260 (10 mg . kg-1 . day-1) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic function, increased cardiac and lung weight, and elevated plasma atrial natriuretic peptide; plasma AVP and plasma renin activity were not increased. Chronic V2R blockade increased urine volume (P < 0.01) and decreased urine osmolality (P < 0.01) but had no natriuretic effects. V2R blockade did not activate the renin-angiotensin system but increased plasma AVP in CHF (P < 0.01). V2R blockade did not influence cardiac remodeling, cardiac function, or survival. These results suggest that AVP plays a major role in water retention through the renal V2R in a rat model of CHF. V2R blockade using OPC-31260 may represent an alternative to standard diuretic therapy in the management of water retention that characterizes heart failure.
The American journal of physiology 07/1998; 275(1 Pt 2):H176-82.
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ABSTRACT: 1. Vasopressin V1a and V2 receptors are differentially regulated in deoxycorticosterone acetate-salt hypertension. This paper investigated whether the changes were due to transcription changes in receptor mRNA assessed by in situ hybridization histochemistry (liver V1a receptor) and by reverse transcription-polymerase chain reaction (kidney V1a and V2 receptor). 2. Systolic blood pressure and plasma vasopressin levels were significantly elevated in deoxycorticosterone acetate-salt rats (n = 24) compared with water-control (n = 28) and salt-control rats (n = 28) (P < 0.001). Plasma sodium was elevated in deoxycorticosterone acetate-salt rats compared with both control groups (P < 0.01) and plasma osmolality was elevated in deoxycorticosterone acetate-salt rats compared with water-control rats (P < 0.05). 3. Binding kinetic studies demonstrated downregulation of liver V1a and kidney V2 receptors in deoxycorticosterone acetate-salt rats compared with water-control and salt-control rats (P < 0.05). This was not associated with any change in liver V1a receptor mRNA (P = 0.95), or in kidney V1a (P = 0.79) or V2 receptor mRNA (P = 0.96). 4. In deoxycorticosterone acetate-salt hypertension, downregulation of liver V1a and kidney V2 receptors occurs in the setting of stable vasopressin gene transcription. These results suggest that changes in receptor processing may be responsible for the differential regulation of vasopressin receptors that occurs in deoxycorticosterone acetate-salt hypertension.
Clinical Science 05/1998; 94(5):517-23. · 4.61 Impact Factor
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Advances in experimental medicine and biology 02/1998; 449:445-6. · 1.09 Impact Factor
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ABSTRACT: Epidermal growth factor (EGF) has been shown to induce a renal diuresis and natriuresis in sheep and stimulate prostaglandin synthesis from inner rat medullary collecting duct cells in culture. The aims of our study were 1) to investigate whether the renal effects of intravenous infusion of EGF were species specific and 2) to determine the mechanism of these effects by studying the interaction between EGF and indomethacin (a prostaglandin synthase inhibitor) in the conscious rat. Sprague-Dawley rats received intravenous infusions of either 0.9% saline or 0.2 or 2.0 micrograms EGF.kg-1.h-1 over a 6-day period after an initial baseline period. Infusion of 2.0 micrograms EGF.kg-1.h-1 caused an increase in urine volume (baseline: 5.5 +/- 0.2 ml to day 5: 9.0 +/- 0.4 ml, P < 0.01) and corresponding polydipsia, but not natriuresis. Administration of indomethacin with 2.0 micrograms EGF.kg-1.h-1 attenuated (P < 0.05) the diuretic (day 5 EGF + vehicle: 12.2 +/- 1.1 ml vs. EGF + indomethacin: 8.7 +/- 0.9 ml) and polydipsic effects of EGF. These studies demonstrate that intravenous infusion of EGF causes a diuretic effect in rats without natriuresis and that prostaglandins play a role in the diuretic effect of EGF in the rat.
The American journal of physiology 06/1997; 272(6 Pt 2):R1853-61.
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ABSTRACT: To characterize the role of arginine vasopressin (AVP) V(1A) or V2 receptors and the possible interaction with the renin-angiotensin system in the pathogenesis of hypertension in spontaneously hypertensive rats (SHR), young male SHR were treated from 6 to 10 wk of age with AVP V(1A) receptor blockade, angiotensin-converting enzyme (ACE) inhibition, combination of V(1A) receptor blockade and ACE inhibition, V2 receptor blockade, and vehicle. Treatments were then withdrawn, and systolic blood pressure (SBP) was measured until 19 wk of age. At both 10 and 19 wk of age, SBP was significantly reduced with V(1A) receptor blockade, ACE inhibition, and combined treatment compared with vehicle treatment, although no treatment normalized SBP to levels of Donryu normotensive rats. Throughout the experimental period, no significant additive effects were observed with combined treatment. At 10 wk of age, plasma AVP concentration and 24-h urinary AVP excretion were increased with AVP V2 receptor blockade. At 19 wk of age, SBP was significantly higher in rats previously treated with V2 receptor blockade (233 +/- 3 mmHg) than with vehicle (221 +/- 2 mmHg) (P < 0.01). Left ventricular mass was significantly reduced in rats previously treated with ACE inhibition or combined treatment. These results suggest that AVP (via V(1A) receptors) and angiotensin II contribute to the pathogenesis of SHR hypertension, whereas the AVP V2 receptor may be involved in preventing the full expression of the hypertension, in male SHR.
The American journal of physiology 02/1997; 272(2 Pt 2):F229-34.
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ABSTRACT: Cyclosporine-induced hypertension is a major problem in transplant therapy. The pathophysiology of this disease is unclear. Cyclosporine increases endothelin synthesis and release, which may contribute to this hypertension. We examined the effects of chronic endothelin receptor blockade with the novel nonpeptide endothelin receptor antagonist bosentan in two animal models of cyclosporine-induced hypertension. Cyclosporine was administered daily to female Wistar rats (10 mg/kg per day SC for 30 days) and marmosets (30 mg/kg per day PO for 20 days). Control rats received vehicle. Tail-cuff systolic pressure was significantly elevated in the cyclosporine-treated animals before the last week of treatment. Bosentan (100 mg/kg) in arabic gum or arabic gum alone was given daily to the rats by gavage during the last 5 days of cyclosporine treatment and to the marmosets for the last 7 days of cyclosporine treatment. Tail-cuff systolic pressure was measured daily during bosentan treatment. Bosentan but not gum alone significantly lowered blood pressure in the cyclosporine-hypertensive rats from 134 +/- l to 122 +/- 3 mm Hg (P<.Ol) and in the cyclosporine-hypertensive marmosets from 156 +/- 2 to 139+/- 4 mm Hg (P<.Ol). There were no differential effects on plasma creatinine concentration, endothelin concentration, or end-organ weights. Bosentan had no effect in the vehicle-treated rats. These data provide further evidence to support a role for endothelin in cyclosporine-induced hypertension and demonstrate the effectiveness of endothelin receptor antagonism as a novel treatment in cyclosporine-induced hypertension.
Hypertension 07/1996; 27(6):1341-5. · 6.21 Impact Factor
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ABSTRACT: 1. We studied the effects of the non-selective, non-peptide, orally active endothelin (ET) receptor antagonist bosentan (Ro 47-0203) on rat hepatic and mesenteric vascular membrane 125I-ET-1 binding characteristics in vitro and ex vivo (after bosentan by gavage in vivo). 2. Bosentan caused a concentration-dependent competitive inhibition of 125I-ET-1 binding to female rat mesenteric vascular (predominantly ETA receptors) and hepatic (predominantly ETB receptors) membranes in vitro and ex vivo. 3. The time course of the inhibition of binding ex vivo after administration of bosentan in vivo was 1-4h for mesenteric vascular (predominantly ETA receptors) binding and 1-16h for hepatic (predominantly ETB receptors) binding. 4. The time course of displacement of 125I-ET-1 binding from mesenteric vascular and hepatic membranes by bosentan in vitro was similar. 5. Since bosentan is significantly excreted by the liver, the prolonged hepatic 125I-ET-1 binding by bosentan presumably represents hepatic accumulation of bosentan, which may have implications for bosentan antagonizing the actions of ET in the liver.
Clinical Science 01/1996; 89(6):575-9. · 4.61 Impact Factor
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ABSTRACT: Abnormalities of the vasopressin system are found in genetic hypertension. This study compares the delayed effects of a brief period of vasopressin V1A receptor blockade and angiotensin-converting enzyme inhibition in young female and male spontaneously hypertensive rats (SHR) on the development of hypertension in adult life. In a separate study, the role of vasopressin in the maintenance of blood pressure in adult SHR was assessed. Young SHR received either the nonpeptide vasopressin V1A receptor antagonist OPC-21268, the angiotensin-converting enzyme inhibitor ramipril, or vehicle from 6 to 10 weeks of age. During the treatment period, OPC-21268 and ramipril reduced systolic blood pressure compared with control SHR (P < .001). Blood pressure in male SHR 7 weeks after treatment withdrawal was 178 +/- 1 mm Hg in ramipril-treated, 184 +/- 1 mm Hg in OPC-21268-treated, and 200 +/- 2 mm Hg in control SHR (P < .001). Similar results were seen in female SHR, although both OPC-21268 and ramipril were less effective antihypertensive agents in female compared with male SHR. The sustained attenuation in blood pressure was not associated with significant cardiovascular structural changes (left ventricular-to-body weight ratio, renal weight-to-body weight ratio, mesenteric resistance artery media-to-lumen ratio). Results of vasopressin V1A receptor binding kinetics and plasma renin or aldosterone concentrations did not suggest a lasting effect of OPC-21268 on the vasopressin system or of ramipril on the renin-angiotensin system following treatment withdrawal.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 12/1995; 26(5):828-34. · 6.21 Impact Factor
