摘要:

ObjectiveThe renin–angiotensin system (RAS) is implicated in the development of hypertensive glomerulosclerosis. However, no experimental evidence exists that clearly demonstrates activation of glomerular RAS in hypertensive nephropathy. We used stroke-prone spontaneously hypertensive rats (SHRSP) to examine whether RAS components are increased in glomeruli of SHRSP and whether this increase leads to an increase in mRNA levels for transforming growth factor-β1(TGF-β1).MethodsWe examined the sequential changes of urinary albumin excretion (UAE), morphology, and glomerular mRNA expression for TGF-β1 and fibronectin (FN) in relation to glomerular mRNA expression for angiotensinogen (ATN), angiotensin converting enzyme (ACE), angiotensin II type 1a (AT1a), and type 1b (AT1b) receptors, and intervention with angiotensin II type 1 receptor antagonist candesartan and equihypotensive hydralazine.ResultsIn SHRSP, UAE was normal at 9 weeks of age, but became higher, beginning at 12 weeks of age, than that in the age-matched Wistar–Kyoto (WKY) rats, while SHRSP showed no glomerulosclerosis until 14 weeks of age; it was marked at 24 weeks. Plasma renin activity and plasma angiotensin II level was equivalent in the 9- and 12-week-old SHRSP and the WKY rats; both parameters, however, were elevated in 24-week-old SHRSP as compared with age-matched control. RNase protection assays showed that glomerular levels of ATN, ACE, and AT1a and AT1b receptors mRNA were significantly increased in 9-, 12-, and 14-week-old, but not in 24-week-old SHRSP, compared with age-matched WKY rats. Northern blot analysis showed that glomerular levels of TGF-β1 and FN mRNA were higher in SHRSP than in WKY rats at all time points. Candesartan reduced UAE to control levels, whereas hydralazine reduced UAE but not to control levels. Candesartan administration for 12 weeks virtually prevented the progression of glomerulosclerosis. While candesartan reduced mRNA levels for RAS components, TGF-β1, and FN to control levels, hydralazine was not effective in this respect.ConclusionResults suggest that increases in glomerular RAS components that occur independently of circulating RAS alter glomerular permselectivity and increase the glomerular expression of TGF-β1 and FN in young SHRSP. Findings in old SHRSP suggest that altered glomerular permselectivity and an increased glomerular expression of TGF-β1 and FN may be associated with the activation of systemic RAS. J Hypertens 2000, 18:1247–1255 © Lippincott Williams & Wilkins.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectivesTo determine the acute effects of continuous positive airway pressure (CPAP) on baroreceptor reflex sensitivity (BRS) for heart rate during sleep in congestive heart failure (CHF) patients with obstructive sleep apnea (OSA).Design and methodsIn eight CHF patients with OSA not previously treated with CPAP, spontaneous BRS was assessed during overnight polysomnography prior to the onset of sleep, and during stage 2 non-rapid eye movement sleep (NREM) before, during and after application of CPAP.ResultsCPAP alleviated OSA and acutely increased the slope of BRS (median, 25%,75%) [from 3.9 (3.5, 4.8) to 6.2 (4.6, 26.2) ms/mmHg,P< 0.05]. Increases in the slope of BRS persisted following withdrawal of CPAP [4.9 (4.3, 6.9) ms/mmHg,P< 0.05]. CPAP also lowered heart rate (from 81.3 ± 4.9 to 76.0 ± 5.7 bpm,P< 0.05), an effect which persisted after its withdrawal (76.7 ± 5.7 bpm,P< 0.05). Systolic blood pressure at the midpoint of the pressure range of BRS sequences fell while on CPAP (from 139 ± 8 to 120 ± 7 mmHg,P< 0.05), and remained lower following CPAP withdrawal (124 ± 9 mmHg,P< 0.05).ConclusionsIn CHF patients with OSA, CPAP increases acutely BRS during sleep, lowers heart rate and resets the operating point for BRS to a lower blood pressure. These effects of CPAP persist after its withdrawal, suggesting that nocturnal CPAP therapy may cause sustained improvement in the neural control of heart rate.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo determine the influence of imidazoline receptors and α2-adrenoceptors in the rostral ventrolateral medulla (RVLM) on the renal sympathetic baroreflex.MethodsThe effects of rilmenidine (4 nmol) and α-methylnoradrenaline (α-MNA, 80 nmol) micro-injected into the RVLM of urethane-anaesthetized rabbits previously implanted with renal nerve recording electrodes were examined before and after micro-injection of the imidazoline receptor/α2-adrenoceptor antagonist idazoxan and the α2-adrenoceptor antagonist 2-methoxyidazoxan (2-MI).ResultsRilmenidine and α-MNA both lowered mean arterial pressure (MAP) by 28% and renal sympathetic nerve activity (RSNA) by 35%, and reduced RSNA upper plateaus and ranges by 30–70%. Rilmenidine decreased both sympathetic burst frequency and amplitude while α-MNA reduced amplitude only. Rilmenidine shifted the RSNA baroreflex curve to the left while α-MNA shifted the curve to the right. Idazoxan (13 nmol) reversed the hypotension and all RSNA effects of rilmenidine, while 2-MI (4 nmol) increased MAP 18% above the control and also reversed all RSNA parameters. By contrast, 2-MI reversed the α-MNA-induced hypotension and partially restored RSNA and the upper plateau of the RSNA baroreflex curve. Idazoxan treatment only partially reversed the hypotension after α-MNA and had no effect on any of the baroreflex curves.ConclusionBoth α-MNA and rilmenidine injected into the RVLM of rabbits produce renal sympathetic inhibition, but differences in the location of the baroreflex curve and the pattern of effects on burst amplitude and frequency suggest different mechanisms of action. The effects of idazoxan suggest that rilmenidine acts via imidazoline receptors. Since 2-MI reversed the actions of α-MNA and also rilmenidine, this suggests that α2-adrenoceptor hypotension can be produced in the rabbit RVLM and that rilmenidine may activate α2-adrenoceptors, possibly as a result of activating imidazoline receptors.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveTo verify whether the normal kidney exerts a supportive, facilitatory action on renal sympathetic nerve activity (RSNA), the effects of unilateral and bilateral nephrectomy on RSNA have been studied.MethodsThe RSNA, rectal temperature (T), rate of breathing (RB), arterial blood pressure (BP) and heart rate (HR) were continuously recorded in three groups of pentobarbital anaesthetized, spontaneously breathing Sprague–Dawley rats: group 1 (n= 5): both kidneys intact; group 2 (n= 5): left surgical nephrectomy; group 3 (n= 5): left surgical nephrectomy and functional exclusion of the right kidney (functional right nephrectomy, FRN), produced by a tight ligature of the renal hilum which was maintained for 3 h. In a fourth group (n= 7), in which nerve activity was not recorded, reopening of the right renal hilum was preceded or followed by intravenous administration of captopril (3 mg/kg).ResultsIn groups 1 and 2 RSNA increased from 22.3 ± 2.1 to 122.9 ± 13.6 and from 26.7 ± 1.2 to 93.2 ± 14.0 impulses/s (mean ± SEM), respectively, without concomitant changes in cardiovascular parameters. In group 3 RSNA decreased from 39.1 ± 3.1 to 13.7 ± 2.6 impulses/s during the 3 h of FRN. In group 3 the reopening of the right renal hilum was followed by a marked increase in BP and HR that was prevented or reversed by intravenous captopril in rats of group 4.ConclusionsThe decrease in RSNA observed in rats during bilateral nephrectomy, in contrast to the increase observed in rats with one or both kidneys intact, suggests that the kidney as a whole exerts a supportive role on sympathetic nerve activity. The hypertension and tachycardia that follows the reopening of the right kidney hilum appears to be caused by the generation of endogenous angiotensin II; this is the first evidence of an acute angiotensin-mediated renal hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveThe present study aimed to characterize the influence of salt intake on the gene expression of the kidney specific chloride channels CLC-K1 and CLC-K2 in the kidneys of salt-resistant and salt-sensitive Dahl rats.DesignFor this purpose Dahl salt-resistant (Dahl-R) and Dahl salt-sensitive rats (Dahl-S) were fed a low (0.02%), normal (0.6%) or high (4%) salt diet for 19 days and CLCK1 and -K2 mRNA expression was semiquantitated in cortex, outer and inner medulla.MethodsKidneys were macroscopically dissected, total RNA was isolated according to the guanidinium–thiocyanate–phenol-chloroform method and messenger RNAs for the kidney specific chloride channels CLC-K1 and CLC-K2 were measured by ribonuclease protection assay.ResultsSystolic blood pressure in high salt-treated Dahl-S rats increased to 204 ± 5 mmHg versus 150 ± 7 mmHg in Dahl-S controls. Dahl R and low salt Dahl-S rats showed no increase in blood pressure. For CLC-K1 mRNA we found an order of abundance inner medulla ≫ outer medulla ≫ cortex. There was no difference in mRNA abundance between Dahl-R and -S, nor any effect of the rate of salt intake on CLC-K1 mRNA abundance in the different kidney zones. CLC-K2 mRNA expression in cortex and outer medulla was similar between Dahl-R and -S rats. In the inner medulla, however, CLC-K2 mRNA was 1.7-fold higher in Dahl-S than in Dahl-R rats. In the cortex we found no influence of salt intake on CLC-K2 mRNA. In outer and inner medulla of Dahl-R rats and Dahl-S rats high salt diet led to a marked downregulation of CLC-K2 mRNA expression. Consequently, CLC-K2 gene expression in the inner medulla was 2.2-fold higher in Dahl-S than in Dahl-R rats in states of high salt diet.ConclusionGiven that the CLC-K2 chloride channel in the outer and inner medulla contributes to salt reabsorption, our findings would suggest that Dahl-S rats have an increased medullary salt reabsorption. This may contribute to the inability of these animals to excrete an increased salt load at a normal renal perfusion pressure leading to the development of hypertension. J Hypertens 2000, 18:1289–1295 & Lippincott Williams & Wilkins.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

BackgroundLeft ventricular hypertrophy (LVH) is present in young spontaneously hypertensive rats (SHR) compared with normotensive Wistar–Kyoto (WKY) rats and treatment of SHR with captopril leads to regression of LVH. Hypertrophy produces changes in gene expression for myofibrillar proteins with increased ratios of skeletal to cardiac actin and β to α-myosin heavy chain (MHC).ObjectivesThe objective of this study was to follow changes in transcript prevalence for these four proteins during ageing and with captopril treatment in SHR and WKY rats.MethodsUntreated SHR and WKY rats were studied at 100, 156, 350 and 450 days. Groups at 100 and 350 days were divided into a treatment group (given captopril) and untreated controls. Transcripts were measured usingin situhybridization.ResultsBoth cardiac and skeletal actin were increased in untreated SHR compared to WKY rats (P< 0.01 andP< 0.05, respectively). α-MHC was increased (P< 0.01) whilst β-MHC was normal in 100-day-old SHR (an age when LVH was present) compared with WKY rats. With ageing, α-MHC declined and β-MHC increased giving the increased ratio of β to α-MHC transcripts reported by other investigators. Treatment of SHR led to a significant decline in skeletal actin transcripts (P< 0.01) and reversed the rise in β-MHC expression that occurred with ageing (P< 0.01).ConclusionsLVH in SHR is associated with increased skeletal and cardiac actin transcripts. Despite unequivocal LVH in SHR at 100 days of age, α rather than β-MHC transcripts were increased. Only with ageing did the classically reported increased ratio of β to α-MHC transcripts become apparent. Captopril treatment reduced skeletal actin transcripts and reversed the increase in β-MHC that occurred with ageing.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveIn addition to its haemodynamic effects, angiotensin II (AngII) is thought to contribute to the development of cardiac hypertrophy via its growth factor properties. The activation of mitogen-activated protein kinases (MAPK) is crucial for stimulating cardiac growth. Therefore, the present study aimed to determine whether the trophic effects of AngII and the AngII-induced haemodynamic load were associated with specific cardiac MAPK pathways during the development of hypertrophy.MethodsThe activation of the extracellular-signal-regulated kinase (ERK), the c-jun N-terminal kinase (JNK) and the p38 kinase was followed in the heart of normotensive and hypertensive transgenic mice with AngII-mediated cardiac hypertrophy. Secondly, we used physiological models of AngII-dependent and AngII-independent renovascular hypertension to study the activation of cardiac MAPK pathways during the development of hypertrophy.ResultsIn normotensive transgenic animals with AngII-induced cardiac hypertrophy, p38 activation is associated with the development of hypertrophy while ERK and JNK are modestly stimulated. In hypertensive transgenic mice, further activation of ERK and JNK is observed. Moreover, in the AngII-independent model of renovascular hypertension and cardiac hypertrophy, p38 is not activated while ERK and JNK are strongly stimulated. In contrast, in the AngII-dependent model, all three kinases are stimulated.ConclusionsThese data suggest that p38 activation is preferentially associated with the direct effects of AngII on cardiac cells, whereas stimulation of ERK and JNK occurs in association with AngII-induced mechanical stress.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveOn high salt intake, Dahl salt-sensitive rats develop cardiac hypertrophy disproportionate to the degree of hypertension. In the present studies, we assessed whether the cardiac hypertrophy induced by high salt depends on the development of hypertension per se, and leads to over-activity of the cardiac renin–angiotensin system (RAS).MethodsCardiac angiotensin converting enzyme (ACE) mRNA and activity, cardiac and plasma angiotensin I and II (AngI, II), as well as plasma renin activity (PRA) were assessed in Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on high (1370 μmol/g food) or regular salt (120 μmol/g food) diet for 2–5 weeks. Cardiac ACE and hypertrophic response in Dahl S on high salt were also assessed after central blockade of sympathetic hyperactivity and hypertension.ResultsIn Dahl S rats, ACE mRNA and activity of the left ventricle (LV) increased markedly after 4–5 weeks of high salt diet compared with Dahl S on the control diet and Dahl R on either diet. Chronic intra-cerebroventricular treatment with Fab fragments blocking brain ‘ouabain’ prevented the hypertension by high salt in Dahl S rats but did not affect the salt-induced increases in LV weight or in LV ACE mRNA and activity. On regular salt diet, Dahl S rats demonstrated significantly lower cardiac AngI and AngII than Dahl R rats. However, high salt intake did not cause significant changes in cardiac AngI and II in either strain. On regular salt diet, PRA, plasma AngI and II were all significantly lower in Dahl S versus R. In Dahl S rats, high salt did not cause further decreases of the already low PRA or plasma AngI and II.ConclusionsThese data indicate a low activity of both circulatory and cardiac RAS in Dahl S versus R rats. The marked cardiac hypertrophy and increase in cardiac ACE mRNA and activity induced by high salt in Dahl S do not depend on the increase in blood pressure. High salt intake did not increase cardiac AngII in Dahl S, suggesting that the increase in ACE mRNA and activity may be relevant for non-angiotensinergic mechanisms involved in cardiac hypertrophy.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveGordon's syndrome comprises hypertension, hyperchloremic acidemia, hyperkalemia and intact renal function. We hypothesize that disturbances of one or more cell membrane ion carriers, handling sodium, chloride and potassium, might be relevant in this disorder and, furthermore, that such disturbances might be related to altered cell membrane composition.Design and methods:In a patient diagnosed with Gordon's syndrome, we assessed the kinetics (Kmand maximal rate) of four membrane sodium transport systems in sodium-enriched erythrocytes, according to the technique of Garay. We also measured the lipid composition of erythrocyte membrane in this patient and 69 essential hypertensive controls, using the Iatroscan technique.Results:Compared to reference values of patients with essential hypertension, this patient exhibited a marked increase in the maximal rate of the Na+−K+−2Cl−cotransport (964.0 μmol/l per cell versus the 391.6 + 222 μmol/l per cell in essential hypertensives). Also, there was an increased concentration of erythrocyte membrane phospatidylethanolamine and a reduced concentration of sphingomyelin (27.9 and 11.1% versus 17.9 ± 3.8% and 18.2 ± 3.4%, respectively).Conclusions:We conclude that this abnormality in membrane Na+−K+−2Cl−cotransport could be responsible for the hyperkalemia, hyperchloremic acidemia and increased reabsorption of sodium observed in this condition and, furthermore, that such disturbance in membrane cotransport might be related to altered phospholipid concentration in cell membranes.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

ObjectiveThis study was designed to evaluate the effect of high-calcium skim milk or potassium-enriched highcalcium skim milk on blood pressure compared with non-enriched skim milk.DesignThis was a randomized double-blind controlled trial. Each milk intervention lasted for 4 weeks, with a minimum of 4 weeks of wash-out between interventions.MethodsWe recruited 38 healthy people, aged over 40 years, to take part in a double-blind, randomized, controlled cross-over study. We asked them to replace their usual liquid milk with two servings per day of skim milk (control), high-calcium skim milk or potassium-enriched high-calcium skim milk. We measured office blood pressures (seated and standing) at the start and after 2 and 4 weeks of milk intervention and we measured daytime ambulatory blood pressures at the start and after 4 weeks of milk intervention. Each milk intervention was interspaced by a 4-week interval.ResultsOffice systolic blood pressure (standing) decreased from 127 ± 16 to 124 ± 16 mmHg (P< 0.05) after 4 weeks of skim milk and from 130 ± 18 to 126 ± 17 mmHg (P< 0.05) after 4 weeks of high calcium skim milk. After 4 weeks of consuming the potassium-enriched high-calcium milk, systolic blood pressure decreased from 125 ± 18 to 117 ± 16 mmHg (P< 0.001) seated, and from 130 ± 16 to 122 ± 15 mmHg (P< 0.001) standing. There were no significant changes in office diastolic blood pressure after any milk. There was no change in ambulatory blood pressure after either skim milk or high-calcium skim milk. After 4 weeks of potassium-enriched high-calcium milk, ambulatory daytime systolic blood pressure decreased from 138 ± 13 to 135 ± 11 mm Hg (P< 0.05) and daytime diastolic blood pressure decreased from 80 ± 8 to78 ± 9 mmHg (P< 0.05).ConclusionsHigh-calcium milk enriched with potassium has a small hypotensive effect in healthy people aged over 40 years.

ISSN:0263-6352    

出版商:OVID    

年代:2000

数据来源: OVID