摘要:

Clinical studies:In clinical renal transplantation studies, recipients of a renal graft from a donor with a genetic predisposition to hypertension had higher blood pressures and required more antihypertensive treatment than recipients of a renal graft from a normotensive donor. In addition, blood pressure normalization in patients suffering from essential hypertension by bilateral nephrectomy and subsequent transplantation of a kidney from a normotensive donor has been reported. The interpretation of these data may be limited by the large number of different factors that can contribute to post-transplantation hyertension in human renal transplant recipients.Experimental studies:In experimental renal transplantation studies the contribution of individual factors to post-transplantation hypertension can be independently assessed. Besides immunological graft rejection and hypertension-induced damage to the renal graft, a genetic predisposition to hypertension in the kidney donor has been demonstrated to be associated with post-transplantation hypertension in the recipient. Thus, normotensive recipients of a renal graft from a genetically hypertensive donor consistently developed post-transplantation hypertension in four different animal models of genetic hypertension. Furthermore, in genetically hypertensive rats bilateral nephrectomy together with transplantation of a kidney from a normotensive donor has been shown to be associated with a decrease in blood pressure.Conclusions:Hypertension following renal transplantation may be due to a variety of factors, including immunological graft rejection, hypertension-induced damage to the renal transplant and a genetic predisposition to hypertension of the kidney donor. The finding that blood pressure is transplanted with the renal graft in genetic hypertension suggests a genetically determined alteration to the kidney as a major factor in the aetiology of primary hypertension. The nature of this factor is just beginning to be understood. Renal transplantation studies in rat models of genetic hypertension, combined with the tools of molecular biology, may help to provide further insights into the role of the kidney in primary hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:The chromosomal location of candidate genes for a disease, especially if the disease is multifactorial, is an important datum. The objective of the present study was to determine the chromosomal location of candidate hypertensinogenic genes, both in humans and in the rat, a species widely used for animal models of human hypertension. The type 1 angiotensin II receptor (AT1) genes are obvious hypertension candidate genes, whereas the SAgene has recently been shown to cosegregate with hypertension in the rat.Design:The chromosomal location of the relevant genes was determined using somatic cell hybrids segregating either human chromosomes or rat chromosomes. The presence of the human or rat genes was determined by the Southern blot method, using rat probes.Results:A single AT1gene (ATI) was detected in the human genome, and was assigned to chromosome 3, whereas two non-syntenic genes were detected in the rat genome, corresponding to the previously identified A and B subtypes. They were assigned to the rat chromosome 17 (At1a) and 2 {AT1b). The Sa gene was assigned to human chromosome 16 and rat chromosome 1, disclosing a new synteny group retained on rat chromosome 1 and human chromosome 16.Conclusions:These chromosomal assignments should be useful for linkage analyses of genes controlling blood pressure. The genes that we studied, and the chromosomes that we identified, deserve special attention in such linkage analyses.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:Few molecular signals for induction of myocardial hypertrophy have been identified. This study was carried out to investigate the action of angiotensin II and endothelin on the growth- and differentiation-related genes Egr-1 (early growth response gene 1) and c-fos in isolated adult rat cardiomyocytes.Methods:Cardiac myocytes from male Wistar-Kyoto rats were isolated and incubated with angiotensin II and endothelin-1 in Dulbecco's modified Eagle's medium. RNA was isolated and blotted, and densitometric analysis was performed. All experiments were repeated at least three times.ResultsEndothelin-1 (10-7mmol/l) induced a 20-25-fold rise in Egr-1 messenger RNA within 15min. This effect was dose-dependent, c-fos was induced 10-20-fold within 15 min with similar dose-response characteristics. Angiotensin II also induced Egr-1 and c-fos with kinetics similar to endothelin but a cofactor from fetal calf serum was needed for full c-fos expression. The protein kinase C activator phorbol 12-myristate 13-acetate also induced Egr-1.Conclusions:The results identify Egr-1 and c-fos as target genes for the action of endothelin and angiotensin II in the adult myocardium suggesting that induction of the genes may be part of the signal transduction pathway for angiotensin II and endothelin in the myocardium.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:To investigate the cardiovascular effect of α-trinositol (D-myo-inositol-1,2,6- trisphosphate; PP56) in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto (WKY) rats. α-Trinositol, a representative of a new group of pharmacological agents, is an inositol phosphate which seems to bind to a single population of binding sites, inhibiting, for example, agonist-induced vasoconstriction. In particular, a-trinositol seems to inhibit agonist-induced (e.g. neuropeptide Y-induced) elevations in intracellular Ca2+levels in vascular smooth muscle cells.Methods:oc-Trinositol was administered as a bolus injection (2-40 mg/kg body weight), followed by a continuous infusion (20-400 mg/kg body weight per h) for 40 min in freely moving SHR and WKY rats.Results:Acute intravenous bolus administration of a-trinositol reduced systolic and diastolic blood pressure, as well as heart rate, in a dose-dependent manner in SHR and WKY rats. After completion of the 40-min infusion the reduction in blood pressure was more pronounced in the SHR than in the WKY control rats. Heart rate did not change in the SHR, whereas it was significantly increased at the highest dosage (400 mg/kg) in the WKY rats. At this dosage, three out of eight SHR died from cardiac arrhythmias after completing the infusion. The lowest dose of a-trinositol administered (2 mg/kg bolus followed by 20 mg/kg per h infusion over 40 min) significantly inhibited the increase in mean arterial pressure induced by neuropeptide Y (2μg/kg per min for 10 min) by approximately 30% in both the SHR and WKY rats. Furthermore, a-trinositol treatment completely inhibited the potentiation induced by neuropeptide Y (0.1 μg/min for 30 min) of the blood pressure responses to intravenous bolus injections of noradrenaline (20 ng), tyramine (40μg) or angiotensin II (10 ng).Conclusions:Our results demonstrate that α-trinositol antagonizes the direct postsynaptic pressor response to exogenous neuropeptide Y, as well as the potentiating effects of neuropeptide Y on other vasoconstrictors in SHR and WKY rats. However, in the SHR α-trinositol lowered basal blood pressure only in the dose range which was non-specific for neuropeptide Y inhibition.Thus, the present study indicates that neuropeptide Y is involved only slightly in the maintenance of high blood pressure in SHR.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:A decreased responsiveness to endothelium-dependent vasodilatory substances is characteristically seen in isolated arteries from spontaneously hypertensive rats (SHR). However, the precise status and role of nitric oxide (NO), which is, at least in part, the endothelium-derived relaxing factor, remains unclear in SHR. The objective of the present study was to evaluate the importance of NO release in vivo.Methods:The effect on systolic blood pressure of chronic administration of NG-nitro-L-arginine methyl ester (L-NAME, an NO-synthase inhibitor) was studied. Twenty SHR and 10 Wistar-Kyoto (WKY) rats were given 25 mg/kg per day L-NAME by gavage. Thirteen SHR and 14 WKY rats given water for the same period were used as controls. Rats were killed after 15 days and the aortic wall cyclic GMP (cCMP, the second messenger of NO) and cGMP-dependent kinase (the effector of cGMP) concentrations were assessed.Results:During the trial, 11 of the 20 SHR given L-NAME died. Mean ± SD systolic blood pressure increased from 131 ± 8 to 171±10mmHg in WKY rats given L-NAME and from 185 ± 10 to 249 ± 22mmHg in SHR given L-NAME. Aortic cGMP content was similar in control WKY rats (2122 ± 707fmol/mg protein) and in control SHR (2098 ± 704fmol/mg protein), and was decreased in the L-NAME-treated WKY rats and SHR to 308 ± 87 and 644 ± 222fmol/mg protein, respectively. The aortic concentrations of cGMP-dependent kinase were not different in any group.Conclusions:Basal release of NO does not appear to be impaired in SHR, but represents a major counter-regulatory mechanism in this genetic model of arterial hypertension.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:This study was undertaken to determine the biochemical and left ventricular functional changes associated with reversal of left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR).Design:Male SHR and normotensive Wistar-Kyoto (WKY) rats, aged 19 weeks, were treated for 3 weeks with vehicle, amlodipine (10mg/kg), benazepril (10mg/kg) or the combination of both agents (4mg/kg amlodipine and 4mg/kg benazepril). Left ventricular function was assessed while blood was infused rapidly, at pharmacologically reduced and pretreatment mean arterial pressure (MAP).Results:All treatments reduced MAP and left ventricular mass significantly in SHR. Myocardial protein, RNA and myocardial collagen content were reduced proportionately in all treatment groups in SHR, but not in WKY rats. DNA remained unchanged in all groups. Increased right ventricular mass was produced by amlodipine in both SHR and WKY rats (SHR +11.3%; WKY +9.8%), but this was prevented by cotreatment with benazepril. Right ventricular protein and collagen increased significantly with amlodipine in SHR but not WKY rats, and there were no changes in right ventricular RNA and DNA contents in either strain. Amlodipine improved, benazepril impaired and the combination of both agents maintained left ventricular pumping ability when pressure was increased abruptly to pretreatment levels in WKY rats. In contrast, when afterload was increased abruptly in SHR to pretreatment levels, neither amlodipine nor benazepril affected pumping ability, although it was enhanced by the combination.Conclusions:These data demonstrate that amlodipine, benazepril and their combination reduced left ventricular mass in SHR. This reversal of LVH was associated with proportional reductions in mycotic protein, RNA and collagen, but not DNA. Therefore, it seems unlikely that LVH reversal with these agents was associated with increased fibrous tissue or impaired left ventricular performance. Finally, addition of the angiotensin converting enzyme inhibitor prevents the increase in right ventricular mass produced by the calcium antagonist.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID

摘要:

Objective:Both atrial natriuretic peptide (ANP) and the dihydropyridine derivative nicardipine lower arterial pressure and induce a shift of plasma fluid from the vascular towards the interstitial compartment. Because some calcium antagonists increase the plasma concentration of ANP, and the effect of ANP on transcapillary fluid shift requires the presence of angiotensin II, we examined the consequences of blocking the ANP and renin-angiotensin systems on the hypotensive and haemoconcentrating effects of nicardipine.Methods:We evaluated the effects of 45-min 0.1 or 1 μg/kg per min nicardipine infusion on arterial pressure and haematocrit in anaesthetized, acutely binephrectomized Sprague-Dawley rats.Results:Infusion of nicardipine resulted in a dose-dependent decrease in arterial pressure. Haematocrit increased by an amount corresponding to the decrease in plasma volume calculated for the relevant dose. In the presence of monoclonal anti-ANP antibodies the nicardipine-induced changes in haematocrit and arterial pressure were not affected. In rats pretreated for 2 weeks with the angiotensin converting enzyme inhibitor enalapril, as well as in rats receiving the angiotensin II receptor antagonist losartan acutely, the nicardipine-induced increase in haematocrit was abolished. In enalapril-treated rats the increase in haematocrit was entirely restored when angiotensin II was infused at a subpressor dose. The nicardipine-induced decrease in arterial pressure was not affected by pharmacological blockade of the renin-angiotensin system.Conclusions:These results demonstrate that the transcapillary shift of fluid induced by nicardipine is independent of ANP and requires the presence of a functional renin-angiotensin system, whereas its hypotensive action is independent of both ANP and angiotensin II.

ISSN:0263-6352    

出版商:OVID    

年代:1993

数据来源: OVID