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1.
Vascular smooth muscle cell membranes from prehypertensive rats of the Milan hypertensive strain (MHS) were used to examine adenylyl cyclase activity and its regulation by guanine nucleotide regulatory proteins (G-proteins). Basal adenylyl cyclase activity was similar in MHS and Milan normontensive strain (MNS) membranes. Forsokolin (10?4 M) produced a significantly greater stimulatory response in MHS membranes, but this was not observed with NaF (10?2 M). Isoporterenol (10?4 M) caused a significantly decreased stimulation of adenylyl cyclase activity in MHS membranes, while prostaglandin E1 (10?5 M) produced similar responses in the two strains. Gi function and GTP responses, as observed by biphasic effects of GTP on isoproterenol-stimulated membranes, were similar in both strains. The levels of Gi2α and Gqα/G11α were similar in the two strains, while the levels of Gsα (44 and 42 kDa forms) and the β-subunit were significantly reduced by ~20% in MHS membranes. The α-subunit of Gi3 was dramatically reduced by ~80% in MHS membranes. The affinities of β-adrenergic receptors for the antagonist, cyanophindolol, were similar in the two strains; however, the number of β-adrenoceptors was substantially reduced in MHS membranes. These findings may be of relevance to altered vascular reactivity and transmembrane ion distribution observed in the MHS.  相似文献   

2.
The part of noradrenergic mechanisms in self-stimulation (SS) operant behaviour was studied in rats. In all experiments systolic blood pressure (BP) in the tail artery was measured by means of photocells. It was found, that small doses of noradrenaline facilitate the SS, while high doses depress or stop it. The depressive effect is accompanied by a marked increase of BP. Effective blockade of beta-adrenoceptive structures by inderal suppresses SS, and the inhibitory effect is accompanied by a small decrease of BP. Suppressing effect of alpha-adrenoblocking agent, phentolamine, is even more pronounced, but is accompanied by a marked decrease of BP. Beta-agonist isadrin causes a marked facilitation of SS without changes of BP. It is suggested that positive reward in the lateral hypothalamus is due to a direct stimulation of beta-adrenoceptive noradrenergic neuronal elements. Chronic neurogenic hypertension is developed by an overloading of the higher nervous activity. In chronic hypertensive rats there is a pronounced suppression of SS. A transient fail of BP caused by injection of catapresan (hemiton) results in a temporary recovery of normal SS behaviour. It may be concluded that reduction of lever-pressing rate during acute and chronic neurogenic hypertensions is related to baroreceptor mechanisms. The role of the autonomic nervous system in SS behaviour is discussed.  相似文献   

3.
 Hypertension and kidney dysfunction in sodium transport observed in the Milan hypertensive strain (MHS) of rats are genetically associated with point mutations of adducin, an actin- and spectrin-binding protein of the membrane cytoskeleton. Polymorphism in the adducin locus has been reported to occur also in cases of human primary hypertension. In this study we show by immunostaining that adducin is localized along the basolateral epithelial membrane surface of the entire proximal and distal tubule with no detectable differences between MHS rats and the normotensive control strain (MNS). However, the total amount of adducin in kidney homogenates is reduced by about 45% in MHS rats as determined by quantitative immunoblotting. In erythrocyte membranes of MHS rats, adducin is reduced approximately 10%. The reduction of renal adducin in MHS rats is mainly caused by a reduction of the adducin pool that is loosely associated with kidney membranes and can be released by the non-ionic detergent, Triton X-100. The Triton-resistant, tightly membrane-bound pool of renal adducin differed by approximately 10% between MHS and MNS rats. Since several ion transporters have been shown to be tethered to the membrane cytoskeleton, we suppose that the reduction of the dynamic, loosely bound pool of adducin in MHS rats might interfere with the normal turnover and incorporation of yet unknown transporters involved in kidney sodium transport. However, the Na+,K+-ATPase appears to be not involved, as indicated by normal distribution and amounts of NA+,K+-ATPase in the kidney of MHS rats revealed by immunostaining and immunoblotting. Accepted: 23 June 1997  相似文献   

4.
Sodium transport was measured in brush-border membrane vesicles prepared from kidney cortex of the Milan hypertensive strain (MHS) rats and the corresponding normotensive controls. In the presence of an outwardly directed proton gradient, 22Na was transiently accumulated in the vesicles. When a transmembrane electrical potential was imposed across membrane vesicles, both the accumulation ratio and the initial uptake were increased, indicating the presence of an electrogenic pathway for sodium in these membranes. The potential-dependent sodium uptake was significantly higher in MHS rats. Kinetic analysis give simple Michaelis Menten curves in the presence and in the absence of a membrane potential. In both conditions Jmax was significantly increased in MHS rats, whereas Km was the same for the two rat strains. Sodium uptake was inhibited by amiloride at concentrations that inhibit Na+-H+ exchange. The presence of the higher, potential-sensitive, sodium uptake in MHS is in agreement with studies on renal physiology which support the hypothesis that an increase in tubular sodium reabsorption may be the primary cause for the development of hypertension in this rat strain.  相似文献   

5.
6.
The mouse oocyte expresses a polypeptide of Mr 120,000 that cross-reacts with an antibody to the brain membrane skeletal protein adducin. Immunofluorescence localization showed a bright chromosomal staining reaction in metaphase I and metaphase II oocytes. Following in vitro fertilization the maternal chromosomes lost their immunoreactivity during pronuclear development. The fertilizing sperm chromatin and male pronucleus did not show any detectable staining reaction. Bright chromosomal fluorescence was again observed in the first mitotic metaphase when both maternal and paternal chromosomes gave a positive staining reaction. In contrast to the immunoreactivity of the maternal meiotic chromosomes, the meiotic chromosomes of male germ line cells failed to exhibit any detectable staining reaction and this difference was confirmed by immunolabeling of oocyte and spermatocyte karyotypes. Mitotic chromosomes in preimplantation embryos, fetal liver, adult intestinal epithelium, and MDCK cells also failed to show any detectable labeling reaction. The results suggest that expression of the immunoreactive chromosomal adducin may be a unique feature of oogenesis.  相似文献   

7.
Renal kallikrein and phospholipase activities were evaluated in a strain of spontaneously hypertensive rats developed by Dr. Bianchi in Milan (MHR). MHR showed lower than normal kallikrein and phospholipase activities before, at 3 weeks of age and following the development of hypertension. Kallikrein and phospholipase activities were directly correlated both in normotensive and spontenously hypertensive rats. The data suggest that MHR have a genetic defect in kallikrein and phospholipase activities, which may play a pathogenetic role in the development of high blood pressure.  相似文献   

8.
Corticosteroids have been shown to play a role in cardiac remodeling, with the possibility of a direct effect of overexpression of 11beta-hydroxysteroid dehydrogenase (11HSD) isoform 2 at the level of the cardiomyocytes. The aim of this study was to examine cardiac steroid metabolism in hypertensive rats with hearts that are hypertrophied and fibrotic and have structural alterations in the coronary circulation. To assess possible alterations of cardiac steroid metabolism the expression and activity of both isoforms of 11beta-hydroxysteroid dehydrogenase (11HSD) were studied in spontaneously hypertensive rats (SHR), their normotensive controls Wistar-Kyoto (WKY), and in Dahl salt-sensitive (DS) and salt-resistant rats (DR) kept on a low- or high-salt diet. Using real-time quantitative RT-PCR and enzyme activity assay we found strain-dependent differences in cardiac metabolism of glucocorticoids. In Dahl rats expression of 11HSD1 and 11HSD2 mRNA was lower in DS than in DR rats and was not influenced by dietary salt intake; 11HSD1 mRNA was expressed at higher level than 11HSD2 mRNA. NADP(+)-dependent cardiac 11HSD activity showed similar distribution as 11HSD1 mRNA-lower activity in DS than in DR rats and no effect of salt intake. In SHR and WKY strains 11HSD2 mRNA expression was significantly higher in WKY than in SHR but no differences were observed in 11HSD1 mRNA abundance and NADP(+)-dependent 11HSD activity. These results show that the heart is able to metabolize glucocorticoids and that this metabolism is strain-dependent but do not support the notion of association between cardiac hypertrophy and changes of 11HSD1 and 11HSD2 expression.  相似文献   

9.
10.
In chloralose anaesthetized and paralyzed normotensive (Wistar, Wistar--Kyoto) and spontaneously hypertensive rats (SHR), a somatosympathetic reflex in the cervical sympathetic trunk elicited by a single electrical shock to forelimb afferent fibres in the median nerve was recorded. It has been shown that the elicited response of SHR is similar to the response of normotensive rats. Amplitude of somatosympathetic reflex in SHR is larger than that of somatosympathetic reflex in normotensive animals. It is supposed that somatosympathetic reflex in hypertensive and normotensive rats is formed in the same way. However, reflex excitability of sympathetic nervous system in SHR is greater.  相似文献   

11.
We measured the concentration of endogenous digoxin-like materials (EDLM) in the serum of spontaneously hypertensive rats (SHR) and three normotensive rat strains at four stages during growth using a sensitive RIA. In the SHR, there was a significant peak in the EDLM level between 0.057-0.087 ngE/mL at 6 to 8 weeks of age, shortly after the onset of hypertension. The EDLM concentration returned to normal levels by 20 weeks of age. Sprague-Dawley and Wistar-Kyoto rats had EDLM levels below 0.050 ngE/mL at all time points studied. In contrast, Fischer 344 rats displayed persistently elevated serum EDLM concentrations that exceeded 0.124 ngE/mL from 3 to 20 weeks of life. We conclude that (1) there are significant interstrain differences in serum EDLM levels in rats; and (2) the SHR has a unique peak in serum EDLM levels at 6 to 8 weeks of age, indicating a possible role for the substance in the inception of hypertension.  相似文献   

12.
Beta-adrenoceptor binding characteristics were determined in different fractions of rat kidney tubules using a [125Iodo]-(-)-cyanopindolol (ICYP) binding assay. The highest amount of binding sites was found in a fraction containing predominantly distal tubular fragments. In a separate series of experiments the ICYP binding characteristics were compared in whole tubular fractions from spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) of different ages. The maximum number of binding sites was significantly higher both in young (3 weeks) and adult (14 weeks) SHR when compared to age-matched WKY. These studies showed the presence of beta-adrenoceptor binding sites in rat kidney tubules and support the potential importance of tubular beta-adrenoceptors in the development of spontaneous hypertension and in the mechanism of antihypertensive action of beta-blockers.  相似文献   

13.
14.
The (Na+,K+)-ATPase activity from the kidney cortex of the Milan hypertensive rat strain (MHS) and the corresponding normotensive control (MNS) was measured both in active solubilized enzyme preparations and in isolated basolateral membrane vesicles. Kinetic analysis of the purified enzyme showed that the Vmax value was significantly higher in MHS rats. The difference between MHS and MNS was not linked to a different number of sodium pumps, but was related to the molecular activity of the enzyme. Using basolateral membrane vesicles, an increased ATP-dependent ouabain-sensitive sodium transport was also demonstrated in MHS rats. These results support the hypothesis that a higher tubular sodium reabsorption may be involved in the pathogenesis of hypertension in this rat strain.  相似文献   

15.
Spontaneously hypertensive (SHR) rats and normotensive Wistar-Kyoto (WKY) rats were subjected to 2 hr of cold-restraint stress at 2–6°C following a 24 hr fast. WKY rats had a significantly greater incidence and degree of ulceration of the gastric glandular mucosa than did SHR rats. Mean arterial pressure, obtained from a chronic arterial cannula, fell during 2 hr of cold-restraint stress in both SHR and WKY rats. Heart rate was unchanged in WKY but fell significantly in SHR. Plasma norepinephrine (NE) and epinephrine (E), determined by radioenzymatic assay, increased significantly following stress. Increased levels of NE remained similar for both SHR and WKY rats, while post-stress levels of E for the SHR rats greatly exceeded E levels for WKY rats. A greater degree of hypothermia was also noted in SHR rats. Decreased stress induced ulcerogenesis in the SHR may be due to the well-known altered hemodynamic and autonomic nervous system reactivity in this strain or other factors not yet discovered.  相似文献   

16.
We report here on the extraction and characterization of angiotensin I (ANG I) and angiotensin II (ANG II) from the brain of rats. High pressure liquid chromatography (HPLC) with different mobile phases combined with specific radioimmunoassays (RIA) proved to be a powerful tool for peptide characterization in biological samples; (Ile5)-ANG I, (Ile5)-ANG II and (Ile5)-ANG III could clearly be identified in cerebrospinal fluid (CSF), incubated in vivo and in vitro with renin, in total brain extracts, as well as in hypothalamus (HT), medulla oblongata (MO), cerebellum (CER) and cortex (CO). Angiotensin cleaved from CSF angiotensinogen and angiotensin extracted from brain showed retention times identical to those of plasma angiotensin and synthetic standard peptides, indicating that their amino acid sequence is probably identical. ANG I and ANG II were highest in the HT and lowest in the CO. Following bilateral nephrectomy (NX) both ANG I and ANG II persisted at control levels. Young 10 week old spontaneously hypertensive rats (SHRSP) showed significantly lower ANG I and ANG II concentrations in the HT compared with Wistar Kyoto rats (WKY). Intracerebroventricular (i.c.v.) administration of the converting enzyme inhibitor captopril caused a significant increase in ANG 1 in nephrectomized SHRSP but not in WKY. These differences were not found in 40 week old SHRSP. The data show that ANG I and ANG II are synthetized in the brain of rats. The lower concentrations and the enhanced accumulation of ANG I after converting enzyme blockade in nephrectomized young SHRSP indicate an increased turnover of angiotensin in hypertensive rats.  相似文献   

17.
Amiodarone, a benzofuran derivative, is a very effective antiarrhythmic medication, but has potential to cause side effects. Although its cytotoxicity potential is very well-known, there are few reports about its genotoxicity effects. Since amiodarone has not been investigated in genotoxicity studies, and the spontaneously hypertensive rat (SHR) is a well-characterized model for hypertension, the aim of the present study was to perform cytogenetic analysis on chromosome aberrations in bone marrow cells of SHRs and normotensive Wistar-Kyoto rats (WKYs) that received oral amiodarone treatment for 4 weeks. Amiodarone activity was also monitored using electrocardiograms. The presence of bradycardia in amiodarone-treated rats confirmed that this drug was really active. Metaphase analysis on bone marrow cells showed that there were significant differences in total chromosomal damage and percentage abnormal metaphase between WKY and SHR negative controls. In the SHR negative control, the frequencies of basal chromosomal aberrations and abnormal metaphases were significantly higher (p < 0.05). There were high numbers of chromosomal aberrations in all amiodarone-treated groups, compared with negative controls. In amiodarone-treated groups, the most frequent chromosomal aberration was chromatid breaks. More chromosomal aberrations were found in WKYs that received amiodarone, with a statistically significant difference in comparison with negative controls (p < 0.05). However, in SHR rats there was no significant difference between the amiodarone and negative groups regarding chromosomal damage induction. These results showed that treatment with amiodarone was genotoxic in WKYs, but not in SHRs. Further studies are needed to confirm whether amiodarone is genotoxic or efficient and harmless, among humans undergoing therapy.  相似文献   

18.
19.
A human small intestine lambda gt11 cDNA library was screened using antisera prepared against the deglycosylated protein backbone of human colon cancer xenograft mucin. Three cDNAs were isolated from this screening, designated SMUC 40-42. These cDNAs were all found to contain tandem repeats of 69 nucleotides which encoded a threonine- and proline-rich protein consensus sequence of PTTTPITTTTTVTPTPTPTGTQT. RNA blots probed with one of these cDNAs, SMUC 41, exhibited large, polydisperse hybridization bands at approximately 7,600 bases. Band intensities were strongest when human small intestine, colon, and colon cancer poly(A)+ RNA was used. In vitro translation of poly(A)+ RNA from human small intestine, colon, and colon cancer cells produced a 162,000-dalton peptide that was immunoprecipitated with antibodies to deglycosylated mucin. SMUC 41 was also used to probe DNA blots, which indicated the presence of restriction fragment length polymorphisms in the intestinal mucin gene. These findings may be important in assessing the abnormal mucins found associated with several human diseases.  相似文献   

20.
The purpose of this study was to determine whether -adrenergically mediated cardiovascular functions such as arterial pressure (AP), heart rate (HR), stroke volume (SV), cardiac output (CO), peripheral resistance (Rp), arterial impedance (Zc), mean arterial compliance (Cm) and pulse wave reflection (Pb) were altered in the spontaneously hypertensive rat (SHR) compared to the normotensive Wistar Kyoto rat (WKY). In pentobarbital-anesthetized and artificially ventilated rats, the aortic pressure wave was recorded with a high-fidelity Millar sensor, and aortic flow wave with an electromagnetic flow probe. The pressure and flow waves were subjected to Fourier transform so as to analyze impedance spectra. Acute -adrenergic blockade was produced by an intravenous injection of propranolol (nonselective) and atenolol (selective 1-blocker) at doses of 2 and 5 mg/kg, respectively. Steady-state parameters were obtained 15–20 min after intravenous administration. The SHR had higher AP, HR, Rp and Zc than the WKY. SV and CO remained unaltered while Cm was lower. In response to propranolol, the mean AP was increased by 7 mm Hg in the WKY, but did not change in the SHR. Moreover, significant decreases occurred in HR, CO and Cm in addition to increases in Rp, Zc and Pb. These changes between the SHR and WKY were only slight. Atenolol caused decreases in AP, HR and CO in both SHR and WKY, but did not significantly alter the Rp, Zc, Cm and Pb. Again, the atenolol-induced changes in AP, HR and CO did not appear to be significantly different between SHR and WKY. The results indicate that -adrenergic effects on the heart, Windkessel and resistance vessels are neither greatly enhanced nor impaired during the development of hypertension. In the hypertensive state, significant -adrenergic mechanisms still exert tonic vasodilatory effects on the large and small arterial system.  相似文献   

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