| 1. |
- Fu, Michael, 1963, et al.
(författare)
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Decreased density of mesenteric arteries but not of myocardial endothelin receptors and function in rats with chronic ischemic heart failure.
- 1993
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Ingår i: Journal of cardiovascular pharmacology. - 0160-2446. ; 22:2, s. 177-82
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Tidskriftsartikel (refereegranskat)abstract
- Mesenteric artery and cardiac ventricular endothelin receptors and endothelin-1-induced pressor responses were studied in normal rats and rats with chronic congestive heart failure induced by myocardial ischemia (4 weeks after coronary artery ligation). In mesenteric arteries of rats with chronic ischemic heart failure, endothelin receptor density was significantly decreased by 59%, whereas the dissociation constant was increased 2.8-fold, as compared with controls. There were, however, no changes in endothelin-receptor density or the dissociation constant in cardiac ventricular membrane preparations from rats with congestive heart failure as compared with controls. In pithed rats with congestive heart failure there was a reduced pressor response to a bolus injection of endothelin-1 (800 pmole/kg body weight), while the vasodilatory response was unaltered as compared with sham-operated controls. These results demonstrate that there is a decreased vascular endothelin-receptor function due to a down-regulated endothelin receptor. The in vivo data indicate that this is due to impaired endothelin A but not endothelin B receptor function. Thus, there is an impaired arterial but not cardiac ventricular endothelin receptor-mediated signalling system in the rat with chronic ischemic heart failure.
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| 2. |
- Fu, Michael, 1963, et al.
(författare)
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Hypersensitivity of Gi protein mediated muscarinic receptor adenylyl cyclase in chronic ischaemic heart failure in the rat.
- 1993
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Ingår i: Cardiovascular research. - 0008-6363. ; 27:11, s. 2065-70
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim was to study the Gi protein mediated muscarinic signalling system in the myocardium of rats with chronic ischaemic heart failure. METHODS: Chronic ischaemic heart failure was induced by myocardial ischaemia (four weeks after coronary artery ligation) in rats. The densities and agonist affinities of muscarinic receptors, and the functional activity and concentration of Gi proteins were studied. RESULTS: In failing hearts, the activity of adenylyl cyclase stimulated by guanyliminodiphosphate (Gpp(NH)p) was decreased by 46%. Stimulated activities of adenylyl cyclase by both sodium fluoride and forskolin, however, remained unchanged. Carbachol depressed forskolin stimulated adenylyl cyclase more in membranes from failing hearts than those from normal hearts. The functional level of Gs protein as measured by a reconstitution assay in sarcolemmal membrane did not differ between the two groups. Furthermore, muscarinic receptors exhibited superhigh and low affinities for agonist in failing hearts whereas those in control hearts displayed only high and low affinities. No significant difference in the peptide equivalent amount of membrane bound Gi protein was found in either group. CONCLUSIONS: The experimental chronic failing heart due to myocardial ischaemia showed a depressed myocardial adenylyl cyclase signalling system. This may be due to the hypersensitivity of the Gi protein mediated muscarinic receptor-adenylyl cyclase system as shown by the increased inhibition of Gpp(NH)p mediated adenylyl cyclase, more potent inhibition of stimulated adenylyl cyclase by carbachol, and the superhigh affinity of the muscarinic receptors for carbachol.
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| 3. |
- Sun, Xiao-Feng, 1959-
(författare)
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Expression of ras and p53, DNA ploidy and 5-phase fraction in human colorectal adenocarcinoma
- 1993
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The accumulation of oncogene and anti-oncogene alterations play an important role in the development of colorectal adenocarcinomas. These specific gene alterations cause changes of DNA ploidy and cell proliferation and, in turn, DNA instability might lead to more genetic changes. In the present work, the expression of ras p21 (79 cases) and p53 protein (293 cases) was investigated by immunohistochemistry, and DNA ploidy and S-phase fraction (279 cases) were measured by flow cytometry on colorectal adenocarcinomas.Overexpression of ras p21, nuclear and cytoplasmic p53 were found in 58%, 39% and 25% of the tumours, respectively, while in normal colorectal cases, only 35% were ras positive and no case showed p53 staining. Overexpression of ras was significantly associated with a high S-phase fraction. The frequencies of ras and nuclear p53 staining tended to be increased in DNA non-diploid tumours compared with diploid tumours. Cytoplasmic p53 positive tumours were more common in the proximal colon, while DNA non-diploid tumours were more frequent in the distal colon and rectum. The intensity of ras staining was significantly related to grade of differentiation and increased from Dukes' stage A to C tumours. Cytoplasmic p53 staining increased from Dukes' stage A to D tumours. In multivtiriate survival analyses of patients with Dukes' stage A-C tumours, the prognosticsignificance of ras expression remained even after adjustment for both stage and DNA ploidy. Nuclear p53 and cytoplasmic p53 staining prognosticated clinical Outcome independent of stage, DNA ploidy and each other. DNA non-diploidy predicted an unfavourable survival irrespective of stage, nuclear and cytoplasmic p53 expression. A highS-phase fraction was significantly associated with poor survival in univariate analysis but not after adjustment for other prognostic factors. Analyses in subgroups of tumours showed that the prognostic importance of cytoplasmic p53 expressionwas greater in patients with DNA diploid tumours than in those with non·diploid tumours, and that DNA ploidy exhibited prognostic effect in patients with Dukes' stage B tumours as well as in those with stage C tumours. We conclude that immunohistochemistry and flow cytometry may be used to detect overexpression ofras p21, nuclear p53 and cytoplasmic p53 as wellas abnormal DNA content, and that these alterations may be implicated in different biological mechanisms of colorectal adenocarcinomas and provide important prognostic information.
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