Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.796888
Title: Vascular G-proteins in genetic hypertension : levels and function in two rat models
Author: Clark, Catherine Jane
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1993
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Abstract:
The cause of human essential hypertension is not known, but it is characterised by increased vascular smooth muscle (VSM) contractility. Similar changes are present in rodent models of genetic hypertension, which have been extensively studied in order to elucidate their pathogenetic mechanisms. The work of this thesis has utilised two such models, namely the spontaneously hypertensive rat (SHR) and the Milan hypertensive strain (MHS). .Altered regulation of adenylyl cyclase, the enzyme which produces the second messenger and vasodilator, adenosine 3',5'-cyclic monophosphate (cAMP), has been reported in SHR vascular tissues; however, the roles of its guanine nucleotide regulatory proteins, G-proteins, (stimulatory, GS, and inhibitory, Gi) in this abnormality have not been examined in detail. The regulation of adenylyl cyclase activity (ACA) has not been studied in any tissue from the MHS. Hence, it was of interest to investigate the regulation of ACA in VSM from the SHR and MHS, and examine the contribution from GS and Gi to any abnormalities found. The pathogenetic mechanisms leading to hypertension in the SHR and MHS are probably different, and it was also of interest to compare the alterations in the regulation of ACA in the two models. Altered regulation of ACA was shown in VSM from both hypertensive models. No significant differences were shown in the levels of the various G-protein subunits among SHR, Wistar-Kyoto (WKY) and Wistar VSM membranes. The function of Gi was also similar in these three strains; however, data suggest that the activity of GS may be decreased in the SHR, and alterations in the level/activity of the adenylyl cyclase catalytic subunit may also exist in this strain. The adenylyl cyclase system was studied in VSM from two age-groups of MHS rats. Significant reductions in the levels of Gsa (44 and 42kDa forms), Gi3? and the beta-subunit were observed in both young (prehypertensive) and adult (hypertensive) MHS rats in comparison to age-matched controls. The function of Gi was similar in MHS and Milan normotensive strain (MNS) membranes from both age-groups. As Gi function was unchanged in the presence of a substantial reduction in the level of Gi3alpha, it appears that Gi3 does not contribute to the inhibition of adenylyl cyclase in these rat VSM membranes, and instead may participate in altered transmembrane ion fluxes in the MHS. It was observed that GS function may also be decreased in the MHS, and this may, in part, be explained by reduced levels of its alpha-subunits. Again, as in the SHR, data suggest that changes are likely in the level/activity of the catalytic subunit of adenylyl cyclase in the MHS. The stimulatory responses of ACA to isoproterenol in the two hypertensive models were contrasting. In adult SHR membranes, a decreased response to isoproterenol was observed in comparison to controls. Membranes prepared from young MHS rats also exhibited a decreased stimulatory response to isoproterenol in comparison to, age-matched controls; however, this effect was reversed with age, and an increased response to isoproterenol was measured in adult MHS membranes. This difference in response to isoproterenol with age was paralleled by appropriate alterations in beta-adrenergic receptor number in the MHS. It is unlikely that these alterations in isoproterenol response (and beta-adrenergic receptor number) are primarily responsible for the hypertension in MHS rats, as if this were the case, the trend would be expected to be reversed, as in the SHR. A more likely explanation is that these alterations represent some form of compensatory mechanism to the increasing blood pressure and possible increased VSM contractility in the MHS. Alterations in isoproterenol response may play varying roles in the pathogenesis of hypertension in these models, being of primary importance in the SHR, but serving as a compensatory relief to increasing blood pressure in the MHS.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.796888  DOI: Not available
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