Immunization against components of the renin-angiotensin system offers a potential alternative to daily medication in some patients with hypertension or heart failure. Our primary objective was to determine whether a sustained antibody titre to Ang I (angiotensin I) can be achieved in hypertensive patients. The secondary objective was to determine whether the antibodies block the renin system. Patients (n=27) with essential hypertension responsive to an ACEi (angiotensin-converting enzyme inhibitor) or ARB (angiotensin blocker) were randomly assigned to receive three or four injections of the Ang I vaccine PMD3117 or aluminium hydroxide (Alhydrogel trade mark ) over a 6 week period. Antibody titre was measured prior to each injection and every 30 days until disappearance. Indices of renin blockade were changes in renin and aldosterone (blood and urine) and a within-patient comparison of the pre- and post-vaccination rise in 24 h ambulatory blood pressure after 2 weeks of withdrawal of ACEi or ARB. The anti-(Ang I) antibody titre rose from the second injection in both regimes and peaked on day 64. Median half-life was 85 (95% CI, 44 and 153) days (where CI is confidence interval). Vaccination did not influence blood pressure, but significantly blunted the fall in plasma renin following withdrawal of ACEi or ARB. At 42 days after the first injection, aldosterone excretion was decreased by PMD3117 to 6 (95% CI, 1 and 31)% of values in patients receiving Alhydrogel trade mark (P=0.012). In patients with essential hypertension, PMD3117 generated a prolonged antibody response to Ang I. Biochemical measurements show evidence of blockade of the renin system, but higher titres will be required to achieve a decrease in blood pressure.
1 Male, Sprague-Dawley rats were actively immunized with novel angiotensin vaccines, and their pressor responses to exogenous angiotensin I (AI) and angiotensin II (AII) were assessed in vivo. Serum antibody titres were also measured. 2 The most eective vaccine consisted of an AI analogue conjugated with a tetanus toxoid carrier protein and adjuvanted with aluminium hydroxide. When this vaccine was injected on days 0, 21 and 42, pressor responses to AI on day 63 were signi®cantly inhibited (maximum, 8.9 fold shift), but responses to AII were unaected. The anti-angiotensin antibody titre was increased 32,100 fold, and, uniquely, these antibodies also cross-reacted with angiotensinogen. 3 These ®ndings indicate that active immunization against AI may be a useful approach for treating cardiovascular disorders involving the renin-angiotensin system.
Aims We aim to modulate the renin-angiotensin system (RAS) by active immunization against angiotensin I hormone (AI), potentially providing a novel conjugate vaccine treatment for hypertension in man. Methods Immunization studies in rat and human subjects compare the effectiveness of tetanus toxoid (TT) and keyhole limpet haemocyanin (KLH) vaccines for immunotherapy following conjugation with an AI peptide analogue ( AI ). Cardiovascular responses were assessed in immunized rats and human subjects (two-dose trial only), following increasing i.v. infusions of either AI or angiotensin II hormone (AII). Results The AI -TT and AI -KLH conjugate vaccines induced an equivalent immune response, and inhibition of the pressor effects to exogenous AI in rats. Single-dose clinical trials with both conjugate vaccines only resulted in an immune response to the KLH carrier protein. A two-dose clinical trial of AI -KLH conjugate vaccine resulted in a significant immune response to AI . A shift in diastolic blood pressure (DBP) dose-response was demonstrated following challenge with AI and AII for the study volunteer showing the largest anti-AI IgG induction. Conclusion KLH was shown to be a suitable alternative to TT as a carrier protein for AI , thus supporting continued evaluation of our AI -KLH conjugate vaccine for treatment of hypertension in man.
The goal of this study is to explain the molecular basis of the marked deinduction of Xenopus albumin synthesis and secretion accompanying the activation of vitellogenin genes by estrogen. We have characterized by restriction analysis, DNA sequencing and hybrid-selected translation of mRNA, a cloned cDNA specifying the two 74-kDa albumins which constitute the predominant circulating form of albumin in Xenopus luevis. Using this recombinant DNA plasmid as a hybridization probe, we have determined the steady-state levels of albumin mRNA, the rate of transcription of the two 74-kDa albumin genes and the stability of the mRNA in male and female Xenopus hepatocytes in vivo and in primary cell cultures following estrogen treatment.In both whole liver and cultured hepatocytes estradiol caused a rapid drop in the steady-state levels of 74-kDa albumin mRNAs, which was reversed spontaneously in the continued presence of the hormone. The concentration of albumin mRNA was substantially higher in male than in female hepatocytes, the hormonal effect being more marked in male than in female hepatocytes.The decrease in steady-state levels of mRNA was anticipated in male hepatocytes by a 70% inhibition of rate of transcription of albumin genes within 2 h of exposure to estradiol, as measured by run-off transcription in liver nuclei isolated from animals treated in vivo or by determining the absolute transcription rate in cell cultures. In the latter the diminished transcription rate returned to normal within 12 h in the continued presence of the hormone.Estradiol caused a threefold destabilization of albumin mRNA in both male and female hepatocyte cultures to tliz = 3 h and 2 h respectively. The combined effects on rate of transcription and mRNA stability largely explain the changes in the steady-state levels of mRNA caused by hormone administration.Comparison of the kinetics of transcription rates of vitellogenin and albumin genes in vivo and in vitro reveals a striking reciprocity in the selective activation of the inducible genes and deinduction of the constitutively expressed genes at the early stages of response of Xenopus hepatocytes to estrogen.
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