Raised blood pressure, not renin-angiotensin systems, causes cardiac fibrosis in TGR m(Ren2)27 rats.

OBJECTIVES: Elevated systemic arterial blood pressure is associated with left ventricular hypertrophy and fibrosis. It has been suggested that both circulating and local myocardial renin-angiotensin systems play a role in mediating these responses. Here we describe the natural history of ventricular hypertrophy and fibrosis in the transgenic (mRen2)27 rat--a monogenetic model--which has a high tissue expression of the murine renin transgene, and suffers severe hypertension. We further explored the relative contribution of both hypertensive burden and circulating and tissue renin-angiotensin systems to the fibrotic process. METHODS: The transgenic rats were treated from 28 days old with (1) a hypotensive dose of the ACE inhibitor ramipril which inhibited both tissue and circulating ACE activity, (2) the calcium antagonist amlodipine, or (3) a non-hypotensive dose of ramipril which inhibited about 60% of tissue ACE activity with little effect on circulating ACE. Normotensive Sprague-Dawley rats were used as controls. RESULTS: The transgenics developed left ventricular hypertrophy along with perivascular and interstitial fibrosis which became progressively worse up to 24 weeks of age. Both the high dose of ramipril and amlodipine prevented the hypertrophy and fibrosis, whereas tissue ACE inhibition without lowering blood pressure had no effect, and actually led to a worsening of the fibrosis by 24 weeks. CONCLUSIONS: These results suggest that the development of left ventricular hypertrophy and fibrosis in the transgenic (mRen2)27 rat are regulated by blood pressure and not activity of the renin-angiotensin systems and that progression of fibrosis at 24 weeks involves a mechanism unrelated to local renin-angiotensin activity.

Inhibition of tissue angiotensin converting enzyme activity prevents malignant hypertension in TGR(mREN2)27.

BACKGROUND: Activation of the renin-angiotensin system has been implicated strongly in the transition from benign to malignant hypertension. However, the concomitant rise in blood pressure might also have a direct effect on the vascular wall by initiating fibrinoid necrosis and myointimal proliferation. Ascertaining the relative importance of these two factors in this process has proved difficult. TGR(mREN2)27 heterozygotes (HanRen2/Edin- -) have previously been shown to develop malignant hypertension spontaneously and exhibit the characteristic features of human malignant hypertension. OBJECTIVE: Tissue renin-angtiotensin systems have been implicated in the pathogenesis of malignant hypertension. We set out to determine whether inhibition of this system might protect against development of the disease in a rat model. METHOD: Male TGR(mREN2)27 heterozygotes (n = 24) were given a non-hypotensive dose of the angiotensin converting enzyme inhibitor ramipril (5 microg/kg per day) from 28 to 120 days of age, untreated rats acting as controls (n = 40). The incidences of malignant hypertension were compared. Systolic blood pressure was measured by tail-cuff plethysmography during treatment; tissue and plasma angiotensin converting enzyme levels and renal histological changes were assessed at the end of the treatment period or upon development of malignant hypertension. RESULTS: Sixty-three per cent of control rats and 4% of angiotensin converting enzyme inhibitor-treated rats had developed malignant hypertension by 120 days despite there having been no significant difference in systolic blood pressure throughout the course of treatment. Angiotensin converting enzyme activities in kidney, heart and resistance vessels, though not that in plasma, were significantly lower in the treated rats. The degree of medial wall thickening did not differ between the two groups whereas evidence of tissue injury (e.g. intimal fibrosis, fibrinoid necrosis and nephron injury) was significantly less common among rats in the angiotensin converting enzyme inhibitor-treated group. CONCLUSIONS: Tissue angiotensin converting enzyme inhibition at a non-hypotensive dose almost completely prevented mortality from malignant hypertension and significantly reduced tissue injury in this model, implicating angiotensin II rather than high blood pressure as the principal 'vasculotoxic' agent in malignant hypertension.

Measurement of exposure to mouse urinary proteins in an epidemiological study.

OBJECTIVES: To develop an assay to measure airborne mouse urinary protein (MUP) and to assess the occupational exposure to MUP in the workforce of three establishments as part of an epidemiological study examining the influence of aeroallergen exposure on the development of allergic respiratory disease. METHODS: Personal air samples were collected from nine exposure groups during a workshift. A sensitive and reproducible competitive inhibition assay, which used rabbit antisera specific for MUP, was developed and used to measure the occupational exposure to MUP. RESULTS: The personal measurements of MUP showed that people with direct contact with mice (animal technicians) had the highest exposure followed in decreasing order by those working with anaesthetised animals or their tissue (postmortem workers and scientists) and those with indirect contact with mice (supervisors, office workers, and slide production workers). The only difference in concentrations of MUP between the three establishments were found for cage cleaners, which reflected differences in working practises for this exposure category. Air samples collected during the performance of specific tasks showed that high exposures to MUP were associated with handling mice, indirect contact with mice, and washing floors. CONCLUSIONS: Exposure to mouse urinary proteins has been measured in the occupational environment. This information can be used to determine the relation between exposure to MUP and the development of allergic and respiratory disease.