Montgomery, Hugh Edward; (1997) Tissue renin-angiotensin systems and cardiovascular disease. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Circulating/endocrine renin-angiotensin systems (RAS) play an important role in mammalian blood pressure homeostasis. Renin acts on angiotensinogen to yield angiotensin I, itself cleaved by circulating/endothelially-bound angiotensin converting enzyme (ACE) to yield the vasoconstrictor angiotensin II (All). All also stimulates adrenal aldosterone release. However, tissue RAS may also exist. All generated by such local systems may control tissue growth and injury responses. This thesis examines the role of RAS in mammalian cardiovascular physiology and pathophysiology in an animal model and in humans. The transgenic TGR(mRen-2d)27 rat expresses the mouse renin-gene in diffuse tissues and is spontaneously hypertensive. Using RNase protection assay and reverse-transcription PCR, transgene expression was identified in the right ventricle, kidney, lung and aorta. The blood-pressure profile of heterozygote male TGRs was characterised by serial measurement of systolic blood pressure (SBP) under light halothane anaesthesia using tail-cuff photoplethysmography. Blood pressure rose steeply after 3 days of age, reaching a maximum at day 69 (mean 256±11 mmHg). Thereafter, blood pressure slowly fell and continued to do so to 120 days (mean 216±30mmHg). The ACE-inhibitor Ramipril (10µg/kg/day) reduced both vascular ACE activity and SBP, whilst 1mg/kg/day reduced blood pressure to that of normotensive control animals. Calcium channel blockade (Amlodipine), even at doses of 20mg/kg/day, could not reduce SBP to normotensive levels, and hydrallazine therapy had no consistent hypotensive action. These data suggest a role for local vascular All in the pathogenesis of the TGR hypertensive phenotype. A high incidence of malignant hypertension (MH) was shown to occur amongst TGRs. Tissue ACE inhibition with non-hypotensive doses of ramipril which inhibited tissue (but not circulating) ACE activity (5µg/kg/day) were protective, reducing MH- related death rates from 63% to 4.3% and reducing scores for renovascular damage. Left ventricular hypertrophy (LVH) and collagen deposition amongst untreated TGRs was also reduced by ramipril treatment in a dose-dependent fashion, and partly through a non-hypotensive mechanism: 5µg/kg/day reduced both LV mass and collagen content at 70 and 120 days. A polymorphism of the human ACE gene has been described which consists of the presence (Insertion, or I allele) or absence (deletion, D allele) of a 287 base pair fragment. The D allele is associated with higher circulating and tissue ACE activity. It has been postulated that increased cardiac ACE activity may play a role in the development and progression of idiopathic dilated cardiomyopathy (IDC) in humans. However, no excess frequency of the D allele or DD genotype was found amongst 99 individuals with IDC when compared to 364 controls and within patients the D allele did not consistently correlate with markers of disease severity or progression. Physiological left ventricular growth was studied in UK male military recruits exposed to 10 weeks of physical training. The D allele correlated in a dose-response fashion with increases in left ventricular wall thickness and mass. Plasma beta natriuretic factor (BNP) levels correlate with LV mass, and rose with training to the greatest extent in those of DD genotype. Finally, prevalence of electrocardiographic measures of LVH increased more in those individuals of DD genotype than those of II genotype. These data support a role for tissue RAS in the control of human physiological LV growth.

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