IV. RESULTADOS Y DISCUSIÓN
4.1. El medio ambiente en el constitucionalismo estándar: las bases de la
2.431 General Comments
High circulating RAS activity does not therefore seem to be the cause of the hypertension in the TGR(mREN-2)27 rat. High local tissue RAS activity might be responsible: co-expression of native and transgenic renin genes allows a role for transgenic stimulation of local tissue renin-angiotensin systems in the development of hypertension in this model. Systolic blood pressure in mature female TGRs falls in 2 stages with 13 day of treatment with Lisinopril 20 mg/kg (by 30-40%) or losartan lOmg/kg/day. Rapid inhibition of plasma ACE might account for the initial rapid fall in
ACE inhibition (Moriguchi et al. 1994). The role of expression in many different tissues has been studied.
2.432 Role of brain RAS in the aetiology of the hypertensive phenotype
In the TGR, tissue-specific down-regulation of Ren-2 gene transcription occurs at 2-4 weeks of life in areas of the brain concerned with sympathetic outflow (Zhao et al.
1993). However, sympathetic outflow in TGRs is similar to that seen in genetically hypertensive Lyon rat control (Lo et al. 1993) and ganglion blockade produces a similar percentage fall in BP in both, suggesting a similar contribution of sympathetic activity to the hypertension in both. These data suggest that the hypertensive phenotype is not centrally or sympathetically-driven.
2.433 Role of renal RAS in the aetiology of the hypertensive phenotype
Renal levels of native and transgene renin mRNA are low, and fall as hypertension develops (Zhao et al. 1993) making it unlikely that the kidney is the driving force behind the hypertensive phenotype (Bachmann et al. 1992; Bader et al. 1992). Nonetheless, transgenic rats have a degree of RAS-mediated salt and water retention (Lo et al. 1993). Tubular sodium resorption in isolated kidneys is increased, and the natiuretic and diuretic response to frusemide in vivo is greater. Although this might be thought to account for the TGR sensitivity to the hypotensive effect of ACE inhibitors, captopril produces an tznri-natiuretic effect in these animals not seen in controls, while hypotension induced by a calcium channel blocker has the opposite effect (Hirth- Dietrich et al. 1994).
2.434 Role of adrenal RAS in the aetiology of the hypertensive phenotype
The high levels of Ren-2 transcript found in the adrenal gland precede the development of hypertension in the TGR (Zhao et al. 1993) and might in theory generate hypertension by one of five mechanisms:
(i) In c re a sin g a ld o ste ro n e g e n e ra tio n , p r o d u c in g s a lt a n d w a te r retention. It is possible that local ATII generation could have a paracrine effect within the adrenal in stimulating aldosterone synthesis or release. Basal steroid synthesis (assessed by urinary steroid hormone and metabolite excretion) may be increased
urinary levels. Plasma corticosterone levels are similar in Sprague Dawley controls and transgenic homozygotes but higher in heterozygotes than in controls(Sander, Bader et al. 1992). The adrenal tissue maximal response (assessed by urinary aldosterone and deoxycorticosterone levels) to ACTH stimulation is greater in the TGR in vivo (Sander et al. 1992) but strangely not in vitro using dispersed zona glomerulosa cells from female TGR(mREN2)27 animals (Rocco et al. 1994). In any event, basal urinary corticosteroid and mineralocorticoid/aldosterone levels are only 2-fold raised (Mulhns et al. 1990; Sander et al. 1992), and treatment with the aldosterone antagonist spironolactone does not significantly lower blood pressure making hypertension due to pure mineralocorticoid excess unlikely (Sander et al. 1992). This finding has been confirmed in both young developing rats and in mature animals (Bader et al. 1992). (i t ) D irect gen eration o f A TII, acting as a circu latin g vasoconstrictor. Plasma ATII is not significantly elevated in the TGR (see above)
(Hi ) The generation o f excessive catecholam ines. Plasma catecholamines are not significantly elevated in the TGR (Bachmann et al. 1992).
( i v ) C irculating adren al proren in is taken up by tissues (e.g. vascular wall) and converted to active renin (Kim et al. 1990), driving a local RAS to produce local ATII. Plasma prorenin levels rise in parallel with plasma ATI levels and blood pressure in the heterozygote TGR (Sander et al. 1992). Male TGR adrenal prorenin release in response to ACTH is greater (maximal 10-fold rise in plasma prorenin) than in controls (four-fold rise). However, prorenin levels do not correlate individually with BP (Veniant et al. 1995), and bilateral adrenalectomy (with oral NaCl or dexamethasone maintenance), markedly reduces circulating prorenin and total renin levels with little effect on blood pressure (Bachmann et al. 1992; Tokita et al. 1994a). ( v ) G eneration o f high circulating renin activity (see above). The possible correlation between plasma renin and BP is debated (Sander et al. 1992; Veniant et al.
1995).
2.435 Role of ovarian RAS in the aetiology of the hypertensive phenotype
Kidney native and transgene renin transcription and plasma ATII (57% reduction) fall after ovariectomy in TGR(mREN2)27 females. In SHRs, total renin levels did not
Plasma prorenin levels fell non-significantly, but total plasma renin fell, and plasma active renin fell by 48%. This might suggest either a) ovarian hormone-dependent regulation of gene transcription or b) a role for the ovary in conversion of prorenin to renin in TGR (Bachmann et al. 1993). Although steroid control of renin gene expression is different in the female TGR than in controls the overall involvement of this factor in the genesis of the hypertension seems negligible. Blood pressure is also higher in male heterozygote TGRs than females.
2.436 Role of vascular RAS in the aetiology of the hypertensive phenotype
Thus, high circulating RAS activity, as well as adrenal, renal, cerebral, hepatic and ovarian RAS do not seem to be driving the hypertension although this is clearly due to RAS activity somewhere. Vascular RAS activity may be responsible. Angiotensin peptide release from isolated perfused hindlimbs of adult (12-18 week old) female TGRs was significantly raised when compared to controls (Hilgers et al. 1992), and is not significantly reduced by bilateral nephrectomy. The site of transgene expression in the hind-limb was not determined, but it was suggested that expression might be vascular in order to explain the very high renin release. Basal plasma ATII was significantly depressed in this study, as has been confirmed by others (see above). The sensitivity of blood pressure to RAS antagonism (above), the high vascular ATII generation and low plasma ATII levels all suggest that vascular Ren-2 expression may be driving the hypertension, which in turn suppresses native ATII generation elsewhere in the body.