Similar renoprotection after renin-angiotensin-dependent and -independent antihypertensive therapy in 5/6-nephrectomized Ren-2 transgenic rats: are there blood pressure-independent effects?

1. Hypertension plays a critical role in the progression of chronic kidney disease (CKD) to end-stage renal disease (ESRD), but it has also been postulated that antihypertensive drugs that block the renin-angiotensin system (RAS) show class-specific renoprotective actions beyond their blood pressure (BP)-lowering effects. 2. Because this notion has recently been questioned, in the present study we compared the effects of a RAS-dependent antihypertensive therapy (a combination of trandolapril, an angiotensin-converting enzyme inhibitor (ACEI) and losartan, an angiotensin-II (AngII) receptor subtype 1A receptor antagonist) with a 'RAS-independent' antihypertensive therapy (a combination of labetalol, an alfa- and beta-adrenoreceptor antagonist with the diuretics, hydrochlorothiazide and furosemide) on the progression of CKD after 5/6 renal ablation (5/6 NX) in Ren-2 renin transgenic rats (TGR), a model of AngII-dependent hypertension. Normotensive transgene-negative Hannover Sprague-Dawley (HanSD) rats after 5/6 NX served as controls. 3. RAS-dependent and -independent antihypertensive therapies normalized BP and survival rate, and prevented the development of cardiac hypertrophy and glomerulosclerosis to the same degree in 5/6 NX HanSD rats and in 5/6 NX TGR. The present findings show that renoprotection, at least in rats after 5/6 NX, is predominantly BP-dependent. When equal lowering of BP was achieved, leading to normotension, cardio- and renoprotective effects were equivalent irrespective of the type of antihypertensive therapy. 4. These findings should be taken into consideration in attempts to develop new therapeutic approaches and strategies aimed to prevent the progression of CKD and to lower the incidence of ESRD.

Effects of chronic cytochrome P-450 inhibition on the course of hypertension and end-organ damage in Ren-2 transgenic rats.

The aim of the present study was to evaluate the effects of inhibition of cytochrome P-450 (CYP) activity by 1-aminobenzotriazole (ABT) and by CoCl(2), first, on the development of hypertension when treatment was started in young male heterozygous Ren-2 transgenic rats (TGR) and, second, on blood pressure (BP) when treatment was started in adult TGR with established hypertension. Normotensive Hannover Sprague-Dawley (HanSD) rats served as controls. In addition, the renal cortical activities of omega-hydroxylase, the enzyme catalyzing the formation of 20-hydroxyeicosatetraenoic acid (20-HETE), and of epoxygenase, the enzyme responsible for epoxyeicosatrienoic acids (EETs) production, and urinary excretion of 20-HETE and EETs in TGR and HanSD rats were assessed. TGR have higher renal tissue omega-hydroxylase activity and urinary excretion of 20-HETE but have significantly lower renal epoxygenase activity and urinary excretion of EETs than HanSD rats. Treatment of young TGR with ABT and CoCl(2) attenuated the development of hypertension and cardiac hypertrophy and prevented glomerulosclerosis. Administration of ABT and CoCl(2) in adult TGR decreased BP, cardiac hypertrophy, but did not reduce glomerulosclerosis. Our data suggest that altered production and/or action of CYP-derived metabolites play a permissive role in the development and maintenance of hypertension in TGR by enhancing ANG II-induced vasoconstriction.

AT1 receptor antisense therapy transiently lowers blood pressure in Ren-2 transgenic rats.

The effectiveness of antisense (AS) phosphorothioated oligodeoxynucleotides (AS-ODN) targeted to the angiotensin (ANG) type 1 (AT1) receptor, was studies in Ren-2 transgenic rats (TGR), whose ANG II-dependent hypertension can be attributed to the insertion of a single mouse renin gene. Our results show that a single intraarterial bolus injection of AT1-AS in 30-day-old rats results in a prolonged lowering of systolic blood pressure (SBP) for a period of 18 days with an average difference in SBP of 30 mm Hg between AS-treated and untreated TGR. No effect of AS therapy on SBP has been observed in control HanSD animals. However, at the end of the experiment, i.e. on day 100 of age, there were no differences in mean arterial pressure, proteinuria or cardiac hypertrophy between AS-treated and untreated TGR. Thus, no persistent effect of this therapy was observed after a single bolus injection. Collectively, the data show a prolonged antihypertensive effect of AT1 receptor antisense oligonucleotides during the developmental phase of hypertension in TGR when applied as a single treatment in prehypertensive animals which, however, does not persist up to the maintenance phase of hypertension in adulthood.

Long-term prevention of hypertension and end-organ damage in Ren-2 transgenic rats is achieved only with persistent but not transient AT1 receptor blockade.

The aim of this study was first to evaluate the effects of persistent or transient blockade of the angiotensin II (ANG II) receptor AT(1) on the development of hypertension and end-organ damage in hypertensive Ren-2 transgenic rats (TGR), and second to assess the potential role of AT(2) receptors in the control of blood pressure (BP) in this monogenetic model of hypertension. Male heterozygous TGR and Hannover Sprague-Dawley (HanSD) rats fed a normal salt diet were treated from day 32 of age either persistently until the end of the experiment (day 100 of age) or transiently until day 56 of age with the selective AT(1) receptor antagonist candesartan or with the combination of candesartan and the AT(2) receptor antagonist PD 123319. Persistent treatment with candesartan completely prevented the rise in BP, proteinuria and the increase in left ventricular weight/body weight ratio, whereas transient treatment with candesartan was effective only as long as the drug was administered. In the presence of candesartan, PD 123319 was without effect. Our results show that in male heterozygous TGR persistent candesartan treatment completely prevented hypertension and end-organ damage as long as the drug was administered, whereas transient AT(1 )receptor blockade had no long-term effects.

Early-onset endothelin receptor blockade in hypertensive heterozygous Ren-2 rats.

Male heterozygous Ren-2 transgenic rats and Hannover Sprague-Dawley rats fed a normal or high-salt diet were either untreated or treated with the nonselective receptor ET(A)/ET(B) receptor blocker bosentan or the selective ET(A) receptor blocker, ABT-627, known as atrasentan. Survival rate was partly increased by bosentan and fully normalized by atrasentan. Bosentan did not significantly influence the course of hypertension in TGR, whereas atrasentan significantly decreased BP on both diets. Atrasentan substantially reduced proteinuria, cardiac hypertrophy, glomerulosclerosis and left ventricular ET-1 tissue concentration on both diets. Our data indicate that ET(A) receptor blockade is superior to nonselective blockade in attenuating hypertension, end-organ damage and improving survival rate.