Effect of selective angiotensin antagonists on the antidiuresis produced by angiotensin-(1-7) in water-loaded rats

In the present study we evaluated the nature of angiotensin receptors involved in the antidiuretic effect of angiotensin-(1-7) (Ang-(1-7)) in water-loaded rats. Water diuresis was induced in male Wistar rats weighing 280 to 320 g by water load (5 ml/100 g body weight by gavage). Immediately after water load the rats were treated subcutaneously with (doses are per 100 g body weight): 1) vehicle (0.05 ml 0.9 percenr NaCl); 2) graded doses of 20, 40 or 80 pmol Ang-(1-7); 3) 200 nmol Losartan; 4) 200 nmol Losartan combined with 40 pmol Ang-(1-7); 5) 1.1 or 4.4 nmol A-779; 6) 1.1 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 7) 4.4 nmol A-779 combined with graded doses of 20, 40 or 80 pmol Ang-(1-7); 8) 95 nmol CGP 42112A, or 9) 95 nmol CGP 42112A combined with 40 pmol Ang-(1-7). The antidiuretic effect of Ang-(1-7) was associated with an increase in urinary Na+ concentration, an increase in urinary osmolality and a reduction in creatinine clearance (CCr: 0.65 ñ 0.04 ml/min vs 1.45 ñ 0.18 ml/min in vehicle-treated rats, P<0.05). A-779 and Losartan completely blocked the effect of Ang-(1-7) on water diuresis (2.93 ñ 0.34 ml/60 min and 3.39 ñ 0.58 ml/60 min, respectively). CGP 42112A, at the dose used, did not modify the antidiuretic effect of Ang-(1-7). The blockade produced by Losartan was associated with an increase in CCr and with an increase in sodium and water excretion as compared with Ang-(1-7)-treated rats. When Ang-(1-7) was combined with A-779 there was an increase in CCr and natriuresis and a reduction in urine osmolality compared with rats treated with Ang-(1-7) alone. The observation that both A-779, which does not bind to AT1 receptors, and Losartan blocked the effect of Ang-(1-7) suggests that the kidney effects of Ang-(1-7) are mediated by a non-AT1 angiotensin receptor that is recognized by Losartan.

Renal actions of angiotensin-(1-7)

The heptapeptide angiotensin-(1-7) is considered to be a biologically active endproduct of the renin-angiotensin system. This angiotensin, which is devoid of the most known actions of angioatensin II such as induction of drinking behavior and vasoconstriction, has several selective effects in the brain and periphery. In the present article we briefly review recent evidence for a physiological role of angiotensin-(1-7) in the control of hydroelectrolyte balance.

Angiotensin-1(1-7) is a potent antidiuretic peptide in rats

We have shown previously that angiotensin (1-7) (Asp-Arg Val-Tyr-Ile-His-Pro) is a biologically active endogenous angiotensin which is a major product of angiotensin I processing by an angiotensin converting enzyme (ACE)-independent pathway. Intense staining for angiotensin (1-7) immunoreactivity was demonstrable in brain areas related to the maintenance of hydromineral balance, suggesting the involvement of this peptide in this process. In the present study we investigated the antidiuretic effect of angiotensin (1-7), by determining its effect on the water diuresis produced by an ip water load (5 ml/100 g) in male Wistar rats. The peptide had a pronounced antidiuretic effect when administered peripherally in doses ranging from 5.5 to 22 pmol/100 g. In contrast, angiotensin - (1-7) and vasopressin (AVP) showed that both peptides act in the same molar range althouth AVP was slightly more potent than angiotensin (1-7). Urine volumes for 22 pmol/100 g angiotensin (1-7) were 0.85 ñ 0.26 and 3.47 ñ 0.36 ml for hours 1 and 2, respectively, whereas they were 0.54 ñ 0.40 and 2.38 ñ 0.64 ml for 10 pmol/100 g AVP. There was apparent additivity of effect when 10 pmol of each peptide were administered simultaneously (0.0 and 1.72 ñ 0.45 ml vs 2.58 ñ 0.45 and 3.85 ñ 0.35 ml for hours 1 and 2, respectively). The unexpected potency of this peptide in reducing water diuresis and its localization in brain areas related to AVP release suggest a role for angiotensin (1-7) in the mechanisms involved in the maintenance of hydroelectrolyte balance