SUMMARY1. Balloons were implanted at the junction of the superior vena cava and right atrium of the rat. Inflation of the balloon stretched the vein-atrial junction but did not cause a change in either arterial or central venous blood pressure.2. Inflating the balloon attenuated spontaneous night-time water intake and the drinking responses to 24 h water deprivation and subcutaneous (s.c.) isoprenaline (10 jug/kg body wt.).3. Water intake after i.P. hyperoncotic colloid (polyethylene glycol 20 M) was virtually abolished when the balloon was inflated immediately before giving access to water (4 h after injection).4. Inflating the balloon had no effect on drinking following i.v. hypertonic saline (5 ml 2M-NaCl/kg body wt.).5. These results support the hypothesis that volume receptors on the right side of the heart are involved in controlling water intake.

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New Findings r What is the central question of this study?Angiotensin-converting enzyme 2 (ACE2), an enzyme which converts angiotensin II (Ang II) into angiotensin-(1-7) [Ang-(1-7)] and terminates the effects of Ang II, is a negative regulator of activated renin-angiotensin system (RAS). Cardiac overexpression of ACE2 has shown conflicting results on myocardial fibrosis in contrast to marked anti-hypertensive and anti-remodelling properties. r What is the main finding and its importance?Recombinant hACE2 administration attenuates oxidative stress, NADPH oxidase activity and ERK1/2 signalling and high blood pressure confirming its beneficial role in two rat models of hypertension.Angiotensin-converting enzyme 2 (ACE2), a monocarboxypeptidase capable of metabolizing angiotensin II (Ang II) into angiotensin-(1-7) [Ang-(1-7)], has emerged as a potential therapeutic target. We hypothesized that ACE2 is a negative regulator of Ang II-mediated pathological effects in vivo. In Wistar-Kyoto (WKY) rats, Ang II infusion (0.1 μg min −1 kg −1 ) induced a pressor response, activation of NADPH oxidase and generation of superoxide in the heart, kidney and blood vessels; these effects were significantly blunted by recombinant human ACE2 (rhACE2; 2 mg kg −1 ), in association with a lowering of plasma Ang II and elevation of Ang-(1-7) levels. In the spontaneously hypertensive rat (SHR) model, rhACE2 (2 mg kg −1 day −1 ) delivered over a 14 day period partly corrected the hypertension, the NADPH oxidase activation and the increased superoxide generation in the heart, kidney and blood vessels. Treatment with rhACE2 inhibited Ang II-mediated phosphorylation of the myocardial extracellular signalregulated kinase 1/2 pathway in WKY rats, with congruent results seen in SHR hearts. Hence, rhACE2 is an important negative regulator of the Ang II-induced pressor response and NADPH oxidase activation and suppresses pathological myocardial signalling, thereby providing a novel therapeutic agent with which to antagonize an activated renin-angiotesin system.

The spleen is an important site of atrial natriuretic factor (ANF)‐induced fluid extravasation into the systemic lymphatic system. The mechanism underlying this process was studied in a blood‐perfused (1 ml min−1) rat spleen using the double occlusion technique. To ensure that our observations were spleen specific, a similar protocol was repeated in the hindquarters. Rat ANF(1‐28), infused into the splenic artery of anaesthetized male rats, caused a dose‐dependent (0.3‐59 pmol min−1) increase in microvascular pressure from 11.3 ± 0.7 to 14.9 ± 0.5 mmHg and in post‐capillary resistance from 7.2 ± 0.6 to 10.1 ± 1.1 mmHg ml−1. ANF elicited no change in splenic pre‐capillary resistance or in hindquarter haemodynamics. Intrasplenic ANF (6.5 pmol min−1) caused a sustained increase in intrasplenic fluid efflux from 0.1 ± 0.1 to 0.3 ± 0.1 ml min−1, and in capillary filtration coefficient (Kf) from 1.2 ± 0.5 to 2.4 ± 0.6 ml mmHg−1 min−1 (100 g tissue)−1. Mechanical elevation of splenic intravascular pressure (from 11.3 ± 0.7 to 22.4 ± 0.2 mmHg) significantly increased intrasplenic fluid extravasation (from 0.4 ± 0.3 to 1.4 ± 0.3 ml min−1). The natriuretic peptide receptor‐C (NPRC)‐specific agonist C‐ANF(4‐23) (12.5 and 125 pmol min−1) did not alter splenic intravascular pressure or pre‐/post‐capillary resistance. The ANF antagonist A71915 (8.3 and 83 pmol min−1), which blocks ANF‐stimulated cGMP production via natriuretic peptide receptor‐A (NPRA), inhibited the ANF‐induced changes in splenic microvascular pressure and post‐capillary resistance. It is concluded that ANF enhances the extravasation of isoncotic fluid from the splenic vasculature both by raising intrasplenic microvascular pressure (increased post‐capillary resistance) and by increasing filtration area. The constrictive activity of ANF on the splenic vasculature is mediated through NPRA.

We recently demonstrated that fluid is filtered out of the splenic circulation and into the lymphatic system. The current experiments were designed to investigate the importance of this route of fluid extravasation in endotoxemia. Lipopolysaccharide (LPS) was infused into conscious intact and splenectomized rats (150 microg x kg(-1). h(-1) i.v. for 18 h). In the intact rats, mean arterial pressure (MAP) fell from 101+/-2.4 to 88+/-3.9 mm Hg (n = 7) and then stabilized at about 90 mm Hg. Hematocrit rose from 41+/-0.9 to 45+/-0.4% at 40 min, at which time plasma volume had fallen from 4.7+/-0.12 to 4.0+/-0.05 ml/100 g body wt. In the splenectomized rats MAP did not fall and hematocrit did not rise. There also was no change in plasma volume, i.e., splenectomy prevented the hypotension and hemoconcentration customarily induced by LPS. In a second series of experiments, splenic arterial and venous blood flows were simultaneously measured in anesthetized rats infused with LPS (150 microg x kg(-1) x h(-1)). LPS increased splenic fluid efflux. We conclude that during endotoxemia the initial fall in circulating blood volume may be attributed to fluid extravasation from the splenic vasculature.

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The mechanisms whereby maternal nutritional manipulation through pregnancy result in altered blood pressure in the offspring may include changes in fetal and newborn and adult renal prostaglandin (PG) synthesis, metabolism, and receptor expression. Since the postnatal effects of nutrient restriction on the renal PG synthesis and receptor system during nephrogenesis in conjunction with nephron numbers and blood pressure have not been evaluated in the rat, the present study examined the effect of reducing maternal food intake by 50% of ad libitum through pregnancy on young male rats. Six control-fed mothers and eight nutrient-restricted pregnant rats with single litter mates were used at each sampling time point, most of which occurred during nephrogenesis. Offspring of nutrient-restricted dams were lighter from birth to 3 days. This was accompanied by reduced PGE2, with smaller kidneys up to 14 days. Nutrient restriction also decreased mRNA expression of the PG synthesis enzyme, had little effect on the PG receptors, and increased mRNA expression of the degradation enzyme during nephrogenesis and the glucocorticoid receptor in the adult kidney. These mRNA changes were normally accompanied by similar changes in protein. Nephron number was also reduced from 7 days up to adulthood when blood pressure (measured by telemetry) did not increase as much as in control offspring during the dark, active period. In conclusion, maternal nutrient restriction suppressed renal PG concentrations in the offspring, and this was associated with suppressed kidney growth and development and decreased blood pressure.kidney; nutrient restriction; offspring; prostaglandins MATERNAL NUTRIENT RESTRICTION during pregnancy has been previously shown to affect the renal development of the offspring. In the sheep, nutrient restriction targeted to the period of early kidney development subsequently increases organ size as well as affecting kidney shape and promotes glucocorticoid receptor (GCR) mRNA abundance (32). Global nutrient restriction (9) and protein restriction in particular can both reduce the total number of nephrons formed in developing rat kidneys, but this does not necessarily result in raised blood pressure in the offspring (11). The mechanisms by which maternal nutritional manipulation acts to compromise fetal development and ultimately adult health remain uncertain. It has been proposed that this is dependent in part on increased maternal corticosterone concentrations acting directly on the fetus (16). This proposal is supported by the finding that maternal administration of dexamethasone, which crosses the placenta to the fetus during pregnancy, can cause similar cardiovascular outcomes as observed with maternal food deprivation (40); indeed, dexamethasone administration also results in reduced maternal food consumption, suggesting a behavioural effect on appetite (37, 40). Recently, it has been shown that a transient increase in maternal corticosterone on days 14 and 15 of pregnancy in rats can impair development of the intra-...

SUMMARY1. Ovine prolactin injected intravenously in doses of 10'0, 5 0, 1-0, 0-1 and 0 mg/kg body wt. caused neither drinking nor a change in urine output in normal water replete male and female rats.2. The water intake of male rats subjected to 48 hr water deprivation was substantially increased after injection of prolactin.3. The water intake of male and female rats injected i.P. with a hyperoncotic solution of polyethylene glycol (20 M) was significantly increased after injection of prolactin.4. Prolactin was found to act synergistically with a subthreshold dose ofangiotensin II amide to cause significant drinking and fluid retention.5. The drinking responses of male and female rats injected i.v. with hypertonic saline were not modified by prolactin.6. It is concluded that prolactin may act to increase the net water gain of animals suffering a deficit of the extracellular fluid space but is without effect on stimuli arising from deficits in the intracellular fluid space.