Glomerular and tubular effects of nitric oxide (NO) are regulated by angiotensin II (Ang II) in an age-dependent manner through activation of both angiotensin receptors (AT1Rs and AT2Rs) in conscious lambs.

Renin-angiotensin (RAS) and nitric oxide (NO) systems and the balance and interaction between them are considered of primary importance in maintaining fluid and electrolyte homeostasis. It has been suggested that the effects of NO may be modulated at least in part by the angiotensin (Ang) II, yet the roles of angiotensin receptor type 1 (AT1R) and type 2 (AT2R) are not well understood. Even though both Ang II and NO are elevated at birth and during the newborn period, their contribution to the adaptation of the newborn to life after birth as well as their physiological roles during development are poorly understood. The aim of this study was to determine if NO regulation of renal function during postnatal maturation is modulated by Ang II through activation of AT1R or AT2R or both receptors. Glomerular and tubular effects of either AT1R selective antagonist ZD 7155, AT2R selective antagonist PD 123319, and both antagonists ZD 7155 plus PD 123319, were measured in 1- (N = 9) and 6-week-old (N = 13) conscious, chronically instrumented lambs before and after removal of endogenous NO with L-arginine analogue, L-NAME. Two-way analysis of variance (ANOVA) procedures for repeated measures over time with factors age and treatment were used to compare the effects of the treatments on several glomerular and tubular variables in both groups. This study showed that L-NAME infusion after pre-treatment with ATR antagonists did not alter glomerular function in 1- or 6-week-old lambs. NO effects on electrolytes handling along the nephron during postnatal development were modulated by Ang II through AT1R and AT2R in an age-dependent manner. Selective inhibition of AT1R and AT2R increased excretion of Na+, K+, and Cl- in 6- but not in 1-week-old lambs. In 6-week-old lambs, urinary flow rate increased by 200%, free water clearance increased by 50%, and urine osmolality decreased by 40% after L-NAME was added to the pre-treatment with ZD 7155 plus PD 123319. When L-NAME was added either to ZD 7155 or PD 123319, the same trend in the alterations of these variables was observed, albeit to a lower degree. In conclusion, in conscious animals, during postnatal maturation, Ang II modulates the effects of NO on glomerular function, fluid, and electrolyte homeostasis through AT1Rs and AT2Rs in an age-dependent manner. Under physiological conditions, AT2Rs may potentiate the effects of AT1R, providing evidence of a crosstalk between ATRs in modulating NO effects on fluid and electrolyte homeostasis during postnatal maturation. This study provides new insights on the regulation of renal function during early postnatal development showing that, compared with later in life, newborns have impaired capacity to regulate glomerular function, water, and electrolyte balance.

Renal effects of angiotensin II in the newborn period: role of type 1 and type 2 receptors.

BACKGROUND: Evidence suggests a critical role for the renin-angiotensin system in regulating renal function during postnatal development. However, the physiological relevance of a highly elevated renin-angiotensin system early in life is not well understood, nor which angiotensin receptors might be involved. This study was designed to investigate the roles of angiotensin receptors type 1 (AT1R) and type 2 (AT2R) in regulating glomerular and tubular function during postnatal development. METHODS: The renal effects of the selective antagonist to AT1R, ZD 7155 and to AT2R, PD 1233319 were evaluated in two groups of conscious chronically instrumented lambs aged ~ one week (N = 8) and ~ six weeks (N = 10). Two experiments were carried out in each animal and consisted of the assessment of renal variables including glomerular and tubular function, for 30 min before (Control) and 60 min after infusion of ZD 7155 and PD 123319, respectively. Statistical significance was determined using parametric testing (Student t-test, analysis of variance ANOVA) as appropriate. RESULTS: ZD 7155 infusion was associated with a significant decrease in glomerular filtration rate and filtration fraction at one but not six weeks; urinary flow rate decreased significantly in older animals, whereas sodium excretion and free water clearance were not altered. There was an age-dependent effect on potassium handling along the nephron, potassium excretion decreasing after ZD 7155 infusion in younger but not in older lambs. PD 123319 had no significant effects on glomerular filtration rate and tubular function in either age group. CONCLUSIONS: These results provide evidence to support an important role for AT1Rs in mediating the renal effects of angiotensin II during postnatal maturation in conscious developing animals. In contrast to a role for AT2Rs later in life, there appears to be no role for AT2Rs in influencing the renal effects of Angiotensin II in the postnatal period.

Developmentally regulated effects of severe hemorrhage on cardiovascular homeostasis and the arterial baroreflex control of heart rate.

The purpose of this study was to investigate in developing animals, the cardiovascular responses to severe hemorrhage at which compensatory mechanisms fail and when blood pressure remains decreased after blood loss. Two groups of conscious lambs (Group I: one to two weeks, N = 7; group II: six to seven weeks, N = 7) were studied. Mean arterial pressure, systolic and diastolic pressures, and heart rate were measured for 20 min before (Control, C) and for 60 min after a fixed hemorrhage of 30% of blood volume. The arterial baroreflex control of heart rate was assessed before (C), and at 30 and 60 min intervals after hemorrhage. Mean arterial pressure decreased for up to 60 min after hemorrhage in both groups of lambs. In group I, heart rate decreased from 200 ± 29 (C) to 164 ± 24 beat min(-1) at 30 min then increased to 232 ± 45 beat min(-1) at 60 min, whereas heart rate remained unaltered in group II. With respect to the arterial baroreflex control of heart rate, by 30 min after hemorrhage in group I, there was a decrease in the heart rate range over which the baroreflex operates (P1) from 192 ± 13 (C) to 102 ± 9 beats min(-1); by 60 min after hemorrhage, there was a decrease in minimum heart rate (P4) from 72 ± 10 (C) to 32 ± 25 beats min(-1). In group II, P1 decreased to a lesser extent than group I from 134 ± 21 (C) to 82 ± 10 beats min(-1) at 30 min; minimum heart rate (P4) decreased from 40 ± 15 (C) to 24 ± 9 and 20 ± 13 beats min(-1) at 30 and 60 min, respectively. These results provide the first assessment of the arterial baroreflex control of heart rate following blood loss and new evidence that the cardiovascular responses to severe hemorrhage are developmentally regulated.

Angiotensin receptors modulate the renal hemodynamic effects of nitric oxide in conscious newborn lambs.

This study aimed to elucidate the roles of both angiotensin II (ANG II) receptors - type 1 (AT1Rs) and type 2 (AT2Rs) - separately and together in influencing hemodynamic effects of endogenously produced nitric oxide (NO) during postnatal development. In conscious, chronically instrumented lambs aged ~1 week (8 ± 1 days, N = 8) and ~6 weeks (41 ± 2 days, N = 8), systolic, diastolic, and mean arterial pressure (SAP, DAP, MAP) and venous pressure (MVP), renal blood flow (RBF), and renal vascular resistance (RVR) were measured in response to the l-arginine analog, l-NAME after pretreatment with either the AT1R antagonist, ZD 7155, the AT2R antagonist, PD 123319, or both antagonists. The increase in SAP, DAP, and MAP by l-NAME was not altered by either ATR antagonist in either age group. The increase in RBF after l-NAME was, however, altered by both ATR antagonists in an age-dependent manner, which was mediated predominantly through AT2Rs in newborn lambs. These findings reveal that there is an age-dependent interaction between the renin-angiotensin (RAS) and the NO pathway in regulating renal but not systemic hemodynamics through both ATRs, whereas AT2Rs appear to be important in the renal hemodynamic effects of NO early in life.

Do angiotensin type 2 receptors modulate haemodynamic effects of type 1 receptors in conscious newborn lambs?

INTRODUCTION AND HYPOTHESIS: It was hypothesized that in the immediate newborn period, when the renin-angiotensin system (RAS) is activated, angiotensin type 2 receptors (AT2Rs) buffer the haemodynamic effects of angiotensin type 1 receptors (AT1Rs), as occurs in adult animals when the RAS is activated. MATERIALS AND METHODS: Arterial (systolic, diastolic, and mean) pressures (SAP, DAP, MAP), mean venous pressures (MVP) and renal blood flows (RBF) were measured in conscious, chronically instrumented lambs aged ~1 (8±2 days, N=8) and 6 weeks (41±4 days, N=11). In each animal, measurements were made before and after administration of the selective AT1R antagonist ZD 7155 (experiment one) and the selective AT2R antagonist PD123319 (experiment two) as well as both antagonists, ZD 7155 and PD 123319 (experiment three). RESULTS: Haemodynamic responses to combined inhibition of both AT1Rs and AT2Rs were similar to inhibition of AT1Rs alone: there was a significant decrease in SAP, DAP, and MAP and a significant increase in RBF within minutes of concomitant administration of ZD 7155 and PD 123319 in both age groups. These responses were similar to responses to ZD 7155 alone, whereas PD 123319 alone did not alter any of the measured variables. CONCLUSIONS: AT2Rs do not counterbalance the pressor and renal vasoconstrictor effects elicited by activation of AT1Rs in the immediate newborn period. During this time, AT1Rs appear to predominate in eliciting the haemodynamic effects of angiotensin II (ANG II), whereas the role of the upregulated AT2Rs remains elusive.

Nitric oxide and angiotensin II regulate cardiovascular homeostasis and the arterial baroreflex control of heart rate in conscious lambs.

To investigate the potential role of angiotensin II (Ang II) type 1 receptors (AT(1)Rs) as well as endogenously produced nitric oxide (NO) in regulating cardiovascular homeostasis during ontogeny, experiments were carried out in conscious lambs aged approximately 1 week (N = 9) and 6 weeks (N = 11). The arterial baroreflex control of heart rate (HR) was assessed before and after intravenous (IV) infusion of the selective AT(1)R antagonist, ZD 7155, before and after IV administration of the L-arginine analogue, N(G)-nitro-L-arginine methyl ester (L-NAME). In both groups, after ZD 7155 alone, mean arterial pressure decreased then increased after L-NAME. At 1 but not 6 weeks, HR decreased after ZD 7155 as well as after L-NAME. At 1 but not 6 weeks, there was a decrease in the HR range after ZD 7155 and after ZD 7155 + L-NAME, as compared to control. There was also a decrease in minimum HR after ZD 7155 + L-NAME at 1 week. These data provide new evidence that, together, Ang II and NO regulate cardiovascular homeostasis as well as the arterial baroreflex of HR early in life which may help to explain the activation of these two systems early in life.

Cyclooxygenase (COX) Inhibitors and the Newborn Kidney.

This review summarizes our current understanding of the role of cyclo-oxygenase inhibitors (COXI) in influencing the structural development as well as the function of the developing kidney. COXI administered either during pregnancy or after birth can influence kidney development including nephronogenesis, and can decrease renal perfusion and ultrafiltration potentially leading to acute kidney injury in the newborn period. To date, which COX isoform (COX-1 or COX-2) plays a more important role in during fetal development and influences kidney function early in life is not known, though evidence points to a predominant role for COX-2. Clinical implications of the use of COXI in pregnancy and in the newborn infant are also evaluated herein, with specific reference to the potential effects of COXI on nephronogenesis as well as newborn kidney function.

Indomethacin abolishes core temperature, but not cardiovascular or renal, responses to lipopolysaccharide in conscious lambs.

1. Core temperature (Tc), cardiovascular and renal responses to lipopolysaccharide (LPS), as well as the role of endogenously produced prostaglandins (PG) in influencing these responses, were investigated in the present study in conscious, chronically instrumented lambs. 2. Core temperature, mean arterial pressure, heart rate (HR), renal blood flow (RBF) and several parameters of renal function were measured for 30 min before and for 5 h after intravenous injection of 0.03 µg/kg of the LPS Salmonella abortus equi (n = 9) or saline vehicle (n = 9). 3. After injection of LPS, Tc increased with a latency of 40 min, duration of 130 min and magnitude of 1.5°C. Mean arterial pressure increased within 110 min of LPS injection and then decreased below baseline within 5 h, concomitant with an increase in HR. There was a sustained increase in RBF after LPS injection and a significant increase in urinary flow rate, as well as Na(+) and Cl(-) excretion. 4. To determine the role of PGs in the responses to LPS observed, additional experiments were performed in another group of conscious lambs that had been pretreated with the non-selective cyclo-oxygenase inhibitor indomethacin (10 mg/kg; n = 6). 5. Although indomethacin abolished the Tc response to LPS, it had no significant effect on the cardiovascular and renal responses to LPS. There were no effects of saline vehicle on any of the variables measured. 6. These data provide evidence that, in conscious young lambs, cardiovascular and renal responses to LPS do not appear to be mediated by endogenously produced PGs and that they are independent of pyrogen-induced changes in Tc.

Kappa opioids modulate the arterial baroreflex control of heart rate in conscious young sheep.

The present study tested the hypothesis that kappa-opioids modulate the arterial baroreflex control of heart rate in conscious young sheep. Various parameters governing the arterial baroreflex control of heart rate were assessed before and after activation of kappa-opiate receptors (KOR) by i.v. administration of the specific KOR agonist U-50488H (experiment 1) or vehicle (experiment 2) to conscious, chronically instrumented lambs aged 42 +/- 2 days (n = 6). The 2 experiments were administered in random order at minimum intervals of 48 h. Thirty min after U-50488H treatment, there was an increase in diastolic and mean arterial pressure and in heart rate, returning to control levels by 90 min. A significant increase in the arterial pressure at the midpoint of the baroreflex range and in the minimum heart rate as well as a significant decrease in the heart rate range over which the arterial baroreflex operates were also seen at 30 min after U-50488H, gradually returning to control levels over 120 min. Vehicle had no effect on any of the parameters governing the arterial baroreflex control of heart rate. These data provide the first direct evidence that under physiological conditions in young lambs, the arterial baroreflex control of heart rate is altered after administration of the specific KOR agonist U-50488H, revealing a previously unidentified role for this opioid receptor.

Renal responses to the kappa-opioid-receptor agonist U-50488H in conscious lambs.

In adult animals and humans, activation of kappa-opioid receptors results in a diuresis. The aim of the present study was to investigate whether kappa-opioids are also diuretic early in life and whether this is altered during postnatal maturation. Therefore, the renal effects of the kappa-opioid-receptor agonist U-50488H were measured in two separate age groups of conscious lambs at two stages of postnatal maturation (approximately 1 wk and approximately 6 wk) under physiological conditions. To evaluate whether the renal responses to U-50488H resulted from receptor-dependent effects, responses to U-50488H were also tested in the presence of the specific kappa-opioid-receptor antagonist 5'-guanidinonaltrindole (GNTI). Urinary flow rate, free water clearance, and electrolyte excretions and clearances were measured for 30 min before and for 90 min after intravenous injection of U-50488H or vehicle. An increase in urinary flow rate accompanied by an increase in free water clearance occurred in response to administration of U-50488H but not vehicle. There were no effects of U-50488H on electrolyte excretions or clearances at either 1 or 6 wk of postnatal life. Although there were no effects of GNTI on any of the measured or calculated variables, the aforementioned diuretic response to U-50488H was abolished by pretreatment with GNTI in both age groups. We conclude that kappa-opioid receptors are diuretic early in life and that this response does not appear to be altered as postnatal maturation proceeds. Therefore, these data provide evidence that activation of kappa-opioid receptors early in life may lead to alterations in fluid balance.

Systemic and renal hemodynamic effects of the AT1 receptor antagonist, ZD 7155, and the AT2 receptor antagonist, PD 123319, in conscious lambs.

Experiments were carried out to investigate age- and dose-dependent effects of the selective AT(1) receptor antagonist, ZD 7155, and the selective AT(2) receptor antagonist, PD 123319, on systemic and renal hemodynamics in conscious, chronically instrumented lambs aged approximately 1 and approximately 6 weeks of postnatal life. Mean arterial pressure (MAP), mean venous pressure (MVP), and renal blood flow (RBF) were measured for 10 min before and for 120 min after ZD 7155, PD 123319, or vehicle. In both age groups, administration of ZD 7155 decreased renal vascular resistance (RVR) and increased RBF within 5 min. These responses lasted less than 90 min but were not dose-dependent. MAP decreased by 30 min after administration of ZD 7155 in both age groups at doses >/=400 microg kg(-1); the remaining decreased for up to 120 min, depending upon the dose. Pressor responses to angiotensin II (ANG II) were abolished within 5 min of administration of all doses of ZD 7155, at both 1- and 6 weeks. PD 123319 had no detectable effects on systemic or renal hemodynamics or on the pressor responses to ANG II. Therefore, under physiological conditions in conscious newborn animals, ANG II modulates both resting blood pressure and RVR through activation of AT(1) but not AT(2) receptors.

Modulation of systemic and renal haemodynamics by kappa-opioids in conscious lambs.

The purpose of the present study was to determine the cardiovascular effects of the kappa-opioid receptor agonist U-50488H at two stages of postnatal maturation under physiological conditions. Experiments were carried out firstly to define systemic and renal haemodynamic responses to kappa-opioid receptor activation and, secondly, to determine whether these effects are altered during postnatal maturation. To investigate whether the responses to U-50488H resulted from receptor-dependent effects, responses to U-50488H were also tested in the presence of the specific kappa-opioid receptor antagonist 5'-guanidinonaltrindole (GNTI). Experiments were carried out in two groups of conscious, chronically instrumented lambs aged approximately 1 and approximately 6 weeks. Mean arterial pressure, mean venous pressure and renal blood flow (RBF) were measured for 30 min before and 90 min after i.v. injection of U-50488H or vehicle. Heart rate increased in both age groups of lambs within 10 min of U-50488H administration. Mean arterial pressure decreased for 50 min following U-50488H administration at 1 week but, in contrast, increased transiently at 10 min in 6-week-old lambs, returning to control levels by 20 min. In both age groups, there was a sustained decrease in RBF following U-50488H. The aforementioned responses to U-50488H were abolished by pretreatment with GNTI. These data provide the first measurements of systemic and renal haemodynamic responses to kappa-opioid receptor activation during postnatal maturation.

Nitric oxide modulates renal vasoconstrictor effect of endothelin-1 in conscious lambs.

To test the hypothesis that nitric oxide (NO) buffers the renal vasoconstrictor effects of endothelin-1 (ET-1) early in life, renal haemodynamic responses to ET-1 were measured in the presence and absence of endogenously produced NO in conscious lambs. Renal haemodynamic effects of ET-1 were measured for 5 min before (control) and 20 min after intraarterial injection of ET-1 before and after pretreatment with 20 mg/kg of the L-arginine analogue N(G)-nitro-L-arginine methyl ester (L-NAME), (experiment 1) and its inactive isomer D-NAME (experiment 2) in conscious lambs aged approximately 1 week (N=7) and approximately 6 weeks (N=6). The two experiments were carried out in random order at intervals of 24-48 h. In lambs aged approximately 6 weeks, a marked increase in renal vascular resistance (RVR) was elicited by ET-1 administration; this response was enhanced twofold following pretreatment with L-NAME. In 1-week-old lambs, however, an increase in RVR in response to ET-1 occurred only after pretreatment with L-NAME. Therefore, we accept our hypothesis and conclude that NO buffers the renal vasoconstrictor effects of ET-1 early in life.

Dose-dependent systemic and renal haemodynamic effects of angiotensin II in conscious lambs: role of angiotensin AT1 and AT2 receptors.

The present experiments were designed to measure the effects of acute administration of angiotensin (ANG) II on mean arterial pressure (MAP) and renal blood flow (RBF) in conscious, chronically instrumented lambs at two different stages of postnatal maturation, and to determine the receptors through which these effects of ANG II are elicited. Experiments consisted of haemodynamic measurements for 10 s before (Control) and for 60 s after intravenous (i.v.) administration of one of 11 doses of ANG II (0-200 ng kg(-1)). Administration of ANG II was associated with a dose-dependent increase in MAP to a maximal effective concentration (EC100) of 100 ng kg(-1) in lambs aged 1 and 6 weeks. Administration of ANG II has caused a dose-dependent decrease in RBF, with EC100 values of 50 ng kg(-1) in 1-week-old lambs, and 25 ng kg(-1) in 6-week-old lambs. Responses to ANG II at the EC(50) were also measured in the presence of the specific ANG II AT(1) receptor antagonist, ZD 7155, the specific AT2 receptor antagonist, PD 123319, and vehicle. Administration of ZD 7155, but not PD 123319 or vehicle, abolished the MAP and RBF responses to ANG II in both age groups. In addition, MAP decreased and RBF increased in both age groups after administration of ZD 7155, but not PD 123319; the effects were similar in both age groups. These data provide new information that pressor and renal vasoconstrictor effects of ANG II during the first 6 weeks of postnatal life in lambs are elicited by activation of AT1 but not AT2 receptors.

Age-dependent cardiovascular, renal and endocrine responses to furosemide in conscious lambs.

1. The present study was performed to investigate some of the physiological responses to furosemide during postnatal maturation. 2. In 1- (n = 8) and 6-week old (n = 10) conscious, chronically instrumented lambs at least 3 days after surgery, three experiments were performed at intervals of 24-48 h and in random order. Various parameters of cardiovascular and endocrine function, as well as cumulative urinary flow rates, were measured before and after intravenous injection of 0 mg/kg (experiment one), 0.25 mg/kg (experiment two; low dose) and 5 mg/kg (experiment three; high dose) furosemide. 3. After high-dose furosemide, mean venous pressure decreased and there was a transient increase in mean arterial pressure in lambs aged 6 weeks. At 1 week of age, heart rate increased after high-dose furosemide and renal blood flow decreased. After high-dose furosemide, plasma renin activity increased in both groups of lambs, although the effects were greater in 1-week-old lambs. Plasma levels of arginine vasopressin increased after high-dose furosemide in lambs aged 1 but not 6 weeks. Cumulative urinary flow rate responses to furosemide were similar in 1- and 6-week-old lambs. 4. These data provide new information that cardiovascular and endocrine responses to furosemide are developmentally regulated.

Renal responses to hemorrhage are age dependent in conscious sheep.

Experiments were carried out in conscious, chronically instrumented lambs (n = 8) and young adult sheep (n = 11) to investigate age-dependent renal responses to hemorrhage. Various parameters of renal function were measured for 1 h before and 1 h after either 10% hemorrhage (experiment 1) or 20% hemorrhage (experiment 2). The two experiments were carried out in random order at intervals of 2-5 days. There were no effects of 10-20% hemorrhage on renal plasma flow in either age group. Blood pressure decreased after 20% but not 10% hemorrhage in both age groups. Glomerular filtration rate and filtration fraction decreased after 20% hemorrhage in both age groups, the decrease being greater in lambs than young adult sheep. In response to 20% hemorrhage, urinary flow rate and urinary Na+ excretion rate decreased by 40 min after hemorrhage in young adult sheep but not lambs and remained decreased for 60 min; urinary chloride excretion rate showed a similar response. In lambs but not young adult sheep, free water clearance increased by 20 min after 20% hemorrhage and remained above control at 60 min. Urinary osmolality decreased at 20 min after 20% hemorrhage in young adult sheep but not lambs, returning to control levels by 40 min. These data provide new information that renal responses to hypotensive hemorrhage appear to be developmentally regulated.

Age-dependent effects of captopril on the arterial baroreflex control of heart rate in conscious lambs.

To test the hypothesis that angiotensin (ANG) II modulates the arterial baroreflex control of heart rate (HR) in an age-dependent manner, various parameters governing the arterial baroreflex control of HR were assessed before and after removal of endogenously produced ANG II by administration of the angiotensin-converting enzyme (ACE) inhibitor, captopril, to conscious, chronically instrumented lambs aged approximately 1 week (8 +/- 1 days; n = 8) or approximately 6 weeks (46 +/- 5 days; n = 8). After administration of captopril, systolic, diastolic and mean arterial pressures decreased significantly from control levels and HR increased; however, the effects were greater in 1- than in 6-week-old lambs. In 1-week-old lambs, after administration of captopril, there was also a significant increase in the slope coefficient, a decrease in minimum HR and a decrease in the point of maximum gain. In 6-week-old lambs, there were no effects of captopril on any of the parameters governing the arterial baroreflex. Therefore, we accept our hypothesis and conclude that the role of ANG II in modulating cardiovascular homeostasis appears to be more predominant in the newborn than later in life.

Techniques for recording renal sympathetic nerve activity in awake, freely moving animals.

The methods described here allow recording of sympathetic nerve discharge in awake, freely moving animals, and follow a historical perspective of the different techniques developed over the years to record sympathetic discharge. The length of time each system is viable for recording varies from days to weeks. Also included are special hints for the surgical implantation of recording electrodes, types of recording electrodes and cables, as well as the minimum equipment necessary for recording sympathetic discharge. Lastly, a section on troubleshooting includes how to remove movement artifacts and extraneous noise, and minimize the destruction of leads common in recording in awake, freely moving animals. This article is written for the beginner or novice with an emphasis on what is needed when embarking on recording sympathetic nerve discharge in awake, freely moving animals.

Renal sympathetic nerves do not modulate renal responses to haemorrhage in conscious lambs.

The present study was designed to investigate the renal responses to hypotensive haemorrhage early in life and the role of renal sympathetic nerves in modulating these renal responses. To this end, experiments were carried out in conscious, chronically instrumented lambs with either intact renal nerves (n = 7, Intact) or bilateral renal denervation performed at the time of surgery (n = 5, Denervated). Parameters of renal function were measured before and after 20% haemorrhage (experiment 1) and 0% haemorrhage (experiment 2), the latter serving as a time control. The two experiments were performed in random order at intervals of 24-48 h. Within 20 min of hypotensive haemorrhage in intact lambs, glomerular filtration rate decreased by approximately 60%; this response was not altered by renal denervation. Since renal plasma flow remained constant after haemorrhage, the filtration fraction also decreased. After 20% haemorrhage, urinary flow rate decreased in intact lambs; this response was also not altered by renal denervation. Excretion rates of Na+ and K+ as well as urinary osmolality and free water clearance were not altered by haemorrhage in either intact or denervated lambs. These data provide the first description of renal responses to haemorrhage early in life. In addition, the present findings provide new information that renal responses to haemorrhage early in life do not appear to be modulated by renal sympathetic nerves.

Endothelin-1 produces no renal vasoconstriction in conscious newborn lambs.

Experiments were carried out to investigate the effects of endothelin-1 (ET-1) on renal vascular tone during development under physiological conditions in conscious lambs. Renal blood flow (RBF), renal vascular resistance (RVR), mean arterial pressure (MAP), and heart rate (HR) were measured in conscious, chronically instrumented lambs aged approximately 1 week and 6 weeks before and after intra-arterial (i.a.) injection of 0, 100, 200, and 400 ng/kg body weight of ET-1. In addition, plasma levels of ET-1 were measured in 39 sheep aged 5-85 days. In 6-week-old lambs, i.a. injection of ET-1 was associated with a rapid dose-dependent decrease in RBF that resulted from a dose-dependent increase in RVR. In 1-week-old lambs, there was no renal vasoconstriction observed after ET-1 administration, even at the highest dose tested. In response to i.a. injection of ET-1 to 1-week-old and 6-week-old lambs, MAP increased and there was a concomitant decrease in HR; these effects were dose dependent but not age dependent. Plasma levels of ET-1 were 10.7+/-4.2 pg/ml at 5-10 days, and remained constant throughout the first 3 months of life in conscious sheep. We conclude that ET-1 is not a renal vasoconstrictor agent in the immediate newborn period, and that the effects of ET-1 on renal vascular tone appear to be developmentally regulated.