Francine G. Smith

Prenatal exposure to nicotine impairs protective responses of rat pups to hypoxia in an age-dependent manner.

Experiments were carried out on rat pups to investigate the interaction between prenatal exposure to nicotine and postnatal age on protective responses that promote survival during exposure to hypoxia. From days 6 or 7 of gestation, pregnant rats received either nicotine (approximately 6 mg of nicotine tartrate/kg of body weight per day) or vehicle continuously via a 28-day osmotic minipump. On postnatal days 1--2, 5--6 and 10--11, the pups were exposed either to a single period of hypoxia produced by breathing an anoxic gas mixture (97% N(2) and 3% CO(2)) and their time to last gasp determined, or they were exposed repeatedly to hypoxia and their ability to autoresuscitate from primary apnea determined. Prenatal exposure to nicotine decreased the time to last gasp, but only in the 1--2-day-old animals. The total number of gasps was, however, increased in this age group due to the effect of nicotine on the gasping pattern. Furthermore, prenatal exposure to nicotine decreased the number of successful autoresuscitations and influenced the cardiorespiratory events preceding death in the 1--2- and 5--6-day-old pups but not in the 10--11-day-old pups. Thus, our experiments show that prenatal exposure to nicotine impairs protective responses of rat pups that may sustain life during exposure to hypoxia in an age-dependent manner.

Mechanisms regulating renal sodium excretion during development.

The present review focuses on the ontogeny of mechanisms involved in renal sodium excretion during renal maturation. The effect of birth on renal excretion of sodium and the role played by the different tubular segments in the regulation of sodium excretion during maturation are discussed. The influence of circulating catecholamines and renal sympathetic innervation in regulating sodium excretion during renal development is reviewed. The effects of aldosterone, atrial natriuretic factor, and prostaglandins on sodium regulation during renal maturation are discussed. Special emphasis is given to the potential role of glucocorticoids in modulating sodium excretion early in life.

Dose-dependent effects of nitric oxide synthase inhibition on systemic and renal hemodynamics in conscious lambs.

The present experiments were carried out to determine the role of nitric oxide in influencing systemic and renal hemodynamics in conscious young sheep. Parameters of cardiovascular function were measured before and for 4 h after intravenous injection of either L-NAME (NG-nitro-L-arginine methyl ester) or D-NAME (N(G)-nitro-D-arginine methyl ester) at doses of 10, 20, or 40 mg/kg in 13 conscious, chronically instrumented young sheep aged 43 +/-5 days. Blood pressure increased and heart rate decreased in a dose-dependent manner following administration of L-NAME. Renal vascular resistance was increased for 10 min following a dose of 10 mg/kg of L-NAME and for 120 min following a dose of 40 mg/kg of L-NAME. The renal vasodilatory response to close arterial injection of 1 microg/kg of acetylcholine was attenuated by L-NAME in a dose-dependent manner. These experiments provide the first information that under normal physiological conditions in conscious young animals, nitric oxide influences systemic and renal hemodynamics.

Renal hemodynamic effects of L-NAME during postnatal maturation in conscious lambs

Abstract. The purpose of the present study was to investigate the effects of the L-arginine analogue, NG-nitro-L-arginine methyl ester, L-NAME, in modulating renal hemodynamics during postnatal maturation in conscious chronically instrumented lambs. To this end, renal hemodynamic responses to intravenous injection of 10, 20, and 40 mg/kg L-NAME, as well as its inactive enantiomer D-NAME, were measured for 4 h in conscious lambs approximately 1 week (n=10), 3 weeks (n=12), and 6 weeks (n=14) of age. Administration of L-NAME was associated with an increase in renal vascular resistance (RVR) leading to a decrease in renal blood flow. One-week-old lambs were more sensitive to the effects of L-NAME, a marked increase in RVR occurring after the smallest dose administered at 1 week but not at 3 and 6 weeks of age. Renal hemodynamic effects of L-NAME as well as the duration of the responses were also age dependent, such that changes in RVR were greatest and most prolonged in 1-week-old lambs. In addition, a smaller dose of L-NAME was required to attenuate acetylcholine-induced renal vasodilation in lambs aged 1 week compared with older animals. Our data provide new evidence to support the premise that endogenously produced nitric oxide plays a predominant role in regulating renal vascular tone early in life.

Renal denervation alters cardiovascular and endocrine responses to hemorrhage in conscious newborn lambs

To investigate the role of renal sympathetic nerves in modulating cardiovascular and endocrine responses to hemorrhage early in life, we carried out three experiments in conscious, chronically instrumented lambs with intact renal nerves (intact; n = 8) and with bilateral renal denervation (denervated; n = 5). Measurements were made 1 h before and 1 h after 0, 10, and 20% hemorrhage. Blood pressure decreased transiently after 20% hemorrhage in intact lambs and returned to control levels. In denervated lambs, however, blood pressure remained decreased after 60 min. After 20% hemorrhage, heart rate increased from 170 +/- 16 to 207 +/- 18 beats/min in intact lambs but not in denervated lambs, in which basal heart rates were already elevated to 202 +/- 21 beats/min. Despite an elevated plasma renin activity (PRA) measured in denervated (12.0 +/- 6.4 ng ANG I . ml-1 . h-1) compared with intact lambs (4.0 +/- 1.1 ng ANG I . ml-1 . h-1), the increase in PRA in response to 20% hemorrhage was similar in both groups. Plasma levels of arginine vasopressin increased from 11 +/- 8 to 197 +/- 246 pg/ml after 20% hemorrhage in intact lambs but remained unaltered in denervated lambs from baseline levels of 15 +/- 10 pg/ml. These observations provide evidence that in the newborn, renal sympathetic nerves modulate cardiovascular and endocrine responses to hemorrhage.To investigate the role of renal sympathetic nerves in modulating cardiovascular and endocrine responses to hemorrhage early in life, we carried out three experiments in conscious, chronically instrumented lambs with intact renal nerves (intact; n = 8) and with bilateral renal denervation (denervated; n = 5). Measurements were made 1 h before and 1 h after 0, 10, and 20% hemorrhage. Blood pressure decreased transiently after 20% hemorrhage in intact lambs and returned to control levels. In denervated lambs, however, blood pressure remained decreased after 60 min. After 20% hemorrhage, heart rate increased from 170 ± 16 to 207 ± 18 beats/min in intact lambs but not in denervated lambs, in which basal heart rates were already elevated to 202 ± 21 beats/min. Despite an elevated plasma renin activity (PRA) measured in denervated (12.0 ± 6.4 ng ANG I ⋅ ml-1 ⋅ h-1) compared with intact lambs (4.0 ± 1.1 ng ANG I ⋅ ml-1 ⋅ h-1), the increase in PRA in response to 20% hemorrhage was similar in both groups. Plasma levels of arginine vasopressin increased from 11 ± 8 to 197 ± 246 pg/ml after 20% hemorrhage in intact lambs but remained unaltered in denervated lambs from baseline levels of 15 ± 10 pg/ml. These observations provide evidence that in the newborn, renal sympathetic nerves modulate cardiovascular and endocrine responses to hemorrhage.

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 ∼1 week (8 ± 1 days; n = 8) or ∼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.

Angiotensin type 1 and type 2 receptors during ontogeny: cardiovascular and renal effects

The renin-angiotensin system (RAS) is a major component of cardiovascular and renal homeostasis, maintaining blood pressure and water and electrolyte balance in health and disease. Whilst knowledge regarding the RAS in adult organisms has substantially increased over the last three decades, physiological effects and levels of functioning of the system during the perinatal period are poorly understood. It has been shown, however, that the RAS is subject to remarkable developmental changes that involve all system components, including the main active biologic peptide, angiotensin II (Ang II) and the receptors through which these effects are mediated, type 1 receptors (AT1Rs) and type 2 receptors (AT2Rs). The pattern of developmental changes suggests a relevant physiological role for the RAS in the critical cardio-renal adaptations to life after birth. In adulthood, the majority of the physiological functions of Ang II are mediated by activation of AT1Rs, whilst the roles for AT2Rs are less clear. Although the integrity of the AT1R signalling pathway is a pre-requisite for normal renal development, the physiological effects mediated by A1TRs during ontogeny are not well characterized. Much less is known regarding the roles that AT2Rs may play in regulating cardio-renal homeostasis in the newborn, despite the fact that the RAS appears to be a major player in fetal programming of disease. This article reviews current knowledge regarding the temporal and spatial expression pattern of ATRs during ontogeny, the cardiovascular and renal effects mediated by the ATRs early in life, as well as the clinical relevance for ATRs in the newborn period.

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 EC50 were also measured in the presence of the specific ANG II AT1 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.

Renal haemodynamic effects of B2 receptor agonist bradykinin and B2 receptor antagonist HOE 140 in conscious lambs.

The present study was designed to test the hypothesis that the high renal vascular resistance characteristic of the newborn results from age‐dependent changes in the responsiveness of the renal vasculature to kinins. Two studies were carried out in conscious, chronically instrumented lambs aged 1 and 6 weeks. Firstly, we measured the renal blood flow response to intra‐arterial injection of the B2 receptor agonist bradykinin over the range of doses 0‐800 ng kg‐1. The ED50 renal blood flow response to bradykinin was 50 ng kg‐1 in both age groups of lambs. Secondly, we measured the effects of intravenous administration of 12.5 μg kg‐1 of the specific B2 receptor antagonist HOE 140; this dose attenuated the renal blood flow response to 50 ng kg‐1 of bradykinin in both age groups. HOE 140 administration was associated with an age‐dependent increase in mean arterial pressure, with little effect on heart rate or renal vascular resistance. This study provides new information regarding the effects of kinins in modulating renal haemodynamics during postnatal maturation. We reject our hypothesis and conclude that the high renal vascular resistance of the newborn does not appear to result from age‐dependent changes in the responsiveness of the renal vasculature to endogenous kinins.

Renin and Heart Rate Responses to Haemorrhage are Age Dependent in Conscious Lambs

The present experiments were carried out in conscious lambs (1‐2 weeks old, n= 9) and older sheep (11‐12 weeks old, n= 11) to determine whether the cardiovascular and endocrine responses to 0, 10 and 20% haemorrhage were developmentally regulated. The major novel finding of our study is that throughout the first 3 months of postnatal life, there is a similar decrease in mean arterial pressure and a similar restoration of pressure to pre‐haemorrhage levels, for the same degree of blood loss, yet the mechanisms used to restore pressure appear to be age dependent as follows. In lambs, but not in older sheep, heart rate increased for 1 h after 20% haemorrhage. Activation of the renin‐angiotensin system was also greater and more prolonged in lambs than in older sheep following haemorrhage, and occurred at a lesser degree of blood loss. Plasma arginine vasopressin responses to haemorrhage were, however, similar in both age groups. These data provide new information that some of the mechanisms used to restore arterial pressure following blood volume depletion appear to be age dependent.