Intrarenal haemodynamic and glomerular responses to inhibition of nitric oxide formation in rabbits.

1. The renal effects of inhibiting nitric oxide (NO) formation using N-nitro-L-arginine (NOLA, 20 mg kg-1) were examined using micropuncture techniques in pentobarbitone-anaesthetized rabbits. 2. Renal vascular resistance doubled from 2.7 +/- 0.5 to 5.0 +/- 1.1 mmHg ml-1 min-1 after NOLA (P < 0.01), with similar percentage increases in both pre- (149 +/- 38%, P < 0.01) and postglomerular (158 +/- 42%, P < 0.01) resistance. 3. Glomerular capillary pressure rose from 33 +/- 1 to 40 +/- 1 mmHg after NOLA (P < 0.01) but despite this, glomerular filtration rate (GFR) and single nephron glomerular filtration rate did not significantly change. 4. Blood pressure increased 18 +/- 1 mmHg (P < 0.001) within 10 min of NOLA administration and remained near this level for the next 90 min. 5. The glomerular ultrafiltration coefficient (Kf) decreased significantly from 0.085 +/- 0.022 to 0.035 +/- 0.006 nl s-1 mmHg-1 (P < 0.05). 6. Urine flow and sodium excretion increased markedly (26 +/- 9 to 337 +/- 102 microliters min-1 and 5 +/- 2 to 342 +/- 12 mumol min-1 respectively, (P < 0.001)) and sodium fractional excretion rose from 1.0 +/- 0.3 to 8.0 +/- 2.2% (P < 0.01). 7. Thus, administration of NOLA to rabbits caused vasoconstriction of both pre- and postglomerular vessels, diuresis and natriuresis without significant change in GFR, and a reduction in Kf. The results suggest that NO may play an important role in the regulation of renal haemodynamics and glomerular function.     

Role of angiotensin II in the pressor response to cortisol in fetal sheep during late gestation

Glucocorticoids increase blood pressure in utero, but the mechanisms responsible are unclear. This study investigated the hypothesis that the hypertensive effects of cortisol depend upon a functional renin-angiotensin system (RAS). The study examined, in the sheep fetus, whether blockade of the Ang II type 1 (AT(1)) specific receptor prevented the cortisol-induced increase in blood pressure. From 124 +/- 1 days of gestation (term 145 +/- 2 days), 27 chronically catheterized sheep fetuses were infused i.v. for 5 days with one of the following: (1) saline (0.9% NaCl at 2.5 ml day(-1), n= 6); (2) cortisol (3-5 mg kg(-1) day(-1), n= 7); (3) AT(1) receptor antagonist (GR138950, 1-3 mg kg(-1) day(-1) in saline, GRS, n= 7); or (4) cortisol and GR138950 (GRC, n= 7). On all days of infusion, plasma cortisol was greater in both groups of cortisol-treated fetuses than in the respective control fetuses (P < 0.05), and GR138950 prevented the pressor response to exogenous Ang II. Over 5 days of infusion, blood pressure increased by a maximum of 7.6 +/- 1.4 mmHg (mean +/-s.e.m., P < 0.05) in the cortisol-, but not saline-infused, fetuses. Blockade of the AT(1) receptor caused significant reductions in blood pressure in both GRS- and GRC-treated groups (P < 0.05); in the GRS-treated fetuses, the fall in blood pressure was significant from the first day of infusion, while in GRC-treated fetuses the decrement was not significant until the second day (P < 0.05). Over the period of the infusion, decreases in arterial blood pH andP(a,O(2)), and an increase inP(a,CO(2)), were observed in the fetuses treated with the AT(1) receptor antagonist (P < 0.05). Therefore, in the sheep fetus, 5 days of AT(1) receptor antagonism suppresses the cortisol-induced rise in blood pressure. These results suggest that cortisol may increase blood pressure within 24 h of administration by a mechanism that is independent of the fetal RAS. Thereafter, Ang II, via the AT(1) receptor, may mediate, in part, the hypertensive effects of cortisol in utero.     

Effects of Gestation on Ovine Fetal and Maternal Angiotensin Receptor Subtypes in the Heart and Major Blood Vessels

Previous studies in fetal sheep have concluded that (a) the vascular AT(1) angiotensin II (Ang II) receptor subtype is present in the external umbilical artery, but not in other systemic blood vessels, and (b) carotid arterial rings contract in vitro in response to Ang II. These contractions are blocked by the AT(1) specific receptor antagonist losartan. The aim of the present study was to resolve the apparent contradiction of these earlier conclusions, by examining the distribution of Ang II receptor subtypes in different regions of the ovine fetal cardiovascular system, and to find out at what stage in development AT(1) receptors first appear. We measured AT(1) and AT(2) receptors in hearts, carotid arteries, aortae and umbilical vessels from fetal sheep aged 65-144 days (term approximately 150 days), and in hearts and aortae from lambs, and adult pregnant and non-pregnant ewes. Both AT(1) and AT(2) receptors were present in aortae of fetuses > 118 days gestation, and carotid arteries of fetuses > 121 days gestation, while in younger fetuses only AT(2) receptors were found. The proportion of carotid artery and aortic AT(1) receptors increased with age, while the proportion of AT(2) receptors decreased. The internal umbilical artery contained both subtypes, but there was no relationship between receptor density and gestational age. The external umbilical artery had only AT(1) receptors. The highest density of Ang II receptors was found in the fetal heart where the AT(2) subtype predominated. The density of fetal cardiac Ang II receptors declined with age (r = -0.44, P < 0.02) due to the decrease in the AT(2) subtype. The density in late gestation fetal hearts was greater than in lamb or adult hearts (P < 0.001). Our study shows that fetal systemic blood vessels contain AT(1) receptors, and we have documented for the first time that the appearance of AT(1) receptors is both different in different regions of the fetal cardiovascular system and is developmentally regulated. Together with the in vitro contractile studies, this suggests that Ang II can play an important role in fetal blood pressure regulation via AT(1) receptors in the fetal systemic vasculature, as well in the umbilicoplacental vessels. Experimental Physiology (2001) 86.1, 71-82.     

Effects of placental insufficiency on the ovine fetal renin-angiotensin system

We postulated that chronic placental insufficiency would be associated with reduced expression of renal renin and angiotensinogen genes in the fetal sheep. Placental development was restricted in ewes by removing the majority of caruncles prior to mating (placentally restricted (PR) group). The weights of PR fetuses were significantly reduced (P < 0.05, 2.98 +/- 0.33 kg) compared to control fetuses (4.20 +/- 0.30 kg). Kidney weights were also significantly reduced in the PR fetuses (P < 0.05, 8.4 +/- 0.9 g) compared with control fetuses (12.2 +/- 1.3 g). The ratios of renal renin/-actin mRNA levels were significantly reduced in PR fetuses (P < 0.001, 0.35 +/- 0.02) when compared to control animals (0.98 +/- 0.13). The renal angiotensinogen mRNA/18S rRNA ratio was significantly lower (P < 0.05, 0.28 +/- 0.13) in PR fetuses compared with control fetuses (0.72 +/- 0.10), while hepatic angiotensinogen was unaffected. There was a positive correlation between renal renin mRNA and renal angiotensinogen mRNA levels (r = 0.65, P < 0.05, n = 12). It is unlikely that these changes in renal angiotensinogen and renin mRNA were due to the small increment in plasma cortisol levels (< 5 nmol l-1). There was, however, a positive correlation between arterial PO2 and renal renin mRNA (r2 = 0.77, P < 0.01). Plasma renin levels were not different between the two groups. Thus, restriction of nutrient and oxygen supply throughout fetal life was associated with suppression of renal renin and renal angiotensinogen gene expression, with no effect on hepatic angiotensinogen mRNA levels. This specific suppression of fetal renal renin and angiotensinogen expression could alter the activity of the intrarenal RAS and so affect growth and development of the kidney.     

The Effects of Maternal Depression on Fetal Heart Rate Response to Vibroacoustic Stimulation

To better understand the effects of untreated maternal depression on the fetus, this study examined fetal heart rate (FHR) and FHR reactivity to vibroacoustic stimulation in pregnant women with untreated depression. The 20 participants were 32- to 36-week pregnant women divided into groups with depression (N = 10) and without depression (N = 10) based on the Beck Depression Inventory (BDI; Beck, 1977; Beck & Steer, 1987). Participants were attached to a fetal heart monitor, and 10 min of baseline FHR were recorded. A vibroacoustic stimulus (VAS) was presented, and an additional 10 min of FHR were recorded. Fetuses of mothers with depression had an elevated baseline FHR and a 3.5-fold delay in return to baseline FHR after VAS presentation. Additionally, mothers with depression had significantly higher anxiety levels and took fewer prenatal vitamins during pregnancy. Delayed habituation of FHR in the fetuses of mothers with depression may be due to alterations in the internal hormonal environment and could have implications for postnatal information processing.     

The effects of asphyxia on renal function in fetal sheep at midgestation

To determine whether damage to the fetal kidneys plays a role in the formation of hydrops fetalis following a severe asphyxial episode, six chronically catheterised fetal sheep, at 0.6 gestation (90 days; term 150 days), were subjected to 30 min of complete umbilical cord occlusion. During the occlusion period, mean arterial pressure, heart rate and renal blood flow decreased (   P < 0.001  ). There were falls in arterial pH and P _O2 and a rise in P _CO2 (   P < 0.001  ). Urine flow rate decreased (   P < 0.005  ), as did the excretion rates of sodium and osmoles (   P < 0.05  ). However, by 60 min after release of occlusion, urine flow rate was similar to control values. By the end of day 1, most renal variables returned to normal. At post-mortem, 72 h after occlusion, all asphyxiated fetuses showed gross signs of hydrops. Body weight was higher (   P < 0.05  ) due to fluid accumulation in the peritoneal (   P < 0.001  ) and pleural cavities (   P < 0.05  ) as well as subcutaneously (   P < 0.05  ). Amniotic/allantoic fluid volume was increased (   P < 0.05  ). Kidney histology was normal except for clusters of apoptotic cells in some proximal tubules. In conclusion, this severe asphyxial episode caused surprisingly little damage to the kidney and the changes in renal function were very transient. Thus renal damage was not important in the development of hydrops. Possibly, the midgestation fetal kidney has a limited capacity to increase urinary salt and water excretion in response to increased fluid delivery across the placenta.     

The effects of maternal depression on fetal heart rate response to vibroacoustic stimulation

To better understand the effects of untreated maternal depression on the fetus, this study examined fetal heart rate (FHR) and FHR reactivity to vibroacoustic stimulation in pregnant women with untreated depression. The 20 participants were 32- to 36-week pregnant women divided into groups with depression (N = 10) and without depression (N = 10) based on the Beck Depression Inventory (BDI; Beck, 1977; Beck & Steer, 1987). Participants were attached to a fetal heart monitor, and 10 min of baseline FHR were recorded. A vibroacoustic stimulus (VAS) was presented, and an additional 10 min of FHR were recorded. Fetuses of mothers with depression had an elevated baseline FHR and a 3.5-fold delay in return to baseline FHR after VAS presentation. Additionally, mothers with depression had significantly higher anxiety levels and took fewer prenatal vitamins during pregnancy. Delayed habituation of FHR in the fetuses of mothers with depression may be due to alterations in the internal hormonal environment and could have implications for postnatal information processing.     

Interactions between maternal subtotal nephrectomy and salt: effects on renal function and the composition of plasma in the late gestation sheep fetus

Effects of altered maternal salt intake between 122 and 127 days gestation (term is 150 days) were studied in eight fetuses carried by ewes which had renal insufficiency caused by subtotal nephrectomy (STNxF) and seven fetuses carried by intact ewes (IntF). Plasma sodium and osmolality were increased in ewes with subtotal nephrectomy on a high-salt intake (0.17 m NaCl in place of drinking water for 5 days; P < 0.05). The STNxF had normal body weights. A high maternal salt intake did not affect fetal blood pressure or heart rate. Plasma osmolality was higher in STNxF (P < 0.001), and plasma sodium and osmolality were increased by high salt (P < 0.001 and P < 0.04, respectively). The STNxF had higher urinary osmolalities (P = 0.002), which were also increased by a high maternal salt intake (P = 0.03). Renal blood flow fell in STNxF in response to a high maternal salt intake, but increased in IntF (P = 0.003). In STNxF but not IntF, glomerular filtration rate and urinary protein excretion were positively related to fetal plasma renin levels (P < or = 0.01). It is concluded that the salt intake of pregnant ewes with renal insufficiency affects maternal and fetal osmolar balance, fetal plasma sodium and fetal renal function. Since STNxF also had altered renal haemodynamic responses to high maternal salt and evidence of renin-dependent glomerular filtration and protein excretion, we suggest that interactions between dietary salt and pre-existing maternal renal disease impair glomerular integrity and function in the fetus.     

Changes in central artery blood pressure and wave reflection during a cold pressor test in young adults

The relative contribution of sympathetic nervous system (SNS)-induced increase in peripheral vascular resistance on central artery blood pressure (BP) and aortic wave reflection (augmentation index; AIx) is not completely understood. Central BP and wave reflection characteristics were measured using radial artery applanation tonometry before, during a 3-min cold pressor test (CPT), and 90 and 180-s post-CPT in 15 young, healthy adults (25 +/- 1 years). The CPT resulted in a greater magnitude of change in the estimated aortic systolic (31 vs. 23%, P < 0.05) and pulse (31 vs. 13%, P < 0.05) BP compared with the change in brachial artery BP. Additionally, the CPT resulted in an increased mean arterial pressure (MAP) (P < 0.05) and AIx (10 +/- 2 vs. 26 +/- 2%, P < 0.05). The change in MAP during the CPT was correlated to the change in AIx (r = 0.73, P < 0.01) and inversely related to roundtrip duration of the reflected wave to the periphery and back (r = -0.57, P < 0.05). The present study suggests that cold pressor testing results in a significant increase in arterial wave reflection intensity, possibly due to an increased MAP. However, the greater increase in systolic and pulse BP in the central compared with the peripheral circulation suggests that increased central artery wave reflection intensity contributes to increased left ventricular myocardial oxygen demand during CPT-induced hypertension.     

Role of angiotensin-converting enzyme 2 and angiotensin(1-7) in 17beta-oestradiol regulation of renal pathology in renal wrap hypertension in rats

17beta-Oestradiol (E2)-mediated inhibition of angiotensin-converting enzyme (ACE) protects the E2-replete kidney from the progression of hypertensive renal disease. Angiotensin-converting enzyme 2 (ACE2), a homologue of ACE, counters the actions of ACE by catalysing the conversion of angiotensin II (Ang II) to angiotensin(1-7) [Ang(1-7)]. We investigated E2 regulation of ACE2 in the renal wrap (RW) model of hypertension in rats. After 6 weeks on a high-sodium diet (4% NaCl), the activity of ACE2 was reduced in the renal cortex by 31%, which was mirrored by similar decreases in ACE2 protein (30%) and mRNA expression (36%) in the ovariectomized RW rat (RW-OVX); E2 replacement prevented these effects. The RW-OVX rats exhibited greater renal injury, including 1.7-fold more tubulointerstitial fibrosis and 1.6-fold more glomerulosclerosis than E2-replete females (RW-Intact and RW-OVX+E2). Angiotensin(1-7) infusion prevented these exacerbating effects of ovariectomy on renal pathology; no differences in indicators of renal injury were observed between RW-OVX-Ang(1-7) and RW-Intact rats. These renal protective effects of Ang(1-7) infusion were not attributable to increased ACE2 activity or to changes in heart rate or body weight, since these parameters were unchanged by Ang(1-7) infusion. Furthermore, Ang(1-7) infusion did not attenuate renal injury by reducing mean arterial pressure (MAP), since infusion of the peptide did not lower MAP but rather caused a slight increase during a 6 week chronic treatment for Ang(1-7). These results suggest that E2-mediated upregulation of renal ACE2 and the consequent increased Ang(1-7) production contribute to E2-mediated protection from hypertensive renal disease. These findings have implications for E2-deficient women with hypertensive renal disease and suggest that therapeutics targeted towards increasing ACE2 activity and Ang(1-7) levels will be renal protective.     

Endogenous hydrogen peroxide in paraventricular nucleus mediating cardiac sympathetic afferent reflex and regulating sympathetic activity

We previously reported that reactive oxygen species (ROS) in paraventricular nucleus (PVN) mediated cardiac sympathetic afferent reflex (CSAR). The present study investigated the role of endogenous hydrogen peroxide (H₂O₂), a ROS, in the PVN in mediating the CSAR and regulating sympathetic activity. The CSAR was evaluated by the response of renal sympathetic nerve activity (RSNA) to epicardial application of bradykinin (BK) in rats. Bilateral microinjection of polyethylene glycol-catalase (PEG-CAT, an analogue of endogenous catalase) or polyethylene glycol-superoxide dismutase (PEG-SOD, an analogue of endogenous superoxide dismutase) into the PVN abolished the CSAR, decreased baseline RSNA and mean arterial pressure (MAP). Moreover, pretreatment with PEG-CAT or PEG-SOD blocked the enhanced CSAR and RSNA responses induced by exogenous angiotensin II (Ang II) in the PVN. Aminotriazole (ATZ, a catalase inhibitor) alone potentiated the CSAR, increased RSNA and MAP, but failed to augment the Ang II-induced CSAR enhancement responses. Pretreated with PEG-SOD, ATZ still increased baseline RSNA and MAP but inhibited the CSAR and Ang II-induced CSAR and RSNA enhancement responses. These results suggested that endogenous H₂O₂ in the PVN mediated both the CSAR and Ang II-induced CSAR enhancement responses. H₂O₂ in the PVN were involved in regulating sympathetic activity and arterial pressure.     

Renal sympathetic and circulatory responses to activation of the exercise pressor reflex in rats

We investigated the role played by the exercise pressor reflex in sympathetic regulation of the renal circulation in rats. In mid-collicular decerebrate rats, mean arterial pressure (MAP), heart rate (HR), left renal cortical blood flow (RCBF) and left renal sympathetic nerve activity (RSNA) were recorded before and during 30 s of static contraction of the left triceps surae muscles evoked by electrical stimulation of the tibial nerve, which activates both metabo- and mechanosensitive muscle afferents, and during 30 s of passive stretch of the left Achilles tendon, which selectively activates mechanosensitive muscle afferents. Static contraction (n = 17, +344 +/- 34 g developed tension) significantly (P < 0.05) increased MAP (+14 +/- 3 mmHg), HR (+6 +/- 1 beats min(-1)) and RSNA (n = 11, +19 +/- 5%) and significantly decreased renal cortical vascular conductance (RCVC, n = 11, -11 +/- 2%). Passive stretch (n = 20, +378 +/- 11 g) also significantly increased MAP (+11 +/- 2 mmHg), HR (+7 +/- 2 beats min(-1)) and RSNA (n = 15, +14 +/- 4%) and significantly decreased RCVC (n = 11, -12 +/- 3%). RCBF showed no significant changes during static contraction or passive stretch. Renal denervation abolished the decrease in RCVC during contraction (n = 12) or stretch (n = 13). These data indicate that both the exercise pressor reflex and its mechanically sensitive component, the muscle mechanoreflex, induced renal cortical vasoconstriction through sympathetic activation in rats.     

Hemodynamic effect produced by microinjection of angiotensins at the caudal ventrolateral medulla of spontaneously hypertensive rats

In the present study, the effect of caudal ventrolateral medulla (CVLM) microinjection of angiotensin-(1-7) (Ang-(1-7)) and angiotensin II (Ang II) on mean arterial pressure (MAP), heart rate (HR) and pulsatile vascular blood flow (VBF; Transonic System) of the femoral, renal or mesenteric arteries was evaluated in male Wistar and spontaneously hypertensive rats (SHR) anesthetized with urethane. The vascular resistance (VR) was calculated by the ratio between the changes in MAP and VBF. Ang-(1-7) (40 ng) and Ang II (40 ng) microinjection into the CVLM caused similar depressor effects in Wistar rats and SHR. The hypotensive effect produced by Ang-(1-7) into the CVLM of Wistar rats was accompanied by a decrease in femoral (DeltaVR/VRbaseline=-0.12+/-0.04 vs. 0.001+/-0.03; after saline) and renal (DeltaVR/VRbaseline=-0.10+/-0.02 vs. -0.003+/-0.02; after saline) vascular resistance. On the other hand, the Ang II hypotensive effect in Wistar rats produced only changes in renal vascular resistance (DeltaVR/VRbaseline=-0.16+/-0.02 vs. -0.003+/-0.02; after saline). In SHR, the hypotensive effect produced by Ang-(1-7) and Ang II caused decrease in renal vascular resistance (DeltaVR/VRbaseline=-0.18+/-0.03 and -0.13+/-0.01, respectively, as compared with saline, DeltaVR/VRbaseline=-0.06+/-0.02), but did not alter the femoral or mesenteric vascular resistance. These data show that Ang II and Ang-(1-7) hypotensive effect at the CVLM involves the participation of different vascular beds. Further, the lack of involvement of the femoral vascular bed in SHR suggests that hypertension may induce alteration in the neural control of the different vascular beds, at least at the CVLM.     

Role of Nitric Oxide in Hypoxic Cerebral Vasodilatation in the Ovine Fetus

To investigate the role of nitric oxide (NO) in fetal cerebral circulatory responses to acute hypoxia, near-term fetal sheep were instrumented with laser Doppler probes placed in the parasagittal parietal cortices and vascular catheters in the sagittal sinus and brachiocephalic artery. After a 3 day recovery period, responses of cortical blood flow (CBF) to hypoxia were compared with and without inhibition of nitric oxide synthase (NOS). After an initial 30 min baseline period, fetuses were given a bolus followed by a continuous infusion of N ^ω-nitro- l -arginine methyl ester ( l -NAME), or saline vehicle as control. After administration of l -NAME, CBF decreased by 14 ± 6 % (   P < 0.01  ) despite increases in arterial blood pressure of 15 mmHg, resulting in an ∼60 % increase in cerebrovascular resistance. Thirty minutes following initiation of l -NAME or vehicle infusion, fetal systemic hypoxia was induced by allowing the ewes to breathe 10–11 % oxygen. In control fetuses CBF increased progressively to 145 ± 9 % of baseline (   P < 0.01  ) after 30 min, while cortical release of cyclic guanylate cyclase (cGMP), an index of NOS activity, increased 26 ± 8 % (   P < 0.05  ). In contrast, CBF in l -NAME-treated fetuses increased to only 115 % of the reduced CBF baseline, whereas cortical release of cGMP did not change significantly. In summary, basal levels of NO lower resting cortical vascular resistance by ∼15 % in the fetal sheep. Inhibition of NO synthesis attenuates hypoxic cerebral relaxation but does not completely prevent the characteristic increases in CBF. Hypoxic increases in NO directly increase cortical production of cGMP and inhibition of NO synthesis ablates these changes in cGMP.     

Long-term effects of a midgestational asphyxial episode in the ovine fetus

We and others have shown previously that fetuses at midgestation can survive 30 min of complete umbilical cord occlusion, although hydrops fetalis (or gross fetal edema) results. To investigate whether this hydrops resolves by late gestation and if there are any long-term consequences of the asphyxial insult on the heart and kidneys, eight fetuses were subjected to 30 min of complete umbilical cord occlusion at 0.6 gestation (90 days; term 150 days) and were compared to a sham group (n = 10). During the occlusion period, fetuses became severely hypoxemic, hypercapnemic, and acidotic, with both blood pressure and heart rate decreasing. Most variables had returned to normal by 2-hr recovery. At 129 +/- 1 days of gestation, approximately 40 days post occlusion, some fetuses were still slightly hydropic as skin fold measurements were increased (P < 0.01), although fetal body weight was not different from the sham group. The two groups had similar heart and kidney weights, ventricular cardiac myocyte nucleation, and glomerular number. By contrast, brain weight was reduced by 37% (P < 0.001) and the cerebral lateral ventricles were grossly dilated. Lungs were 50% smaller than in sham fetuses (P < 0.001). Thus, the hydrops that develops at midgestation as a result of a severe asphyxial episode can, but does not always, fully resolve by late gestation. Also, while fetuses at midgestation can survive this asphyxial episode with no long-term impact in renal or cardiac size, nephron number, or cardiomyocyte nucleation, the brain and lungs are severely affected.     

Haemodynamic changes in IUGR fetus with chronic hypoxia evaluated by fetal heart-rate monitoring and Doppler measurement of blood flow velocity

The measurement of fetal blood flow velocity and 24 h monitoring of fetal heart-rate (FHR) using a computer were performed to clarify the haemodynamics of growth-retarded fetuses with chronic hypoxia. One hundred normal-growth and 18 growth-retarded fetuses were analysed. All the growth-retarded fetuses with chronic hypoxia were characterised by abnormal blood flow velocity waveforms (with the pulsatility index in the descending aorta below the −1·0 SD and in the middle cerebral artery above the +1·0 SD for our reference range, from 100 normal-growth fetuses). In the latter, the incidence of accelerations of defined size and variability in FHR patterns showed a diurnal variation after 30 weeks' gestation. The initial change in FHR patterns during hypoxia in 11 growth-retarded fetuses, resulting in fetal distress, was a derangement of diurnal variations in FHR patterns, followed by a decrease in variability. A rapid increase in blood flow velocity in the middle cerebral artery with the advance of hypoxia was observed before the onset of distress. Maternal low-dose oxygen inhalation elicited a temporary increase in FHR variability in the growth-retarded but not in normal fetuses. Re-inhalation after 1 h elicited a similar change, suggesting that intermittent rather than continuous, oxygen inhalation may be more effective.     

Maternal nutrient restriction in sheep: hypertension and decreased nephron number in offspring at 9 months of age

Pregnant ewes were fed either a 50% nutrient-restricted (NR; n = 8) or a control 100% (C; n = 8) diet from day 28 to day 78 of gestation (dGA; term = 150 dGA). Lambs were born naturally, and fed to appetite throughout the study period. At 245 ± 1 days postnatal age (DPNA), offspring were instrumented for blood pressure measurements, with tissue collection at 270 DPNA. Protein expression was assessed using Western blot, glomerulus number determined via acid maceration and hormone changes by radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). NR lambs had higher mean arterial pressure (MAP; 89.0 ± 6.6 versus 73.4 ± 1.6 mmHg; P < 0.05), fewer renal glomeruli (57.8 ± 23.8 versus 64.6 ± 19.3 × 10⁴; P < 0.05), increased expression of angiotensin converting enzyme (ACE) in the renal cortex (942 ± 130 versus 464 ± 60 arbitrary pixel units (apu); P < 0.03), and increased angiotensin II receptor AT2 expression in the renal medulla (63.3 ± 12.1 versus 19.5 ± 44.2 × 10⁴ apu; P < 0.03). All data are presented as mean ± s.e.m. The present data indicate that global maternal nutrient restriction (50%) during early to mid-gestation impairs renal nephrogenesis, increases MAP, and alters expression of AT2 and ACE without an associated change in birth weight. These data demonstrate the existence of a critical window of fetal susceptibility during early to mid-gestation that alters kidney development and blood pressure regulation in later life.     

Role of Nitric Oxide and Renal Nerves in the Renal Responses to Acute Volume Expansion in Anaesthetized Rats

An investigation was undertaken into the potential role of nitric oxide (NO) and its interaction with renal sympathetic nerves in mediating renal responses to acute saline volume expansion (VE). Groups of anaesthetized Wistar rats with innervated and denervated kidneys were subjected to VE, 0.25 % body wt min-1 for 40 min, in the presence and absence of nitric oxide synthase (NOS) inhibitors, NG-nitro-L-arginine-methyl-ester (L-NAME, non-selective), aminoguanidine (AG, relatively selective for inducible NOS (iNOS)), and 7-nitroindazole (7-NI, relatively selective for neuronal NOS (nNOS)). Pretreatment with L-NAME or AG enhanced the cumulative sodium excretion (CuU(Na)V) after 40 min VE in the innervated kidneys by 27 and 23 % (both P < 0.001), respectively, compared to the untreated control group, whereas they were without effect in the denervated kidneys. Cumulative urine flow (CuUV) after VE in L-NAME- and AG-treated groups was enhanced in both kidneys, by some 17-21 % in the denervated (P < 0.01) and 37-39 % in the innervated kidneys (P < 0.001) by comparison with the corresponding untreated controls. 7-NI had no effect on CuUV, but reduced CuU(Na)V in the denervated kidneys by 25 % (P < 0.01) when compared to the control group. The results suggested that NO, possibly generated by endothelial NOS (eNOS) and iNOS, was a contributory factor in mediating the renal response to VE. There appeared to be a tonic inhibitory action of NO on water excretion which was renal nerve independent, whereas its impact on sodium handling appeared to be dependent upon a background level of renal nerve activity. Experimental Physiology (2001) 86.1, 47-54.     

急性压力超负荷诱导心肌内分泌活化

目的：探讨压力超负荷致心肌肥大的跨膜信号传递机制。方法：利用放射免疫法及分光光度法动态观察压力超负荷后大鼠心肌组织血管紧张素转换角活性，血管紧张素Ⅱ、内皮索和一氧化氢含量的变化，并观察它们与压力超负荷心肌肥大的关系。结果：随大鼠动脉血压逐步升高，心肌组织中血管紧张素转换酶活性，血管紧张素Ⅱ、内皮素含量均迅速升高（P＜0．05），并持续保持高水平，血管紧张素Ⅱ升高早于内皮系，而一氧化氛含量迅速降低并持续受抑（P＜0．05）。结论：心肌内分泌活化可能是介导压力超负荷致心肌肥大的重要机制。     

Skeletal muscle metaboreflex is enhanced in postmenopausal women

This study determined whether an elevated muscle metaboreflex contributes to the excessive blood pressure response to exercise in postmenopausal women. Thirty healthy female volunteers were studied (15 postmenopausal and 15 premenopausal). Stroke volume, heart rate, cardiac output (CO), systolic blood pressure, diastolic blood pressure, and total vascular conductance (TVC) were continuously assessed throughout the experiment. To activate the muscle metaboreflex, occlusion of the vasculature was induced via inflation of a blood pressure cuff (2 min) on the upper arm following static handgrip exercise. Muscle metaboreflex activation increased mean arterial pressure (MAP) in both groups. However, this pressor response was greater in the postmenopausal women (ΔMAP: 21.4 ± 3 vs. 14.5 ± 2 mmHg) (P < 0.05) even though the corresponding increase in CO was less (ΔCO: 0.0 ± 0.2 vs. 0.3 ± 0.2 l/min) (P < 0.05). TVC decreased in both the groups but was more pronounced in the postmenopausal group (ΔTVC: -10.7 ± 2.6 vs. -17.1 ± 3.6 ml/min/mmHg) (P < 0.05). In conclusion, the exaggerated blood pressure response to exercise in postmenopausal women is mediated, in part, by an overactive metaboreflex that is associated with enhanced peripheral vasoconstriction.