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.     

Arterial hemodynamics during head-up tilt in conscious dogs

The purpose of this study was to measure the major arterial hemodynamic responses to head-up tilt in the conscious dog. After recovery from surgery for instrumentation, and after habituation to tilt, the dogs were tilted from horizontal to 75 degrees for 5 min. The arterial hemodynamic response after the initial cardiovascular adjustments to the tilt consisted of no change in heart rate and significantly increased arterial blood pressure, with significantly reduced stroke volume and cardiac output. Both renal blood flow and terminal aorta blood flow declined significantly, even more than cardiac output. Muscular exertion was not part of the tilt response because upright standing on the hindlimbs elicited a sustained increase in heart rate and a significantly smaller increase in estimated total peripheral resistance. When compared with the orthostatic response in humans, the increase in arterial pressure was exaggerated in the dogs.     

Effects of renal denervation on cardiovascular and renal responses to ACE inhibition in conscious lambs

Smith, Francine G., Suzanne Chan, and Saskia N. De Wildt.Effects of renal denervation on cardiovascular and renal responsesto ACE inhibition in conscious lambs. J. Appl.Physiol. 83(2): 414-419, 1997.Cardiovascular andrenal effects of either the angiotensin-converting enzyme inhibitorcaptopril or vehicle were measured in chronically instrumented lambs inthe presence (intact; n = 6) andabsence of renal sympathetic nerves (denervated; n = 5) to determine whether there wasan interaction between the renin-angiotensin system and renalsympathetic nerves early in life. Captopril caused a similar decreasein mean arterial pressure (P < 0.001) in intact and denervated lambs, predominantly through a decreasein diastolic pressure. Heart rate was increased from 177 ± 34 to213 ± 22 (SD) beats/min during captopril compared with vehicleinfusion in intact lambs. In denervated lambs, basal heart rates wereelevated to 218 ± 33 beats/min; there was no further increase inheart rate during captopril compared with vehicle infusion. Captoprilinfusion caused a decrease in renal vascular resistance but only in theabsence of renal nerves. These findings provide evidence to suggestthat early in life there is an interaction between renal sympatheticnerves and the renin-angiotensin system in regulating renalhemodynamics and the baroreflex control of the heart.

     

Pulmonary hemodynamics in fetal lambs during development at normal and increased oxygen tension.

During the latter third of gestation, the number of resistance vessels in the lungs of the fetal sheep increases by 10-fold even after correction for lung growth. We measured pulmonary arterial pressure and blood flow directly and calculated total pulmonary resistance (pressure divided by flow) in intrauterine fetal lambs at 93-95 days and at 136 days of gestation (term is 145-148 days). In addition, we used a hyperbaric chamber to increase oxygen tension in the fetuses and measured the effect on the pulmonary circulation. When corrected for wet weight of the lungs, pulmonary blood flow did not change with advancing gestation (139 +/- 42 to 103 +/- 45 ml.100 g-1.min-1). Pulmonary arterial pressure increased (42 +/- 5 to 49 +/- 3 mmHg); thus total pulmonary resistance increased with advancing gestation from 0.32 +/- 0.12 to 0.55 +/- 0.21 mmHg.100 g.min.ml-1. If the blood flow is corrected for dry weight of the lungs, neither pulmonary blood flow nor total pulmonary resistance changed with advancing gestation. Increasing oxygen tension increased pulmonary blood flow 10-fold in the more mature fetuses but only 0.2-fold in the less mature fetuses. At the normal low oxygen tension of the fetus, pulmonary blood flow does not increase between these two points of gestation in the fetal lamb despite the increase in vessel density in the lungs. However, during elevated oxygen tension, pulmonary blood flow does increase in proportion to the increase in vessel density.     

Utilization of acetate by chick brain during postnatal maturation.

1. The study of the compartmentation of glutamate metabolism has been performed in the chick brain in vivo and in vitro in the presence of [U-14C]acetate between day 1 and day 30 of postnatal maturation. 2. The compartmentation of glutamate metabolism in vivo appears between day 1 and day 4 after hatching in the cerebral hemispheres and optic lobes. It is however more precocious in the optic lobes. In the cerebellum, it appears later, at about day 4 after hatching. The compartmentation of glutamate metabolism appears at the same time as the rapid incorporation of glucose into amino acids takes place in the cerebral hemispheres and the optic lobes. 3. In the chick telencephalon in vitro, the compartmentation of glutamate metabolism is visible from day 1 after hatching onwards. This difference is undoubtedly linked to the absence of an interference of glucose metabolism with acetate metabolism in vitro, and to the presence of a third compartment in the cerebral slices.     

Autonomic and behavioral thermoregulation in guinea pigs during postnatal maturation

Fewell, James E., Maria Kang, and Heather L. Eliason.Autonomic and behavioral thermoregulation in guinea pigs during postnatal maturation. J. Appl.Physiol. 83(3): 830-836, 1997.Serial experimentswere carried out on seven chronically instrumented Hartley-strainguinea pigs at 1, 3, and 5 wk of age to define their autonomic andbehavioral thermoregulatory profiles and to test the hypothesis thatthey have the mechanisms in place shortly after birth that allow themto optimize their energy expenditure for thermoregulation by selectinga thermal environment that requires the lowest metabolic oxygenrequirements. Each animal was studied in both a thermocline todetermine selected ambient temperature and in a metabolic chamberto determine the thermoregulatory response to forced changes in ambienttemperature. In the thermocline, the guinea pigs at all postnatal agesselected an ambient temperature that placed core temperature, oxygenconsumption, thermal conductance, heart rate, and respiratory rate atlevels comparable to those observed at ambient temperatures in whichminimal oxygen consumption occurred in the metabolic chamber. Thus ourexperiments provide evidence that guinea pigs have theneurophysiological mechanisms in place shortly after birth that allowthem to optimize their energy expenditure for thermoregulation byselecting a thermal environment that corresponds to the lowestmetabolic oxygen requirements.

     

Soluble guanylyl cyclase during postnatal porcine pulmonary maturation

The nitric oxide (NO)/cGMP pathway plays a key role in the regulation of pulmonary vascular tone during the transition from the fetal to the neonatal circulation, and it is impaired in pathophysiological conditions such as pulmonary hypertension. In the present study, we have analyzed the changes in the function and expression of soluble guanylyl cyclase (sGC) in pulmonary arteries during early postnatal maturation in isolated third-branch pulmonary arteries from newborn (3-18 h of age) and 2-wk-old piglets. The expression of sGC beta(1)-subunit in pulmonary arteries increased with postnatal age both at the level of mRNA and protein. The catalytic region of porcine sGC beta(1) was sequenced, showing a 92% homology with the human sequence. This age-dependent increase in sGC expression correlated with increased vasorelaxant responses to the physiological sGC activator NO and to the exogenous sGC activator YC-1, but not to the membrane-permeable cGMP analog 8-bromoguanosine 3',5'-cyclic monophosphate. In conclusion, an increased expression of sGC in pulmonary conduit arteries from 2-wk-old compared with newborn piglets explains, at least partly, the age-dependent increase in the vasorelaxant response of NO and other activators of sGC.     

Systemic and regional hemodynamics in conscious rats during 24-hour antiorthostatic posture

The systemic and regional hemodynamics during antiorthostatic hypokinesia were studied in male Wistar rats using the radioactive microsphere technique. The animals were hanged up by the tail with the head tilted down (30 degrees) and were able to exercise using only front limbs. Twenty four hours long exposure to antiorthostasis induced significant changes in systemic hemodynamics as well as in regional blood flow in skeletal muscles, spleen, liver and pancreas. Antiorthostasis induced blood flow changes in lungs, heart and brain were less pronounced.     

Aminophylline modulation of the mouse respiratory network changes during postnatal maturation.

Aminophylline is a respiratory stimulant commonly used for the treatment of central apnea. Experiences from clinical practice, however, revealed that aminophylline is not reliably effective in preterm infants, whereas it is normally effective in infants and mature patients. In an established animal model for postnatal development of respiratory control mechanisms, we therefore examined the hypothesis that the clinical observations reflect a developmental change in the sensitivity of the central respiratory network to methylxanthines. The medullary respiratory network was isolated at different postnatal ages (postnatal days 1-13; P1-P13) in a transverse mouse brain stem slice preparation. This preparation contains the pre-B?tzinger complex (PBC), a region that is critical for generation of respiratory rhythm. Spontaneous rhythmic respiratory activity was recorded from the hypoglossal (XII) rootlets and from neurons in the PBC by using the whole cell patch clamp technique. Bath-applied aminophylline [20 microM] increased the frequency (+41%) in neonatal animals (P1-P6) without affecting the amplitude of respiratory burst activity in XII rootlets. The same concentration of aminophylline did not have any significant effect on the frequency of respiratory XII bursts but increased the amplitude (+31%) in juvenile animals (P7-P13). In the same age group, aminophylline also augmented the amplitude and the duration of respiratory synaptic drive currents in respiratory PBC neurons. The data demonstrate that augmentation of the respiratory output is due to direct enhancement of central respiratory network activity and increase of synaptic drive of hypoglossal motoneurons in juvenile, but not neonatal, animals. This indicates a developmental change in the efficacy of aminophylline to reinforce central respiratory network activity. Therefore, we believe that the variable success in treating respiratory disturbances in premature infants reflects maturational changes in the expression of receptors and/or intracellular signal pathways in the central respiratory network.     

Utilization of 3-hydroxybutyrate by chick cerebral hemispheres during postnatal maturation.

1. The utilization of 3-hydroxybutyrate has been studied in the chick telencephalon during its post-hatching maturation. 2. In the 1-day-old chick the blood concentration of 3-hydroxybutyrate appears to be relatively high and its value is 5 times that estimated in the 4- and 30-day-old chicks. 3. The determination of the cerebral arteriovenous differences of 3-hydroxybutyrate shows that the brain of the newly-hatched chick takes up 3 times more actively this ketone body than the brain of the 4-day-old bird does. 4. During incubation in a non-oxygenated and an oxygenated physiological medium, in the presence of 3-hydroxy [3-14C]butyrate, the specific radioactivity of the dicarboxylic amino acids in the 1-day-old chick brain slices is higher than in those of the 30-day-old chick, particularly in the oxygenated medium. 5. Thirty minutes after a subcutaneous injection of 3-hydroxy [3-14C]butyrate, the specific radioactivity of the dicarboxylic amino acids in the 1-day-old chick telencephalon is 3-4 times higher than that in the 4- and 30-day-old chick. 6. In conclusion, in the brain of the newly hatched chick, 3-hydroxybutyrate is an efficient precursor in the biosynthesis of dicarboxylic amino acids, particularly glutamate, and, as glucose, it is metabolically related to the "large compartment" of glutamate. 7. These results have been discussed comparatively to those previously obtained in the developing rodent brain.     

Regional hemodynamics during postexercise hypotension. I. Splanchnic and renal circulations.

Moderate exercise elicits a relative postexercise hypotension that is caused by an increase in systemic vascular conductance. Previous studies have shown that skeletal muscle vascular conductance is increased postexercise. It is unclear whether these hemodynamic changes are limited to skeletal muscle vascular beds. The aim of this study was to determine whether the splanchnic and/or renal vascular beds also contribute to the rise in systemic vascular conductance during postexercise hypotension. A companion study aims to determine whether the cutaneous vascular bed is involved in postexercise hypotension (Wilkins BW, Minson CT, and Halliwill JR. J Appl Physiol 97: 2071-2076, 2004). Heart rate, arterial pressure, cardiac output, leg blood flow, splanchnic blood flow, and renal blood flow were measured in 13 men and 3 women before and through 120 min after a 60-min bout of exercise at 60% of peak oxygen uptake. Vascular conductances of leg, splanchnic, and renal vascular beds were calculated. One hour postexercise, mean arterial pressure was reduced (79.1 +/- 1.7 vs. 83.4 +/- 1.8 mmHg; P < 0.05), systemic vascular conductance was increased by approximately 10%, leg vascular conductance was increased by approximately 65%, whereas splanchnic (16.0 +/- 1.8 vs. 18.5 +/- 2.4 ml.min(-1).mmHg(-1); P = 0.13) and renal (20.4 +/- 3.3 vs. 17.6 +/- 2.6 ml.min(-1).mmHg(-1); P = 0.14) vascular conductances were unchanged compared with preexercise. This suggests there is neither vasoconstriction nor vasodilation in the splanchnic and renal vasculature during postexercise hypotension. Thus the splanchnic and renal vascular beds neither directly contribute to nor attenuate postexercise hypotension.     

Dose effect of captopril on renal hemodynamics and proteinuria in conscious, partially nephrectomized rats

The effect of varying doses of captopril, an angiotensin I-converting enzyme inhibitor, on renal hemodynamics, systemic arterial pressure, and the progression of chronic renal disease in conscious, three-quarter nephrectomized adult male Sprague-Dawley rats was studied. Six weeks following nephrectomy (Week 0), rats were randomly divided into five groups. Group 2 (n = 8), 3 (n = 8), 4 (n = 9), and 5 (n = 5) were given 5, 10, 20, and 40 mg/kg captopril, respectively, daily in drinking water. Group 1 (n = 7) and sham-operated controls (n = 7) were given water only. On Weeks -6, 0, 2, and 4, renal function was assessed by 24-hr urinary protein excretion and plasma creatinine. Systolic blood pressure was measured at these times by the tail cuff method. Following Week 4, glomerular filtration rate and effective renal plasma flow were measured in conscious rats by single injection clearance of [3H]inulin and [14C]tetraethylammonium bromide, respectively. Group 1 had significantly higher (P less than 0.05) 24-h urinary protein excretion, plasma creatinine, and systolic pressure compared with Group 5 and controls by Week 4, whereas values for these parameters for Groups 2-4 ranged between these extremes. Although systolic pressures were not significantly different (P greater than 0.05), Group 2 had significantly lower proteinuria than Group 1 (P less than 0.05) at Week 4. Total kidney glomerular filtration rate was similarly decreased in Groups 1-5 compared with control rats. Total kidney effective renal plasma flow was higher in captopril-treated groups than in Group 1, whereas systolic blood pressure was similar or lower, indicating that captopril reduced renal vascular resistance. Furthermore, unlike Groups 1-3, the groups receiving higher doses of captopril (4 and 5) did not develop anemia associated with chronic renal disease. In conclusion, captopril attenuated renal functional deterioration in a dose-related manner. The effect on proteinuria was evident at low doses of captopril which did not significantly reduce systemic blood pressure and was accompanied by an increase in effective renal plasma flow and a decrease in renal vascular resistance.     

Modulation of renal hemodynamics by renal eicosanoids during vasopressor infusions in man

Pressor doses of norepinephrine (NE) (n = 8) and angiotensin II (A II) (n = 5) were infused in normal volunteers to determine whether the systemic administration of vasopressor hormones influence renal eicosanoid production and whether, in turn, the eicosanoids produced could modulate renal hemodynamics and electrolyte excretion. At the doses administered, both pressor substances induced the expected rise in blood pressure, a significant decrease (P less than 0.05) in renal blood flow and a proportionally smaller fall in glomerular filtration rate, resulting in a consistent augmentation in filtration fraction. Fractional sodium excretion was concomitantly reduced. NE infusion produced only slight modifications in urinary prostaglandin (PG)E2, 2,3-dinor-6-keto-PGF1 alpha and thromboxane (TX)B2, while urinary 6-keto-PGF1 alpha and PGF2 alpha were increased by 38% and 176% respectively. The increase in urinary 6-keto-PGF1 alpha (the non-enzymatic degradation product of PGI2, predominantly of cortical origin) was proportional to the level of circulating NE (r = 0.78, P less than 0.05) and to the renal vascular resistance (r = 0.85, P less than 0.01), suggesting an immediate compensatory role for PGI2 in response to the NE-induced pressor stimulus. The renal production of PGE2 and PGF2 alpha (predominantly medullary) was inversely correlated with the filtration fraction: the greater the increase in PGE2 and PGF2 alpha the lower the elevation in filtration fraction or the decline in renal blood flow upon NE administration. All infusion variably stimulated the renal eicosanoid production: PGE2, 41%; PGF2 alpha, 102%; 6-keto-PGF1 alpha, 38%; 2,3-dinor-6-keto-PGF1 alpha, 38%; and TXB2, 25%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Postnatal maturation of vagal respiratory reflexes in preterm and full-term lambs.

The postnatal development of ventilatory reflexes originating from bronchopulmonary receptors was assessed in preterm vs. full-term lambs. Ventilation and arterial pressure were repeatedly measured in 10 preterm (gestational age, 132 days) and 7 full-term lambs without sedation from day 1 to day 42. The Hering-Breuer inhibitory reflex (slowly adapting stretch receptors) was assessed by the increase in expiratory time during end-inspiratory occlusion. The pulmonary chemoreflex (C-fiber endings) was assessed by the initial apnea + bradycardia + systemic hypotension and the secondary tachypnea after capsaicin intravenous injection. Results show the following. 1) Premature birth did not modify the maturation of the Hering-Breuer reflex. 2) Whereas a classic pulmonary chemoreflex was observed in the very first hours of life in preterm lambs, the tachypneic component of this reflex was weaker than in full-term lambs on day 1. 3) Premature birth led to a reversed postnatal maturation of this tachypneic response (tendency to increase with postnatal age). Our findings suggest that premature birth in lambs modifies postnatal maturation of the pulmonary chemoreflex.     

Thermoregulation in rats during early postnatal maturation: importance of nitric oxide

Experiments were carried out to determine the role of nitric oxide in mediating autonomic and behavioral thermoregulatory control in rat pups on postnatal days 1-2, 5-6, and 10-11. For an experiment, each pup received a subcutaneous injection of vehicle, NG-nitro-D-arginine methyl ester (D-NAME; 100 mg/kg), or NG-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg) before being placed in a metabolic chamber or in a thermocline with a linear temperature gradient of 23 to 43 degrees C. In the metabolic chamber, oxygen consumption and core temperature were measured as ambient temperature was decreased from 40 to 15 degrees C over a 60-min period. Decreasing ambient temperature elicited an increase in oxygen consumption in all age groups that received vehicle or d-NAME. The lower critical temperature and peak oxygen consumption upon exposure to cold after vehicle were 41 +/- 10 ml x kg(-1) x min(-1) at 30 degrees C, 43 +/- 12 ml x kg(-1) x min(-1) at 28 degrees C, and 55 +/- 11 ml x kg(-1) x min(-1) at 25 degrees C in the 1- to 2-, 5- to 6-, and 10- to 11-day-old pups, respectively. Administration of L-NAME abolished the oxygen consumption response to cold in the 1- to 2- and 5- to 6-day-old pups and significantly attenuated the oxygen consumption response to cold in the 10- to 11-day-old pups. Selected ambient temperature in the thermocline was not significantly affected by prior administration of D-NAME or L-NAME compared with vehicle. Thus our data provide evidence that the nitric oxide system plays a role in mediating autonomic but not behavioral thermoregulatory control in rat pups during early postnatal maturation.     

Epoxyeicosatrienoic Acid inhibition alters renal hemodynamics during pregnancy

In this study we examined the expression of cytochrome P450 (CYP) 2C and CYP2J isoforms in renal proximal tubules and microvessels isolated from rats at different stages of pregnancy. We also selectively inhibited epoxyeicosatrienoic acid (EET) production by the administration of N-methanesulfonyl-6-(2-proparyloxyphenyl)hexanamide (MSPPOH 20 mg/kg/day iv) to rats during Days 14-17 of gestation and to age-matched virgin rats and determined the consequent effects on renal function. Western blot analysis showed that CYP2C11, CYP2C23, and CYP2J2 expression was significantly increased in the renal microvessels of pregnant rats on Day 12 of gestation. In the proximal tubules, CYP2C23 expression was significantly increased throughout pregnancy, while the expression of CYP2C11 was increased in early and late pregnancy and the expression of CYP2J2 was increased in middle and late pregnancy. MSPPOH treatment significantly increased pregnant rats' mean arterial pressure, renal vascular resistance, and sodium balance but significantly decreased renal blood flow, glomerular filtration rate, and urinary sodium excretion, as well as fetal pups' body weight and length. In contrast, MSPPOH treatment had no effect on renal hemodynamics or urinary sodium excretion in age-matched virgin rats. In pregnant rats, MSPPOH treatment also caused selective inhibition of renal cortical EET production and significantly decreased the expression of CYP2C11, CYP2C23, and CYP2J2 in the renal cortex, renal microvessels, and proximal tubules. These results suggest that upregulation of renal vascular and tubular EETs contributes to the control of blood pressure and renal function during pregnancy.