Fetal cerebral and peripheral circulatory responses to hypoxia after nitric oxide synthase inhibition

2001 ◽  
Vol 281 (2) ◽  
pp. R381-R390 ◽  
Author(s):  
Andrew P. Harris ◽  
Sabah Helou ◽  
Christine A. Gleason ◽  
Richard J. Traystman ◽  
Raymond C. Koehler
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Treated Group ◽  
Arterial Oxygen ◽  
Control Group ◽  
Fetal Sheep ◽  
Arterial Oxygen Content ◽  
Arterial Blood ◽  
Nos Inhibitor ◽  
Oxide Synthase

The increase in cerebral blood flow (CBF) during hypoxia in fetal sheep at 0.6 gestation is less than the increase at 0.9 gestation when normalized for differences in baseline CBF and oxygen consumption. Nitric oxide (NO) synthase (NOS) catalytic activity increases threefold during this period of development. We tested the hypothesis that administration of the NOS inhibitor N ω-nitro-l-arginine methyl ester (l-NAME) decreases the CBF response to systemic hypoxia selectively at 0.9 gestation. We also tested whether any peripheral vasoconstriction during hypoxia is potentiated byl-NAME at 0.9 gestation. Administration ofl-NAME increased arterial blood pressure and decreased microsphere-determined CBF during normoxia in fetal sheep at both 0.6 and 0.9 gestation. With subsequent reduction of arterial oxygen content by ∼50%, the percent increase in forebrain CBF in a control group (57 ± 11%; ± SE) and l-NAME-treated group (51 ± 6%) was similar at 0.6 gestation. Likewise, at 0.9 gestation, the increase in CBF was similar in control (90 ± 25%) andl-NAME (80 ± 28%) groups. At 0.9 gestation,l-NAME treatment attenuated the increase in coronary blood flow and increased gastrointestinal vascular resistance during hypoxia. We conclude that NO exerts a basal vasodilatory influence in brain as early as 0.6 gestation in fetal sheep but is not an important mechanism for hypoxic vasodilation in brain at either 0.6 or 0.9 gestation. Thus the developmental increase in NOS catalytic capacity does not appear to be responsible for developmental increases in the CBF response to hypoxia during this period. In contrast, NO modulates the vascular response to hypoxia in heart and gastrointestinal tract.

Fetal sheep endocrine responses to sustained hypoxemic stress after chronic fetal placental embolization

1997 ◽  
Vol 272 (5) ◽  
pp. E817-E823 ◽  
Author(s):  
R. Gagnon ◽  
J. Murotsuki ◽  
J. R. Challis ◽  
L. Fraher ◽  
B. S. Richardson
Keyword(s):  
Blood Flow ◽  
Oxygen Content ◽  
Regional Distribution ◽  
Arterial Oxygen ◽  
Control Group ◽  
Fetal Sheep ◽  
Arterial Oxygen Content ◽  
Placental Blood ◽  
Chronic Hypoxemia ◽  
Placental Blood Flow

The purpose of this study was to determine the endocrine and circulatory responses of the ovine fetus, near term, to sustained hypoxemic stress superimposed on chronic hypoxemia. Fetal sheep were chronically embolized (n = 7) for 10 days between 0.84 and 0.91 of gestation via the descending aorta until arterial oxygen content was decreased by approximately 30%. Control animals (n = 8) received saline only. On experimental day 10, both groups were embolized over a 6-h period until fetal arterial pH decreased to approximately 7.00. Regional distribution of lower body blood flows was measured on day 10, before and at the end of acute embolization. On day 10, the chronically embolized group had lower arterial oxygen content (P < 0.05), Po2 (P < 0.01), and placental blood flow (P < 0.05) than controls and higher prostaglandin E2 (PGE2) and norepinephrine plasma concentrations (both P < 0.05). In response to a superimposed sustained hypoxemic stress, there was a twofold greater increase in PGE2 in the chronically embolized group than in the control group (P < 0.05). However, the increase in fetal plasma cortisol in response to superimposed hypoxemic stress was similar in both groups, despite significantly lower adrenocorticotropic hormone and adrenal cortex blood flow responses in the chronically hypoxemic group (both P < 0.05). We conclude that PGE2 response to a sustained superimposed reduction in placental blood flow, leading to metabolic acidosis, is enhanced under conditions of chronic hypoxemia and may play an important role for the maintenance of the fetal cortisol response to an episode of superimposed acute stress.

Selective iNOS Inhibition Attenuates Acetylcholine- and Bradykinin-induced Vasoconstriction in Lipopolysaccharide-exposed Rat Lungs 

1999 ◽  
Vol 91 (6) ◽  
pp. 1724-1724 ◽  
Author(s):  
Lars G. Fischer ◽  
Damian J. Horstman ◽  
Klaus Hahnenkamp ◽  
Nancy E. Kechner ◽  
George F. Rich
Keyword(s):  
Nitric Oxide ◽  
Exhaled Nitric Oxide ◽  
Control Group ◽  
Biochemical Engineering ◽  
Inos Inhibitor ◽  
Nos Inhibitor ◽  
Inos Inhibitors ◽  
Oxide Synthase ◽  
Inos Inhibition ◽  
Dose Dependent

Background Nonselective nitric oxide synthase (NOS) inhibition has detrimental effects in sepsis because of inhibition of the physiologically important endothelial NOS (eNOS). The authors hypothesized that selective inducible NOS (iNOS) inhibition would maintain eNOS vasodilation but prevent acetylcholine- and bradykinin-mediated vasoconstriction caused by lipopolysaccharide-induced endothelial dysfunction. Methods Rats were administered intraperitoneal lipopolysaccharide (15 mg/kg) with and without the selective iNOS inhibitors L-N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg), dexamethasone (1 mg/kg), or the nonselective NOS inhibitor Nomega-nitro-L-arginine methylester (L-NAME, 5 mg/kg). Six hours later, the lungs were isolated and pulmonary vasoreactivity was assessed with hypoxic vasoconstrictions (3% O2), acetylcholine (1 microg), Biochemical Engineering, and bradykinin (3 microg). In additional lipopolysaccharide experiments, L-NIL (10 microM) or 4-Diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP, 100 microM), a selective muscarinic M3 antagonist, was added into the perfusate. Results Exhaled nitric oxide was higher in the lipopolysaccharide group (37.7+/-17.8 ppb) compared with the control group (0.4+/-0.7 ppb). L-NIL and dexamethasone decreased exhaled nitric oxide in lipopolysaccharide rats by 83 and 79%, respectively, whereas L-NAME had no effect. In control lungs, L-NAME significantly decreased acetylcholine- and bradykinin-induced vasodilation by 75% and increased hypoxic vasoconstrictions, whereas L-NIL and dexamethasone had no effect. In lipopolysaccharide lungs, acetylcholine and bradykinin both transiently increased the pulmonary artery pressure by 8.4+/-2.0 mmHg and 35.3+/-11.7 mmHg, respectively, immediately after vasodilation. L-NIL and dexamethasone both attenuated this vasoconstriction by 70%, whereas L-NAME did not. The acetylcholine vasoconstriction was dose-dependent (0.01-1.0 microg), unaffected by L-NIL added to the perfusate, and abolished by 4-DAMP. Conclusions In isolated perfused lungs, acetylcholine and bradykinin caused vasoconstriction in lipopolysaccharide-treated rats. This vasoconstriction was attenuated by administration of the iNOS inhibitor L-NIL but not with L-NAME. Furthermore, L-NIL administered with lipopolysaccharide preserved endothelium nitric oxide-dependent vasodilation, whereas L-NAME did not.

Peripheral chemoreflex activation and cardiac function during hypoxemia in near term fetal sheep without placental compromise

2021 ◽  
Author(s):  
Juulia Lantto ◽  
Tiina Erkinaro ◽  
Mervi Haapsamo ◽  
Heikki Huhta ◽  
Leena Alanne ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Carotid Artery ◽  
Arterial Oxygen ◽  
Sheep Model ◽  
Fetal Sheep ◽  
Descending Aorta ◽  
Arterial Blood ◽  
Near Term ◽  
Peripheral Chemoreflex

A drop in arterial oxygen content activates fetal chemoreflex including an increase in sympathetic activity leading to peripheral vasoconstriction and redistribution of blood flow to protect the brain, myocardium, and adrenal glands. By using a chronically instrumented fetal sheep model with intact placental circulation at near-term gestation, we investigated the relationship between peripheral chemoreflex activation induced by hypoxemia and central hemodynamics. 17 Åland landrace sheep fetuses at 115-128/145 gestational days were instrumented. Carotid artery was catheterised in 10 fetuses and descending aorta in 7 fetuses. After a 4-day recovery, baseline measurements of fetal arterial blood pressures, blood gas values, and fetal cardiovascular hemodynamics by pulsed Doppler ultrasonography were obtained under isoflurane-anesthesia. Comparable data to baseline was collected 10 (acute hypoxemia) and 60 minutes (prolonged hypoxemia) after maternal hypo-oxygenation to saturation level of 70-80% was achieved. During prolonged hypoxemia, pH and base excess (BE) were lower, and lactate levels higher in the descending aorta than in the carotid artery. During hypoxemia mean arterial blood pressure (MAP) in the descending aorta increased, while in the carotid artery MAP decreased. In addition, right pulmonary artery pulsatility index values increased, and the diastolic component in the aortic isthmus blood flow velocity waveform became more retrograde. Both fetal ventricular cardiac outputs were maintained even during prolonged hypoxemia when significant fetal metabolic acidemia developed. Fetal chemoreflex activation induced by hypoxemia decreased the perfusion pressure in the cerebral circulation. Fetal weight-indexed LVCO or AoI Net Flow-ratio did not correlate with a drop in carotid artery blood pressure.

Differential sympathetic nerve responses to nitric oxide synthase inhibition in anesthetized rats

1995 ◽  
Vol 269 (4) ◽  
pp. R807-R813 ◽  
Author(s):  
T. Hirai ◽  
T. I. Musch ◽  
D. A. Morgan ◽  
K. C. Kregel ◽  
D. E. Claassen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sympathetic Nerve ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Before And After ◽  
Important Means ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Tonic Excitation

Recent studies have suggested that the interaction between the sympathetic nervous system and nitric oxide (NO) or nitrosyl factors may be an important means by which arterial blood pressure is regulated. We investigated whether NO synthase (NOS) inhibition modulates basal sympathetic nerve discharge (SND) in baroreceptor-innervated and -denervated, chloralose-anesthetized Sprague-Dawley rats. We recorded mean arterial pressure (MAP), renal SND, and lumbar SND before and after administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg iv). Two minutes after L-NAME administration in baroreceptor-innervated rats, MAP increased (+23 +/- 3 mmHg), whereas renal (-45 +/- 6%, n = 7) and lumbar (-35 +/- 2%, n = 6) SND significantly decreased from control levels. These changes persisted for up to 20 min after L-NAME administration. In baroreceptor-denervated rats, L-NAME increased MAP (+40 +/- 6 mmHg) and decreased lumbar SND (n = 7) (-37 +/- 10% from control at 20 min post-L-NAME). In contrast, renal SND progressively increased (+33 +/- 8% at 20 min post-L-NAME) from control after L-NAME administration in baroreceptor-denervated rats (n = 7). These results demonstrate that NOS inhibition can produce nonuniform changes in SND in baroreceptor-denervated rats and suggest that endogenous nitrosyl factors provide tonic excitation to lumbar SND, whereas they provide a tonic restraint to renal SND.

Effects of l-Epinephrine and l-Norepinephrine on the Splanchnic Bed of Intact Dogs

1957 ◽  
Vol 189 (3) ◽  
pp. 576-579 ◽  
Author(s):  
E. Allbaugh Farrand ◽  
R. Larsen ◽  
Steven M. Horvath
Keyword(s):  
Blood Pressure ◽  
Blood Flow ◽  
Splanchnic Blood Flow ◽  
Arterial Oxygen ◽  
Arterial Oxygen Content ◽  
Metabolic Functions ◽  
Arterial Blood ◽  
Anesthetized Dogs ◽  
Change In Mean ◽  
Infusion Period

The changes in splanchnic blood flow and related metabolic functions which occurred as the result of the infusion of 0.1 µg/kg/min. of l-epinephrine and l-norepinephrine for 10 minutes were measured in anesthetized dogs. l-Epinephrine elicited a marked increase in estimated splanchnic blood flow and no change in mean arterial pressure. While a significantly increased mean arterial blood pressure was observed following the administration of l-norepinephrine, no change in estimated splanchnic blood flow occurred. Arterial oxygen content was increased significantly with both drugs. Utilization of oxygen by the splanchnic bed was not changed during the infusion of either drug but was increased during the postepinephrine infusion period.

Regional adrenal blood flow responses to adrenocorticotropic hormone after chronic embolization of the fetal placental circulation in sheep

1996 ◽  
Vol 148 (3) ◽  
pp. 517-522 ◽  
Author(s):  
A M Carter ◽  
J R G Challis ◽  
P Svendsen
Keyword(s):  
Blood Flow ◽  
Adrenal Cortex ◽  
Adrenocorticotropic Hormone ◽  
Maternal Blood ◽  
Arterial Oxygen ◽  
Fetal Sheep ◽  
Cortical Blood Flow ◽  
Arterial Oxygen Content ◽  
Blood Flows ◽  
Placental Blood

Abstract To ascertain whether repeated hypoxic stress would alter the response of the adrenal cortex to adrenocorticotropic hormone (ACTH), by premature activation of the hypothalamic–pituitary–adrenal axis, we studied fetal sheep subjected to daily reduction of arterial oxygen content by embolization of the fetal placental circulation with 15 μm microspheres for 8 days from about day 124 of gestation (term ∼147 days) and sham-embolized controls. Starting before the final embolization (or shamembolization) on day 8, and continuing for 24 h, the fetus was given an intravenous infusion of ACTH1–24 (0·5 μg/h) or vehicle. Fetal and maternal blood samples were taken for determination of immunoreactive cortisol, and regional adrenal and fetal placental blood flows were measured by the microsphere technique at three time points: 1 h before infusion, 3 h after the start of the infusion (1 h after embolization), and after 24 h of infusion. Prior to infusion of ACTH or vehicle, fetal placental blood flow was lower in microsphere-embolized fetuses than in sham-embolized controls (199 ± 15 vs 292 ± 25 ml/min per 100 g tissue; mean ± s.e.; P<0·01). However, plasma cortisol and adrenal cortical blood flow did not differ between embolized fetuses and controls. Adrenal vascular responses to the 24-h infusion of ACTH were similar in embolized and shamembolized fetuses. Adrenal cortical blood flow increased 3-fold (P<0·05) due to decreased vascular resistance (P<0·01), with no change in adrenal medullary blood flow. Thus, while daily embolization of the fetal placental circulation caused a sustained decrease in cotyledonary blood flow, no evidence of altered responsiveness of the adrenal cortex to ACTH was found in these experiments. Journal of Endocrinology (1996) 148, 517–522

Nitric oxide modulates sympathoexcitatory cardiac-cardiovascular reflexes elicited by bradykinin

2001 ◽  
Vol 281 (5) ◽  
pp. H2010-H2017 ◽  
Author(s):  
S. C. Tjen-A-Looi ◽  
N. T. Phan ◽  
J. C. Longhurst
Keyword(s):  
Nitric Oxide ◽  
Pressor Response ◽  
Reflex Response ◽  
Cardiovascular Reflexes ◽  
Control Group ◽  
Neural Modulation ◽  
Arterial Blood ◽  
Nos Inhibitor ◽  
Pressor Reflex ◽  
Cardiac Afferents

A number of studies have demonstrated an important role for nitric oxide (NO) in central and peripheral neural modulation of sympathetic activity. To assess the interaction and integrative effects of NO release and sympathetic reflex actions, we investigated the influence of inhibition of NO on cardiac-cardiovascular reflexes. In anesthetized, sinoaortic-denervated and vagotomized cats, transient reflex increases in arterial blood pressure (BP) were induced by application of bradykinin (BK, 0.1–10 μg/ml) to the epicardial surface of the heart. The nonspecific NO synthase (NOS) inhibitor N G-monomethyl-l-arginine (l-NMMA, 10 mg/kg iv) was then administered and stimulation was repeated. l-NMMA increased baseline mean arterial pressure (MAP) from 129 ± 8 to 152 ± 9 mmHg and enhanced the change in MAP in response to BK from 32 ± 3 to 39 ± 5 mmHg ( n = 9, P < 0.05). Pulse pressure was significantly enhanced during the reflex response from 6 ± 4 to 27 ± 6 mmHg after l-NMMA injection due to relatively greater potentiation of the rise in systolic BP. Both the increase in baseline BP and the enhanced pressor reflex were reversed by l-arginine (30 mg/kg iv). Because l-NMMA can inhibit both brain and endothelial NOS, the effects of 7-nitroindazole (7-NI, 25 mg/kg ip), a selective brain NOS inhibitor, on the BK-induced cardiac-cardiovascular pressor reflex also were examined. In contrast to l-NMMA, we observed significant reduction of the pressor response to BK from 37 ± 5 to 18 ± 3 mmHg 30 min after the administration of 7-NI ( n = 9, P < 0.05), an effect that was reversed by l-arginine (300 mg/kg iv, n = 7). In a vehicle control group for 7-NI (10 ml of peanut oil ip), the pressor response to BK remained unchanged ( n = 6, P > 0.05). In conclusion, neuronal NOS facilitates, whereas endothelial NOS modulates, the excitatory cardiovascular reflex elicited by chemical stimulation of sympathetic cardiac afferents.

Inducible nitric oxide synthase is involved in acid-induced gastric hyperemia in rats and mice

2003 ◽  
Vol 285 (1) ◽  
pp. G154-G162 ◽  
Author(s):  
Mia Phillipson ◽  
Johanna Henriksnäs ◽  
Maria Holstad ◽  
Stellan Sandler ◽  
Lena Holm
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Nitric Oxide Synthase ◽  
Gastric Mucosa ◽  
Rt Pcr ◽  
Mucosal Permeability ◽  
Doppler Flowmetry ◽  
Blood Flow Increase ◽  
Nos Inhibitor ◽  
Oxide Synthase

The role of different isoforms of nitric oxide synthase (NOS) in the gastric mucosal hyperemia, induced by 155 mM luminal hydrochloric acid (pH ≈ 0.8) without a barrier breaker, was investigated. Rats were anesthetized with Inactin (120 mg/kg ip), and mice were anesthetized with Forene (2.2% in 40% oxygen gas at 150 ml/min); the gastric mucosa was exteriorized. Gastric mucosal blood flow was measured with laser-Doppler flowmetry (LDF) in rats treated with Nω-nitro-l-arginine (l-NNA; unspecific NOS inhibitor), l- N6-(1-iminoethyl)lysine [l-NIL; inducible (i) NOS inhibitor], or S-methyl-l-thiocitrulline [SMTC; neuronal (n) NOS inhibitor], 10 mg/kg, followed by 3 mg · kg–1 · h–1 iv, in iNOS-deficient (–/–) and nNOS(–/–) mice. mRNA was isolated from the gastric mucosa in iNOS(–/–) and wild-type (wt) mice, and real-time RT-PCR was performed. The effect of 155 mM acid on gastric mucosal permeability was determined by measuring the clearance of 51Cr-EDTA from blood to lumen. LDF increased by 48 ± 13% during 155 mM HCl luminally, an increase that was abolished by l-NNA, SMTC, or l-NIL. In iNOS wt mice, LDF increased by 33 ± 8% during luminal acid. The blood flow increase was attenuated substantially in iNOS(–/–) mice. RT-PCR revealed iNOS mRNA expression in the gastric mucosa in the iNOS wt groups. The blood flow increase in response to acid was not abolished in nNOS(–/–) mice (nNOS-sufficient mice, 39 ± 18%; heterozygous mice, 25 ± 19%; –/– mice, 19 ± 7%). Mucosal permeability was transiently increased during 155 mM HCl. The results suggest that iNOS is constitutively expressed in the gastric mucosa and is involved in acid-induced hyperemia, suggesting a novel role for iNOS in gastric mucosal protection.

scholarly journals Vasodilator tone in the llama fetus: the role of nitric oxide during normoxemia and hypoxemia

2005 ◽  
Vol 289 (3) ◽  
pp. R776-R783 ◽  
Author(s):  
Emilia M. Sanhueza ◽  
Raquel A. Riquelme ◽  
Emilio A. Herrera ◽  
Dino A. Giussani ◽  
Carlos E. Blanco ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Vascular Resistance ◽  
Control Group ◽  
Blood Flows ◽  
Vasoconstrictor Effect ◽  
Vascular Beds ◽  
Oxide Synthase

The fetal llama responds to hypoxemia, with a marked peripheral vasoconstriction but, unlike the sheep, with little or no increase in cerebral blood flow. We tested the hypothesis that the role of nitric oxide (NO) may be increased during hypoxemia in this species, to counterbalance a strong vasoconstrictor effect. Ten fetal llamas were operated under general anesthesia. Mean arterial pressure (MAP), heart rate, cardiac output, total vascular resistance, blood flows, and vascular resistances in cerebral, carotid and femoral vascular beds were determined. Two groups were studied, one with nitric oxide synthase (NOS) blocker NG-nitro-l-arginine methyl ester (l-NAME), and the other with 0.9% NaCl (control group), during normoxemia, hypoxemia, and recovery. During normoxemia, l-NAME produced an increase in fetal MAP and a rapid bradycardia. Cerebral, carotid, and femoral vascular resistance increased and blood flow decreased to carotid and femoral beds, while cerebral blood flow did not change significantly. However, during hypoxemia cerebral and carotid vascular resistance fell by 44% from its value in normoxemia after l-NAME, although femoral vascular resistance progressively increased and remained high during recovery. We conclude that in the llama fetus: 1) NO has an important role in maintaining a vasodilator tone during both normoxemia and hypoxemia in cerebral and femoral vascular beds and 2) during hypoxemia, NOS blockade unmasked the action of other vasodilator agents that contribute, with nitric oxide, to preserving blood flow and oxygen delivery to the tissues.

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