PubMed Health⌕ Search

Biomedical subjects

S M Black

Publications and source records attributed to S M Black.

At least 19 recordsLinked to original sources

Scottish anatomy departments: adapting to change.

OBJECTIVE: To document changes to the academic infrastructure of Scottish departments of anatomy over the past 20 years and compare the strategic approaches adopted by each institution to ensure continued provision of the subject to medical students. DESIGN Interviews with principal anatomy staff members to obtain targeted information (staff numbers, staff recruitment, student numbers, staff:student ratio and contact hours in the medical curriculum) by investigating three temporal snapshots chosen at 10 year intervals (academic years 1983/4, 1993/4 and 2003/4). PARTICIPANTS: Principal teaching staff members from the anatomy departments at the five Scottish medical schools: University of Aberdeen, University of Dundee, University of Edinburgh, University of Glasgow and the University of St Andrews. Additional information was forthcoming from the admissions office of each University. RESULTS: Over the past 20 years the Scottish anatomy schools have weathered a variety of external and internal influences and each school has adopted very individual strategies to the delivery and maintenance of their subject. Some schools have unquestionably been more affected than others but all have responded in a unique way to the demands of the disciplines they choose to subserve. In general, each school has seen a decline in the compliment of teachers (staff + demonstrators) whereas the student number has increased dramatically. Each department has micromanaged its proportions of lectures, dissecting room practical time and tutorials to best fit their student base, staff capabilities and the requirements of, and/or alterations to, the medical curriculum offered in their institution.

Anatomy↗

Anatomy in Scotland: 20 years of change.

BACKGROUND AND AIMS: To document changes in the educational infrastructure of anatomy in Scotland over the past 20 years. To investigate the possible impact of the GMC 1993 recommendations and assess the preparedness of Scottish anatomy to meet the implications of the proposed amendment to the I984 Anatomy Act. RESULTS: Over the past 2 years in Scotland, the total number of teaching staff in anatomy (full time, part time and honorary) has decreased by over 24%, full time teaching staff numbers have decreased by more than 33% and the number of clinical demonstrators by more than 70%. However, medical student intake has risen by 38% and the overall student number experiencing anatomical teaching (medicine, science and dentistry) has more than doubled, resulting in a current average staff:student ratio of 1:58. Anatomy contact hours between staff and medical students have decreased by just over 60% in the last 20 years. CONCLUSIONS: In the last 20 years, contact hours and staffing levels have decreased substantially in Scotland whilst student numbers (medical, science and dental) have increased significantly. On average the anatomical input to the medical curriculum decreased by 28% between 1983 and 1993 but post the GMC initiative, there was a further decrease of 45% resulting in current medical students in Scotland experiencing a 60% reduction in contact anatomy time compared to their peers in the early 1980's. The decline in anatomical infrastructure is not a reassuring indicator of its ability to meet substantial future demands.

Anatomy↗

Role for endothelin-1-induced superoxide and peroxynitrite production in rebound pulmonary hypertension associated with inhaled nitric oxide therapy.

Our previous studies have demonstrated that inhaled nitric oxide (NO) decreases nitric oxide synthase (NOS) activity in vivo and that this inhibition is associated with rebound pulmonary hypertension upon acute withdrawal of inhaled NO. We have also demonstrated that inhaled NO elevates plasma endothelin-1 (ET-1) levels and that pretreatment with PD156707, an ETA receptor antagonist, blocks the rebound hypertension. The objectives of this study were to further elucidate the role of ET-1 in the rebound pulmonary hypertension upon acute withdrawal of inhaled NO. Inhaled NO (40 ppm) delivered to thirteen 4-week-old lambs decreased NOS activity by 36.2% in control lambs (P<0.05), whereas NOS activity was preserved in PD156707-treated lambs. When primary cultures of pulmonary artery smooth muscle cells were exposed to ET-1, superoxide production increased by 33% (P<0.05). This increase was blocked by a preincubation with PD156707. Furthermore, cotreatment of cells with ET-1 and NO increased peroxynitrite levels by 26% (P<0.05), whereas preincubation of purified human endothelial nitric oxide synthase (eNOS) protein with peroxynitrite generated a nitrated enzyme with 50% activity relative to control (P<0.05). Western blot analysis of peripheral lung extracts obtained after 24 hours of inhaled NO revealed a 90% reduction in 3-nitrotyrosine residues (P<0.05) in PD156707-treated lambs. The nitration of eNOS was also reduced by 40% in PD156707-treated lambs (P<0.05). These data suggest that the reduction of NOS activity associated with inhaled NO therapy may involve ETA receptor-mediated superoxide production. ETA receptor antagonists may prevent rebound pulmonary hypertension by protecting endogenous eNOS activity during inhaled NO therapy.

Administration, Inhalation↗

Altered endothelium-dependent relaxations in lambs with high pulmonary blood flow and pulmonary hypertension.

Congenital heart disease associated with increased pulmonary blood flow produces pulmonary hypertension. To characterize vascular alterations in the nitric oxide (NO)-cGMP cascade induced by increased pulmonary blood flow and pulmonary hypertension, 10 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). When the lambs were 4-6 wk of age, we assessed responses of pulmonary arteries (PAs) and pulmonary veins (PVs) isolated from lungs of control and shunted lambs. PVs from control and shunted lambs relaxed similarly to exogenous NO (S-nitrosyl-acetyl-penicillamine), to NO produced endogenously (zaprinast and A-23187), and to cGMP (atrial natriuretic peptide). In contrast, relaxations to A-23187 and zaprinast were blunted in PAs isolated from shunted lambs relative to controls. Inhibitors of NO synthase (NOS) and soluble guanylate cyclase constricted control but not shunt PAs, indicating reduced basal NOS activity in shunt PAs. Pretreatment of shunt PAs with the substrates L-arginine and sepiapterin, a precursor for tetrahydrobiopterin synthesis, did not augment A-23187 relaxations. However, pretreatment with superoxide dismutase and catalase significantly enhanced A-23187 relaxations in shunt PAs. We conclude that increased pulmonary blood flow induces an impairment of endothelium-dependent relaxation that is selective to PAs. The impaired relaxation may be mediated in part by excess superoxide production.

3',5'-Cyclic-GMP Phosphodiesterases↗

Inhaled nitric oxide-induced rebound pulmonary hypertension: role for endothelin-1.

Clinically significant increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO). Endothelin (ET)-1 is a vasoactive peptide produced by the vascular endothelium that may participate in the pathophysiology of pulmonary hypertension. The objectives of this study were to determine the effects of inhaled NO on endogenous ET-1 production in vivo in the intact lamb and to determine the potential role of ET-1 in the rebound pulmonary hypertension associated with the withdrawal of inhaled NO. Seven 1-mo-old vehicle-treated control lambs and six PD-156707 (an ET(A) receptor antagonist)-treated lambs were mechanically ventilated. Inhaled NO (40 parts per million) was administered for 24 h and then acutely withdrawn. After 24 h of inhaled NO, plasma ET-1 levels increased by 119.5 +/- 42.2% (P < 0.05). Western blot analysis revealed that protein levels of preproET-1, endothelin-converting enzyme-1alpha, and ET(A) and ET(B) receptors were unchanged. On acute withdrawal of NO, pulmonary vascular resistance (PVR) increased by 77.8% (P < 0.05) in control lambs but was unchanged (-5.5%) in PD-156707-treated lambs. Inhaled NO increased plasma ET-1 concentrations but not gene expression in the intact lamb, and ET(A) receptor blockade prevented the increase in PVR after NO withdrawal. These data suggest a role for ET-1 in the rebound pulmonary hypertension noted on acute withdrawal of inhaled NO.

Administration, Inhalation↗

Shear stress regulation of endothelial NOS in fetal pulmonary arterial endothelial cells involves PKC.

We have shown that increased pulmonary blood flow at birth increases the activity and expression of endothelial nitric oxide (NO) synthase (eNOS). However, the signal transduction pathway regulating this process is unclear. Because protein kinase C (PKC) has been shown to be activated in response to shear stress, we undertook a study to examine its role in mediating shear stress effects on eNOS. Initial experiments demonstrated that PKC activity increased in response to shear stress. NO production in response to shear stress was found to be biphasic, with an increase in NO release up to 1 h, a plateau phase until 4 h, and another increase between 4 and 8 h. PKC inhibition reduced the initial rise in NO release by 50% and the second increase by 70%. eNOS mRNA and protein levels were also increased in response to shear stress, whereas PKC inhibition prevented this increase. The stimulation of PKC activity with phorbol ester increased eNOS gene expression without increasing NO release. These results suggest that PKC may play different roles in shear stress-mediated release of NO and increased eNOS gene expression.

Animals↗

sGC and PDE5 are elevated in lambs with increased pulmonary blood flow and pulmonary hypertension.

Utilizing aortopulmonary vascular graft placement, we established a lamb model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. We previously demonstrated that endothelial nitric oxide synthase (eNOS) is increased in lambs at age 4 wk. However, these lambs display a selective impairment of endothelium-dependent pulmonary vasodilation that is suggestive of a derangement downstream of NO release. Thus our objective was to characterize potential alterations in the expression and activity of soluble guanylate cyclase (sGC) and phosphodiesterase type 5 (PDE5) induced by increased pulmonary blood flow and pulmonary hypertension. Late-gestational fetal lambs (n = 10) underwent in utero placement of an aortopulmonary vascular graft (shunt). Western blotting analysis on lung tissue from 4-wk-old shunted lambs and age-matched controls showed that protein for both subunits of sGC was increased in shunted lamb lungs compared with age-matched controls. Similarly, cGMP levels were increased in shunted lamb lungs compared with age-matched controls. However, PDE5 expression and activity were also increased in shunted lambs. Thus although cGMP generation was increased, concomitant upregulation of PDE5 expression and activity may have (at least partially) limited and accounted for the impairment of endothelium-dependent pulmonary vasodilation in shunted lambs.

3',5'-Cyclic-GMP Phosphodiesterases↗

ET-1 stimulates pulmonary arterial smooth muscle cell proliferation via induction of reactive oxygen species.

Recent studies implicate reactive oxygen species (ROS) such as superoxide anions and H(2)O(2) in the proliferation of systemic vascular smooth muscle cells (SMCs). However, the role of ROS in SMC proliferation within the pulmonary circulation remains unclear. We investigated the effects of endothelin-1 (ET-1), a potential SMC mitogen, on ROS production and proliferation of fetal pulmonary artery SMCs (FPASMCs). Exposure to ET-1 resulted in increases in superoxide production and viable FPASMCs after 72 h. These increases were prevented by pretreatment with PD-156707. Treatment with pertussis toxin blocked the effects of ET-1, whereas cholera toxin stimulated superoxide production and increased viable cell numbers even in the absence of ET-1. Wortmannin, LY-294002, diphenyleneiodonium (DPI), 4-(2-aminoethyl)benzenesulfonyl fluoride, and apocynin also prevented the ET-1-mediated increases in superoxide production and viable cell numbers. Exposure to H(2)O(2) or diethyldithiocarbamate increased viable cell number by 37% and 50%, respectively. Conversely, ascorbic acid and DPI decreased viable cell number, which appeared to be due to an increase in programmed cell death. Our data suggest that ET-1 exerts a mitogenic effect on FPASMCs via an increase in ROS production and that antioxidants can block this effect via induction of apoptosis. Antioxidant treatment may therefore represent a potential therapy for pulmonary vascular diseases.

Animals↗

Alterations in endogenous nitric oxide production after cardiopulmonary bypass in lambs with normal and increased pulmonary blood flow.

BACKGROUND: After cardiopulmonary bypass (CPB), altered vascular reactivity is a major source of complications, particularly for children with increased pulmonary blood flow. Although changes in agonist-induced NO activity are well described after CPB, potential changes in basal NO production and their role in post-CPB pulmonary hypertension remain unclear. By using aortopulmonary vascular graft placement in the fetal lamb (shunt lambs), we established a unique model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. The objective of the present study was to investigate potential alterations in endogenous NO production after CPB in lambs with normal and increased pulmonary blood flow. METHODS AND RESULTS: Vascular pressures and blood flows were monitored in 1-month-old lambs (n=7) with increased pulmonary blood flow and 6 age-matched control lambs. After shunt closure, hypothermic CPB (25 degrees C) was performed for 2 hours. The hemodynamic variables were monitored for 4 hours after CPB. Before, during, and after CPB, peripheral lung biopsies were performed to determine tissue NO, nitrite, nitrate, and cGMP concentrations; total NO synthase (NOS) activity; and endothelial NOS protein levels. Hypothermic CPB increased both mean pulmonary arterial pressure and left pulmonary vascular resistance (P:<0.05). The increase in pulmonary arterial pressure induced in shunt lambs was greater than that induced in control lambs (P:<0.05). Four hours after CPB, tissue concentrations of NO, nitrite, nitrate, and cGMP were decreased to approximately 70% of pre-CPB levels in both control and shunt lambs (P:<0.05). Total NOS activity and endothelial NOS protein levels were unchanged. CONCLUSIONS: Modest decreases in basal NO production, the inability to increase NO production, or both may play a role in the altered pulmonary vascular reactivity after CPB. The decrease in NO is independent of gene expression. However, other mechanisms for this decrease, such as substrate or cofactor availability, warrant further study.

Animals↗

Nitric oxide synthase activity and inhibition after neonatal hypoxia ischemia in the mouse brain.

Despite the emergence of therapies for hypoxic-ischemic injury to the mature nervous system, there have been no proven efficacious therapies for the developing nervous system. Recent studies have shown that pharmacological blockade of neuronal nitric oxide synthase (nNOS) activity can ameliorate damage after ischemia in the mature rodent. We have previously shown that elimination of nNOS neurons, either by targeted disruption of the gene or by pharmacological depletion with intraparenchymal quisqualate, can decrease injury after hypoxia-ischemia. Using a simpler pharmacological approach, we studied the efficacy of a systemically administered NOS inhibitor, 7-nitroindazole, a relatively selective inhibitor of nNOS activity. Using multiple doses and concentrations administered after the insult, we found that there was only a trend for protection with higher doses of the drug. A significant decrease in NOS activity was seen at 18 h and 5 days in the cortex, and at 2 h and 18 h in the hippocampus after the hypoxia-ischemia. nNOS expression decreased and remained depressed for at least 18 h after the insult. When nNOS expression was normalized to MAP2 expression, a decrease was seen at 18 h in the cortex and at 2 and 18 h in the hippocampus. These data suggest that further inhibition of NOS activity at early timepoints may not provide substantial benefit. At 5 days after the insult, however, NOS activity and normalized nNOS expression returned to baseline or higher in the hippocampus, the region showing the most damage. These data suggest that delayed administration of nNOS inhibitor after hypoxic-ischemic injury might be beneficial.

Animals↗

Pulmonary blood flow alters nitric oxide production in patients undergoing device closure of atrial septal defects.

OBJECTIVE: To determine the effect of pulmonary blood flow (Qp) on nitric oxide (NO) production in patients with increased Qp due to an atrial septal defect (ASD). BACKGROUND: Alterations in pulmonary vascular NO production have been implicated in the development of pulmonary hypertension secondary to increased Qp. In vitro, acute changes in flow or shear stress alter NO production. However, the effect of Qp on lung NO production in vivo is unclear. METHODS: Nineteen patients (2.4-61 years of age, median 17) with secundum ASD undergoing device closure were studied. Before, and 30 min after ASD closure, exhaled NO and plasma nitrate concentration were measured by chemiluminescence (NOA 280, Sievers, Boulder, Colorado). RESULTS: Before ASD closure, all patients had increased Qp (Qp: systemic blood flow [Qs] of 2.0 +/- 0.7) and normal mean pulmonary arterial pressure (13.4 +/- 3.1 mm Hg). Atrial septal defect device closure decreased Qp from 6.0 +/- 2.5 to 3.6 +/- 1.3 L/min/m2 (p < 0.05). Mean pulmonary arterial pressure was unchanged. Associated with the decrease in Qp, both exhaled NO (-22.1%, p < 0.05) and plasma nitrate concentrations (-17.9%, p < 0.05) decreased. CONCLUSIONS: These data represent the first demonstration that acute changes in Qp alter pulmonary NO production in vivo in humans. Exhaled NO determinations may provide a noninvasive assessment of pulmonary vascular NO production in patients with congenital heart disease. Potential correlations between exhaled NO, pulmonary vascular reactivity and pulmonary hypertension warrant further study.

Adolescent↗

Altered regulation of the ET-1 cascade in lambs with increased pulmonary blood flow and pulmonary hypertension.

Plasma concentrations of endothelin-1 (ET-1) are increased in children with congenital heart disease associated with increased pulmonary blood flow. However, the role of ET-1 in the pathophysiology of pulmonary hypertension remains unclear. Preproendothelin-1 gene expression is increased in adults with advanced pulmonary hypertension. To characterize potential early molecular alterations in the ET-1 cascade induced by increased pulmonary blood flow and pulmonary hypertension, fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). RNase protection assays and Western blot analysis were performed on lung tissue prepared from 4-wk-old shunt lambs and age-matched controls. Endothelin-converting enzyme-1 [the enzyme responsible for the production of active ET-1 from big ET-1, mRNA (411%, p<0.05)] and protein (170%, p<0.05) were increased in lung tissue prepared from shunt lambs, compared with age-matched controls. Endothelin type A receptor (the receptor that mediates vasoconstriction), mRNA (246%, p<0.05), and protein (176%, p<0.05) also were increased in lung tissue prepared from shunt lambs compared with age-matched controls. Conversely, endothelin type B receptor (the receptor that mediates vasodilation), mRNA (46%, p<0.05), and protein (65%, p<0.05) were decreased in shunt lambs. Both the mRNA and protein levels for preproendothelin-were unchanged. Thus we conclude that increased pulmonary blood flow and pulmonary hypertension induce early alterations in the ET-1 cascade that result in increased ET-1 production, increased ET-1-mediated vasoconstriction, and decreased vasodilation. These early alterations in gene expression may contribute to the development of pulmonary hypertension and its associated enhanced pulmonary vascular reactivity.

Animals↗

Capillary morphogenesis during human endothelial cell invasion of three-dimensional collagen matrices.

Here, we describe assay systems that utilize serum-free defined media to evaluate capillary morphogenesis during human endothelial cell (EC) invasion of three-dimensional collagen matrices. ECs invade these matrices over a 1-3-d period to form capillary tubes. Blocking antibodies to the alpha2beta1 integrin interfere with invasion and morphogenesis while other integrin blocking antibodies do not. Interestingly, we observed increased invasion of ECs toward a population of underlying ECs undergoing morphogenesis. In addition, we have developed assays on microscope slides that display the invasion process horizontally, thereby enhancing our ability to image these events. Thus far, we have observed intracellular vacuoles that appear to regulate the formation of capillary lumens, and extensive cell processes that facilitate the interconnection of ECs during morphogenic events. These assays should enable further investigation of the morphologic steps and molecular events controlling human capillary tube formation in three-dimensional extracellular matrices.

Animals↗

Both neuronal NO synthase and nitric oxide are required for PC12 cell differentiation: a cGMP independent pathway.

PC12 cells are used as a model system to study neuronal differentiation. Nerve growth factor (NGF) triggers a differentiation pathway in PC12 cells. Neurite outgrowth (a morphological marker of differentiation) in PC12 cells is significantly reduced in the presence of the NOS inhibitor l-NAME, but not d-NAME, implicating NOS in the differentiation process. Previously we have shown that the neuronal NO synthase (nNOS) isoform is induced in PC12 cells in the presence of NGF. Thus, we wished to further evaluate the role of nNOS and NO in PC12 cell differentiation. When a dominant negative mutant nNOS expression vector was transiently transfected into NGF-treated PC12 cells, it significantly reduced PC12 cell neurite outgrowth. Thus, we concluded that the NO required for PC12 cell differentiation, in response to NGF, is produced by nNOS. NO alone was insufficient to induce differentiation as cells treated with the NO donor, sodium nitroprusside did not produce neurites. Treatment of PC12 cells with oxyhemoglobin (an NO scavenger) was also found to significantly reduce the number of neurites produced by PC12 cells treated with NGF. Thus, NO appears to be necessary, but not sufficient, to induce differentiation, and its mode of action appears to be extracellular. A well documented action of NO is to activate soluble guanylate cyclase. Thus, we determined the role of soluble guanylate cyclase activation as a means by which NO induces PC12 cell differentiation. However, in the presence of NGF (to prime PC12 cells for differentiation) and l-NAME (to specifically remove the NO component), 8Br-cGMP (a cGMP analog) failed to induce PC12 cell differentiation. In addition, blockade of sGC activity with specific inhibitors failed to block NGF-induced PC12 cell differentiation. We conclude that the NO required for PC12 cell differentiation is produced by nNOS and that the NO exerts its effects on surrounding PC12 cells in a sGC/cGMP independent manner.

Animals↗

Use of chimeric forms of neuronal nitric-oxide synthase as dominant negative mutants.

Because the functional form of neuronal nitric-oxide synthase (nNOS) is a homodimer, we investigated whether we could disrupt dimer formation with inactive nNOS chimeras acting as dominant negative mutants. To test this hypothesis, we either expressed the heme and reductase regions of rat nNOS as single domains or produced fusion proteins between the rat nNOS heme domain and various other electron-shuttling proteins. A dominant negative potential of these constructs was demonstrated by their ability to reduce NOS activity when transfected into a cell line stably expressing rat nNOS. In the presence of these nNOS mutant proteins, cellular levels of inactive nNOS monomers were significantly increased, indicating that their mechanism of action is through the disruption of nNOS dimer formation. These dominant negative mutants should prove valuable in analyzing the role of nNOS in biological systems.

Animals↗

Chimeric forms of neuronal nitric oxide synthase identify different regions of the reductase domain that are essential for dimerization and activity.

Nitric oxide synthase (NOS) is the enzyme responsible for the conversion of L-arginine to L-citrulline and nitric oxide. Dimerization of the enzyme is an absolute requirement for catalytic activity. Each NOS monomer contains an N-terminal heme-binding domain and a C-terminal reductase domain. It is unclear how the reductase domain is involved in controlling dimerization and whether dimer formation alone controls enzyme activity. Our initial studies demonstrated that no dimerization or activity could be detected when the reductase domain of rat neuronal NOS (nNOS) was expressed either separately or in combination with the heme domain. To further evaluate the reductase domain, a set of expression plasmids was created by replacing the reductase domain of nNOS with other electron-transport proteins, thereby creating nNOS chimeric fusion proteins. The rat nNOS heme domain was linked with either cytochrome P450 reductase, adrenodoxin reductase, or the reductase domain from Bacillus megaterium cytochrome P450, BM-3. All the chimeric enzymes retained the ability to dimerize but were unable to metabolize L-arginine (<8% of wildtype activity levels), indicating that dimerization alone is insufficient to produce an active enzyme. Because the greatest regions of homology between electron-transport proteins are in the flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), and nicotinamide adenine dinucleotide phosphate (NADPH) binding regions, we produced truncation mutants within the nNOS reductase domain to investigate the role of these sequences in the ability of nNOS to dimerize and to metabolize L-arginine. The results demonstrated that the deletion of the final 56 amino acids or the NADPH-binding region had no effect on dimerization but produced an inactive enzyme. However, when the FAD-binding site (located between amino acids 920 and 1161) was deleted, both activity and dimerization were abolished. These results implicate sequences within the FAD-binding site as essential for nNOS dimerization but sequences within amino acids 1373 to 1429 as essential for activity.

Animals↗

Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism for rebound pulmonary hypertension.

Life-threatening increases in pulmonary vascular resistance have been noted on acute withdrawal of inhaled nitric oxide (NO), although the mechanisms remain unknown. In vitro data suggest that exogenous NO exposure inhibits endothelial NO synthase (NOS) activity. Thus the objectives of this study were to determine the effects of inhaled NO therapy and its acute withdrawal on endogenous NOS activity and gene expression in vivo in the intact lamb. Six 1-mo-old lambs were mechanically ventilated and instrumented to measure vascular pressures and left pulmonary blood flow. Inhaled NO (40 ppm) acutely decreased left pulmonary vascular resistance by 27. 5 +/- 4.7% (P < 0.05). This was associated with a 207% increase in plasma cGMP concentrations (P < 0.05). After 6 h of inhaled NO, NOS activity was reduced to 44.3 +/- 5.9% of pre-NO values (P < 0.05). After acute withdrawal of NO, pulmonary vascular resistance increased by 52.1 +/- 11.6% (P < 0.05) and cGMP concentrations decreased. Both returned to pre-NO values within 60 min. One hour after NO withdrawal, NOS activity increased by 48.4 +/- 19.1% to 70% of pre-NO values (P < 0.05). Western blot analysis revealed that endothelial NOS protein levels remained unchanged throughout the study period. These data suggest a role for decreased endogenous NOS activity in the rebound pulmonary hypertension noted after acute withdrawal of inhaled NO.

Administration, Inhalation↗

Inducible nitric oxide synthase and the effect of aminoguanidine in experimental neonatal meningitis.

This study explored the role of inducible nitric oxide (NO) synthase (iNOS) in an infant rat model of group B streptococcal meningitis. Brain iNOS activity increased during meningitis (P < .001), and iNOS was detected by immunocytochemistry in the walls of meningeal vessels and cells of the cerebrospinal fluid (CSF) inflammation. Animals treated with iNOS inhibitor aminoguanidine (AG; 130 mg/kg every 8 h) had reduced NO production (P < .05), higher CSF bacterial titers (P < .05), and increased incidence of seizures (P < .01) compared with untreated infected animals. AG also increased areas of severe hypoperfusion in the cortex (31% +/- 14% in controls vs. 56% +/- 16% in AG; P < .01) and the extent of cortical neuronal injury, both when administered at the time of infection (P < .05) and in established meningitis (P < .02). Thus, NO produced by iNOS may be beneficial in this model of experimental meningitis by reducing cerebral ischemia.

Animals↗