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Biomedical subjects

W R Clarke

Publications and source records attributed to W R Clarke.

At least 19 recordsLinked to original sources
PubMed2006

Zeeman splitting in ballistic hole quantum wires.

We have studied the Zeeman splitting in ballistic hole quantum wires formed in a (311)A quantum well by surface gate confinement. Transport measurements clearly show lifting of the spin degeneracy and crossings of the subbands when an in-plane magnetic field B is applied parallel to the wire. When B is oriented perpendicular to the wire, no spin splitting is discernible up to B = 8.8 T. The observed large Zeeman splitting anisotropy in our hole quantum wires demonstrates the importance of quantum confinement for spin splitting in nanostructures with strong spin-orbit coupling.

Journal Article↗
PubMed2004

Frequency, risk factors, anatomy, and course of unilateral neglect in an acute stroke cohort.

OBJECTIVE: To delineate the frequency, course, risk factors, and neuroanatomy of hemispatial neglect in a large stroke cohort. METHODS: One thousand two hundred eighty-one patients with acute stroke were enrolled in a multicenter trial of an anticoagulant. Presence and severity of neglect were assessed with the NIH Stroke Scale (NIHSS) neglect item, assessing tactile extinction and visuospatial neglect at entry, daily for 1 week, and at 3 months. Head CT scans were obtained on day 7, and infarct location and size were characterized. RESULTS: Neglect was common at presentation, occurring in 43% of right brain-lesioned (RBL) patients and 20% of left brain-lesioned (LBL) patients (p < 0.001). At 3 months, neglect was present in 17% of RBL patients and in 5% of LBL patients (p < 0.001). In RBL patients, neglect was most frequently associated with lesions involving the (in descending order) temporal, parietal, frontal, occipital lobes, basal ganglia, and thalamus. Neglect was more common and persistent with cortical than with subcortical lesions. Increasing age was associated with increased risk of neglect in RBL patients, whereas gender and handedness did not significantly affect neglect frequency. CONCLUSIONS: This series confirms that hemispatial neglect may occur with damage to several supratentorial structures but is most common and persistent with lesions of the right temporoparietal cortex. Increasing age is associated with neglect, particularly after right brain lesions. Gender and handedness do not exert a marked effect on the likelihood of the occurrence of neglect.

Acute Disease↗
PubMed2001

Effect of prior aspirin use on stroke severity in the trial of Org 10172 in acute stroke treatment (TOAST).

BACKGROUND AND PURPOSE: Although the efficacy of aspirin in reducing stroke incidence is clear, its role in reducing stroke severity is disputed. This study compares stroke severity between patients who did or did not take aspirin in the week before stroke and enrollment in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). METHODS: Of 1275 patients randomized, 509 reported aspirin use in the week before stroke; 766 did not. Clinical stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Supplementary Motor Examination (SME) at trial entry and at 3 months. Using these scales, we compared the categorization of stroke severity (mild, moderate, and severe) and mean scores between aspirin users and nonusers. RESULTS: The difference in distribution of baseline NIHSS scores was statistically significant between aspirin users and nonusers (P=0.006), with a greater percentage of milder strokes among aspirin users. The difference in mean baseline NIHSS scores was also significantly lower in aspirin users (8.2) and nonusers (9.3) (P=0.003). The distribution of baseline SME scores and mean SME scores also showed lower stroke severity in aspirin users than in nonusers (P=0.048 and P=0.004, respectively). At 3 months, differences in stroke severity measured by the SME but not the NIHSS remained statistically significant. Seven-day and 3-month mortality did not differ significantly. CONCLUSIONS: In this study aspirin use is associated with milder clinical deficits at stroke onset. These deficits may affect prognosis and influence response to treatment. Future clinical trials should ensure that prestroke aspirin use is comparable in study groups.

Aged↗
PubMed2001

Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.

BACKGROUND: It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure. METHODS: We randomly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan (300 mg daily), amlodipine (10 mg daily), or placebo. The target blood pressure was 135/85 mm Hg or less in all groups. We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration, the development of end-stage renal disease, or death from any cause. We also compared them with regard to the time to a secondary, cardiovascular composite end point. RESULTS: The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group (P=0.02) and 23 percent lower than that in the amlodipine group (P=0.006). The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group (P=0.003) and 37 percent lower in the irbesartan group than in the amlodipine group (P<0.001). Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups (P=0.07 for both comparisons). These differences were not explained by differences in the blood pressures that were achieved. The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group (P=0.008) and 21 percent more slowly than in the amlodipine group (P=0.02). There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point. CONCLUSIONS: The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes. This protection is independent of the reduction in blood pressure it causes.

Adult↗
PubMed2001

Differences between anterior and posterior circulation stroke in TOAST.

BACKGROUND AND PURPOSE: Clinicians have tended to view anterior circulation (AC) and posterior circulation (PC) strokes as separate entities, with different underlying pathogenesis, natural histories, and potential responsiveness to interventions such as anticoagulation. We sought to explore differences between AC and PC stroke in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST). METHODS: For patients enrolled in TOAST, prospective clinical information was collected including outcome at 3 months. Data on vascular distribution were obtained from the clinical impression of the investigators. Group comparisons for categorical data were performed using Fisher's exact test. Independent sample t tests and analysis of covariance were used for all continuous data. RESULTS: The analysis included 1,039 patients with AC stroke and 180 patients with PC stroke. There were fewer women in the PC than in the AC groups, but otherwise there were no differences in demographics, risk factors or stroke subtypes between the two groups. Headache (AC 8.7%, PC 15%, p = 0.013) and vomiting (AC 3.5%, PC 17.8%, p < 0.001) were more common among PC patients. Mean baseline National Institutes of Health Stroke Scale (NIHSS) score was lower (less severe) among PC (6.1) than AC patients (9.5; p < 0.001). On univariate analysis, favorable outcome at 3 months was more common for PC patients in both the placebo group (PC 82%, AC 71%, p = 0.04) and heparinoid group (PC 87%, AC 73%, p = 0.005). However, multivariate analysis, controlling for gender, history of previous stroke and baseline NIHSS score, showed no difference in outcome between PC and AC stroke. For favorable outcome, there was no interaction between vascular distribution and treatment category, suggesting that the effect of heparinoid did not differ between PC and AC strokes. CONCLUSION: Patients with PC stroke seem to have a better long-term outcome than do AC patients, but this difference is no longer apparent when controlling for important prognostic variables. PC patients did not show any particular benefit from anticoagulation, and the efficacy of heparinoid did not vary between AC and PC stroke. While AC and PC patients do differ in some respects, it may be inappropriate to single out PC patients for anticoagulant treatment.

Aged↗
PubMed2001

Preview of a new trial of extracranial-to-intracranial arterial anastomosis: the carotid occlusion surgery study.

In 1985, the International Study of Extracranial-to-Intracranial Arterial Anastomosis demonstrated no benefit from extracranial-to-intracranial arterial bypass operations in treatment of patients with extensive cerebrovascular disease including those with occlusions of the internal carotid artery. Interest in the potential use of extracranial-to-intracranial arterial bypass operations, however, has been rekindled by evidence that some patients with occlusion of the internal carotid artery have a poor collateral circulation and a high risk for recurrent ischemic events. Other patients with adequate perfusion after occlusion have a low likelihood for recurrent stroke. Restricting surgical treatment to only those patients judged to have a high risk for recurrent stroke might improve the usefulness of the bypass operation. A new clinical trial is proposed, testing the potential usefulness of extracranial-to-intracranial arterial bypass operations for treatment of carefully selected patients with occlusion of the internal carotid artery. Several issues that are being addressed in this new trial are described in this article.

Arteriovenous Anastomosis↗
PubMed2000

Is there a Persian Gulf War syndrome? Evidence from a large population-based survey of veterans and nondeployed controls.

PURPOSE: Concerns have been raised about whether veterans of the Gulf War have a medical illness of uncertain etiology. We surveyed veterans to look for evidence of an illness that was unique to those deployed to the Persian Gulf and was not seen in comparable military controls. SUBJECTS AND METHODS: A population-based sample of veterans (n = 1,896 from 889 units) deployed to the Persian Gulf and other Gulf War-era controls (n = 1799 from 893 units) who did not serve in the Gulf were surveyed in 1995-1996. Seventy-six percent of eligible subjects, including 91% of located subjects, answered questions about commonly reported and potentially important symptoms. We used factor analysis, a statistical technique that can identify patterns of related responses, on a random subset of the deployed veterans to identify latent patterns of symptoms. The results from this derivation sample were compared with those obtained from a separate validation sample of deployed veterans, as well as the nondeployed controls, to determine whether the results were replicable and unique. RESULTS: One half (50%) of the deployed veterans and 14% of the nondeployed controls reported health problems that they attributed to military service during 1990-1991. Compared with the nondeployed controls, the deployed veterans had significantly greater prevalences of 123 of 137 (90%) symptoms; none was significantly lower. Factor analysis identified three replicable symptom factors (or patterns) in the deployed veterans (convergent correlations > or =0.85). However, these patterns were also highly replicable in the nondeployed controls (convergent correlations of 0.95 to 0.98). The three factors also accounted for similar proportions of the common variance among the deployed veterans (35%) and nondeployed controls (30%). CONCLUSIONS: The increased prevalence of nearly every symptom assessed from all bodily organ systems among the Gulf War veterans is difficult to explain pathophysiologically as a single condition. Identification of the same patterns of symptoms among the deployed veterans and nondeployed controls suggests that the health complaints of Gulf War veterans are similar to those of the general military population and are not consistent with the existence of a unique Gulf War syndrome.

Adult↗
PubMed2000

Multiple chemical sensitivity syndrome: symptom prevalence and risk factors in a military population.

OBJECTIVE: To assess the prevalence of and risk factors for self-reported symptoms suggestive of multiple chemical sensitivities/idiopathic environmental intolerance (MCS/IEI) in Persian Gulf War (PGW) veterans from Iowa and a comparison group of PGW-era military personnel. METHODS: A population-based sample of Iowa military personnel was surveyed using a cross-sectional telephone interview. Study participants were randomly drawn from 1 of 4 domains: PGW active duty, PGW National Guard/Reserve, non-PGW active duty, and non-PGW National Guard/Reserve. A complex sample survey design was used selecting participants from the following substrata: age, sex, race, rank, and military branch. The criteria for MCS/IEI were developed using expert consensus and the medical literature. RESULTS: A total of 3695 study participants (76% of those eligible) completed the telephone survey. The prevalence of symptoms suggestive of MCS/IEI in all participants was 3.4%. Veterans of the PGW reported a significantly higher prevalence of symptoms suggestive of MCS/IEI than did non-PGW military personnel (5.4% vs 2.6%); greater sensitivity to organic chemicals, vehicle exhaust, cosmetics, and smog; and more lifestyle changes. The following risk factors for MCS/IEI were identified with univariate analysis: deployment to the Persian Gulf, age (>25 years), female sex, receiving a physician diagnosis of MCS, previous professional psychiatric treatment, previous psychotropic medication use, current psychiatric illness, and a low level of preparedness. Multiple logistic regression analysis identified several independent risk factors for MCS/IEI, including deployment to the Persian Gulf, age, sex, rank, branch of service, previous professional psychiatric treatment, and current mental illness. CONCLUSIONS: Self-reported symptoms suggestive of MCS/IEI are relatively frequent in a military population and are more common among PGW veterans than comparable controls. Reported chemical sensitivities and accompanying behavioral changes were also frequent. After adjusting for age, sex, and training preparedness, previous professional psychiatric treatment and previous psychotropic medication use (before deployment) showed a robust association with symptoms suggestive of MCS.

Adult↗
PubMed2000

The Irbesartan type II diabetic nephropathy trial: study design and baseline patient characteristics. For the Collaborative Study Group.

BACKGROUND: Diabetic nephropathy is the most common cause of end-stage renal disease in the developed world. Angiotensin-converting enzyme inhibitors have been demonstrated to be renoprotective in type I diabetes and are now the standard of care for both hypertensive and non-hypertensive type I diabetic patients with any level of proteinuria. The role of blockade of the renin-angiotensin system in type II diabetic patients is not defined. The Collaborative Study Group has initiated the Irbesartan Type II Diabetic Nephropathy Trial (IDNT), studying the effect of the angiotensin II receptor antagonist irbesartan on progression of renal disease and mortality in type II diabetic patients with overt nephropathy and hypertension. Here we report the study design and baseline patient characteristics. METHODS: To qualify, hypertensive type II patients, age 30-70 years, must have a 24 h urinary protein excretion of >900 mg and a serum creatinine 90-265 micromol/l (1.0-3. 0 mg/dl) in women and 110-265 micromol/l (1.2-3.0 mg/dl) in men. Three treatment arms include irbesartan, placebo and amlodipine, with every attempt made to achieve similar blood pressure levels in all treatment arms. A total of 1650 patients will be enrolled utilizing approximately 225 clinics worldwide. The primary outcome measure is time to event to the composite end-point of doubling of serum creatinine, end-stage renal disease or death. The secondary outcome measure is time to composite end-point of fatal or non-fatal cardiovascular events. The average length of patient follow-up is expected to be approximately 36 months. RESULTS: The baseline characteristics of the study subjects are: age 59+/-8 years, duration of diabetes 15+/-9 years, height 168+/-11 cm (5 ft 6 in), weight 87+/-19 kg (192 lb), body mass index 31+/-7 kg/m(2), blood pressure 156+/-18 mmHg/85+/-11 mmHg, serum creatinine 150+/-53 micromol/l (1.7+/-0.6 mg/dl), creatinine clearance 66+/-34 ml/min and 24 h urine protein 4.0+/-3.5 g/day.

Adult↗
PubMed1999

Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST).

OBJECTIVE: To examine the responses to early IV administration of an anticoagulant or placebo started within 24 hours of stroke among persons with an ipsilateral occlusion or severe stenosis of the internal carotid artery (ICA) identified by carotid duplex imaging. BACKGROUND: Patients with ischemic stroke of the cerebral hemisphere secondary to an ipsilateral occlusion or severe stenosis of the ICA generally have a poor prognosis. Early, accurate identification of these patients might permit improved treatment. METHODS: Exploratory analysis of outcomes at 7 days and 3 months was performed among patients enrolled in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) who had an ischemic stroke in the cerebral hemisphere ipsilateral to an occlusion or a stenosis >50% of the ICA identified by carotid duplex imaging. RESULTS: Regardless of treatment, patients with duplex evidence of an occlusion of the ICA had more severe strokes and poorer outcomes at 7 days and 3 months than patients who had a stenosis. Favorable outcomes at 7 days were noted in 64 of 119 patients given danaparoid (53.8%) and 41 of 108 patients treated with placebo (38.0%; p = 0.023). By 3 months, favorable outcomes were noted in 82 patients given danaparoid (68.3%) and 58 patients administered placebo (53.2%; p = 0.021). CONCLUSIONS: Early identification by duplex imaging of an occlusion or severe stenosis of the ICA ipsilateral to a hemispheric ischemic stroke might improve selection of patients who could be treated with emergent anticoagulation. Further testing of this approach is needed.

Anticoagulants↗
PubMed1999

Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST).

OBJECTIVE: To compare the baseline National Institutes of Health Stroke Scale (NIHSS) score and the Trial of Org 10172 in Acute Stroke Treatment (TOAST) stroke subtype as predictors of outcomes at 7 days and 3 months after ischemic stroke. METHODS: Using data collected from 1,281 patients enrolled in a clinical trial, subtype of stroke was categorized using the TOAST classification, and neurologic impairment at baseline was quantified using the NIHSS. Outcomes were assessed at 7 days and 3 months using the Barthel Index (BI) and the Glasgow Outcome Scale (GOS). An outcome was rated as excellent if the GOS score was 1 and the BI was 19 or 20 (scale of 0 to 20). Analyses were adjusted for age, sex, race, and history of previous stroke. RESULTS: The baseline NIHSS score strongly predicted outcome, with one additional point on the NIHSS decreasing the likelihood of excellent outcomes at 7 days by 24% and at 3 months by 17%. At 3 months, excellent outcomes were noted in 46% of patients with NIHSS scores of 7 to 10 and in 23% of patients with scores of 11 to 15. After multivariate adjustment, lacunar stroke had an odds ratio of 3.1 (95% CI, 1.5 to 6.4) for an excellent outcome at 3 months. CONCLUSIONS: The NIHSS score strongly predicts the likelihood of a patient's recovery after stroke. A score of > or =16 forecasts a high probability of death or severe disability whereas a score of < or =6 forecasts a good recovery. Only the TOAST subtype of lacunar stroke predicts outcomes independent of the NIHSS score.

Anticoagulants↗
PubMed1999

Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators.

OBJECTIVE: To study the relation between acute blood glucose level and outcome from ischemic stroke. BACKGROUND: Hyperglycemia may augment acute ischemic brain injury and increase the risk of hemorrhagic transformation of the infarct. METHODS: The authors analyzed the relation between admission blood glucose level (within 24 hours from ischemic stroke onset) and clinical outcome in 1,259 patients enrolled in the Trial of ORG 10172 in Acute Stroke Treatment (TOAST)-a placebo-controlled, randomized, double-blind trial to test the efficacy of a low-molecular weight heparinoid in acute ischemic stroke. Very favorable outcome was defined as a Glasgow Outcome Scale score of 1 and a modified Barthel index of 19 or 20. Neurologic improvement at 3 months was defined as a decrease by > or =4 points on the NIH Stroke Scale compared with baseline or a final score of 0. Hemorrhagic transformation of infarct was assessed within 10 days after onset of stroke with repeat cerebral CT. Stroke subtype as lacunar or nonlacunar (atherothromboembolic, cardioembolic, and other or undetermined etiology) was classified by one investigator after completion of stroke evaluation according to study protocol. RESULTS: In all strokes combined (p = 0.03) and in nonlacunar strokes (p = 0.02), higher admission blood glucose levels were associated with worse outcome at 3 months according to multivariate logistic regression analysis adjusted for stroke severity, diabetes mellitus, and other vascular risks. In lacunar strokes, the relationship between acute blood glucose level and outcome was related to treatment. In the placebo group, higher admission blood glucose levels were associated with better outcome at 3 months. However, in the active drug group, as the glucose level increased from 50 to 150 mg/dL, the probability of a very favorable outcome decreased sharply and remained relatively unchanged as the glucose level increased further (p = 0.002, for overall effect of glucose on outcome). Acute blood glucose level was not associated with symptomatic hemorrhagic transformation of infarcts or with neurologic improvement at 3 months. CONCLUSIONS: During acute ischemic stroke hyperglycemia may worsen the clinical outcome in nonlacunar stroke, but not in lacunar stroke, and is not associated with an increased risk of hemorrhagic transformation of the infarct.

Acute Disease↗
PubMed1999

Quality of life and health-services utilization in a population-based sample of military personnel reporting multiple chemical sensitivities.

We sought to assess quality of life and health-services utilization variables in persons with symptoms suggestive of multiple chemical sensitivity/idiopathic environmental intolerance (MCS/IEI) among military personnel. We conducted a cross-sectional telephone survey of a population-based sample of Persian Gulf War (PGW) veterans from Iowa and a comparison group of PGW-era military personnel. A complex sample survey design was used, selecting subjects from four domains: PGW active duly, PGW National Guard/Reserve, non-PGW active duty, and non-PGW National Guard/Reserve. Each domain was substratified by age, gender, race, rank, and military branch. The criteria for MCS/IEI were developed by expert consensus and from the medical literature. In the total sample, 169 subjects (4.6%) of the 3695 who participated (76% of those eligible) met our criteria for MCS/IEI. Persons who met the criteria for MCS/IEI more often reported the following than did other subjects: more than 12 days in bed due to disability, Veteran's Affairs disability status, Veteran's Affairs disability compensation, medical disability, and unemployment. MCS/IEI cases also had higher outpatient rates of physician visits, emergency department visits, and inpatient hospital stays. Subjects who met the criteria for MCS/IEI more often reported impaired functioning on each Medical Outcomes Study 36-Item Short Form subscale, compared with those who did not meet the criteria. We concluded that although the diagnosis of MCS/IEI remains controversial, the persons who met our criteria for the disorder are functionally impaired.

Cross-Sectional Studies↗
PubMed1999

Therapeutic equivalence of Spiros dry powder inhaler and Ventolin metered dose inhaler. A bioassay using methacholine.

Because chlorofluorocarbons (CFCs) contribute to depletion of stratospheric ozone, CFC-containing metered-dose inhalers (MDIs) such as Ventolin and Proventil are being phased out of production. In terms of delivery of albuterol to the lungs, we compared an alternative delivery system, the Spiros dry-powder inhaler (DPI), with Ventolin, using a methacholine challenge-based clinical bioassay. Twenty-four adults and adolescents with asthma completed this double-blind, four-period crossover study. Doses evaluated were one and three actuations each of Spiros and Ventolin (90- and 270-microgram albuterol base). A methacholine challenge (Cockcroft method) was initiated 3 h before and 0.25 h after albuterol. Predose PC(20)FEV(1) values were not significantly different between study days. Postdose PC(20)FEV(1) results met standard bioassay study validity criteria: i.e., a significant dose-response relationship was present (p = 0.0002); tests for deviation from parallelism and overlap of dose-response curves were nonsignificant (p = 0.08, 0.69). By using Finney 2-by-2 bioassay analysis, we estimate that each Spiros actuation delivers 1.12 times as much albuterol to the airways as one Ventolin actuation (90% confidence interval, 0.68 to 1.94). There were no significant differences in markers of systemic effects (vital signs, potassium, and blood glucose concentrations). We conclude that Spiros and Ventolin inhalers deliver comparable quantities of albuterol to the airways.

Adolescent↗
PubMed1998

Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity.

An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1998

Dipyridamole potentiates pulmonary vasodilation induced by acetylcholine and nitric oxide in the ovine fetus.

Nitric oxide (NO) modulates pulmonary vascular resistance (PVR) in the normal fetus by increasing the cyclic guanosine 3',5'-monophosphate (cGMP) content of pulmonary vascular smooth muscle cells. Although several vasodilator stimuli, including acetylcholine, decrease fetal PVR through the release of endogenous NO, fetal pulmonary vasodilation is often transient despite prolonged treatment. Because cGMP is hydrolyzed and inactivated by cGMP-specific (type 5) phosphodiesterases (PDE5), we hypothesized that PDE5 activity contributes to high fetal PVR and limits the capability of the fetal pulmonary circulation to dilate or sustain vasodilation in response to cGMP-dependent stimuli. To test this hypothesis, we studied the hemodynamic effects of dipyridamole in 19 late-gestation fetal lambs. To determine whether dipyridamole-induced vasodilation is dependent upon basal NO release, we measured the response to dipyridamole before and after pretreatment with the NO synthase antagonist nitro-L-arginine (L-NA) in five fetal lambs. L-NA completely blocked dipyridamole-induced pulmonary vasodilation. To evaluate the effect of dipyridamole on pulmonary vasodilation due to the stimulated release of NO, we studied effects of prolonged intrapulmonary acetylcholine infusions, with and without concomitant administration of low-dose dipyridamole, in six fetal lambs. During prolonged (2-h) infusions, acetylcholine and dipyridamole individually caused transient pulmonary vasodilation. When administered together, pulmonary vasodilation was of greater magnitude and was sustained for the entire study period. To determine the effects of dipyridamole on endothelium-independent pulmonary vasodilation, we investigated the hemodynamic effects of inhaled NO (5 and 20 ppm) alone and in combination with dipyridamole during mechanical ventilation with low FlO2. The combination of dipyridamole with inhaled NO resulted in a greater degree of pulmonary vasodilation than that achieved with inhaled NO alone. We conclude that dipyridamole-induced pulmonary vasodilation is dependent on endogenous (basal) NO production and that dipyridamole potentiates vasodilator responses to endothelium-dependent and -independent dilators in the ovine fetal pulmonary circulation. We speculate that PDES activity opposes vasodilation and maintains high PVR in the normal fetal lung.

Acetylcholine↗