Early HIV Infections Among Men Who Have Sex with Men in Five Cities in the United States.

We tested blood samples from men who have sex with men (MSM) to detect early HIV infection. Early HIV included both acute (infected past 30 days) and recent (estimated recency past 240 days). Acute infections were defined as screen immunoassay (IA) negative/NAAT-positive or IA-positive/Multispot-negative/NAAT-positive. Recent infections were defined as avidity index cutoff <30 % on an avidity-based IA and, (1) not reporting antiretroviral therapy use or, (2) HIV RNA >150 copies/mL. Of 937 samples, 26 % (244) were HIV-infected and of these 5 % (12) were early. Of early infections, 2 were acute and 10 recent; most (8/12) were among black MSM. Early infection was associated with last partner of black race [adjusted relative risk (ARR) = 4.6, confidence intervals (CI) 1.2-17.3], receptive anal sex at last sex (ARR = 4.3, CI 1.2-15.0), and daily Internet use to meet partners/friends (ARR = 3.3, CI 1.1-9.7). Expanding prevention and treatment for black MSM will be necessary for reducing incidence in the United States.

Increased rainfall is associated with increased risk for legionellosis.

Legionnaires' disease (LD) is caused by Legionella species, most of which live in water. The Mid-Atlantic region experienced a sharp rise in LD in 2003 coinciding with a period of record-breaking rainfall. To investigate a possible relationship, we analysed the association between monthly legionellosis incidence and monthly rainfall totals from January 1990 to December 2003 in five Mid-Atlantic states. Using negative binomial model a 1-cm increase in rainfall was associated with a 2.6% (RR 1.026, 95% CI 1.012-1.040) increase in legionellosis incidence. The average monthly rainfall from May to September 1990-2002 was 10.4 cm compared to 15.7 cm from May to September 2003. This change in rainfall corresponds to an increased risk for legionellosis of approximately 14.6% (RR 1.146, 95% CI 1.067-1.231). Legionellosis incidence increased during periods of increased rainfall; identification of mechanisms that increase exposure and transmission of Legionella during rainfall might lead to opportunities for prevention.

On the use of zero-inflated and hurdle models for modeling vaccine adverse event count data.

We compared several modeling strategies for vaccine adverse event count data in which the data are characterized by excess zeroes and heteroskedasticity. Count data are routinely modeled using Poisson and Negative Binomial (NB) regression but zero-inflated and hurdle models may be advantageous in this setting. Here we compared the fit of the Poisson, Negative Binomial (NB), zero-inflated Poisson (ZIP), zero-inflated Negative Binomial (ZINB), Poisson Hurdle (PH), and Negative Binomial Hurdle (NBH) models. In general, for public health studies, we may conceptualize zero-inflated models as allowing zeroes to arise from at-risk and not-at-risk populations. In contrast, hurdle models may be conceptualized as having zeroes only from an at-risk population. Our results illustrate, for our data, that the ZINB and NBH models are preferred but these models are indistinguishable with respect to fit. Choosing between the zero-inflated and hurdle modeling framework, assuming Poisson and NB models are inadequate because of excess zeroes, should generally be based on the study design and purpose. If the study's purpose is inference then modeling framework should be considered. For example, if the study design leads to count endpoints with both structural and sample zeroes then generally the zero-inflated modeling framework is more appropriate, while in contrast, if the endpoint of interest, by design, only exhibits sample zeroes (e.g., at-risk participants) then the hurdle model framework is generally preferred. Conversely, if the study's primary purpose it is to develop a prediction model then both the zero-inflated and hurdle modeling frameworks should be adequate.

Enhanced airway Th2 response after allergen challenge in mice deficient in CC chemokine receptor-2 (CCR2).

To evaluate the role of CCR2 in allergic asthma, mutant mice deficient in CCR2 (CCR2(-/-)) and intact mice were sensitized with i.p. OVA with alum on days 0 and 7, and challenged by inhalation with nebulization of either OVA or saline. Airway hyperreactivity, measured by the methacholine-provoked increase in enhanced pause, was significantly increased (p < 0.05) in OVA-challenged CCR2(-/-) mutant mice, compared with comparably challenged CCR2(+/+) mice. OVA-challenged CCR2(-/-) mutants also were also found to have enhanced bronchoalveolar lavage fluid eosinophilia, peribronchiolar cellular cuffing, and Ig subclass switching, with increase in OVA-specific IgG(1) and IgE. In addition, RNase protection assay revealed increased whole lung expression of IL-13 in OVA-challenged CCR2(-/-) mutants. Unexpectedly, serum monocyte chemotactic protein-1 levels were 8-fold higher in CCR2(-/-) mutants than in CCR2(+/+) mice sensitized to OVA, but OVA challenge had no additional effect on circulating monocyte chemotactic protein-1 in either genotype. Ag stimulation of lymphocytes isolated from OVA-sensitized CCR2 mutants revealed a significant increase (p < 0.05) in IL-5 production, which differed from OVA-stimulated lymphocytes from sensitized CCR2(+/+) mice. These experiments demonstrate an enhanced response in airway reactivity and in lung inflammation in CCR2(-/-) mutant mice compared with comparably sensitized and challenged CCR2(+/+) mice. These observations suggest that CC chemokines and their receptors are involved in immunomodulation of atopic asthma.

Intratracheal priming with ovalbumin- and ovalbumin 323-339 peptide-pulsed dendritic cells induces airway hyperresponsiveness, lung eosinophilia, goblet cell hyperplasia, and inflammation.

Dendritic cells (DC) are the primary APC responsible for the capture of allergens in the airways and the shuttling of processed allergens to the draining lymph nodes where Ag presentation and T cell activation take place. The mechanism of this Ag handling and presentation in asthma is poorly understood. In addition, the feasibility of asthma induction by DC priming has not been directly tested. In this report an asthma model using intratracheally (i.t.) injected splenic DC was used to address these issues. DC pulsed with a model Ag OVA or the major MHC class II-restricted OVA T epitope peptide OVA(323-339) and instilled i.t. primed mice to exhibit asthma-like diseases. With OVA as the Ag, mice exhibit airway hyperresponsiveness (AHR), lung eosinophilia and inflammation, and pulmonary goblet cell hyperplasia. In OVA(323-339)-immunized mice, AHR and goblet cell hyperplasia were noted, with little eosinophilia and parenchymal inflammation. The latter finding provides evidence for dissociating AHR from eosinophilia. In both cases mediastinal node hypertrophy occurred, and high levels of Th2 cytokines were produced by the lung and mediastinal lymph node cells (LNC). Interestingly, mediastinal LNC also produced high levels of Th1 cytokines. Lung cells produced much less Th1 cytokines than these LNC. These results demonstrate that DC when introduced i.t. are potent in inducing asthma-like diseases by recruiting lymphocytes to the lung-draining lymph nodes and by stimulating Th2 responses and also suggest that the lung environment strongly biases T cell responses to Th2.

Dental guards: helpful or hazards?--a case report.

Dental guards are an airway adjunct recommended for patients at risk for dental injury during airway instrumentation; however, reportedly only 2% of anesthesiologists use dental guards during intubation. In this case report, a 64-year-old patient was admitted for a right retromastoid craniectomy with microvascular decompression of the fifth cranial nerve. The patient had crowns on all her maxillary teeth. The anesthesia team, which consisted of a student anesthetist, Certified Registered Nurse Anesthetist, and anesthesiologist, planned to prevent dental damage through the use of a dental guard (Bay Medical, Clearwater, Fla). Prior to intubation a dental guard was inserted on the upper teeth. Induction, intubation, and surgery were uneventful, but in the recovery area the patient complained of a sore throat. After transfer to the intensive care unit, the patient continued to complain of secretions and sore throat and was noted to have hoarseness. When a Yankauer suction catheter was inserted, the dental guard was discovered in the patient's mouth. Apparently during the busy sequence of events following intubation, the dental guard was overlooked and was displaced into the posterior oropharynx. Recommendations for the proper use of dental guards are needed to avoid complications; however, there is a scarcity of information available in the conventional anesthesia literature regarding this intubation adjunct. We recommend careful documentation, clear communication with all team members, and attention to avoid displacement during subsequent airway manipulation.

P-selectin and ICAM-1 mediate endotoxin-induced neutrophil recruitment and injury to the lung and liver.

The role of leukocyte adhesion molecules in endotoxin-induced organ injury was evaluated by administering intraperitoneal Salmonella enteritidis lipopolysaccharide (LPS) to wild-type (WT) mice, P-selectin-deficient mice, intercellular adhesion molecule (ICAM)-1-deficient mice, and P-selectin-ICAM-1 double-mutant mice. In WT mice, there was a sevenfold increase in the number of neutrophils present in the pulmonary vascular lavage fluid, and there were sevenfold more intracapillary neutrophils by electron-microscopic (EM) morphometry at 4 h after intraperitoneal LPS compared with that in control mice. Extravascular albumin accumulation increased approximately twofold in the lungs and liver of WT mice treated with LPS. In the double-mutant mice, although overall mortality after intraperitoneal LPS was not attenuated, there was a significant delay in mortality in the P-selectin-ICAM-1-deficient mutants compared with that in WT mice after intraperitoneal LPS (P < 0.01). Moreover, compared with LPS-treated WT mice, lung and liver extravascular albumin accumulation was significantly lower in LPS-treated P-selectin-ICAM-1 double-mutant mice. Lung myeloperoxidase activity, normalized per 1,000 circulating neutrophils, increased after endotoxin in WT and P-selectin-deficient mice but not in P-selectin-ICAM-1 double-mutant mice. In addition, lung and liver myeloperoxidase activity per 1,000 circulating neutrophils in endotoxin-treated ICAM-1-deficient mice and P-selectin-ICAM-1 double mutants was significantly lower compared with that in endotoxin-treated WT mice. These data suggest that P-selectin and ICAM-1 significantly contribute to lung and liver injury after systemic endotoxemia.

Intra-alveolar macrophage-inflammatory peptide 2 induces rapid neutrophil localization in the lung.

Endotoxin-induced lung injury is characterized by neutrophil infiltration of the lungs. The various mechanisms which mediate movement of neutrophils from vascular space to lung interstitium and alveoli remain unclear. Macrophage-inflammatory protein 2 (MIP-2) is a potent chemoattractant for neutrophils and may play a significant role in recruiting neutrophils in acute lung injury in rats. Experiments were performed in male Sprague Dawley rats to: (1) evaluate the kinetics of neutrophil influx in the lung following intraperitoneal administration of Salmonella enteritidis lipopolysaccharide (LPS); (2) determine the expression of transcripts for chemokines and adhesion molecules in the lung following intraperitoneal LPS; and (3) elucidate the effects of intra-alveolar instillation of recombinant rat MIP-2 on neutrophil influx into the lung. Intraperitoneal LPS resulted in an increase in neutrophil sequestration in the lung capillaries of rats as early as 45 min following administration, and there was a parallel increase in lung myeloperoxidase activity. There were also major increases in mRNA in whole-lung homogenates of LPS-treated rats for chemokines MIP-2 and KC (cytokine-induced neutrophil chemoattractant) and adhesion molecules P- and E-selectin at 1 and 2 h following LPS. When recombinant rat MIP-2 was instilled into the alveolar space of rats through a catheter wedged into a bronchus, there was profound neutrophil localization both in the vascular and alveolar space which significantly differed (P < 0.05) from the contralateral lungs of the same animals, and lungs of control animals instilled with control buffer. These observations reveal that MIP-2 is a potent chemoattractant in rat lungs, and suggest that chemoattractants locally released in alveoli can recruit neutrophils to those alveoli. This suggests that alveolar macrophages may play an important role in neutrophil sequestration in sepsis and other inflammatory lung diseases which produce a neutrophilic alveolitis.

Role of interleukin-1 in endotoxin-induced lung injury in the rat.

The effects of the recombinant interleukin-1 receptor antagonist (rIL-1ra) on the systemic vascular and lung injury following intraperitoneal Salmonella enteritidis lipopolysaccharide (LPS) were determined in male Sprague-Dawley rats. Initial experiments identified that maximal mortality occurred with an intraperitoneal LPS dose of 20 mg/kg, and this dose was used in subsequent experiments. Albumin permeability, measured in an ex vivo perfused heart-lung preparation from the rats 2 h after injection of LPS, was increased with endotoxin as was the wet:dry weight ratio. Pretreatment of the rats with intravenous rIL-1ra, 1 to 10 mg/kg, followed by a continuous intravenous infusion at 30 to 50 micrograms/kg/min resulted in restoration of blood pressure at 100 min following endotoxin administration. Moreover, coadministration of rIL-1ra with endotoxin totally prevented the rise in albumin permeability of the pulmonary vasculature and the increase in wet:dry lung weight ratios observed in rats treated with LPS alone. LPS injected intraperitoneally caused a marked decrease in circulating leukocyte count, an effect not reversed by rIL-1ra. RNA extraction of whole-lung homogenates revealed that mRNA for IL-1 beta was constitutively expressed in the absence of endotoxin, but transcripts increased progressively from 0.5 to 2 h after endotoxin administration. Increases in mRNAs for tumor necrosis factor-alpha (TNF-alpha) and for macrophage inflammatory protein-2 (MIP-2), a potent neutrophil chemoattractant, were also observed from 0.5 until 2 h after endotoxin administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of angiotensin II in renal vasoconstriction with acute hypoxemia and hypercapnic acidosis in conscious dogs.

To evaluate the role of renin-angiotensin in the renal vasoconstriction with combined acute hypoxemia and hypercapnic acidosis preceded by acute hypoxemia, we studied eight conscious mongrel uninephrectomized dogs with chronic renal catheters and controlled sodium intake (80 mEq/24 h x 4 days). The animals were studied during combined acute hypoxemia and hypercapnic acidosis (PaO2 34 +/- 1 mm Hg, PaCo2 57 +/- 1 mm Hg, pH 7.20 +/- 0.01) preceded by 80 min of acute hypoxemia (PaO2 34 +/- 1 mm Hg) during: (a) intrarenal infusion of vehicle (n = 8); or (b) intrarenal administration of the angiotensin II antagonist [Sar1,Ala8]-AII, 70 ng kg-1 min-1 (n = 8). The combination of acute hypoxemia and hypercapnic acidosis resulted in diminished effective renal plasma flow and increased renal vascular resistance during intrarenal vehicle infusion. Intrarenal [Sar1,Ala8]-AII did not abolish the renal vasoconstriction in the initial 20 min of this combined blood gas derangement but resulted in a more prompt return of the renal vascular variables toward control levels with continuation of the blood gas derangement for an additional 20 min, suggesting a role for angiotensin in renal vasoconstriction. These observations suggest that while renin-angiotensin may not mediate the initial renal vasoconstriction in the first 20 min of combined acute hypoxemia and hypercapnic acidosis, in uninephrectomized conscious dogs, it attenuates the spontaneous recovery of renal hemodynamic variables to baseline as the blood gas derangement continues.

Successful transplantation of marginally acceptable thoracic organs.

OBJECTIVE: This study evaluates the efficacy of personally inspecting marginal thoracic organ donors to expand the donor pool. SUMMARY BACKGROUND DATA: The present donor criteria for heart and lung transplantation are very strict and result in exclusion of many potential thoracic organ donors. Due to a limited donor pool, 20-30% of patients die waiting for transplantation. METHODS: The authors have performed a prospective study of personally inspecting marginal donor organs that previously would have been rejected by standard donor criteria. RESULTS: Fourteen marginal hearts and eleven marginal lungs were inspected. All 14 marginal hearts and 10 of the marginal lungs were transplanted. All cardiac transplant patients did well. The mean ejection fraction of the donor hearts preoperatively was 39 +/- 11% (range 15-50%). Postoperatively, the ejection fraction of the donor hearts improved significantly to 55 +/- 3% (p < 0.002). Nine of the ten lung transplant patients did well and were operative survivors. Our donor pool expanded by 36% over the study period. CONCLUSIONS: The present donor criteria for heart and lung transplantation are too strict. Personal inspection of marginal thoracic donor organs will help to maximize donor utilization.

Lobbying: the best kind can be self-taught.

The Pennsylvania Medical Society pays professional staff to lobby for its members, as do almost all specialty groups in each state and in Washington, DC. Paid lobbyists have specific legislative responsibilities, but their efforts cannot be the only ones put forth on behalf of physician interests.

Combined acute hypoxemia and hypercapnic acidosis increases atrial natriuretic polypeptide in conscious dogs.

To evaluate the changes in atrial natriuretic polypeptide during acute hypoxemia and acute hypercapnic acidosis, conscious mongrel dogs with controlled sodium intake were evaluated in four protocols: (1) 80 min of acute hypoxemia (PaO2 = 34 +/- 1 mm Hg) followed by 40 min of combined hypoxemia and hypercapnic acidosis (PaO2 = 38 +/- 1 mm Hg, PaCO2 = 60 +/- 3 mm Hg, pH = 7.15 +/- 0.03) (n = 7); (2) 40 min of combined acute hypoxemia and hypercapnic acidosis (PaO2 = 36 +/- 1 mm Hg, PaCO2 = 56 +/- 2 mm Hg, pH = 7.20 +/- 0.03) induced immediately following control measurements (n = 5); (3) 120 min of acute hypercapnic acidosis (PaCO2 = 58 +/- 1 mm Hg, pH = 7.20 +/- 0.01) (n = 5), and (4) 120 min of normoxemia and normocapnia (n = 7). These studies did not observe any association between urinary sodium excretion and circulating atrial natriuretic polypeptide during acute blood gas derangements in conscious dogs. The natriuresis with acute hypoxemia or acute hypercapnic acidosis was unaccompanied by change in plasma atrial natriuretic polypeptide concentrations. Conversely, the rise in circulating atrial natriuretic polypeptide during combined acute hypoxemia and hypercapnic acidosis was not associated with an increase in urinary sodium excretion. These observations do not exclude a role for atrial natriuretic polypeptide in altering sodium excretion during acute blood gas derangements, since the effects of this autacoid on renal sodium excretion may have been offset by other counterregulatory mechanisms of sodium excretion activated during the acute blood gas derangement.

Role of intrarenal angiotensin II and alpha-adrenoceptors in renal vasoconstriction with acute hypoxemia and hypercapnic acidosis in conscious dogs.

To evaluate our previous observation of renal vasoconstriction during combined acute hypoxemia and hypercapnic acidosis preceded by acute hypoxemia, we studied 13 conscious mongrel uninephrectomized dogs with chronic renal catheters and controlled sodium intake (80 meq/day for 4 days). Five dogs were studied during combined acute hypoxemia (PaO2, 37 +/- 1 mm Hg) and hypercapnic acidosis (PaCO2, 59 +/- 1 mm Hg; pH 7.20 +/- 0.01). Each dog was studied during infusion of 1) the intrarenal vehicle (n = 5), 2) the intrarenal alpha 1-antagonist prazosin (0.2 micrograms.kg-1.min-1, n = 5), 3) intrarenal [Sar1,Ala8]angiotensin II (70 ng.kg-1.min-1, n = 5), and 4) intrarenal prazosin and [Sar1,Ala8]angiotensin II (n = 4). Immediate induction of combined hypoxemia and hypercapnic acidosis after control measurements during intrarenal vehicle infusion resulted in a decrease in effective renal plasma flow and glomerular filtration rate, increase in renal vascular resistance, and decrease in filtered sodium load in the first 20 minutes of the blood gas derangement. Intrarenal administration of [Sar1,Ala8]angiotensin II failed to reverse the effects of the combined blood gas derangement on renal function. In contrast, intrarenal prazosin administration either alone or in combination with [Sar1,Ala8]angiotensin II abrogated the increase in renal vascular resistance, decrease in glomerular filtration rate, and fall in filtered sodium load. These studies identify a major role for alpha 1-adrenoceptors in the renal vasoconstriction during combined hypoxemia and hypercapnic acidosis.

Hypercoagulability in a patient with Marfan syndrome.

A 39 year old man with Marfan syndrome presented with multiple pulmonary emboli and renal, hepatic, and splenic infarcts of unknown aetiology. The combination of thromboemboli and physical features initially suggested homocystinuria; however, laboratory examination showed no evidence for this disorder. Laboratory evaluation identified no coagulation abnormalities. This patient represents the unusual occurrence of hypercoagulability in a patient with Marfan syndrome.

Effect of V1/V2-receptor antagonism on renal function and response to vasopressin in conscious dogs.

To characterize effects of V1- and V2-receptor stimulation on renal function, eight conscious mongrel female dogs were studied in four separate studies greater than or equal to 2 wk apart during the following six consecutive 20-min periods: 1) intrarenal administration of the full V1/V2-receptor antagonist SKF 105494 (100 ng.kg-1.min-1) during basal circulating vasopressin (VP) levels (n = 3), 2) elevation of renal arterial plasma VP concentrations by intrarenal administration of exogenous arginine VP (0.05 mU.kg-1.min-1, n = 5), 3) simultaneous administration of SKF 105494 at (100 ng.kg-1.min-1) with intrarenal administration of exogenous VP (0.05 mU.kg-1.min-1; n = 5), and 4) intrarenal vehicle alone (n = 5). When administered during conditions of basal circulating endogenous VP, the full receptor antagonist effects were limited to opposition of hydrosmotic effects of VP. Elevation of renal arterial plasma VP levels through infusion of exogenous VP resulted in decreased renal plasma flow, glomerular filtration rate, osmolar clearance, urinary flow rate, and free water clearance and increased urine osmolality. These effects were all abolished by simultaneous administration of V1/V2-receptor antagonist. These data suggest that, under basal low levels of circulating VP, VP only influences renal water excretion. However, when plasma VP concentrations are elevated, VP may contribute to renal vasoconstriction and secondarily to reduced solute excretion, in addition to its effects on free water clearance.

First single lung transplant in Virginia.

Lung transplantation is now established as a clinical reality for patients with irreversible, lethal pulmonary conditions. We report the first successful application of this treatment modality in Virginia.

Role of vasopressin in renal vascular changes with hypoxemia and hypercapnic acidosis in conscious dogs.

To evaluate the role of vasopressin in the renal changes during combined acute hypoxemia and acute hypercapnic acidosis, eight conscious female mongrel dogs prepared with controlled sodium intake at 80 meq/24 h for 4 days were studied in one of the following six protocols: acute hypoxemia (80 min, arterial PO2 34 +/- 1 mmHg) followed by combined acute hypoxemia and hypercapnic acidosis (40 min, arterial PO2 35 +/- 1 mmHg, arterial PCO2 58 +/- 1 mmHg, pH = 7.20 +/- 0.01) during 1) intrarenal vehicle at 0.5 ml/min (N = 8); or 2) intrarenal infusion of vasopressin V1-receptor antagonist [d(CH2)5Tyr(Me)]AVP at 5 ng.kg-1.min-1 (N = 5); and with normal gas exchange during 3) intrarenal vasopressin at 0.05 mU.kg-1.min-1 (N = 8); 4) simultaneous infusion of intrarenal vasopressin and [d(CH2)5Tyr(Me)]AVP, 5 ng.kg-1.min-1 (N = 4); 5) intrarenal [d(CH2)5Tyr(Me)]AVP, 5 ng.kg-1.min-1 (N =4); and 6) intrarenal vehicle at 0.5 ml/min (N = 7). Intrarenal infusion of a subpressor dose of vasopressin resulted in a transient decrease in glomerular filtration rate and effective renal plasma flow over the first 20 min of infusion, suggesting that vasopressin induced nonsustained vasoconstriction of the renal vasculature. Intrarenal administration of [d(CH2)5Tyr-(Me)]AVP failed to block the fall in glomerular filtration rate or effective renal plasma flow when renal arterial blood vasopressin levels were elevated by intrarenal administration of exogenous vasopressin or by elevated systemic arterial endogenous circulating vasopressin during combined acute hypoxemia and hypercapnic acidosis. These data suggest that vasopressin (V1-receptor stimulation) does not play an important role in the renal vasoconstriction during combined acute hypoxemia and hypercapnic acidosis in conscious dogs.

Effect of alpha-adrenergic blockade on the cardiovascular responses to hypoxemia and hypercapnic acidosis in conscious dogs.

In order to evaluate the role of the alpha-adrenergic system in the systemic and renal hemodynamic changes of the acute combined blood gas derangement, seven conscious mongrel dogs in careful sodium balance (80 mEq/day for 4 days) were evaluated. Each animal was evaluated during combined acute hypoxemia (PaO2 = 35 +/- 1 mm Hg) and hypercapnic acidosis (PaCO2 = 56 +/- 2 mm Hg; pH = 7.18 +/- 0.01) with (i) vehicle (D5W) alone and (ii) alpha 1-adrenergic blockade with prazosin, 0.1 mg/kg iv. Mean arterial pressure increased during the combined blood gas derangement with vehicle. In contrast, mean arterial pressure fell during combined acute hypoxemia and hypercapnic acidosis with alpha 1-adrenergic blockade. The mechanism for abrogation of the rise in mean arterial pressure during the combined blood gas derangement by alpha 1-adrenergic blockade appeared to be through attenuation of the rise in cardiac output rather than an exaggerated fall in total peripheral resistance. These observations suggest that the alpha-adrenergic system is important in circulatory homeostasis during the combined blood gas derangement.

Augmentation of hypoxic pulmonary vasoconstriction in the isolated perfused rat lung by in vitro antagonists of endothelium-dependent relaxation.

The role of the endothelium in hypoxic constriction of the intact pulmonary vascular bed has not been clearly elucidated. To test for a possible role for endothelium-derived relaxing factor(s) (EDRF) in the hypoxic pressor response, isolated, whole blood-perfused rat lungs from male Sprague-Dawley rats treated with meclofenamate were prepared. Three protocols were performed, including: (a) normal saline (control); (b) the putative EDRF inhibitors, eicosatetraynoic acid (ETYA, 1 X 10(-4) M) or nordihydroguaiaretic acid (NDGA, 1 X 10(-4) M) versus vehicle DMSO; and (c) the putative EDRF inhibitor hydroquinone (HQ, 1 X 10(-4) M) versus vehicle ethyl alcohol (ETOH). The pulmonary pressor response to angiotensin II (Ang II, 0.25 micrograms) injections alternated with 6-min periods of hypoxic ventilation (3% O2, 5% CO2) was measured before and after the administration of saline, inhibitors, or vehicles. The administration of the EDRF inhibitors ETYA, NDGA, and HQ resulted in a marked accentuation of the hypoxic pressor response that was not seen in the controls (P less than 0.05). In separate experiments, lungs precontracted with norepinephrine (1 X 10(-6) M) were pretreated with edrophonium (1 X 10(-4) M) and then observed for endothelium-dependent vasodilator responses to acetylcholine at increasing doses (1 X 10(-7)-1 X 10(-4) M). Administration of ETYA, NDGA, or HQ abrogated the observed vasodilatation to acetylcholine, which was not seen with vehicles alone (P less than 0.01). These studies suggest an important role for the endothelium in pulmonary vascular responsiveness to alveolar hypoxia through possible release of a relaxing factor(s) that attenuates the degree of pulmonary arterial constriction.