Platelets and the vascular responses to arachidonic acid in dogs.

UNLABELLED: Platelets are rich in components of the prostaglandin synthetase system which converts arachidonic acid into vasoactive and platelet-active prostanoate and nonprostanoate compounds. Repeated injections of arachidonic acid in dogs cause hypotension of reproducible magnitude and lower circulating platelet counts with each injection. However, the circulatory response to injected arachidonic acid was unchanged when platelet-poor blood was exchanged in dogs. Moreover, in the hind limb preparation and the isolated lung lobe, the vasoactive responses to arachidonic acid were indistinguishable whether perfused with whole blood or an artificial perfusate. CONCLUSION: the vascular responses to arachidonic acid do not appear dependent on the presence of platelets.

Vasoconstrictor response to arachidonic acid in the isolated hind limb of the dog.

1 Arachidonic acid(AA) (25-200 mug/kg) produced a dose-related increase in perfusion pressure in dog isolated hind limbs perfused with either blood or a platelet-free perfusate. 2 Prostaglandin E2 produced vasodilation while prostaglandin F2 alpha produced no vascular change at these administered doses. 3 Phentolamine did not alter the arachidonic acid response, eliminating possible alpha-adrenoceptor mediation. 4 Aspirin and idomethacin blocked the vasoconstrictor response to AA. 5 This study indicates that a vasoactive intermediate in prostaglandin synthesis can be elaborated in the absence of platelets.

Effect of verapamil on the pulmonary vasoconstrictor action of prostaglandin F2 alpha and a synthetic PGH2 analogue.

1 The vasopressor response to prostaglandin F2 alpha (PGF2 alpha) and to ((15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano)-prosta-5Z, 13E-dienoic acid) (U-46619) in the canine isolated lung lobe was significantly attenuated following the administration of verapamil. 2 The pressor response to arachidonic acid (AA) was not affected by the presence of verapamil. 3 The pulmonary pressor effect of PGF2 alpha and U-46619 is dependent, at least in part, on Ca2+ influx into vascular smooth muscle cells. 4 The pulmonary pressor response to AA cannot be attributed to PGF2 alpha or to endoperoxide intermediates but to some other product dependent on intracellular calcium stores.

Tromboxane B2 inhibits the pulmonary inactivation of prostaglandin E2 in the dog.

1 The systemic vasodepressor response to intravenously administered prostaglandin E2 (PGE2, 0.3, 1.0 and 3.0 micrograms/kg) is potentiated during intravenous infusion of thromboxane B2 (TXB2, 1.0 micrograms kg-1 min-1) in the anaesthetized dog. 2 The augmented haemodynamic response returns toward control values following cessation of the TXB2 infusion. 3 The systemic haemodynamic responses to intra-arterially administered PGE2, PGF2 alpha and PGI2 as well as intravenously administered PGF2 alpha and PGI2 are not altered by TXB2 infusion. 4. This study suggests that TXB2 inhibits the pulmonary inactivation of PGE2. 5 Arachidonic acid metabolites may interact, producing haemodynamic responses differing from their individual effects.

Effect of TMB-8 on the pulmonary vasoconstrictor action of prostaglandin F2 alpha and the thromboxane mimic, U 46619.

1 TMB-8 (8-(N,N-diethylamino)octyl-3,4,5 trimethoxybenzoate HCl), an intracellular calcium antagonist, had no direct action on the pulmonary vasculature of the perfused canine lung lobe preparation. 2 The pulmonary pressor response to the thromboxane mimic, U46619, was not affected by TMB-8. 3 The vasopressor response to prostaglandin F2 alpha (PGF 2 alpha) was significantly attenuated but not completely blocked by TMB-8. 4 We conclude that the pulmonary pressor response to PGF 2 alpha is dependent on both intracellular and extracellular calcium pools for contraction and that U46619 facilitates either solely extracellular calcium influx or mobilizes an intracellular calcium pool not inhibited by TMB-8.

The acute and insidious onset of pulmonary metastatic transitional cell carcinoma.

Transitional cell carcinoma is a common urologic neoplasm. Although pulmonary metastases from this tumor are often not appreciated clinically, they are frequently documented in autopsy studies. Therefore, the clinical recognition of this condition can be problematic. To illustrate this point, we present three patients with progressive unexplained dyspnea and histories of transitional cell carcinoma. Since ineffective and possibly detrimental therapeutic approaches may be initiated, a high index of suspicion for pulmonary metastatic embolization must be maintained. Early histologic identification of these metastatic emboli and initiation of effective chemotherapy may prove beneficial for improved quality of life.

Mechanical ventilation in hematopoietic stem cell transplantation: can We effectively predict outcomes?

BACKGROUND: Survival rates from mechanical ventilation (MV) in allogeneic bone marrow transplantation are poor, but little is known about the need for and outcomes from MV in patients who undergo autologous hematopoietic stem cell transplantation (AHSCT). STUDY OBJECTIVE: To determine the frequency of and risk factors for the use of MV in recipients of AHSCT and to identify predictors of survival in mechanically ventilated AHSCT patients. DESIGN: Retrospective, cohort analysis SETTING: Tertiary-care, university-affiliated medical center. PATIENTS: One hundred fifty-nine consecutive patients who underwent AHSCT. INTERVENTIONS: Patient surveillance and data collection. MEASUREMENTS AND RESULTS: The primary outcome measure was the need for MV, and the secondary end point was survival after MV. Of 159 patients, 17 required MV (10. 7%). Three variables were associated with the need for MV: increasing age, use of total body irradiation in the conditioning regimen, and treatment with amphotericin B. As a screening test to predict the need for MV, no risk factor had a sensitivity or specificity > 82%. Three of the 17 mechanically ventilated patients (17.6%) survived to discharge. Only the mean APACHE (acute physiology and chronic health evaluation) II score separated survivors from nonsurvivors (21.7 vs 31.4; p = 0.029). Both the duration of MV and the length of stay in the ICU were similar in survivors and nonsurvivors. CONCLUSIONS: We conclude that MV is infrequently needed following AHSCT. Although survival after MV in these patients is limited, clinical variables do not reliably allow clinicians to prospectively identify patients destined to die.

Project back-on-track at 1 year: a delinquency treatment program for early-career juvenile offenders.

OBJECTIVE: This study assessed the effectiveness of Project Back-on-Track, an after-school diversion program that uses a multimodal approach for the treatment of early-career juvenile offenders. METHOD: Project Back-on-Track completers (30 of 41 enrollees; 73%), aged 9 to 17 years, 63% female, participated in a 4-week cycle of treatment consisting of group and family therapies, parent groups, educational sessions, community service projects, and empathy-building exercises. These youths attended the program 2 hours per day, 4 days a week, allowing for 32 hours of contact with the program per cycle; parents attended the program for 15 hours per cycle. Most youths were referred for violent offenses and met criteria for conduct disorder. RESULTS: Project Back-on-Track completers were significantly less likely than matched controls to have committed subsequent criminal offenses at 12 months. In addition, they had significantly fewer subsequent criminal charges at 9- and 12-month follow-up intervals than the control group. By decreasing the frequency of criminal recidivism, it is estimated that Project Back-on-Track resulted in savings to society of approximately $1,800 per youth enrolled after 1 year. CONCLUSION: At 1-year follow-up, findings suggest that treatment through Project Back-on-Track was effective in reducing criminal recidivism and costs in a population of early-career juvenile offenders.

Upper airway complications of smoking.

Tobacco smoke has a myriad of acute and chronic effects on the upper airway. These problems can range from aggravating inflammatory reactions to life threatening malignancies. Cessation of smoking is the key to successful resolution of many upper airway complaints. An increased awareness of these disease processes can improve early diagnosis and appropriate treatment. A better awareness of these processes may facilitate physicians in counseling patients about smoking.

Multidisciplinary airway stent team: a comprehensive approach and protocol for tracheobronchial stent treatment.

Tracheobronchial stents are being used with increasing frequency to treat major airway obstruction from both malignant and benign processes. Traditionally, stents have been placed via rigid bronchoscopy, flexible bronchoscopy, or fluoroscopy by members of various individual disciplines. We describe a novel multidisciplinary airway stent team (MAST) protocol for tracheobronchial stent placement and endoscopic management of major airway obstruction. A patient with symptoms of airway obstruction is generally first evaluated with a computed tomography scan and a videotaped flexible bronchoscopy. These studies are reviewed by the team otolaryngologist, pulmonologist, and interventional radiologist. A treatment plan, including the type and location of stents and the need for adjuvant therapies, is formulated. Stent placement is performed in the operating room under general anesthesia. Rigid bronchoscopy, with flexible bronchoscopy and fluoroscopy as needed, allows precise stent placement and the best use of various therapeutic methods. The MAST protocol combines the skills, knowledge, and unique therapeutic options of specialists from otolaryngology, pulmonology, and interventional radiology. This approach allows optimal stent placement and the use of other endobronchial therapies, including laser ablation, balloon dilation, photodynamic therapy, cryotherapy, and brachytherapy. A protocol with representative case reports is presented, along with a review and comparison of several of our most commonly used stents. Otolaryngologists who practice bronchoesophagoscopy, by virtue of their operative skill and knowledge of airway management, are well equipped to become leaders of MASTs and are encouraged to initiate MASTs at their institutions.

Effects of intracellular and extracellular calcium blockers on the pulmonary vascular responses to PGF2 alpha and U46619.

In this study, TMB-8, an intracellular calcium antagonist, and verapamil, an extracellular calcium antagonist, were used simultaneously to elucidate the role of calcium in the pulmonary vasopressor response induced by PGF2 alpha and U46619. The pulmonary vasoconstrictor action of these two agonists was evaluated in the canine isolated lung lobe preparation. Lobar arterial pressure was constantly monitored and changes in arterial pressure were recorded as a percentage from baseline. Control responses to PGF2 alpha (42.0 +/- 8.2%) and U46619 (47.2 +/- 7.0%) were obtained prior to the administration of TMB-8 and verapamil. After administration of TMB-8 and verapamil, the PGF2 alpha (7.4 +/- 3.1%) and U46619 (28.8 +/- 6.2%) responses were significantly attenuated. We conclude that the PGF2 alpha pressor response is dependent on a TMB-8-sensitive intracellular calcium pool and a verapamil-sensitive slow-channel calcium influx. In contrast, the degree of attenuation of the U46619 response was similar to the vasopressor response in the presence of verapamil alone, as described previously. This indicates a direct dependence on extracellular calcium. An additional source of calcium insensitive to verapamil and TMB-8 may also be activated and contribute to the pulmonary vasoconstrictor action. These results suggest that each agonist possesses a mechanism of action distinctly different from the other.

Effect of cyclooxygenase inhibition on the pulmonary vasodilator response to furosemide.

Furosemide is a potent vasodilator of the systemic arterial and venous systems. The mechanism of vasodilatation, however, remains unclear. We investigated the vasodilatory effect of furosemide and its relation to endogenous prostaglandins (PGs). In the isolated canine lung lobe, furosemide significantly decreased mean pulmonary artery pressure. This effect was inhibited by indomethacin. Furosemide also attenuated the pulmonary vasoconstrictor response to the endoperoxide analog U46619 and PGF2 alpha. The pulmonary pressor response to a submaximal constrictor dose of arachidonic acid was significantly enhanced by furosemide, however, the pressor response to a maximal constrictor dose of arachidonic acid was attenuated, although not significantly. In animals pretreated with indomethacin, furosemide had no effect on the vascular response to PGF2 alpha, but the response to U46619 was significantly increased. Prostacyclin reduced pulmonary perfusion pressure and inhibited the pressor response to PGF2 alpha and U46619. Furosemide failed to alter inactivation of PGE2 on pulmonary lobe transit. We conclude that: 1) the vasodilatory activity of furosemide is mediated by increased production and not decreased metabolism of an endogenous cyclooxygenase product; 2) the effect of prostacyclin on vascular reactivity is similar to that of furosemide; and 3) local formation of prostacyclin by vascular tissue most likely mediates the vascular activity of furosemide.

Cardiovascular responses to leukotriene C4 in the rat.

Bolus injections of leukotriene C4, (LTC4; 0.1 to 10 micrograms/kg) were administered to anesthetized closed-chest rats i.v., before and min after administration of indomethacin (2 mg/kg). Systemic arterial pressure (SAP) and pulmonary arterial pressure (PAP) were monitored continuously. LTC4 produced dose-dependent changes in SAP and PAP. The characteristic SAP response to LTC4 (4 micrograms/kg) consisted of an initial transient rise (16 mm Hg), followed by a sustained decrease (18 mm Hg). LTC4 produced only a decrease in PAP (4 mm Hg). Cardiac output (CO) and heart rate (HR) were measured in the control period and during the maximum increase and decrease in SAP. Decreases in CO (32 ml/min) and HR (15 beats/min) occurred during the initial rise in SAP and further declined (36 ml/min and 21 beats/min, respectively) during the systemic hypotensive phase. Total peripheral resistance markedly increased during the transient rise in SAP (67%). Indomethacin potentiated the transient rise in SAP and attenuated systemic and pulmonary hypotensive responses induced by LTC4. Decreases in CO and HR induced by LTC4 were also attenuated by indomethacin, but total peripheral resistance was not significantly altered. These observations describe a characteristic hemodynamic response to LTC4 in the rat that reflects the composite actions of LTC4 as well as those of prostanoate compounds that may be synthesized and released after LTC4 administration.

Cardiovascular and pulmonary effects of thromboxane B2 in the dog.

The hemodynamic properties of thromboxane B2 (TxB2), a product of prostaglandin endoperoxide metabolism, have not been thoroughly described. TxB2 is a bronchoconstrictor, but its effects on the systemic circulation and circulating platelets are unknown. Its precursor, thromboxane A2(TxA2), is a potent vasoconstrictor as well as a platelet-aggregating agent. Using intact anesthetized dogs, we investigated the effects of TxB2 on pulmonary artery pressure (PAP), airway pressure (AP), systemic arterial pressure (SAP), and myocardial contractility (MC). Vascular responses were evaluated in relation to changes in platelet population and aggregability. Intravenous TxB2 (25 and 50 micrograms/kg) increased AP (mean 62% and 69%) and PAP (50% and 86%), respectively, whereas SAP and MC responses were inconsistent. Left ventricular injections (25 micrograms/kg) also increased AP (36%) and PAP responses were inconsistent. Left ventricular injections (25 micrograms/kg) also increased AP (36%) and PAP (36%). Intraventricular administration of TxB2 produced a consistent elevation of SAP (10%) with a concomitant fall in MC (11%). These vascular responses were not consistent with alterations in platelet number or aggregability. A tachyphylactic response to TxB2 developed in AP and PAP at both dose levels and with both routes of administration. Intravenous and intraventricular TxB2 (25 micrograms/kg) produced a parallel decreasing response in PAP, suggesting the possible saturation of TxB2 binding sites or the depletion of a catabolic enzyme in the lung.

Antagonism of the pulmonary vasoconstrictor response to prostaglandin F2alpha by N-dimethylamino substitution of prostaglandin F2alpha.

Efforts to develop an in vivo prostaglandin (PG) antagonist have met with limited success. In this study, N-dimethylamino analogs of PGF2alpha which have proven to be effective in vitro prostaglandin antagonists, were tested for antagonism to the PGF2alpha and arachidonic acid (AA) responses in the canine lung lobe preparation. PGF2alpha (1 microgram/kg) and AA (100 microgram/kg) increased lobar arterial pressure by 54 and 83%, respectively. Infusion of analogs did not change lobar arterial pressure. N-dimethylamine PGF2alpha (0.8-3.2 microgram/ml) antagonized the PGF2alpha response by 66 to 79%. N-dimethylamide PGF2alpha (1.6-8.0 microgram/ml) produced a dose-dependent antagonism (24-75%) with an IC50 value of 3.8 microgram/ml. Neither analog significantly attenuated the pulmonary response to AA. Thus, these N-dimethylamino analogs of PGF2alpha exhibit a potency which is superior to previous in vivo prostaglandin antagonists. In addition, they have effectively differentiated the pulmonary vascular responses of AA and PGF2alpha.

Cardiovascular responses to PGI2 (prostacyclin) in the dog.

Arachidonic acid (AA) produces characteristic hemodynamic changes in the canine circulation. These responses are blocked by prostaglandin (PG) synthetase inhibitors, indicating that AA and its nonprostanoic metabolites are not vasoactive. The hemodynamic effects of the cyclic endoperoxides, thromboxanes, and PGD2, PG2, and PGF2a differ from those produced by AA. PGI2, a newly identified product of AA, is reported to relax arterial strips. However, its cardiac and systemic effects are unknown. In 12 open-chest, anesthetized dogs, PGI2 (0.25-5.0 microgram/kg) produced a dose-related decrease in systemic arterial pressure (BP) and myocardial contractile force (MCF). In five left ventricular bypass preparations, PGI2 produced only a slight decrease in MCF at all doses, whereas the BP decreases were parallel to those in the intact preparation. AA, PGD2, PGE2, and PGI2 were administered in random order by bolus intravenous injections in approximately equidepressor doses to intact dogs. BP fell with each agent (AA, 300 microgram/kg, -25 percent; PGD2, 5 microgram/kg, -26 percent; PGE2, 5 microgram/kg, -26 percent PGI2, 0.5 microgram/kg, -26 percent). The vasodepressor action of PGI2 was approximately 10 times greater than that of PGD2 and PGE2. Pulmonary arterial pressure (PAP) rose significantly with PGD2 and PGE2 (AA, -1 percent; PGD2 +66 percent; PGE2, +20 percent; PGI2, -1 percent). Only PGE2 had a significant effect on MCF (AA, +7 percent; PGD2, +5 percent, PGE2, +20 percent; PGI2, -0.3). At this dose, PGI2 resembles AA in that it has little effect on either PAP or MCF. Of all known AA metabolites the response to PGI2 most closely resembles that of exogenous AA in the dog.

Catheterization of the pulmonary artery in the closed-chest rat.

A simple technique has been devised to catheterize the pulmonary artery in rats for measurement of pulmonary artery pressure. A no. 3 1/2 French umbilical vessel catheter (Argyle), angled to 90 degrees over the distal 1 cm, was introduced into the right external jugular vein of the anesthetized (50 mg/kg pentobarbital sodium, ip) rat (male Wistar, 250-350 g). With the angle directed anteriorly, the catheter was inserted 2.5 cm proximally, which placed the catheter in the right atrium. The catheter was rotated 90 degrees counterclockwise and inserted 1.0 cm further, which placed the catheter in the right ventricle. Advancement of the catheter an additional 1.5 cm allowed placement in the pulmonary artery. Placement at each stage was confirmed by the respective pressure contours. This technique is easily and rapidly performed and has many potential applications in measuring parameters of the pulmonary circulation in a variety of small laboratory animals.

Selective antagonism of the systemic vasodepressor response to PGE1 by d,1-11, 15-bisdeoxy PGE1.

Several bisdeoxy PGE1 analogs are potent, competitive antagonists of PGE1-induced colonic contractions in the gerbil. The efficacy of these analogs in antagonizing PGE1-mediated systemic vasodepression has not been previously demonstrated. In this study, serial doses of PGs were administered before, during and after infusion of d,1-11, 15-bisdeoxy PGE1. Bolus injections of PGE1 (3.0 muk/kg), PGE2 (3.0 micrograms/kg) and PGI2 (0.3 microgram/kg) were administered via the right external jugular vein to male Wistar rats. PGE1, PGE2 and PGI2 decreased systemic arterial pressure 41%, 38% and 38%, respectively. The PGE1 analog was infused (200 micrograms/kg/min) through the right common carotid artery. The analog itself had no effect on mean systemic arterial pressure, but maximum reversible inhibition (51%) of PGE1-mediated vasodepression occurred following a 50 minute infusion. No significant effect of the PGE1 analog was observed on PGE2 or PGI2-mediated vasodepression. These data demonstrate the ability to antagonize PGE1-mediated vasodepression, and to differentiate the vascular responses to PGE1 and PGE2 or PGI2.