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Biomedical subjects

A P Fishman

Publications and source records attributed to A P Fishman.

At least 19 recordsLinked to original sources
PubMed1992

Role of lung inflation in control of air breath duration in African lungfish (Protopterus annectens).

Studies were conducted in the African lungfish (Protopterus annectens) to investigate the role of lung inflation on control of the duration of the lung breath. The studies were done in decerebrate spinalectomized animals. Two types of tests were performed: 1) a no-inflation test (airway occluded) in which the lungs were not inflated during an air breath, and 2) an inflation test in which the lungs were inflated at the onset of the lung breath to different levels of intrapulmonary pressure (2.5, 5.0, 7.5, and 10.0 cmH2O). Lung inflation shortened the duration of the lung breath. The relationship between intrapulmonary pressure and breath duration was curvilinear and similar to the relationship between tidal volume and inspiratory duration in mammals. Likewise, the relationship could be described by a hyperbola with a linear relationship between intrapulmonary pressure and the inverse of breath duration. This relationship was essentially not affected by changing the composition of the gas used to inflate the lungs: air, oxygen, or nitrogen. Vagotomy, however, largely abolished the effect of lung inflation on breath duration. Because there is such similarity between these results and effect of lung inflation on control of inspiratory time in mammals, it is postulated that neural circuits for control of respiratory timing were already developed and similar in the lungfish. Because the muscles used in the lungfish to ventilate the lung are totally different (buccal force pump) from those in mammals, the neural circuits for timing control and those for shaping the pattern of motor output appear to be separate.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Survival in patients with primary pulmonary hypertension. Results from a national prospective registry.

OBJECTIVE: To characterize mortality in persons diagnosed with primary pulmonary hypertension and to investigate factors associated with survival. DESIGN: Registry with prospective follow-up. SETTING: Thirty-two clinical centers in the United States participating in the Patient Registry for the Characterization of Primary Pulmonary Hypertension supported by the National Heart, Lung, and Blood Institute. PATIENTS: Patients (194) diagnosed at clinical centers between 1 July 1981 and 31 December 1985 and followed through 8 August 1988. MEASUREMENTS: At diagnosis, measurements of hemodynamic variables, pulmonary function, and gas exchange variables were taken in addition to information on demographic variables, medical history, and life-style. Patients were followed for survival at 6-month intervals. MAIN RESULTS: The estimated median survival of these patients was 2.8 years (95% Cl, 1.9 to 3.7 years). Estimated single-year survival rates were as follows: at 1 year, 68% (Cl, 61% to 75%); at 3 years, 48% (Cl, 41% to 55%); and at 5 years, 34% (Cl, 24% to 44%). Variables associated with poor survival included a New York Heart Association (NYHA) functional class of III or IV, presence of Raynaud phenomenon, elevated mean right atrial pressure, elevated mean pulmonary artery pressure, decreased cardiac index, and decreased diffusing capacity for carbon monoxide (DLCO). Drug therapy at entry or discharge was not associated with survival duration. CONCLUSIONS: Mortality was most closely associated with right ventricular hemodynamic function and can be characterized by means of an equation using three variables: mean pulmonary artery pressure, mean right atrial pressure, and cardiac index. Such an equation, once validated prospectively, could be used as an adjunct in planning treatment strategies and allocating medical resources.

Adult↗
PubMed1991

The management of primary pulmonary hypertension.

Primary pulmonary hypertension is a clinical syndrome characterized by pulmonary hypertension in the absence of sufficient underlying cardiac, parenchymal pulmonary, or systemic disease to account for it. The population of patients with primary pulmonary hypertension is a heterogeneous one, both clinically and histologically. As the etiologic mechanisms are unknown, therapy is directed toward the consequences of the pulmonary vascular process. Oxygen supplementation, the use of digoxin and diuretics for symptomatic heart failure, and anticoagulation all may have a role in treating primary pulmonary hypertension, although vasodilator therapy has been the main area of investigation. Screening for vasodilator responsiveness, defining a favorable vasodilator effect, predicting long-term effectiveness, and deciding who to treat have all been controversial. New approaches, such as use of high-dose calcium channel-blocking agents and continuous intravenous infusion of prostacyclin (an investigational agent), have recently been proposed. When medical therapies are exhausted, heart-lung or lung transplantation has increasingly become an option for selected patients.

Heart-Lung Transplantation↗
PubMed1990

Chronic cor pulmonale. Etiology and management.

Cor pulmonale is right ventricular enlargement secondary to pulmonary hypertension. Although most often caused by parenchymal lung disease, derangements of the ventilatory drive, the respiratory pumping mechanism, or the pulmonary vascular bed may also result in right ventricular hypertrophy and dilatation. Arterial hypoxemia (and resultant polycythemia), hypercapnia, and respiratory acidosis all contribute to the increased afterload on the right ventricle. Diagnosis is often difficult, since pulmonary vascular disease, pulmonary hypertension, and cor pulmonale have few specific manifestations, especially early in their evolution. Treatment is primarily directed at the underlying pulmonary or ventilatory disorder, rather than at the right ventricular failure per se. Supplemental oxygen is essential to avoid hypoxia; corticosteroids, anticoagulants, vasodilators, and other specific therapies are used as indicated to treat the underlying pulmonary disorders. When medical therapies fail, lung or heart-lung transplantation has become a possibility for selected patients.

Chronic Disease↗
PubMed1990

Reduction of thyrotropin-releasing hormone concentrations in central nervous system of African lungfish during estivation.

Thyrotropin-releasing hormone (TRH) has been implicated as an important modulator of arousal state in mammals. Changes in the content of TRH in several brain regions accompany hibernation in the ground squirrel. In the present study, the involvement of TRH in the regulation of arousal was further investigated in the African lungfish, Protopterus annectens, which contain high concentrations of TRH throughout its central nervous system and enter a hibernation-like state, estivation. Lungfish were divided into three groups. Group 1 was fed normally, group 2 was starved while aquatic, and group 3 was allowed to enter into a state of estivation. After 3 months, the lungfish were sacrificed and the concentrations of TRH, norepinephrine, dopamine, and serotonin were determined in the telencephalon, diencephalon, medulla, and spinal cord. In estivation, there was a significant decline in the concentration of TRH in the diencephalon, with no alteration in other regions. Starvation had no effect on regional TRH concentrations. The concentration of norepinephrine, dopamine, and serotonin did not change in estivation; however, a significant elevation of norepinephrine in the diencephalon and dopamine in the telencephalon was observed in starvation. Starvation and estivation were associated with significant declines in the protein content of the diencephalon and medulla. The estivation-linked decline in TRH in the diencephalon of the lungfish is similar to the decrease in TRH content in the hypothalamus in hibernating ground squirrels. These findings lend further support to the importance of TRH in the regulation of arousal state.

Adaptation, Physiological↗
PubMed1990

Control of interbreath interval in the African lungfish.

We have performed studies to examine the effect of variations in intrapulmonary pressure on the interval between lung breaths in the African lungfish. Studies were performed in two different preparations. In the first we produced changes in lung pressure using a controlled-infusion pump. Increases in intrapulmonary pressure prolonged the interval between lung breaths. At a pressure of 2.5 cmH2O the average interval was 2.6 +/- 1.8 min (mean +/- SD); at 5.0 cmH2O, 8.1 +/- 3.5 min; and at 7.5 cmH2O, 16.2 +/- 3.8 min. Inflations of the lung early in the interbreath interval had less of an effect on its duration than inflations later in the interval. In the second preparation we used a system in which gas flowed continuously through both lungs. Intrapulmonary pressure was varied by changing outlet pressure and O2 concentration by changing the composition of the gas mixture. This allowed separate control of both O2 concentration and intrapulmonary pressure. At a fixed O2 concentration intrapulmonary pressure increased the duration of the interval between lung breaths. At a fixed pressure, reductions in O2 concentration shortened the interval. There was no significant interactive effect of O2 and pressure. Lung inflation did not alter the frequency of gill ventilation. These results imply that a reflex highly similar to the Hering-Breuer expiratory-promoting reflex was already present in the African lungfish.

Animals↗
PubMed1990

Prostacyclin and acetylcholine as screening agents for acute pulmonary vasodilator responsiveness in primary pulmonary hypertension.

Epoprostenol sodium (prostacyclin) administered intravenously is considered the standard for assessing the ability of the pulmonary circulation to vasodilate. At present, epoprostenol sodium is an investigational drug that has limited availability. In contrast, acetylcholine, also a pulmonary vasodilator, is readily available. Therefore, we assessed the feasibility of using acetylcholine as an alternative to prostacyclin in testing for the capacity of the pulmonary vasculature to vasodilate. Twenty-three patients with primary pulmonary hypertension (mean pulmonary arterial pressure, 58.5 +/- 13.4 mm Hg) received incremental infusions of prostacyclin and acetylcholine to predetermined maximal infusion rates as part of a battery of vasodilator agents administered according to standard protocols (mean, 5.4 +/- 1.2 agents/patient; range, 3-8 agents/patient); the administration of the different agents was timed to avoid synergistic effects. Of all the agents tested, prostacyclin and acetylcholine were most consistently effective in evoking acute pulmonary vasodilation, and both seemed to distinguish patients capable of manifesting acute pulmonary vasodilation from those who were not. However, at maximal doses set by protocol, prostacyclin generally elicited a greater vasodilator response than acetylcholine. The difference in magnitude of response may have been due to use of prescribed dosages of acetylcholine that were submaximal. In other respects, the two agents were similar; both were equally well-tolerated, and side effects were mild and resolved rapidly when the vasodilator infusions were stopped. We conclude that in the majority of patients with primary pulmonary hypertension, acetylcholine appears to be an effective and available substitute for prostacyclin in screening for pulmonary vasodilator responsiveness.

Acetylcholine↗
PubMed1990

Pulmonary veno-occlusive disease and its response to vasodilator agents.

Pulmonary veno-occlusive disease (PVOD) is an uncommon form of unexplained (primary) pulmonary hypertension (PPH) rarely diagnosed during life and generally associated with a progressively deteriorating course. We describe three patients with PVOD; in two of them, diagnosis was established by open lung biopsy. All three patients underwent right heart catheterization and acute vasodilator testing, and each responded favorably to at least one test agent. One patient did not receive chronic vasodilator therapy and died seven months after his initial evaluation. The other two patients were treated with chronic vasodilator therapy; one initially improved, but then experienced progressive right heart failure and died 23 months after the start of therapy, the third patient is alive and clinically improved 72 months after beginning vasodilator therapy. Details of the vasodilator studies, and the rationale for treating this uncommon disorder, are provided.

Aged↗
PubMed1989

Autoradiographic distribution of thyrotropin-releasing hormone receptors in the African lungfish Protopterus annectens.

We used quantitative autoradiography to examine the distribution of thyrotropin-releasing hormone (TRH) receptors in the central nervous system (CNS) of the African lungfish Protopterus annectens. We found that the distribution of TRH receptors throughout the CNS of the lungfish was heterogeneous with the highest concentrations (500-800 fmol/mg protein) in the olfactory bulb and telencephalon, moderately high concentrations (200-500 fmol/mg protein) in the diencephalon, and moderate (50-200 fmol/mg protein) to low (less than 50 fmol/mg protein) concentrations in the brainstem and spinal cord. Except for the motor nuclei of the cranial nerves and spinal cord, TRH receptors were concentrated in the acellular regions. In the telencephalon and diencephalon, the receptor density was inversely related to cellular density. These results provide a neuroanatomic and neuropharmacologic basis for further investigations of TRH in the African lungfish.

Animals↗
PubMed1989

Chromatographic demonstration of reversible changes in endothelial permeability.

This report describes a new in vitro method for measuring the diffusional permeability of an endothelial monolayer and its use in investigating the modulation of permeability by various agents, e.g., isoproterenol, propranolol, dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP), and cytochalasin D. To determine permeability, tracers of different molecular weights were applied simultaneously on a chromatography column containing confluent endothelial cells cultured on porous microcarrier beads. The Sangren-Sheppard model was used to determine the permeability of the endothelial monolayer from the tracer elution profiles. For six radiolabeled tracers the mean (+/- SD) permeabilities (cm/s x 10(-5)) in order of increasing tracer molecular weight were [3H]water, 82.0 +/- 28.8; [14C]urea, 49.5 +/- 9.5; [14C]mannitol, 13.3 +/- 4.7; [14C]-sucrose, 14.1 +/- 2.5; [3H]polyethylene glycol (900 mol wt), 4.80 +/- 1.61; and [3H]polyethylene glycol (4,000 mol wt), 1.97 +/- 1.01. These permeabilities deviate less from in vivo values than those obtained in other in vitro systems and are 10 times higher than in vivo estimates. The values were reproducible for up to the 4 h tested. Modulation of endothelial monolayer permeability was studied in a separate series of experiments. The beta-adrenergic agonist isoproterenol (10(-6) M) decreased the permeability to mannitol by 36% and to polyethylene glycol (900 mol wt) by 49%; in both instances the decrease in permeability was reversed by propranolol. Propranolol alone had no effect. Dibutyryl cAMP (10(-3) M) decreased the permeability to mannitol by 40% and to polyethylene glycol by 47%; permeability returned to base line when dibutyryl cAMP was removed. Cytochalasin D (1 microgram/ml) increased permeability by 350% for mannitol and 380% for polyethylene glycol; the permeability change was reversed after removal of cytochalasin D. The results indicate that cell-column chromatography is a powerful method that can be used to characterize the permeability of endothelial monolayers and to investigate permeability changes produced by various agents.

Animals↗
PubMed1989

Primary pulmonary hypertension. Vascular structure, morphometry, and responsiveness to vasodilator agents.

The use of pharmacologic agents in the treatment of pulmonary hypertension has not proved to be uniformly successful or predictable. One possible reason for the vagaries in response is that the pulmonary vascular lesions are not consistent. We examined the relation between the structure of the pulmonary resistance vessels in unexplained (primary) pulmonary hypertension and the response to pulmonary vasodilators. Our study involved 19 patients with clinically unexplained pulmonary hypertension (mean pressure, 59 +/- 14 mm Hg). After characterizing them clinically and performing control hemodynamic measurements, we determined the acute effects of a series of vasodilator agents that have different mechanisms of action. In 16 patients, lung biopsy material was related to the hemodynamic studies; in nine patients, including six who had undergone open lung biopsy, the hemodynamic studies were related to the pathologic changes found at autopsy. Histologic specimens from all 19 patients were evaluated qualitatively and sorted into three subsets of hypertensive pulmonary arteriopathy: medial hypertrophy (with minimal intimal proliferation), arteriopathy with plexiform lesions (associated predominantly with concentric laminar intimal proliferation and fibrosis), and arteriopathy with microthrombotic lesions (associated predominantly with eccentric intimal proliferation and fibrosis). The 16 lung biopsies were also quantitated by morphometric techniques. Using a decrease in calculated pulmonary vascular resistance of more than 30% accompanied by a decrease in mean pulmonary arterial pressure of at least 10% to define vasodilation, only four patients were responders. The patients varied considerably in their responses to different vasodilator agents. Patients with similar clinical and hemodynamic profiles differed considerably with respect to the nature of their pulmonary vascular obstructive lesions and their responses to vasodilator agents. Qualitative histologic examination of lung tissue did not provide a basis for predicting how individual patients would respond to vasodilator agents. However, quantitative morphologic analysis of the initial open lung biopsy specimens did prove helpful in predicting acute responsiveness to vasodilator agents and the subsequent clinical course of these patients with unexplained (primary) pulmonary hypertension. An intimal area of more than 18% of the vascular cross-sectional area had an 85% predictive value for identifying the patients who did poorly during the first 36 months of follow-up.

Adolescent↗
PubMed1989

The acute administration of vasodilators in primary pulmonary hypertension. Experience from the National Institutes of Health Registry on Primary Pulmonary Hypertension.

The hemodynamic responses to acute vasodilator administration were evaluated in 163 patients who were entered into the National Institutes of Health Registry on Primary Pulmonary Hypertension (PPH) between 1981 and 1985. Of a total of 491 drug administrations in these patients, 135 administrations in 104 patients were performed in a manner acceptable to the Registry. A single vasodilator was tried in 79 patients and more than one vasodilator in 25 patients. Two-thirds of the patients were in New York Heart Association Functional Classes III or IV. When the effects of all vasodilators were grouped together, there were significant decreases from baseline in mean pulmonary artery pressure (60 +/- 2 to 57 +/- 2 mm Hg, p less than 0.05) and total pulmonary resistance index (32.5 +/- 1.7 to 25.1 +/- 1.4 mm Hg/L/min/m2, p less than 0.0001), and increases in cardiac index (2.1 +/- 0.1 to 2.7 +/- 0.1 L/min/m2, p less than 0.0001). Mean systemic blood pressure fell (88 +/- 1 to 79 +/- 1 mm Hg, p less than 0.0001), whereas PaO2 was unchanged (70 +/- 3 to 71 +/- 3 mm Hg, p = NS). A fall in total pulmonary resistance greater than 20% was observed in 55% of the adequate drug trials. Adverse effects occurred in 32 of the total 491 patient-drug trials and were generally minor. Hypotension requiring treatment developed in six patients. There were two deaths attributable to vasodilator administration. Patients who died or had hypotension requiring treatment had higher right atrial pressures than did other treated patients (15 +/- 2 versus 9 +/- 1 mm Hg, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Pulmonary extraction of propranolol in normal and oxygen-toxic sheep.

To help define the mechanisms involved in the handling of propranolol by normal and injured lungs, we studied the pulmonary extraction of [3H]propranolol in 23 unanesthetized sheep. Extraction of propranolol by normal lungs during a single circulation was characterized by 1) subsequent back-diffusion and pulmonary retention of the drug, 2) no evidence of saturable uptake or binding, 3) no effect of isoproterenol or imipramine, and 4) no effect of increasing cardiac output by treadmill exercise. In lungs damaged by oxygen toxicity, [3H]propranolol extraction decreased progressively to 63% of base line, paralleling progressive arterial hypoxemia and hypercapnia. In contrast, [14C]serotonin extraction remained unchanged from base line. Our results suggest that in normal unanesthetized sheep, pulmonary extraction of propranolol occurs primarily by passive diffusion that is flow-limited. Also, lung injury induced by oxygen toxicity in sheep reduces the pulmonary extraction of propranolol. Indeed, in oxygen toxicity, the depressed extraction of propranolol is a more sensitive marker of lung injury than is serotonin extraction.

Animals↗
PubMed1988

Characterization of thyrotropin-releasing hormone in the central nervous system of African lungfish.

Central administration of thyrotropin-releasing hormone (TRH) produces potent effects on various physiological parameters, such as arousal, respiration, and cardiovascular function, in several species. As part of an investigation into the evolution of this tripeptide as a central modulator of these parameters, we examined its distribution in the central nervous system of the African lungfish (Protopterus). Lungfish brains were dissected into three regions: telencephalon, diencephalon, and medulla. Each region was assayed for TRH by radioimmunoassay and for norepinephrine, dopamine, and serotonin by HPLC/electrochemical methods. TRH immunoreactivity (IR-TRH) was present in all regions of lungfish brain examined. The telencephalon contained the highest concentrations of TRH, the diencephalon also contained a high concentration of TRH, and the medulla contained a markedly lower concentration. Similar concentration gradients (telencephalon greater than diencephalon greater than medulla) were observed for norepinephrine, dopamine, and serotonin. The identity of IR-TRH as authentic TRH was confirmed by elution profiles on HPLC. The results of this investigation demonstrated that TRH and the monoamine neurotransmitters are present in high concentrations in various regions of lungfish brain. The lungfish may represent a promising model for further studies of the interactions of TRH with these neurotransmitter systems.

Animals↗
PubMed1988

Permeability characteristics of cultured endothelial cell monolayers.

The purpose of this study was to characterize the permeability characteristics of an in vitro endothelial cell monolayer system and relate this information to available in vivo data. We cultured bovine fetal aortic endothelial cells on fibronectin-coated polycarbonate filters and confirmed that our system was similar to others in the literature with regard to morphological appearance, transendothelial electrical resistance, and the permeability coefficient for albumin. We then compared our system with in vivo endothelium by studying the movement of neutral and negatively charged radiolabeled dextran tracers across the monolayer and by using electron microscopy to follow the pathways taken by native ferritin. There were a number of differences. The permeability of our monolayer was 10-100 times greater than seen in intact endothelium, there was no evidence of "restricted" diffusion or charge selectivity, and ferritin was able to move freely into the subendothelial space. The reason for these differences appeared to be small (0.5-2.0 micron) gaps between 5 and 10% of the endothelial cells. Although the current use of cultured endothelial cells on porous supports may provide useful information about the interaction of macromolecules with the endothelium, there appear to be differences in the transendothelial permeability characteristics of these models and in vivo blood vessels.

Animals↗