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T W Higenbottam

Publications and source records attributed to T W Higenbottam.

At least 55 records · Page 3Linked to original sources
PubMed1993

Effects of aerosol-applied capsaicin, histamine and prostaglandin E2 on airway sensory receptors of anaesthetized cats.

1. Capsaicin, prostaglandin E2 (PGE2) and histamine are potent stimuli for reflex coughing and bronchoconstriction in many species including man. We have studied the effects of solutions of capsaicin, PGE2 and histamine on airway sensory receptors when administered as inhaled aerosols to the lower respiratory tract in anaesthetized, paralysed and artificially ventilated cats. 2. Histamine, administered by aerosol (6 breaths of a 1 mg ml-1 solution) and intravenously (10 micrograms kg-1), caused an increase in the rate of discharge from rapidly adapting stretch receptors (RARs) and caused bronchoconstriction. 3. Six breaths of a capsaicin aerosol generated from solutions of 0.1 or 1 mg ml-1 stimulated six out of nine RARs tested. Bronchoconstriction occurred with and without RAR stimulation. The diluent for the capsaicin aerosol had no significant effect on pulmonary mechanics or rate of RAR discharge. 4. Administration of increasing concentrations (0.001-1 mg ml-1) of PGE2 aerosol given in six breaths (at 6 min intervals) caused a dose-dependent increase in the rate of discharge of eight RARs tested and caused bronchoconstriction. The diluent for the PGE2 aerosol had no effect on pulmonary mechanics or rate of RAR discharge. 5. Inhalation of aerosols of histamine (6 breaths of 1 mg ml-1 solution) and capsaicin (3 breaths of 0.1 mg ml-1 solution) stimulated all six lung C fibre endings studied (3 pulmonary and 3 bronchial). These aerosols of capsaicin and histamine also caused bronchoconstriction. 6. We conclude that solutions of capsaicin and PGE2, when delivered by aerosol to the airway epithelial surface, are not selective stimulants of C fibres. Both agents can stimulate RARs. Activation of some but not all RARs tested, by inhaled capsaicin, suggests that there are subpopulations of capsaicin-sensitive and -insensitive receptors. Stimulation of airway RARs by a range of pharmacologically active agents released by airway inflammation may contribute to reflex coughing and bronchoconstriction in man.

Administration, Inhalation↗
PubMed1993

Prostacyclin (epoprostenol) and heart-lung transplantation as treatments for severe pulmonary hypertension.

OBJECTIVE: To determine whether epoprostenol (prostacyclin, PGI2) or heart-lung transplantation (HLT), or both improves survival of patients with severe pulmonary hypertension. DESIGN: This was a prospective study where the effects of epoprostenol were compared with conventional treatment. Also, the benefits of epoprostenol and HLT were assessed by comparing survival in this group with that of 120 patients at the Mayo Clinic before HLT and epoprostenol treatment became available. PATIENTS AND INTERVENTIONS: Forty four patients were studied; 25 received continuous epoprostenol over a four year period (mean (SD) cardiac index 1.8 (0.4) 1 min-1 m-2 and mean (SD) pulmonary artery pressure (PAP) 70 (16) mm Hg) and 19 did not (cardiac index 2.1 (0.6) 1 min-1 m-2 and PAP 64 (13) mm Hg). Ten patients underwent HLT: seven had received epoprostenol, and three had not. RESULTS: The therapeutic intervention with epoprostenol, or HLT, or both improved survival compared with the Mayo clinic patients (p = 0.05). Most of the benefit was conferred by epoprostenol, which prolonged survival twofold from a median time of eight to 17 months and doubled the changes of successful HLT. The improved survival with epoprostenol was not related to its immediate capacity to cause pulmonary vasodilation. Those patients who had limited acute pulmonary vasodilation when treated with epoprostenol showed the greatest improvement in survival. CONCLUSIONS: These preliminary results indicate that those pulmonary hypertensive patients with the poorest chance of survival can be helped by epoprostenol and by HLT.

Adult↗
PubMed1993

Effects of inhaled capsaicin in heart-lung transplant patients and asthmatic subjects.

We have studied the effects on FEV1 of inhaled capsaicin in concentrations of 3 x 10(-6) to 3 x 10(-1) mg/ml and methacholine (1 to 16 mg/ml) in 15 heart-lung transplant (HLT) patients who had undergone recent transbronchial lung biopsy to determine the relationships in chronically denervated lungs between these different forms of airway hyperreactivity and inflammation. A total of 10 normal subjects and 17 asthmatic subjects were included for comparison. Capsaicin caused bronchodilation in eight HLT patients (FEV1 rising by 6.4 to 26.8%) and bronchoconstriction in two (fall in FEV1 of 7.2 and 7.6%). By contrast, seven asthmatic subjects developed bronchoconstriction after capsaicin (fall in FEV1 5.6 to 40.4%); the remaining 10 asthmatic subjects showed no response. Bronchial hyperresponsiveness to methacholine was most evident in the asthmatic subjects, but six HLT patients demonstrated a > or = to 20% fall in FEV1 with < or = 8 mg/ml of methacholine. All normal subjects were nonresponsive to both agents, and all normal and asthmatic subjects, unlike HLT patients, coughed with capsaicin. No relationship existed between the methacholine and capsaicin responses. In the HLT patients neither form of airway responsiveness was related to the degree of inflammation seen on transbronchial lung biopsy. The results suggest that in normal subjects, although it provokes cough, inhaled capsaicin causes little airway narrowing.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1993

In vitro pulmonary vasorelaxant effect of the phosphodiesterase inhibitor enoximone.

Enoximone is a phosphodiesterase inhibitor that has both positive inotropic and systemic vasorelaxant activities. The latter are mediated by an increase in vascular smooth muscle concentration of cyclic 3'5' guanosine monophosphate. However, the effect of enoximone on pulmonary vasoreactivity is not established. The authors, therefore, have studied its effect on endothelium-dependent relaxation mediated by the endothelium-derived relaxing factor nitric oxide (NO), as well as endothelium-independent relaxation of isolated porcine pulmonary arteries. Enoximone (10(-7) to 10(-4) M) caused a dose-dependent relaxation in all pulmonary arterial rings. This relaxation neither required the presence of the endothelium nor was affected by the addition of the inhibitor of NO synthase omega-nitro-L-arginine methyl ester (10(-4) M). Also, the vasorelaxant response of the rings to the endothelium-dependent vasodilator adenosine diphosphate (10(-10) to 10(-5) M) was not affected by pretreatment with enoximone. The authors conclude that enoximone is a potent vasodilator that relaxes pulmonary vascular rings through mechanisms independent of the endothelium. This endothelium-independent vasodilatory effect of enoximone makes it a potentially valuable drug for the treatment of pulmonary hypertension. This particularly applies to diseases in man where NO production by the endothelial cells is impaired.

Animals↗
PubMed1992

Technique and use of transbronchial biopsy in children and adolescents.

Since July 1988, a total of 92 transbronchial biopsies (TBB) have been performed in 18 patients (aged 3-16 years). Twelve patients (67%) were heart-lung transplant (HLT) recipients undergoing surveillance for pulmonary graft rejection and infection. The remainder included immunocompromised patients at risk of opportunistic infections (n = 4), patients with fibrosing alveolitis (n = 1) and a collagen vascular disorder with suspected lung involvement (n = 1). TBB was performed through either a fiberoptic (n = 50) or a rigid (n = 41) bronchoscope, all under general anesthesia. On one occasion a cardiac bioptome was used through an endotracheal stent. The sensitivity of TBB for diagnosing acute and chronic rejection in HLT patients was 88% and 60%, respectively (specificity, 91% and 100%). Definitive diagnoses were made in 4 (67%) of the non-HLT group. Bronchoalveolar lavage (BAL) was performed during each procedure for microbiological and cytological examination. Thirty-four pathogenic organisms including Pseudomonas aeruginosa (16/34), Staphylococcus aureus (8/34), and Candida albicans (5/34) were isolated from BAL culture. Complications included pneumothorax (8%), transient pyrexia (7%), and dyspnea (2%).

Acquired Immunodeficiency Syndrome↗
PubMed1992

Exercise increases the release of atrial natriuretic peptide in heart transplant recipients.

It is known that atrial natriuretic peptide (ANP) is synthesized, stored and released from the myocytes of mammalian heart, but the role of cardiac autonomic nerves in triggering the release of ANP has not been fully assessed. We have therefore measured plasma ANP concentrations in the right atrium and the main pulmonary artery, together with pulmonary haemodynamics in 10 heart transplant (HT) recipients who underwent graded submaximal bicycle exercise during right-heart catheterisation. Pulmonary arterial blood samples and haemodynamic measurements were obtained at rest, on peak of exercise, and after ten minutes of recovery. A radioreceptor of alpha-human ANP was used to measure ANP levels. Exercise significantly increased ANP levels in both the right atrium from 24 pM (resting values) to 48.5 pM, and the main pulmonary artery from 27.1 pM (resting values) to 58.4 pM. We conclude that HT recipients still retain the ability to increase ANP release in response to graded submaximal dynamic exercise, and that the mechanisms underlying ANP release depend on other factors than the integrity of cardiac innervation in man.

Adult↗
PubMed1992

Cyclosporine in heart transplant recipients: an exercise study of vasopressor effects.

The possible vasopressor effect of cyclosporine (CS) on both the systemic and pulmonary vascular beds has been investigated during bicycle exercise in 12 heart transplant recipients (mean age, 41 years) using pulmonary artery catheter measurements. Eight patients were taking cyclosporine and six azathioprine and prednisolone (AzS) as immunosuppressive therapy. With exercise, CS recipients show a significantly larger rise in systemic pressure than AzS recipients (P less than 0.001), with persistently higher pulmonary pressures (P less than 0.001). This suggests a generalized vasopressor effect of CS on the vasculature.

Adult↗
PubMed1992

Blood cyclosporin concentrations but not doses correlate with acute changes in renal function following heart and heart-lung transplantation.

The relationship between changes in cyclosporin (CyA) dose or CyA blood concentration and the reciprocal creatinine concentration was investigated by cross-correlation analysis over the first 3 postoperative months in 32 consecutive heart and heart-lung recipients. Exploratory analysis suggested that early changes in renal function, probably attributable to recovery from preoperative cardiac failure, obscured later underlying correlations. Therefore, all data up to the first nadir in plasma creatinine following transplantation were excluded from the analysis. Five-day mean CyA doses or blood concentrations were cross-correlated with 5-day mean reciprocal creatinine concentrations measured either in the same 5-day period or with the creatinine measured up to two 5-day periods later. Although a significant correlation was found between CyA dose and blood concentration (the 95% confidence interval of the population correlation coefficient did not overlap zero), there was no relationship between dose and changes in renal function. The blood CyA concentration, however, correlated significantly with the reciprocal creatinine concentration measured in the same 5-day period and was also predictive of changes in creatinine measured in the subsequent 5-day period. Thus, a major criterion for therapeutic drug monitoring had been fulfilled: CyA dosage adjustment based on blood CyA concentrations, as the intermediate therapeutic end point, is helpful in the management of acute nephrotoxicity in heart and heart-lung transplant recipients because of the lack of a dose-effect relationship. Regular CyA monitoring and appropriate dosage adjustment is essential for the management of acute nephrotoxicity in the first 3 months following heart or heart-lung transplantation.

Creatinine↗
PubMed1992

Relationship between chronic hypoxia and in vitro pulmonary relaxation mediated by endothelium-derived relaxing factors in human chronic obstructive lung disease.

Endothelium-derived relaxing factors (EDRF) are paracrine vasodilator substances released by endothelial cells. There is compelling evidence to suggest that EDRF may play an important role in the modulation of vascular tone in the systemic circulation. However, the role of EDRF-mediated pulmonary relaxation in chronic lung disease is unknown. The authors have, therefore, investigated endothelium-dependent relaxation of isolated pulmonary arteries (PAs) obtained from 18 patients undergoing heart-lung transplantation for end-stage chronic hypoxic cor pulmonale (HCP). Control PAs were obtained from 10 patients, none of whom had evidence of HCP, and who underwent lobectomy for lung carcinoma. All vascular rings were studied immediately after lung excision. PA rings from control patients dose-dependently relaxed to cumulative doses of acetylcholine (ACh, 10(-10) to 10(-5) M), achieving a maximal relaxation of 73.2 +/- 4.4% from precontraction to phenylephrine. By contrast, PA rings from HCP patients achieved only 42.1 +/- 6.7% of maximal relaxation (p less than 0.01). Sodium nitroprusside (10(-4) M) relaxed all PA rings, with and without endothelium (carefully removed before study), obtained from both control and HCP patients. The endothelium-dependent maximal relaxation to ACh was positively related to pretransplant values of PaO2 (r = 0.59; p less than 0.01), but no relationship was found with either PaCO2 (r = -0.41) or FEV1 (r = -0.14). The authors conclude that pulmonary relaxation mediated by EDRF is impaired in human HCP and suggest that such impairment may be related to severity of the preexisting chronic hypoxemia.

Acetylcholine↗
PubMed1992

Diurnal variation in FEV1 after heart-lung transplantation.

We have examined the diurnal variation in forced expiratory volume in one second (FEV1) in 25 heart-lung transplantation patients over a four week period in order to study the pathophysiological mechanisms underlying the increased mortality and morbidity which occurs at night in asthma. These patients do not have pulmonary autonomic nervous reflexes, but often have muscarinic receptor hypersensitivity. They also develop mixed cell infiltration of the lung tissue in the course of infection or rejection. Thus, they show many features in common with asthma. Seventeen patients (68%) showed a significant diurnal variation in airway calibre (mean amplitude of FEV1 was 4.6% (SD 3.7%)), which is similar to that reported in normal adults. One patient had a diurnal variation of 34.5% during an episode of rejection. This variation fell to 6.9% after steroid therapy, a change often seen in asthma. There was a correlation between increased amplitude of the variation and the presence in transbronchial biopsies of airway submucosal eosinophils and lymphocytes, associated with a histological diagnosis of acute rejection and with epithelial damage. No association was seen with muscarinic receptor sensitivity. The variation in FEV1 showed no alteration from the normal day/night synchronization, and the peak values were around 1300 h. We conclude that the diurnal variation in FEV1 after heart-lung transplantation is not dependent on autonomic nerve reflexes or muscarinic receptor sensitivity, but is related to the consequences of inflammation described above.

Adult↗
PubMed1991

Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension.

The acute effects of inhaled nitric oxide (NO) (40 ppm in air) on pulmonary (PVR) and systemic (SVR) vascular resistance were compared with those of an intravenous infusion of prostacyclin (24 micrograms/h) in 8 patients with severe pulmonary hypertension and 10 cardiac patients with normal values of PVR. 10 healthy volunteers were studied non-invasively. In the patients with pulmonary hypertension, PVR fell significantly after inhaled NO and after prostacyclin. PVR also fell significantly in the cardiac patients after inhaled NO. Although SVR fell substantially after prostacyclin in patients with pulmonary hypertension, inhaled NO had no effect on SVR in any patient or volunteer. Inhaled NO therefore seems to be both a selective and effective pulmonary vasodilator.

Administration, Inhalation↗
PubMed1991

Impairment of endothelium-dependent pulmonary-artery relaxation in chronic obstructive lung disease.

BACKGROUND: Endothelial cells release endothelium-derived relaxing factor (EDRF) in a variety of vascular beds, including the pulmonary circulation. However, the role of EDRF-mediated pulmonary-artery relaxation in chronic hypoxic lung disease is unknown. METHODS: We studied endothelium-dependent relaxation mediated by EDRF in vitro in pulmonary arteries that had been obtained from 22 patients undergoing heart-lung transplantation for end-stage chronic obstructive lung disease. Control pulmonary arteries were obtained from 15 patients undergoing lobectomy for lung carcinoma who did not have evidence of other chronic lung disease. The responses of all vascular rings (external diameter, 1.2 to 3.4 mm) to the endothelium-dependent vasodilators acetylcholine and adenosine diphosphate were studied immediately after lung excision. RESULTS: Pulmonary arterial rings from the patients with chronic lung disease developed a greater tension (2.19 +/- 0.16 g) in response to phenylephrine (10(-6) M) than the rings from control patients (1.28 +/- 0.18 g, P less than 0.05). Inhibition of EDRF synthesis by treatment with NG-monomethyl-L-arginine (10(-4) M) eliminated this difference, increasing the tension in the rings from the controls (P less than 0.01) but not in those from the patients with chronic lung disease. Rings from control patients relaxed in response to cumulative doses (10(-10) to 10(-5) M) of acetylcholine (maximal relaxation, 81.3 +/- 3.9 percent) and adenosine diphosphate (maximal relaxation, 85.3 +/- 2.6 percent). By contrast, rings from patients with chronic obstructive lung disease achieved only 41.3 +/- 4.8 percent of maximal relaxation in response to acetylcholine (n = 32) and 49.4 +/- 5.5 percent in response to adenosine diphosphate (n = 24) (P less than 0.001, as compared with control rings). Rings from both the controls and the patients with chronic lung disease relaxed similarly in response to the endothelium-independent vasodilator sodium nitroprusside (10(-4) M). There was an inverse correlation between the degree of intimal thickening and the level of maximal relaxation of the rings from the patients with chronic lung disease (r = -0.60, P less than 0.001). Maximal relaxation was also related directly to the partial pressure of arterial oxygen before transplantation (r = 0.68, P less than 0.01) and inversely to the partial pressure of arterial carbon dioxide before transplantation (r = -0.55, P less than 0.01), but not to the forced expiratory volume in one second (r = 0.19, P not significant). CONCLUSIONS: Endothelium-dependent pulmonary-artery relaxation in vitro is impaired in arteries from patients with end-stage chronic obstructive lung disease. Such impairment may contribute to the development of pulmonary hypertension in chronic hypoxic lung disease.

Acetylcholine↗
PubMed1991

Effects of the immunosuppressant cyclosporine on the circulation of heart transplant recipients.

The effect of cyclosporine on the systemic circulation and on heart rate is unknown for heart transplant recipients. Thirty-four heart transplant recipients were studied by right-sided cardiac catheterization after endomyocardial biopsy. A direct linear relation was found between systemic and pulmonary vascular resistance and cyclosporine trough blood levels, which were negatively related to heart rate. The effect of cyclosporine on pulmonary vascular resistance, however, was not statistically significant by multivariate analysis when patient age was considered. In contrast, renal function appeared unrelated to systemic vascular resistance or heart rate. It appears that cyclosporine trough blood levels may have a direct effect on systemic vascular resistance as well as an unexplained negative chronotropic effect on heart rate.

Adult↗
PubMed1991

Endothelium-derived relaxing factor and the pulmonary circulation.

Endothelium-derived relaxing factor (EDRF) is probably identical to nitric oxide (NO) and is released by the vascular endothelium both in the basal unstimulated state and in response to a wide range of physical and chemical stimuli. Since it was first described 10 years ago, evidence is accumulating that it is an important modulator of vascular smooth muscle tone. EDRF acts on the pulmonary vascular bed as on the systemic circulation. EDRF release to pharmacologic stimuli is impaired in pulmonary arteries from patients with chronic hypoxemia. This impairment is associated with severity of respiratory failure and of structural change of vessel walls. Disturbance of EDRF activity may be important in the pathophysiology of pulmonary vascular disease. This brief review describes the current status of experimental studies concerning the possible role of EDRF on the pulmonary circulation in normal conditions and in the pathogenesis of pulmonary hypertension.

Animals↗
PubMed1991

Cytomegalovirus infection in heart-lung transplant recipients: risk factors, clinical associations, and response to treatment.

The risk factors, clinical associations, and response to treatment of cytomegalovirus (CMV) pneumonia and infection were studied in 65 recipients of heart-lung transplantation. There were 29 episodes of CMV pneumonia in 22 patients. In 80% (20/25) of episodes of CMV pneumonia treated with intravenous ganciclovir, the histologic changes resolved and the patient survived. Among seronegative recipients, a seropositive donor was a significant risk factor for CMV pneumonia and infection in the first 90 days after heart-lung transplantation (P = .004 and .002, respectively). Among seropositive recipients, there was no additional risk associated with a sero-positive donor. Rates of CMV pneumonia and infection were significantly increased when treatment with augmented immunosuppression had been given in the preceding 30 days (P less than .001). A significant association was found between CMV pneumonia or infection and pulmonary bacterial infections occurring 30 days before or after such an episode (P less than .001).

Adolescent↗
PubMed1991

Risk factors for obliterative bronchiolitis in heart-lung transplant recipients.

Obliterative bronchiolitis is the major cause of death of long-term survivors of heart-lung transplantation. Of our first 75 patients who have received heart-lung transplantation, 38 have been followed for a year or longer. Eight patients developed clinical evidence of obliterative bronchiolitis within 15 months of transplantation, of whom four died with postmortem confirmation of extensive obliterative bronchiolitis, interstitial and pleural fibrosis, and vascular sclerosis in the heart and lungs. One further patient died before one year after chronic rejection. All nine patients had evidence on transbronchial biopsy of submucosal fibrosis and vascular sclerosis. Twelve of our remaining patients have shown similar areas of lung fibrosis on transbronchial biopsy, and the other eighteen are well and without fibrosis on transbronchial biopsy. Studies of the 274 biopsies obtained from 38 patients confirmed rejection on 182 occasions with more frequent, more persistent, and more severe rejection in the chronic rejection group than in the without-fibrosis or lung fibrosis groups. Opportunistic infection resulted in pneumonia on 19 occasions, and were most commonly found in lung fibrosis patients. We conclude that obliterative bronchiolitis is the likely outcome in patients with early, poorly controlled, severe rejection.

Adult↗