Robert D. Levy

Expression of Endothelin-1 in the Lungs of Patients with Pulmonary Hypertension

BACKGROUNDnPulmonary hypertension is characterized by an increase in vascular tone or an abnormal proliferation of muscle cells in the walls of small pulmonary arteries. Endothelin-1 is a potent endothelium-derived vasoconstrictor peptide with important mitogenic properties. It has therefore been suggested that endothelin-1 may contribute to increases in pulmonary arterial tone or smooth-muscle proliferation in patients with pulmonary hypertension. We studied the sites and magnitude of endothelin-1 production in the lungs of patients with various causes of pulmonary hypertension.nnnMETHODSnWe studied the distribution of endothelin-1-like immunoreactivity (by immunocytochemical analysis) and endothelin-1 messenger RNA (by in situ hybridization) in lung specimens from 15 control subjects, 11 patients with plexogenic pulmonary arteriopathy (grades 4 through 6), and 17 patients with secondary pulmonary hypertension and pulmonary arteriopathy of grades 1 through 3.nnnRESULTSnIn the controls, endothelin-1-like immunoreactivity was rarely seen in vascular endothelial cells. In the patients with pulmonary hypertension, endothelin-1-like immunoreactivity was abundant, predominantly in endothelial cells of pulmonary arteries with medial thickening and intimal fibrosis. Likewise, endothelin-1 messenger RNA was increased in the patients with pulmonary hypertension and was expressed primarily at sites of endothelin-1-like immunoreactivity. There was a strong correlation between the intensity of endothelin-1-like immunoreactivity and pulmonary vascular resistance in the patients with plexogenic pulmonary arteriopathy, but not in those with secondary pulmonary hypertension.nnnCONCLUSIONSnPulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to the vascular abnormalities associated with this disorder.

Reference values for a multiple repetition 6-minute walk test in healthy adults older than 20 years

PURPOSEnTo (1) identify greatest 6-minute walk distance (6MWD) from among several repetitions (best 6MWD) in a wide age range of healthy volunteers to develop reference values for the multiple repetition 6MWD, and (2) investigate the influence of demographics, anthropometrics, and habitual exercise activity on best 6MWD.nnnMETHODSnFour 6MWD were performed on the same day in a 20-meter corridor by 41 male and 38 female healthy volunteers ranging in age from 20 to 80 years. The greatest 6MWD by each subject from among four 6MWDs was the primary outcome measure.nnnRESULTSnEighty-six percent had their best 6MWD after the first walk; an average increase of 43 meters was observed from first to best 6MWD (P < 0.003). Best 6MWD averaged 698 +/- 96 meters and was inversely related to age (P < 0.001), directly to height (P < 0.001), and was greater in men than women (P < 0.0002). A regression model accounted for 41% of between-subject variability in best 6MWD (P < 0.00000001). In a subset of older subjects, predicted 6MWD significantly underestimated measured best 6MWD when reference values were used from another study where test familiarization was not provided, but this difference disappeared when value were used from the present and a third study where test familiarization was provided.nnnCONCLUSIONSnThe present study is the first to provide predicted 6MWD values performed with multiple repetitions and for subjects in the 20-40-year-old age range. Selection of appropriate predicted 6MWD values for interpretation of performance should be guided by subject age and degree of test familiarization provided.

Short-term Pulmonary Vasodilation With l-Arginine in Pulmonary Hypertension

BACKGROUNDnEndothelial dysfunction may contribute to the pathogenesis of pulmonary hypertension through impaired production of the endothelium-derived vasodilator nitric oxide (NO). L-Arginine, the substrate for NO synthase (NOS), has a vasodilatory effect in systemic vascular beds and can correct abnormal endothelium-dependent vasodilation. It has been suggested that these two effects of L-arginine are mediated through NOS metabolism and enhanced NO production. Therefore, we assessed the short-term pulmonary hemodynamic effects of exogenous L-arginine in patients with pulmonary hypertension of various origins.nnnMETHODS AND RESULTSnDuring continuous hemodynamic monitoring, 10 subjects with pulmonary hypertension (mean pulmonary artery pressure [PAP], 54 +/- 5 mm Hg [mean +/- SEM]) received a 30-minute control infusion of hypertonic saline followed by a 30-minute infusion of 500 mg/kg of L-arginine. The hemodynamic effects of L-arginine were compared with those of prostacyclin titrated to maximally tolerated doses. The hemodynamic response to L-arginine was also studied in 5 subjects with heart failure but without pulmonary hypertension (mean PAP, 20 +/- 2 mm Hg) and 5 healthy control subjects. In subjects with pulmonary hypertension, infusion of L-arginine reduced mean PAP by 15.8 +/- 3.6% (P < .005) and pulmonary vascular resistance (PVR) by 27.6 +/- 5.8% (P < .005) compared with decreases of 13.0 +/- 5.5% (P < .005) and 46.6 +/- 6.2% (P < .005), respectively, with prostacyclin. L-Arginine infusion also increased the mean plasma level of L-arginine from 59 +/- 6 mumol/L to 10,726 +/- 868 mumol/L (P < .005), which was associated with a significant increase in the plasma level of L-citrulline, the immediate product of NOS metabolism of L-arginine. Moreover, the peak plasma level of L-citrulline correlated significantly with the reductions in mean PAP (r = .71, P < .05) and PVR (r = .70, P < .05), consistent with vasodilation mediated by NOS metabolism of exogenous L-arginine and increased NO production. L-Arginine also had a modest hypotensive effect in healthy control subjects and reduced systemic vascular resistance in subjects with heart failure in the absence of pulmonary hypertension. However, only small reductions in absolute pulmonary vascular resistance were observed in this latter group in response to L-arginine that did not reach significance.nnnCONCLUSIONSnAn exaggerated short-term pulmonary vasodilatory response to L-arginine in patients with pulmonary hypertension suggests a relative impairment in pulmonary vascular endothelial NO production that may contribute to increased pulmonary vascular tone and thus be important in the pathophysiology of pulmonary hypertension.

Acute effects of glyburide on the regulation of peripheral blood flow in normal humans.

Recent animal studies have demonstrated that selective blockade of ATP-sensitive K+ (KATP) channels of vascular smooth muscle results in a significant increase in peripheral vascular tone. The main aim of this study was to assess whether glyburide, a selective blocker of KATP channels and commonly used antidiabetic agent, influences resting blood flow and reactive hyperemic response of peripheral tissues of normal subjects. Baseline calf blood flow was measured non-invasively in six normal subjects with femoral venous occlusive plethysmography. Calf blood flow was also serially measured every 30-60 s after the release of calf arterial occlusion (10 min duration). Reactive hyperemia was expressed in terms of peak post-occlusive flow, duration of hyperemia and reactive hyperemic volume. In each subject, baseline flow and reactive hyperemia were measured before (control) and every hour for 5 h after the oral ingestion of either 7.5 mg glyburide or a placebo on two separate days. Baseline calf flow declined by 30 and 42% of control values after 1 and 2 h of glyburide intake (P < 0.05) with a return to control values by hours 3, 4 and 5. Peak post-occlusive flow after 1, 2 and 3 h of glyburide ingestion was lower than control values by 22, 30 and 28%, respectively (P < 0.05). The duration of reactive hyperemia after 2 and 3 h of glyburide ingestion was significantly longer than control values (P < 0.05), whereas reactive hyperemic volume remained unaffected by glyburide intake. Placebo elicited no significant changes in baseline flow or reactive hyperemia throughout the 5-h experimental period.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of peak exercise capacity with indexes of peripheral muscle vasodilation.

Since leg muscles receive the majority of cardiac output and consume a large proportion of total oxygen consumption (VO2) during cycle exercise, maximum leg blood flow may be an important determinant of peak VO2 (VO2peak). We investigated the relationships between parameters of active hyperemia after thigh tourniquet occlusion (alone or with calf exercise) with whole body peak exercise capacity during maximum cycle exercise. Twenty-one healthy male subjects, aged 19-39 yr. performed maximum incremental cycle exercise. Calf blood flow, conductance (blood flow/mean blood pressure), vasodilatory capacity (peak/baseline conductance), and duration of vasodilation were then determined with venous occlusive plethysmography under two conditions: 1) after thigh tourniquet occlusion for 10 min; 2) after ischemic calf exercise (thigh tourniquet occlusion with calf exercise to exhaustion). Group mean VO2peak was 120 +/- 35% (standard deviation) predicted. There was a significant relationship between VO2peak/ lean body mass and peak calf conductance after maximum ischemic calf exercise (r = 0.556; P < 0.01). However, VO2peak/lean body mass was more closely correlated with the duration of vasodilation after thigh tourniquet occlusion with ischemic calf exercise (r = 0.861; P < 0.001). These results suggest that the duration of calf vasodilation after maximal ischemic calf exercise appears to be a better index of cycle exercise capacity in healthy subjects.

Failure of acetylcholine to provoke release of material with acetylcholinelike activity from rat brain subcellular particles

Abstract The incubation of brain subcellular particles in distilled water causes release into the incubation fluid of some of the material with acetylcholinelike activity contained in these particles. When minute (maximum 1 μg) amounts of acetylcholine chloride are present in the incubation medium, there is inhibition of such release of endogenous material with acetylcholinelike activity from the particles. Whether this represents inhibition of either the conversion of “bound” acetylcholine into the “free” (active) form or the release of these materials through a direct action on the membrane of these particles is not known. The latter alternative appears more likely, since the depolarizing action of acetylcholine on membranes is well established. Failure of exogenous acetylcholine to provoke the further release of endogenous material with acetylcholinelike activity may well represent a self-regulating mechanism of cholinergic transmitter release.

Effects of ultrasonics on the release of material with acetylcholinelike activity from brain subcellular particles

Abstract When brain subcellular particles containing mainly the fraction with “bound” acetylcholinelike activity is exposed to sound stress for various time intervals, there is release of the bound acetylcholine into solution in the ”free” form. The completeness of the conversion from the bound to the free form is dependent on the time of exposure. It was observed that upon exposure of these subcellular particles to sound frequencies between 18,000–20,000 cycle/sec, there is almost complete release of the bound acetylcholine into the free form; simultaneously there is complete destruction of the subcellular particles. Since substances such as acetylcholine can produce epileptiform activity when applied to the cerebral cortex, it is suggested that in certain human epileptics and in certain strains of mice, convulsive activity could likely be initiated through the release of such substances in the brain following damage of the subcellular structures through sound stress.

Lung transplantation: beyond palliation

Some 4 decades ago, the first thoracic transplant of the modern era was performed. It was a heart, it was carried out in South Africa and although it did not last long, it opened a new door for treating patients dying of advanced cardiopulmonary conditions. Also, possibly a new door towards immortality?nnPerhaps that first heart transplant was too daring for its time, as surely there were many unknowns. However, it indisputably revealed the serious potential for clinical thoracic organ transplantation. Surgeons, physicians and immunologists were stimulated to work together towards improving the understanding of problems related to organ preservation, rejection and the optimising of recipient outcomes.nnThe first successful lung transplants were reported ∼20u2005yrs ago, although a number of earlier bold attempts had been made. Lungs presented a special unique problem, related to continuous unprotected exposure of the allograft to the outside environment. After all, humans breathe over 7,200u2005L of air daily, along with its attendant microbes, particulates and pollutants. Could a new immunosuppressed lung handle that? It seems it most certainly can.nnDespite tentative early concerns, lung allografts perform remarkably well in both the short and longer term. Lung transplantation has become an important treatment option for certain carefully selected patients with a wide array of advanced cardiorespiratory diseases. Over 15,000 lung transplants have been performed in the 20u2005yrs since the procedure has become a clinical reality, and ∼1,400 new transplants are performed annually in approximately 100 centres worldwide. Lung transplantation has become a real therapeutic option, not just palliation, for certain patients suffering from advanced emphysema, cystic fibrosis, pulmonary …

A Student-Community Planned Health Project for the Poor

Abstract A student-community planned clinic was begun in an inner-city high-rise housing development; continuous evening operation has been maintained for two years. The problems encountered included apathy of public officials and medical professionals, wariness of people in the community, lack of money and complications in medical staffing. In spite of these difficulties, an apparently stable community-student-physician relation has developed. During the first year of operation 1426 patients were seen, almost exclusively for minor illness. However, 53 per cent of patients in whom secondary diagnoses were made (9.5 per cent of all patients) had serious medical problems underlying the minor illnesses that led them to seek medical care. Almost 17 per cent of all patients were referred to municipal hospitals or other medical centers in the city. The clinic therefore appeared to provide an effective portal of entry for patients into the existing health-care system of the city.

The Human Lung as an Endothelin Clearance Organ: Normal Function and Derangement in Pulmonary Hypertension

Endothelin (ET) is a recently described circulating peptide released by vascular endothelial cells. It has potent vasoconstrictor and smooth muscle proliferative properties. In most models, ET is a pulmonary vasoconstrictor. Animal studies suggest that the lung acts as a net clearance organ for ET and normally reduces circulating ET levels, but this function has not been examined in humans. The effects of pulmonary hypertension on this clearance function are unknown, and it is also unknown if altered ET clearance (or excessive release) is an initiating step in the development of pulmonary hypertension.