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Biomedical subjects

E K Weir

Publications and source records attributed to E K Weir.

At least 19 recordsLinked to original sources
PubMed1992

The non specificity of specific nitric oxide synthase inhibitors.

L-NAME (Nw-Nitro-L-arginine methylester) and L-NMMA (NG- Monomethyl-L-arginine, monoacetate) are used widely as nitric oxide (NO) synthase inhibitors. Because of their functional groups (alcohols, amines and carboxylates), it appeared that they could interact with iron in a variety of systems. Using three in vitro models we observed these two compounds had inhibitory effects on cytochrome C reduction by ferrous iron, by ferrous iron accelerated by an unsaturated fatty acid or by epinephrine. This suggests that L-NAME and L-NMMA could have effects in iron containing systems found intracellularly apart from their inhibition of (NO) synthesis.

Amino Acid Oxidoreductases↗
PubMed1992

Direct role for potassium channel inhibition in hypoxic pulmonary vasoconstriction.

Cellular mechanisms responsible for hypoxic pulmonary vasoconstriction were investigated in pulmonary arterial cells, isolated perfused lung, and pulmonary artery rings. Three K+ channel antagonists, Leiurus quinquestriatus venom, tetraethylammonium, and 4-aminopyridine, mimicked the effects of hypoxia in isolated lung and arterial rings by increasing pulmonary artery pressure and tension and also inhibited whole cell K+ currents in isolated pulmonary arterial cells. Reduction of oxygen tension from normoxic to hypoxic levels directly inhibited K+ currents and caused membrane depolarization in isolated canine pulmonary arterial smooth muscle cells but not in canine renal arterial smooth muscle cells. Nisoldipine or high buffering of intracellular Ca2+ concentration with [1,2-bis(2)aminophenoxy] ethane-N,N,N',N'-tetraacetic acid prevented hypoxic inhibition of K+ current, suggesting that a Ca(2+)-sensitive K+ channel may be responsible for the hypoxic response. These results indicate that K+ channel inhibition may be a key event that links hypoxia to pulmonary vasoconstriction by causing membrane depolarization and subsequent Ca2+ entry.

Animals↗
PubMed1990

Comparison of the hemodynamic effects of nitric oxide and endothelium-dependent vasodilators in intact lungs.

The effects of endothelium-dependent vasodilation on pulmonary vascular hemodynamics were evaluated in a variety of in vivo and in vitro models to determine 1) the comparability of the hemodynamic effects of acetylcholine (ACh), bradykinin (BK), nitric oxide (NO), and 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP), 2) whether methylene blue is a useful inhibitor of endothelium-dependent relaxing factor (EDRF) activity in vivo, and 3) the effect of monocrotaline-induced pulmonary hypertension on the responsiveness of the pulmonary vasculature to ACh. In isolated rat lungs, which were preconstricted with hypoxia, ACh, BK, NO, and 8-bromo-cGMP caused pulmonary vasodilation, which was not inhibited by maximum tolerable doses of methylene blue. Methylene blue did not inhibit EDRF activity in any model, despite causing increased pulmonary vascular tone and responsiveness to various constrictor agents. There were significant differences in the hemodynamic characteristics of ACh, BK, and NO. In the isolated lung, BK and NO caused transient decreases of hypoxic vasoconstriction, whereas ACh caused more prolonged vasodilation. Pretreatment of these lungs with NO did not significantly inhibit ACh-induced vasodilation but caused BK to produce vasoconstriction. Tachyphylaxis, which was agonist specific, developed with repeated administration of ACh or BK but not NO. Tachyphylaxis probably resulted from inhibition of the endothelium-dependent vasodilation pathway proximal to NO synthesis, because it could be overcome by exogenous NO. Pretreatment with 8-bromo-cGMP decreased hypoxic pulmonary vasoconstriction and, even when the hypoxic pressor response had largely recovered, subsequent doses of ACh and NO failed to cause vasodilation, although BK produced vasoconstriction. These findings are compatible with the existence of feedback inhibition of the endothelium-dependent relaxation by elevation of cGMP levels. Responsiveness to ACh was retained in lungs with severe monocrotaline-induced pulmonary hypertension. Many of these findings would not have been predicted based on in vitro studies and illustrate the importance for expanding studies of EDRF to in vivo and ex vivo models.

Acetylcholine↗
PubMed1990

Enhanced chemiluminescence as a measure of oxygen-derived free radical generation during ischemia and reperfusion.

It has been suggested that oxygen-derived free radicals may contribute to the myocardial injury associated with ischemia and reperfusion. As the presence of enhanced free radical generation is a prerequisite for such damage, several techniques have been used to provide evidence of increased oxygen free radical production during reperfusion; however, all such techniques have substantial limitations. In this study, we used enhanced chemiluminescence to evaluate oxygen free radical generation during ischemia and reperfusion in the isolated Langendorff-perfused rat heart. The chemiluminescent technique, which has high sensitivity and can monitor radical generation continuously, avoids some of the limitations of earlier methods. Chemiluminescence (expressed as counts per second) decreased from 219 +/- 11 at baseline to 142 +/- 9 during ischemia and markedly increased to a peak of 476 +/- 36 during the first 3-5 minutes of reperfusion. This was followed by a slow decline over 11-16 minutes to a steady-state level of 253 +/- 14 (each sequential change in chemiluminescence was highly significant; p less than 0.001). Superoxide dismutase (2,000 units/min) significantly decreased peak reperfusion chemiluminescence to 316 +/- 17 (p less than 0.01). Hearts subjected to a second period of ischemia and reperfusion had a higher peak chemiluminescence (626 +/- 62), which also was significantly attenuated by 1,000 units/min superoxide dismutase (398 +/- 16; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Lymphatic abnormalities in Noonan syndrome: A case report.

Lymphatic abnormalities are not generally recognized as part of the Noonan syndrome. A child with this condition in whom unique and widespread lymphatic abnormalities were demonstrated by lymphography is described. Both T and B lymphocytes were detected in chylous fluid drained from the thorax. In addition, the child was found to have a protein-losing enteropathy and cardiovascular defects. The clinical spectrum of the Noonan syndrome may include animalies of the lymphatic system.

Cardiac Catheterization↗
PubMed1979

Distal airway responses to changes in oxygen and carbon dioxide tensions.

The reactivity of subpleural strips of lung parenchyma reflects primarily the tone of the smooth muscle in the peripheral airways. Lung strips taken from ten dogs relaxed when the oxygen level in the gas bubbling through the bath was reduced from 95% to 18%. Subsequent hypocapnia (carbon dioxide reduced from 5% to 0%) induced contraction of all strips. These changes were reversed when the oxygen or carbon dioxide tensions were restored to control levels. Addition of either indomethacin or meclofenamate, two chemically dissimilar inhibitors of prostaglandin synthetase, reduced the resting tone in each of six strips and prevented the hyperoxic constriction which was observed in paired, control strips (oxygen increased from 18% to 95%). Blockers of histamine and catecholamines had no effect. The reactivity of the distal airways to changes in gas tension provides a mechanism by which ventilation and perfusion can be matched. The action of indomethacin and meclofenamate indicates that a prostaglandin-like substance may be involved in the maintenance of distal airway tone and in the constriction produced by hyperoxia. The addition of prostaglandin F2 alpha or E1, after meclofenamate, in a further nine pairs of strips did not restore the hyperoxic constriction. This suggests that prostaglandins may mediate, rather than merely facilitate, the response.

Animals↗
PubMed1978

Prostaglandin E1 in infants with pulmonary atresia.

Infants with pulmonary atresia are frequently dependent upon the patency of the ductus arteriosus for adequate pulmonary blood flow. Endogenous production of a dilator prostaglandin probably maintains patency of the ductus in utero. Infusion of prostaglandin E1 (PGE1) 0,1 microgram/kg/min was used in 6 infants with pulmonary atresia to increase pulmonary blood flow and systemic oxygenation. The infusion improved the clinical condition of the infants and diminished the degree of central cyanosis. In 3 cases serial measurement of systemic arterial oxygen tension showed a sustained increase. There were no deleterious side-effects. During cardiac catheterization and preparation for operation, PGE1 provides a valuable means of maintaining pulmonary blood flow in infants with pulmonary atresia and a ductus arteriosus.

Ductus Arteriosus, Patent↗
PubMed1978

Does normoxic pulmonary vasodilatation rather than hypoxic vasoconstriction account for the pulmonary pressor response to hypoxia?

A mediator of the pulmonary pressor response to hypoxia has not been found. The pressor phenomenon could be explained if the pulmonary vasodilatation present during normoxia were maintained by a vasodilator substance such as bradykinin. Ventilation of the lungs with air or oxygen causes the release of bradykinin which is rapidly inactivated in the lungs. Inhibition of the inactivating enzyme prevents the development of pulmonary hypertension in response to chronic hypoxia. Bradykinin is formed in the blood and is also present in alveolar macrophages, which arise from precursors in haematopoietic tissue. Formation of bradykinin by granulocytes is critically dependent on the local oxygen tension. The enzyme which inactivates bradykinin also converts angiotensin I to angiotensin II and thus provides a mechanism for interaction between the pulmonary and systemic vasculatures. The rate of inactivation of bradykinin may be altered by small changes in pH. It is postulated that when bradykinin production is reduced during hypoxia the higher tone of the pulmonary vascular smooth muscle, maintained by numerous constrictor stimuli, asserts itself.

Bradykinin↗
PubMed1978

Myocardial infarction in the black population of South Africa: coronary arteriographic findings.

Thirteen Black patients who had classic electrocardiographic evidence of myocardial infarction supported by changes in serum enzymes were investigated by coronary arteriography. Ten of these had occlusive atherosclerosis and in none of these did the associated risk factors such as hypertension or diabetes appear to be operative, and most were manual laborers. Their mean serum cholesterol measurement was found to be 222 mg. per cent, a value which is found in 25 per cent of the urban Black population. In the remaining three patients, the coronary arteries were found to be angiographically normal and two of these were associated with the billowing mitral leaflet syndrome; it is postulated that their myocardial infarction was a result of coronary spasm, or a consequence of fibrin emboli emanating from the redundant mitral leaflets. Based on statistics from our major referring hospital, it is estimated that the prevalence rate from myocardial infarction among general admissions to a medical ward is less than 0.05 per cent, a figure lower than previously reported by clinico-electrocardiographic studies. It would appear that the prevalence of this disease has not increased over the last two decades and the immunity of the Black population is unexplained.

Adult↗
PubMed1978

Non-invasive observations on initial low frequency vibrations of the first heart sound--correlation with the 'presystolic' murmur in mitral stenosis.

The initial low frequency component of the first heart sound, 'M', has been studied in normal subjects, and in patients with vario-s prosthetic mitral valves and with mitral stenosis, using simultaneous low frequency phonocardiography, echocardiography, and apex cardiography. The techniques showed 'M' to have a constant morphology in preisovolumic systole. In mitral stenosis, 'M' and the preisovolumic 'presystolic' murmur appear to be the same phonocardiographic phenomenon. While 'M' was present in sinus rhythm, augmentation of this normal vibration occurred particularly during the short cycles of atrial fibrillation. Leaflet coaption and movement of the ventricular wall as detected echocardiographically do not appear to play a role in its pathogenesis but the sound could emanate from the ventricular wall as it tautens and decreases its compliance at the onset of systole.

Echocardiography↗
PubMed1978

Double outlet right ventricle: clinical and anatomical spectrum.

Thirty-two patients with double outlet right ventricle (DORV) were studied between 1960 and 1976. Associated congenital defects frequently compounded the difficulty of clinical diagnosis. Cardiac catheterisation was performed in 27 patients, and the ventriculograms were studied with particular regard to the relative positions of the great vessels to each other and to the ventricular septal defect. These relationships determine which corrective operation is possible. Correction has been performed in 12 patients with a perioperative mortality of 25%. Although mitral-aortic discontinuity was demonstrated in all cases, consideration of the anatomical spectrum included in the term DORV suggests that discontinuity is not an essential feature. In common with other clinical data and in contrast with necropsy studies, none of our patients was found to show the normal relationship of the great vessels to each other, in which the aorta lies posterior and to the right of the pulmonary artery. The reason for this difference between the clinical and necropsy findings is not apparent. A similar disparity was shown with regard to pulmonary stenosis, which was demonstrated at catheterisation in 68% of the 27 patients (mean gradient 68 +/- 3 mmHg), in contrast with incidences of 18% and 25% in recent necropsy series. Patients in the necropsy studies were frequently neonates or infants, in whom death may have been the result of intractable cardiac failure secondary to excessive pulmonary blood flow. In older patients without pulmonary stenosis and with pulmonary hypertension, frequent observation is imperative so that surgical treatment can be instituted before the development of irreversible pulmonary vascular disease.

Adolescent↗
PubMed1978

Valve replacement for rheumatic aortic incompetence in adolescents.

The timing of valve replacement in patients with rheumatic aortic regurgitation is assessed by balancing the mortality and complications associated with the operation and the prosthetic valves against the natural history of the lesion. The time course without surgery is determined by the severity of the volume overload and the gradual deterioration of myocardial function. We wished to obtain information both on the haemodynamic recovery achieved after aortic valve replacement in young patients and also on the risks of operation in this group. Twenty patients, in whom the aortic valve was replaced at a mean age of 15 years, were reviewed. An improvement in symptoms and in the cardiothoracic ratio on the chest radiograph occurred in every case, and the voltage measurements suggestive of left ventricular hypertrophy on electrocardiogram diminished in all but two. The left ventricular end-diastolic pressure decreased in the 11 patients who were recatheterised after operation. The ejection fraction improved in three patients and stayed the same in three others. While there were no operative deaths in our series the incidence of serious morbidity, in terms of myocardial damage at or after operation, was disappointingly high. Early valve replacement to preserve myocardial function is especially attractive in young patients but cannot be advised if the insertion of the prosthetic valve is associated with appreciable myocardial damage.

Adolescent↗
PubMed1978

Potentiation of hypoxic pulmonary vasoconstriction by ethyl alcohol in dogs.

Pulmonary and systemic hemodynamics and arterial blood gases were measured in anesthetized and mechanically ventilated dogs before and after oral or intravenous administration of ethanol. Increases in mean pulmonary artery pressure and pulmonary vascular resistance occurred. Platelet antiserum-induced thrombocytopenia inhibition of prostaglandin synthesis with meclofenamate, or alpha-adrenergic blockade did not alter the pulmonary pressor response to ethanol. However, the increase in resistance following ethanol was abolished by hyperoxia and potentiated by hypoxia. Thus, it appears that the effect of ethanol is to augment hypoxic pulmonary vasoconstriction, whereas ethanol per se has no independent pulmonary pressor activity.

Administration, Oral↗
PubMed1978

Pulmonary vascular effects of endotoxin in leukopenic dogs.

We have demonstrated previously that in the dog, small doses of endotoxin abolish the pulmonary vasoconstrictor reponse to hypoxia, apparently by stimulating the production of a vasodilator prostaglandin. We previously ruled out platelets as mediators of this endotoxin effect. To evaluate leukocytes as possible mediators, we rendered dogs leukopenic by means of a leukocyte antiserum. However, this did not modify the inhibitory effect of endotoxin on hypoxic pulmonary vasoconstriction. Hence, neither leukocytes nor platelets appear to mediate the endotoxin effect. In the near absence of both platelets and leukocytes, the endotoxin effect can be prevented by inhibiting prostaglandin synthesis with meclofenamate. This suggests that endotoxin prevents hypoxic pulmonary vasoconstriction by acting on the systemic circulation or on the lung (possibly directly on the pulmonary blood vessels) to stimulate the production of a vasodilator prostaglandin.

Animals↗