Monocrotaline-induced cardiopulmonary injury in rats: modification by thiol and nonthiol ACE inhibitors.
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Angiotensin-Converting Enzyme Inhibitors↗
Biomedical subjects
A Molteni
Publications and source records attributed to A Molteni.
Pulmonary endothelial dysfunction induced by unilateral as compared to bilateral thoracic irradiation in rats.
Rats were sacrificed 2 months after a single dose of 10-30 Gy of 60Co gamma rays delivered to either a right unilateral or a bilateral thoracic port. Four indices of lung endothelial function were measured: the activities of angiotensin-converting enzyme (ACE) and plasminogen activator (PLA) and the production of prostacyclin (PGI2) and thromboxane (TXA2). The number of macrophages recovered by bronchoalveolar lavage (BAL) and the degree of right ventricular hypertrophy (an index of pulmonary hypertension) also were determined. Right lung ACE and PLA activity decreased linearly, and PGI2 and TXA2 production increased linearly with increasing radiation dose. The response curves for right unilateral and bilateral thoracic irradiation were not significantly different. In contrast, bilateral irradiation was more toxic than unilateral, since rats exposed to the former exhibited decreased body weight, an increased incidence of pleural effusions, an increase in the number of macrophages recovered by BAL, and right ventricular hypertrophy. These data demonstrate that pulmonary endothelial dysfunction induced by hemithorax irradiation represents a direct response of the endothelium to radiation injury and is not secondary to other phenomena such as shunting of function to the shielded lung.
Animals↗
Monocrotaline-induced cardiopulmonary damage in rats: amelioration by the angiotensin-converting enzyme inhibitor CL242817.
Pulmonary injury induced by the plant alkaloid monocrotaline is partially prevented by the angiotensin-converting enzyme (ACE) inhibitor captopril. CL242817 [(S-[R*,S*])-1-([3-acetylthio]-3-benzoyl-2-methyl-propionyl)- L-proline] is a new orally active ACE inhibitor under evaluation as an antihypertensive agent. To determine whether CL242817 also can modify monocrotaline-induced pulmonary injury, male rats were divided into four groups: control; CL242817 (60 mg/kg/day, po); monocrotaline (2.4 mg/kg/day, po); or monocrotaline plus CL242817, and were sacrificed after 6 weeks of continuous treatment. Rats receiving monocrotaline alone exhibited occlusive medial thickening of the pulmonary arteries, cardiomegaly, and right ventricular hypertrophy. Electron micrographs of monocrotaline-treated lung revealed degeneration of both endothelial and Type I epithelial cells, as well as marked interstitial hypercellularity and fibrosis. Hydroxyproline (collagen) content of monocrotaline-treated lung also increased significantly, confirming the fibrosis observed in the electron micrographs. These structural changes were accompanied by decreased lung ACE and plasminogen activator (PLA) activities, indicative of pulmonary endothelial dysfunction. Concomitant CL242817 treatment ameliorated all anatomic manifestations of monocrotaline injury, particularly the right ventricular hypertrophy, pulmonary arterial occlusion, epithelial degeneration, and interstitial fibrosis. CL242817 also significantly prevented the monocrotaline-induced increase in lung hydroxyproline content. In contrast, concomitant CL242817 did not significantly influence the suppressed lung ACE and PLA activities in monocrotaline-treated rats. CL242817 alone produced retarded weight gain, decreased heart weight relative to body weight, decreased lung hydroxyproline content and ACE activity, and increased serum ACE activity and plasma AII concentration. Thus CL242817 resembles captopril, both in its ability to ameliorate monocrotaline-induced pulmonary injury in rats, and in many of its side effects.
Angiotensin-Converting Enzyme Inhibitors↗
Phase II trial of tamoxifen in chronic lymphocytic leukemia.
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Aged↗
Acute effects of digoxin on total systemic vascular resistance in congestive heart failure due to dilated cardiomyopathy: a hemodynamic-hormonal study.
The effects of the digitalis glycosides on systemic vascular resistance (SVR) in patients with congestive heart failure (CHF) are controversial. Most investigators report a reduction in total SVR, an action that has been attributed primarily to withdrawal of elevated sympathetic tone. Direct proof of this hypothesis is lacking, however, and the roles played by the renin-angiotensin-aldosterone and vasopressin systems have not been fully explored. Moreover, in several studies of patients with CHF, SVR did not decrease after the administration of digitalis. To clarify these issues, the hemodynamic and hormonal effects of digoxin were correlated in 11 normotensive men in sinus rhythm with CHF due to dilated cardiomyopathy. Patients were evaluated at rest and during submaximal exercise before and 6 hours after the intravenous infusion of 1.0 mg of digoxin (mean serum concentration 1.7 ng/ml). With digoxin therapy, heart rate, pulmonary wedge pressure and right atrial pressure declined and cardiac output increased. Although vasopressin was unchanged, both plasma norepinephrine concentrations and plasma renin activity decreased, the reduction in norepinephrine correlating with the increase in cardiac output. Despite these hemodynamic and hormonal effects, there was no change in total SVR at rest or during exercise. It is concluded that the improvement in cardiac function with digoxin in this patient group was a result of the inotropic properties of the drug, without an associated reduction in impedance. The failure of total SVR to decrease despite decreases in plasma norepinephrine levels and plasma renin activity might be explained by concomitant digitalis-induced vasoconstriction, impaired ability of arterioles to dilate in CHF, or offsetting alterations in other vasoactive hormone systems.
Cardiomyopathy, Alcoholic↗
The relationship between endothelial dysfunction and collagen accumulation in irradiated rat lung.
Male rats were killed 2 months (early fibrosis) or 6 months (peak fibrosis) after a range of single doses of 60Co gamma rays to the right hemithorax. Pulmonary arterial perfusion scans were performed at 2 months on animals scheduled for autopsy at 6 months. Lung angiotensin converting enzyme (ACE) activity was used to monitor endothelial function, and hydroxyproline (HP) concentration served as an index of interstitial collagen accumulation (fibrosis). ACE activity also was measured in right lung bronchoalveolar lavage (BAL) fluid and blood serum, to determine whether information obtained from a minimally invasive procedure might serve as an index or predictor of the severity of lung damage. Linear dose-response curves (r = 0.92-0.99) were obtained for right lung arterial perfusion, ACE activity and HP concentration. At 2 months, perfusion decreased 2.7% per Gy, ACE activity (per lung, per mg wet weight, or per mg protein) decreased 3.0-4.2% per Gy, and HP concentration (per g dry weight) increased 1.7% per Gy. At 6 months, the slopes of the response curves were virtually identical to those at 2 months; the Y intercept of the response curve for ACE activity was unchanged, whereas that for HP concentration was 50% higher at 6 than at 2 months. ACE activity and protein concentration in the BAL increased with increasing dose, but the variation within groups was too large, and the sensitivity was too low to serve as a reliable index of lung status. Serum ACE activity was independent of radiation dose at both autopsy times. Thus in rat lung, arterial perfusion, endothelial dysfunction and interstitial fibrosis exhibit similar but not identical radiosensitivities. The dose-effect curves for these three responses of the lung in situ change less than 5% per Gy over the dose range of 10-30 Gy, a smaller variation than would be predicted from endothelial cell survival data based on clonogenic assays in vitro or in vivo.
Animals↗
Monocrotaline-induced pulmonary fibrosis in rats: amelioration by captopril and penicillamine.
The purpose of this study was to determine whether Captopril (an angiotensin converting enzyme inhibitor) or D-penicillamine (an inhibitor of collagen crosslinking) can ameliorate pulmonary fibrosis induced by the plant alkaloid monocrotaline. Rats were randomly assigned to one of six treatment groups: (1) control; (2) Captopril, 60 mg/kg/day, p.o.; (3) D-penicillamine, 30 mg/kg/day, p.o.; (4) monocrotaline, 2.4 mg/kg/day, p.o.; (5) monocrotaline plus Captopril, as above; (6) monocrotaline plus penicillamine, as above; and were killed after 6 weeks of continuous drug administration. Monocrotaline-treated rats exhibited several anatomic correlates of pulmonary hypertension, including cardiomegaly, right heart enlargement, and muscularization of the pulmonary arteries and arterioles. These monocrotaline reactions were accompanied by decreased lung activities of angiotensin converting enzyme (ACE) and plasminogen activator (PLA), indicative of endothelial dysfunction; and by increased lung hydroxyproline concentration, indicative of interstitial fibrosis. The presence of interstitial fibrosis was confirmed by electron microscopy. When given concomitantly with monocrotaline, both Captopril and penicillamine partially prevented the cardiomegaly, right heart enlargement, and vascular muscularization. Both agents also diminished the decreased lung PLA activity and increased hydroxyproline concentration observed in monocrotaline-treated animals. Neither modifying agent influenced the monocrotaline-induced decrease in lung ACE activity. Compared with control rats, the rats receiving Captopril alone exhibited decreased heart weight and increased serum ACE activity, and animals receiving penicillamine alone did not differ significantly from control animals for any of the endpoints studied. These data demonstrate that Captopril and penicillamine ameliorate monocrotaline-induced pulmonary fibrosis in rats. Penicillamine, known to inhibit radiation-induced lung injury, thus is shown to be effective in a second model of pulmonary fibrosis. Perhaps more importantly, the hydroxyproline data demonstrate that the ACE inhibitor Captropril exhibits antifibrotic activity in monocrotaline-treated rat lung.
Animals↗
Effect of subliminal symbiotic activation on hypnotic rapport and susceptibility.
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Humans↗
Effects of etomidate on hormonal responses to surgical stress.
The hormonal responses to surgical stress were examined in 10 patients scheduled for elective gynecologic laparotomy. Anesthesia was induced with either thiopental, 4 mg/kg, or etomidate, 0.35 mg/kg, and maintained with nitrous oxide and enflurane. Plasma cortisol, aldosterone, ACTH, and catecholamines were measured during the 24 h after the induction of anesthesia. The catecholamine responses of the patients whose anesthesia was induced with either drug were similar. The plasma ACTH concentrations for the etomidate group were greater than baseline values and the concentrations in the thiopental group (P less than 0.05) in the fourth and fifth hours. In the patients receiving thiopental, both cortisol and aldosterone concentrations were greater than the baseline value (P less than 0.05) in the second to fourth hours after induction. In the etomidate group, the plasma concentrations of cortisol were less than baseline values (P less than 0.05) in the first and second hours after induction of anesthesia and both cortisol and aldosterone were lower than those in the thiopental group (P less than 0.05) in the half to fourth hours after induction. These results confirm an earlier report of the suppression of cortisol after etomidate administration and, because aldosterone also was suppressed, suggests that etomidate exerts its effect by inhibiting early stages of steroidogenesis in the adrenal cortex.
Adrenocorticotropic Hormone↗
Prolactin, corticotropin, and gonadotropin concentrations following thermal injury in adults.
The concentration of serum prolactin (PRL), plasma corticotropin (ACTH), serum follicle stimulating (FSH), and luteinizing (LH) hormones were measured in 28 adult burned patients (25 males and three females). Morning and night determinations were performed for each hormone. Serum PRL was elevated in males up to the fourth week after the thermal injury. Plasma ACTH increased significantly on the second day postburn and returned gradually to normal on the fifth; serum FSH and LH increased on day 1, then decreased significantly on day 2 and remained low for about 2 weeks. In females, while PRL increased significantly, the gonadotropins were slightly elevated and the ACTH remained within normal limits for the 3 days during which it was possible to study these patients. In all subjects the circadian rhythm of the four measured hormones showed significant variations from the normal pattern.
Adolescent↗
Monocrotaline-induced pulmonary endothelial dysfunction in rats.
To study the role of endothelial damage in the pathogenesis of lung injury induced by the pyrrolizidine alkaloid monocrotaline, three functions (angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) production) associated with the pulmonary endothelium were examined, and were correlated with pulmonary arterial perfusion and ultrastructure in rats receiving monocrotaline in their drinking water (20 mg/liter) for 1-12 weeks. Lung ACE activity increased after 1 week of monocrotaline, then decreased steadily from 1 to 6 weeks, before plateauing at approximately 55% of normal. PLA activity in monocrotaline-treated lungs did not change significantly for the first 2 weeks, then decreased to 59 and 79% of the control value after 6 and 12 weeks, respectively. In contrast, PGI2 production increased progressively, reaching 140 and 270% of the control level after 6 and 12 weeks of monocrotaline treatment, respectively. These endothelial functional changes were not accompanied by significant changes in pulmonary arterial perfusion as visualized by 99mTc lung scans. Electron microscopy of monocrotaline-treated lungs revealed endothelial damage (perivascular and subendothelial edema, degeneration) starting at 1 week, and inflammatory and hemorrhagic reactions starting at 2 weeks. At 6 and 12 weeks, monocrotaline-treated rats also exhibited increased pulmonary arterial wall thickness, right heart enlargement, and cardio- and hepatomegaly. Thus, monocrotaline-induced pulmonary injury is accompanied, and in some cases preceded, by structural and functional abnormalities in the pulmonary endothelium.
Animals↗
Effect of captopril, MK-421 and MK-422 on fibrinolysis determined by 3 "in vitro" assays.
The effect of captopril, MK-421 and MK-422 on fibrinolysis was investigated in vitro with 3 assay methods. Incorporation of captopril, but not MK-421 and MK-422, into fibrin clots resulted in a reduction of fibrinolysis by purified human plasmin. The concentrations of captopril required to demonstrate this effect far exceeded the therapeutic doses. Pre-mixing plasmin with captopril did not lead to a decreased lysis of fibrin plates. Furthermore, none of these agents affected the lysis of 125I-fibrin plates by a mixture of human serum and streptokinase. Captopril and MK-421, and to a much lesser extent MK-422, inhibited the amidolysis of a fluorogenic synthetic substrate by human plasmin; the inhibition was ameliorated by increasing the substrate concentration. Apparently, the inhibition of fibrinolysis by high doses of captopril, and of amidolysis by captopril and MK-421, appears to lie in their effects on the substrate (fibrin and synthetic substrate) rather than on the enzyme (plasmin).
Animals↗
Radiation injury in rat lung. IV. Modification by D-penicillamine.
To determine whether D-penicillamine, known to reduce fibrosis in irradiated rat lung (W. F. Ward, A. Shih - Hoellwarth , and R. D. Tuttle , Radiology 146, 533-537, 1983), also ameliorates radiation injury in the pulmonary endothelium, we measured angiotensin-converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI2) production in the lungs of penicillamine-treated (10 mg/day, po, continuous after irradiation) and untreated rats from 2 weeks to 6 months after a single dose of 25 Gy of 60Co gamma rays to the right hemithorax. Both ACE and PLA activity in the irradiated right lung of untreated rats decreased dramatically between the 1st and 2nd months after exposure, then reached a plateau through 6 months at approximately 25 and 50% of the normal level, respectively. For the first 2 months after irradiation, penicillamine-treated animals exhibited significantly (P less than 0.05) higher activities of both ACE and PLA than did untreated rats. From 3 to 6 months after irradiation, however, the only significant drug effect on these enzymes was a 25% increase in PLA activity at 6 months. PGI2 production by the irradiated lung of untreated rats increased continuously, and at 6 months was approximately 10 times higher than normal. Penicillamine significantly (P less than 0.05) reduced this hypersecretion, and at 6 months after irradiation, PGI2 production by the lungs of drug-treated rats was only half that of untreated animals. In contrast, the drug had no significant effect on enzyme activities in the lungs of sham-irradiated rats. Thus the antifibrotic agent D-penicillamine delays the onset of radiation-induced enzyme dysfunction in the pulmonary endothelium. In addition at 6 months after irradiation, the lungs of penicillamine-treated rats exhibit 25% more PLA activity and only half as severe a hypersecretion of PGI2 as do the lungs of untreated animals. The drug is most effective in ameliorating endothelial damage during the first 2 months after irradiation, preceding the development of interstitial fibrosis. However, the effect of this penicillamine regimen on pulmonary endothelial function is not as large as its effect on collagen accumulation in irradiated rat lung.
Animals↗
Hormone binding in brain tumors.
Brain tumors from 64 patients were studied for the presence of hormone binding. Estradiol binding was detected in 34 patients: 13 of 21 meningiomas, 4 of 8 schwannomas, 1 oligodendroglioma, 1 of 5 benign gliomas, 4 of 5 malignant gliomas, 5 of 11 metastatic tumors, and 6 of 11 pediatric tumors: 1 medulloblastoma, 2 malignant ependymomas, 1 benign astrocytoma, 1 malignant sarcoma, and 1 malignant teratoma. Eleven patients were studied for progesterone binding, which was measurable in 7: 1 schwannoma, 3 meningiomas, 1 malignant sarcoma (pediatric group), 1 astrocytoma--gemistocytic (pediatric group), and 1 metastatic adenocarcinoma. There were 41 females and 23 males in the study. Fifteen females were premenopausal, 18 were postmenopausal, and 8 were in the pediatric group. Of the 34 tumors with measurable estradiol binding, 23 occurred in females. In the progesterone group, 4 of the 7 tumors with measurable binding activity were from female patients. In the pediatric group, estradiol binding was detected in 1 medulloblastoma, 2 malignant ependymomas, 1 malignant teratoma, 1 malignant sarcoma, and 1 astrocytoma. Five of the 6 pediatric tumors with estradiol binding were malignant, and both pediatric tumors with progesterone binding were also malignant. Of the 10 gliomas studied, 4 of the 5 malignant tumors had estradiol binding, whereas only 1 of the 5 benign tumors showed binding. Our studies with the pediatric tumors and the gliomas suggest that a relationship exists between the malignancy of the tumor and the presence of hormone binding. The ubiquitous nature of the presence of hormone binding is discussed, as is the possible correlation between age, sex, histological grade, and significance of hormone binding in brain tumors.
Adolescent↗
Radiation injury in rat lung. II. Angiotensin-converting enzyme activity.
To determine the role of endothelial dysfunction in the pathogenesis of radiation-induced pulmonary injury, lung angiotensin-converting enzyme (ACE) activity, arterial perfusion, and ultrastructure were examined from 1 to 150 days after a single exposure of 25 Gy of 60Co gamma rays to the right hemithorax of rats. Arterial perfusion to the irradiated right lung increased during the first 2 weeks, then decreased to approximately 80% of the left lung value at 30 days postirradiation. Perfusion of the irradiated lung continued to decline, and by 90-150 days was only 40% of that of the shielded lung. ACE activity in the irradiated right lung did not change significantly until 30 days after exposure, when it decreased to 72% of that in the left lung. ACE activity in the right lung declined steadily from 30 to 90 days postirradiation, then reached a plateau through 150 days at less than 20% of normal. Perivascular and interstitial edema was evident at 1 day after irradiation and persisted for 30 days. Endothelial cells exhibited blebbing, fragmentation, and increased basement membrane at 30 days. Mast cells were present in the septa, but interstitial collagen was not increased at that time. From 90 to 150 days postexposure, progressive obliteration of capillaries by fibrotic reactions was observed. Thus decreased ACE activity accompanies radiation-induced hypoperfusion and endothelial ultrastructural changes in rat lung. All of these reactions precede the development of pulmonary fibrosis.
Animals↗
Comparison of antihypertensive effects of captopril and propranolol in essential hypertension.
The antihypertensive effects of the oral converting enzyme inhibitor captopril and of propranolol were evaluated in a single-blind trial of 12 weeks in 19 ambulatory men with moderated essential hypertension (supine diastolic blood pressure [DPB], 100 to 120 mm Hg after receiving placebo for two weeks) whose sodium intake was unrestricted. The captopril group included 12 patients and the propranolol group seven. After the initial dose-finding period of four weeks, supine DBP was significantly reduced in eight patients receiving captopril and in four of the patients receiving propranolol. In these patients DBP decreased throughout the following eight weeks. In the remaining patients from each group, DBP was not reduced by either drug given alone at maximum allowable dosages during dose-finding periods, nor by combined administration in following weeks. No adverse side effects attributable to captopril were noted, except in one patient in whom proteinuria developed after seven weeks. Captopril has potential value in the treatment of moderate essential hypertension.
Adult↗
Estradiol receptor-binding protein in head and neck neoplastic and normal tissue.
Estradiol (E2) receptor-binding protein was measured in 42 neoplasms and normal tissues from the head and neck region. Tissues with high E2 receptor protein content included normal skin and normal mucosa of the nose and the floor of the mouth and of the parotid and submandibular salivary glands. Two of four papillary carcinomas of the thyroid, three of five pleomorphic adenomas of the parotid, four of six squamous cell carcinomas of the oral cavity, one of angiofibroma of the nose, and an eye (sclera) melanoma also had a high content of E2-binding protein. The demonstration of estrogen receptors in these neoplasms may indicate that these tumors also, as many breast lesions, may be hormone-dependent. If this is correct, an appropriate hormonal treatment may influence their biological evolution.
Adenoma↗
Failure of chronic administration of the angiotensin I-converting enzyme inhibitor, Teprotide (SQ 20881), to affect the ultrastructure of the adrenal cortex and the aldosterone secretion in the rat.
Administration of Teprotide (SQ 20881), an angiotensin I-converting enzyme inhibitor for up to 10 weeks at a dose of 3 mg. per kg., subcutaneously, twice a day in the rat, effected no change in the ultrastructure of the adrenal cortex nor in the concentration of serum aldosterone. A significant increase (p less than 0.05) in renin granulation indices which was already apparent after 3 weeks of treatment with Teprotide was even more definitive after 10 weeks (p less than 0.01). Moderate renal hypertrophy was present in rats receiving the drug for 3 weeks. Findings pertaining to aldosterone production differed from those reported following acute administration of Teprotide wherein a decrease in the production of serum aldosterone and an increase in plasma renin activity was observed. It has been suggested that decreased aldosterone production following acute administration of Teprotide is a consequence of decreased stimulus of the zona glomerulosa due to diminished synthesis of angiotensin II. If this is the case, mechanisms other than angiotensin II stimulation of the zona glomerulosa must control aldosterone synthesis, perhaps through hormones of the adrenal cortex. Another possibility could be that angiotensin II synthesis may be obtained, after an interval, through an alternative pathway.
Adrenal Cortex↗