Rheologic genesis of aortic coarctation in a canine model.
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Animals↗
Biomedical subjects
V J Ferrans
Publications and source records attributed to V J Ferrans.
Protective effect of ICRF-187 on doxorubicin-induced cardiac and renal toxicity in spontaneously hypertensive (SHR) and normotensive (WKY) rats.
Loss of body weight, cardiomyopathy, and nephropathy were the main toxic manifestations found when male spontaneously hypertensive rats (SHR) and genetically related Wistar-Kyoto (WKY) rats were given 1 mg/kg doxorubicin iv once a week for 12 weeks. Each of these alterations was more severe in SHR. The most profound effects on body weight were observed from the 7th to the 12th week of dosing. During this period the body weight of SHR declined to preinjection control levels. Weight loss also occurred in WKY given doxorubicin, but was not as profound. Pretreatment with 25 mg/kg ICRF-187 ip attenuated the doxorubicin-induced loss in body weight in both types of animals. The frequency and severity of cardiac and renal lesions were graded on a score of 0 to 4. Alterations were found in hearts of all SHR and four of five WKY given doxorubicin alone. Cytoplasmic vacuolization and myofibrillar loss were more severe in SHR (average score, 2.6) than in WKY (average score, 1.0). At the end of the study mean arterial pressure was also decreased in SHR which had received doxorubicin alone. Pretreatment with ICRF-187 significantly attenuated the severity of the lesions in both SHR (average score, 1.0) and WKY (average score, 0); mean arterial pressure was higher in SHR treated with ICRF-187 and doxorubicin than in saline-treated SHR. Renal alterations, including glomerular vacuolization and tubular dilatation, were found in both strains of rats (average scores, 4.0 in SHR and 3.0 in WKY). ICRF-187 also reduced the severity of renal lesions (average scores, 2.0 in SHR and 1.0 in WKY). Thus, although ICRF-187 significantly alters myocardial, renal, and body weight effects of doxorubicin in both strains of rats, these toxic effects are more severe in SHR than in WKY. SHR provide an useful animal model for the critical examination of agents with potential protective activity against doxorubicin-induced toxicity.
Animals↗
Examination of minoxidil-induced acute cardiotoxicity in miniature swine.
Minoxidil, a vasodilating antihypertensive agent, was given orally in doses of 1, 3 or 10 mg/kg to miniature swine on 2 consecutive days. Mean arterial pressure decreased and heart rate increased most consistently after the 10 mg/kg dose. However, all 3 doses of minoxidil induced myocardial hemorrhages and/or left ventricular papillary muscle necrosis within 24 h after the second dose. Necrosis, characterized by hypercontraction of muscle cells and myofibrillar damage, occurred in 1 of 8 pigs given 1 mg/kg, 3 of 13 given 3 mg/kg and 7 of 14 given 10 mg/kg of minoxidil. The pharmacological effects of minoxidil, hypotension and reflex tachycardia, probably led to ischemia and necrosis in left ventricular papillary muscles. Gross hemorrhages involving the left atrium and to a lesser extent the left ventricle were found in 4 of 8 pigs given 1 mg/kg, 9 of 13 given 3 mg/kg and 11 of 14 given 10 mg/kg of minoxidil. The atrial lesions were manifested grossly by diffuse redness and microscopically by interstitial edema, extravasation of erythrocytes and infiltration of areas around small arteries and arterioles with acute and chronic inflammatory cells. The hemmorhagic areas were concentrated along the epicardial surfaces, and to a lesser extent along the endocardial surfaces. Atrial lesions induced by minoxidil preferentially involve the left atrium in pigs and the right atrium in dogs. These differences may be related to the anatomic patterns of coronary circulation in the 2 species.
Administration, Oral↗
Accumulation of Langerhans' cells on the epithelial surface of the lower respiratory tract in normal subjects in association with cigarette smoking.
Langerhans' cells are a defined subpopulation of the mononuclear phagocyte system known to accumulate in the lung in histiocytosis X, an interstitial lung disorder strongly linked to cigarette smoking. To evaluate the hypothesis that cigarette smoking itself may be associated with the accumulation of Langerhans' cells in the lung, normal nonsmokers (n = 5) and normal smokers (n = 10) were evaluated by bronchoalveolar lavage for the presence of Langerhans' cells as identified by the OKT6 monoclonal antibody and by transmission electron microscopy. While the OKT6 antibody identified 0.1 +/- 0.1% of the cells recovered from nonsmokers, it labeled 1.1 +/- 0.3% of those recovered from smokers (p less than 0.01). Furthermore, while electron microscopy demonstrated no Langerhans' cells among the lavage cells from nonsmokers, 0.4 +/- 0.1% of the cells recovered from normal smokers contained characteristic intracytoplasmic Birbeck granules, positively identifying them as Langerhans' cells. We conclude that cigarette smoking is associated with an expansion in the population of Langerhans' cells on the epithelial surface of the lower respiratory tract. While the mechanisms underlying this accumulation are unknown, it is possible that the properties of these cells contribute to the derangements of the pulmonary parenchyma found in cigarette smoking and establish a biologic link to the already observed epidemiologic association between histiocytosis X and cigarette smoking.
Adult↗
Transforming growth factor beta-1 in acute myocardial infarction in rats.
TGF-beta 1 has been examined in the heart during myocardial infarction caused by ligation of the left coronary artery. Infarcted and uninfarcted myocardium have been compared by immunohistochemical staining of TGF-beta 1 and by Northern blot analysis of mRNA. Normal ventricular myocytes are strongly stained by an antibody to TGF-beta 1. Progressive loss of staining of these myocytes begins within 1 hr after coronary ligation. However, by 24-48 hr after ligation, intense staining of myocytes at the margin of infarcted areas is seen. Northern blots of infarcted myocardium 48 hr after ligation show a 3- to 4-fold increase in the principal 2.4 kb TGF-beta 1 mRNA; there is also a marked increase in a minor 1.9 kb transcript. In the same tissue samples, there is a 2-fold decrease in the mRNA for the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase. The results indicate a significant role for TGF-beta in the response of the heart to injury.
Animals↗
Heparin-binding growth factor-I (endothelial cell growth factor) binds to endothelium in vivo.
Heparin-binding growth factor-I (HBGF-I) produces a significant increase in endothelial cell replication in vitro and may prove useful for endothelial regeneration and endothelial seeding in vivo. Heparin enhances the mitogenic effects of HBGF-I in vitro and may be an important adjunct to its pharmacologic use. Binding studies in the rat were undertaken to determine the feasibility of use of HBGF-I in vivo. For saturation studies, 125I-labeled HBGF-I was administered intravenously at various concentrations with heparin (approximately 5 U/ml blood volume). Further binding studies were conducted with the use of a constant concentration of 125I-labeled HBGF-I (40 ng) with or without heparin (2.5 U/ng HBGF-I). In each case, the rat was perfused with ice-cold saline solution 5 minutes after drug administration and the aorta or carotid arteries were harvested. 125I-labeled HBGF-I with heparin demonstrated saturation binding to rat aortic endothelium at an approximate blood concentration of 10 ng/ml. Scatchard plot analysis of in vivo data revealed a binding constant (KD) of 1.60 +/- 0.004 x 10(-9) mol/L compared with 2 to 8 x 10(-10) mol/L obtained for in vitro binding. Receptor number per cell was approximately 3000 for rat aortic endothelium, compared with a receptor number of 2000 to 20,000 for several endothelial cell lines, including bovine aortic endothelial cells, determined in vitro. 125I-labeled HBGF-I binding to uninjured rat carotid endothelium was significantly increased (p = 0.0001) by heparin (463 +/- 302 cpm to 1172 +/- 403 cpm).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Evaluation of fibronectin gene expression by in situ hybridization. Differential expression of the fibronectin gene among populations of human alveolar macrophages.
Populations of alveolar macrophages recovered from the lower respiratory tract secrete fibronectin, a multi-functional glycoprotein capable of influencing cell migration, attachment, differentiation, and proliferation. Using in situ hybridization of 35S-labeled antisense and sense RNA fibronectin probes, the present study demonstrates that most, but not all, normal alveolar macrophages contain fibronectin mRNA transcripts, and that among those macrophages expressing this gene, the relative amount of fibronectin mRNA transcripts varies from cell to cell. Interestingly, while 66 +/- 3% of normal alveolar macrophages contain fibronectin mRNA transcripts, this is increased to 82 +/- 2% (P less than 0.01) of alveolar macrophages recovered from the lungs of individuals with idiopathic pulmonary fibrosis (IPF), a chronic inflammatory disorder associated with exaggerated amounts of fibronectin in the lower respiratory tract. Furthermore, of the macrophages expressing the fibronectin gene, those from IPF patients contain more fibronectin mRNA transcripts than those from normals. Consistent with this observation, evaluation of tissue samples from IPF patients demonstrated that of all cells present, alveolar macrophages showed the greatest numbers of fibronectin mRNA transcripts per cell. These observations demonstrate that there can be marked cell-to-cell variation in the expression of the gene for a macrophage product such as fibronectin, suggesting that there are processes that modulate similar cells in the same anatomic compartment to vary their expression of the same gene.
Adult↗
Restrictive cardiomyopathy with kappa light chain deposits in myocardium as a complication of multiple myeloma. Histochemical and electron microscopic observations.
kappa Light chain deposits occurring in myocardium as a complication of multiple myeloma were identified ultrastructurally and immunohistochemically in a right ventricular endomyocardial biopsy specimen from a patient who presented with clinical and hemodynamic findings of restrictive cardiomyopathy. These deposits were not evident on routine histopathologic examination; they were Congo red-negative and gave a positive immunoperoxidase reaction for kappa light chains and a negative reaction for lambda chains. They consisted of amorphous, electron-dense granules that formed discontinuous layers adjacent to the plasma membranes of cardiac myocytes, arteriolar endothelial and smooth-muscle cells, and neural elements. These observations underscore the need for critical study of endomyocardial biopsy specimens, using electron microscopy and immunohistochemical reagents, for the precise identification of protein components in tissue deposits in patients suspected of having cardiac amyloidosis or related disorders.
Aged↗
Pretreatment with ICRF-187 allows a marked increase in the total cumulative dose of doxorubicin tolerated by beagle dogs.
To study the influence of ICRF-187 on the functional and morphological effects of very large cumulative doses of doxorubicin, adult beagle dogs were given doxorubicin (1.75 mg/kg i.v.) either alone or 15 min after ICRF-187 (25 mg/kg, i.v.) at 3-week intervals. Control dogs received ICRF-187 (25 mg/kg, i.v.) or 0.9% saline without doxorubicin. Of eight animals receiving doxorubicin alone, two died after a total dose of 12.25 mg/kg and three died after 14 mg/kg; three others were in poor condition at the time of euthanasia after 14 mg/kg. Of eight animals receiving both ICRF-187 and doxorubicin, one died after 35 mg/kg, two died after 43.75 mg/kg and one died after 52.5 mg/kg; two dogs were euthanatized after 43.75 mg/kg because of difficulties encountered in giving i.v. injections, and two dogs survived a total dose of 52.5 mg/kg. All control dogs survived. None of the treatment or control groups developed consistent echocardiographic changes or alterations in mean arterial pressure. Dogs given ICRF-187 and doxorubicin developed PQ interval prolongation after 300 days and ventricular premature beats after 500 days. Each animal receiving doxorubicin alone had severe myocardial lesions (lesion score 3+). Of the animals given ICRF-187 and doxorubicin, one that received 35 mg/kg doxorubicin had no lesions; of four given 43.75 mg/kg, three had no lesions and one had minimal lesions (lesion score 1+); of three given 52.5 mg/kg, one had minimal (lesion score 1+) and two had moderate (lesion score 2+) lesions. Control animals had no myocardial lesions.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Ventricular aneurysms and other lesions produced by the struts of bioprosthetic valves implanted in sheep.
Damage to the posterolateral wall of the left ventricle was found in eight of approximately 700 sheep undergoing mitral valvular replacement as part of animal model studies of bioprosthetic valves. The damage consisted of left ventricular aneurysms in five animals, subacute rupture of the left ventricle in one, acute left ventricular laceration in one, and endocardial scarring in one. Six of the eight bioprostheses were bovine pericardial valves, including five low-profile valves and one standard valve; of the two porcine bioprostheses, one was intentionally oversized and the other was a low-profile supra-annular valve. In each of these animals the damage appeared to have been caused by contact between the most posterior strut of the bioprosthesis and the left ventricular wall.
Animals↗
Pulmonary elastic fiber degradation in paraquat toxicity. An electron microscopic immunohistochemical study.
To study the morphologic alterations of pulmonary elastic fibers in cynomolgus monkeys with paraquat toxicity, peroxidase- and ferritin-labeled antielastin antibodies were used for the light and electron microscopic localization of elastin. One week after paraquat, alveolitis, tissue damage and alveolar dilatation were present; elastic fibers were frayed and more diffusely and intensely stained than those of control animals. In the latter, staining was localized in peripheral regions of the amorphous components and, to a lesser extent, in some microfibrils of elastic fibers. At 3 to 4 weeks, diffuse staining was evident in damaged interstitial elastic fibers and in newly formed elastic fibers in areas of intraalveolar fibrosis. At 8 weeks, the interstitium contained many elastic fibers which showed staining only in peripheral regions of the amorphous components. These observations suggest that: 1) preembedding immunohistochemical staining for elastin is localized in peripheral regions of normal elastic fibers because the antielastin antibody can penetrate into mature and undamaged amorphous components only to a very limited extent; 2) in early stages of paraquat toxicity this staining is more diffuse and intense because elastase from inflammatory cells partially degrades the elastic fibers and permits greater penetration of the antibody into the amorphous materials; 3) in later stages the staining pattern returns to normal as inflammation subsides and elastic fibers are repaired; however, newly formed elastic fibers in areas of intraalveolar fibrosis stain diffusely, reflecting increased penetration of the antibody because of immaturity and incomplete cross-linking, and 4) degeneration of elastic fibers of alveolar walls in paraquat lung may lead to alveolar dilatation, which is associated with irregular fibrosis and constitutes one of the processes of pulmonary structural remodeling in paraquat lung.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Ultrastructural, histochemical, and freeze-fracture evaluation of multilamellated structures in human pulmonary alveolar proteinosis.
Ultrastructural, histochemical, and freeze-fracture studies of material recovered by bronchoalveolar lavage from patients with pulmonary alveolar proteinosis revealed four types (A, B, C, and D) of multilamellated structures (MS). Type A, the major component, consisted of concentric, trilaminar structures which were composed of two electron-dense layers and a central lucent layer (5.7-7.5 nm in overall width) alternating with wider (25-30 nm) electron-lucent intervening layers. Type B MS were formed by concentric lamellae with a 5-5.3-nm periodicity. Type C MS were composed of wavy, electron-dense lamellae with a 4-4.5-nm periodicity. Type D MS were conglomerated masses of intricately arranged double or triple electron-dense layers (7.5-13.5 nm wide) alternating with wider (30-40-nm) electron-lucent layers. The electron-dense lamellae of type A, type C, and type D MS were stained with ruthenium red, the Thiéry method, and concanavalin A, indicating the presence of carbohydrate components. Freeze-fracture studies revealed smooth inner and outer surfaces in type A MS, with the fracture planes passing through the central parts of the trilaminar structures; the intervening layers contained 10-nm particles, which probably are proteins. Type B MS had smooth surfaces, and type C MS had slightly particulate surfaces; while type D MS showed tubular or polygonal structures, 350 nm wide, with rows of particles 7-8 nm in diameter. It is concluded that type A and type D MS contain proteins and carbohydrates, probably in the form of glycoproteins, as well as phospholipids, and are related to tubular myelin. Type B and type C MS are considered to contain mainly phospholipids; type C MS are also considered to contain carbohydrates and to be related to lamellar bodies of type II alveolar epithelial cells.
Adult↗
Morphological study of sarcoplasmic reticulum in the atrioventricular node and bundle cells in guinea pig hearts.
The osmium-ferrocyanide method for staining of the sarcoplasmic reticulum (SR) was used for a morphological investigation of the various components of the SR in the atrioventricular node and bundle (AVNB) cells of guinea pig hearts. On the basis of light microscopic observations, the AVNB tissue in guinea pig hearts can be divided into five regions: atrionodal junction, midnode, proximal bundle, distal bundle, and bundle branches. Electron microscopic observations revealed two types of junctional SR (j-SR) saccules in the cells from all the regions of AVNB tissue. One is similar to that seen in the working cardiac cells, i.e., flattened saccules with junctional granules. The second type is dilated and contains electron-dense granular material throughout its lumen. The flattened type is seen more often than the dilated type in atrionodal junctional cells and midnode cells, whereas the dilated type occurs more often in distal bundle cells and bundle branch cells. In most cells from the atrionodal junction and midnode regions, the j-SR saccules are apposed more often to sarcolemmal areas associated with nonspecialized regions of intercellular junctions than to other sarcolemmal areas. This distribution was not found in the distal bundle and bundle branch cells. Free SR tubules around the myofilament bundles are poorly developed in the midnode cells, generally in accord with the extent of development of myofibrils. Z-tubules are found in cells from all regions but are poorly developed in midnode cells. Corbular SR vesicles are found in cells from all the regions of AVNB tissues but are rare in midnode cells. Thus, each of the regions in the AVNB tissue has a different, characteristic distribution of SR components. Because of their possible relationship to the regulation of the intracellular concentrations of calcium, these differences in SR morphology may contribute to the diverse physiological properties of the different regions of the AV node and bundle.
Animals↗
Animal model of acute pericarditis and its progression to pericardial fibrosis and adhesions: ultrastructural studies.
To study the evolution of pericardial inflammation, we have developed a model of pericarditis in sheep by surgically injecting heat-killed staphylococci and Freund's adjuvant into the pericardial cavity under sterile conditions. The pericarditis evolved through the following phases: 1) inflammatory response, 2) mesothelial cell injury and desquamation, and 3) fibrotic phase. At 3-24 hr there was increased microvascular permeability, which resulted in the exudation of fluid, neutrophils, macrophages, and fibrin into the pericardial cavity and the pericardial interstitium. By 72 hr, large numbers of inflammatory cells were aggregated on the mesothelial surfaces and dispersed throughout the pericardial cavity, either as free-floating cells or located between strands of fibrin. At 6 days, fibrinolysis was apparent along the mesothelial surfaces; and newly formed collagen fibrils were deposited throughout the interstitial spaces and among the aggregated cells. These fibrils provided a matrix for the growth of new blood and lymphatic vessels into new connective tissue on both parietal and visceral pericardial surfaces. At 2 weeks, intrapericardial fibrosis had produced focal adhesions between the pericardial surfaces. At 1 month, extensive areas of the pericardial cavity were obliterated. By 9 months, there was a marked reduction in the numbers of cells and blood vessels and increased deposition of collagen and elastic fibers. The intrapericardial injection of heat-killed staphylococci and adjuvant provides a reproducible animal model to study the time course of pericardial inflammation.
Acute Disease↗
Reduction of chronic doxorubicin cardiotoxicity in beagle dogs by bis-morpholinomethyl derivative of razoxane (ICRF-159).
Addition of morpholinomethyl substituents to razoxane (ICRF-159) produced a compound (bis-4-morpholinomethyl-3,5-dioxopiperazinyl-1,2-propane (MM-159) considerably more water-soluble than razoxane. The increased solubility allowed MM-159 to be examined for protective activity against chronic doxorubicin (DXR) cardiotoxicity. Adult beagle dogs of either sex were given, i.v. at 3-week intervals, either DXR (1.75 mg/kg) alone or DXR 15 min after MM-159 (25 mg/kg). Control animals received MM-159 (25 mg/kg) or saline without DXR. The experiment was terminated 3 weeks after the ninth injection (total DXR dose, 15.75 mg/kg). Of the eight animals given DXR alone, five died after receiving seven to eight injections (12.25-14 mg/kg DXR) and the remaining three were killed after eight injections because they were in poor condition. Marked ascites was noted in four of these eight dogs. When frequency and extent of myocardial lesions (vacuolation and myofibrillar loss) were assessed on a scale from 0 to 4+, severe lesions (3+) were present in all eight dogs given DXR alone, but no abnormalities (lesion score 0) were found in the hearts of three of eight dogs given MM-159 and DXR and the five remaining animals in this group had minimal (1+; four dogs) or mild (2+; one dog) alterations. DXR reduced the erythrocyte count, hemoglobin, and hematocrit when administered alone, but not in combination with MM-159. Such protection against DXR hematologic effects was not noted previously when dogs were pretreated with ICRF-187, the d-isomer of razoxane, despite the fact that pretreatment with ICRF-187 was as effective as MM-159 in reducing chronic DXR cardiotoxicity. It remains to be determined whether there are other differences in biological activity between MM-159 and ICRF-187.
Animals↗
Neurological complications of cardiovascular therapy.
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Cardiac Catheterization↗
Amelioration of chronic anthracycline cardiotoxicity by ICRF-187 and other compounds.
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Acetylcysteine↗
Pathology of bioprosthetic cardiac valves.
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Animals↗