Beta-adrenergic hormone-receptor interactions in the hypertrophied and failing myocardium.
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Adenosine Triphosphate↗
Biomedical subjects
C Limas
Publications and source records attributed to C Limas.
Rapid recovery of cardiac beta-adrenergic receptors after isoproterenol-induced "down"-regulation.
Desensitization of beta-receptor-linked adenylate cyclase occurs after prolonged occupancy of the beta-receptors by their agonists. We have followed the development and recovery from "down"-regulation of beta-receptors in enzymatically dissociated cardiac myocytes by using the hydrophilic antagonist [3H]-CGP-12177 to identify surface-bound beta-receptors. After in vitro incubation with (-)-isoproterenol, almost 50% of the beta-receptors are lost within 10 minutes. Isoproterenol-mediated cyclic adenosine monophosphate accumulation by isolated myocytes was also decreased after a 15-minute preincubation with isoproterenol. "Lost" beta-receptors can, however, be recovered when isoproterenol-pretreated, washed cardiac myocytes are incubated at 37 degrees C, 85 +/- 7% of the lost beta-receptors have returned to the cell surface after 20 minutes of incubation. The requirements for such recycling were investigated. Receptor recovery does not depend on de novo protein synthesis, since it is unaffected by prior exposure to cycloheximide. It is, however, dependent on cellular energy, because it is prevented by adenosine triphosphate depletion and involves a lysosomal step since it is inhibited by the lysomotropic agent, chloroquine. In addition, the Golgi apparatus and the microtubules are involved in the beta-receptor recycling to the cell surface, as evidenced by the inhibitory effects of monensin and colchicine, respectively. The mechanism of isoproterenol-induced down-regulation of cardiac beta-receptors involves a rapid, reversible cycling to and from the cytosol and the cell membrane. This intracellular receptor traffic is energy dependent, requires several structures, including lysosomes and microtubules, and may be modified by pathological processes involving the heart.
Adenosine Triphosphate↗
Comparative effects of hydralazine and captopril on the cardiovascular changes in spontaneously hypertensive rats.
Vascular changes that develop during the course of blood pressure rise in spontaneously hypertensive rats (SHRs) can be modified by antihypertensive therapy. It is not known, however, whether there is selectivity in the structural response to specific antihypertensive drugs. This issue was examined by comparing the effects of a direct vasodilator (hydralazine) and a converting enzyme inhibitor (captopril) on morphologic aspects of the cardiovascular system. Male SHRs, 21 weeks of age, were given either hydralazine (HCl plus hydrochlorothiazide, captopril plus hydrochlorothiazide, or hydrochlorothiazide alone. Untreated age-matched SHRs and Wistar-Kyoto normotensive rats (WKYs) were used as controls. Animals were sacrificed at 27-28 weeks of age. Both hydralazine and captopril lowered significantly the blood pressure of SHRs, whereas hydrochlorothiazide alone was ineffective. The heart/body weight ratios were dramatically reduced in captopril-treated SHRs to below the level of WKYs; hydralazine induced only a very modest (5%) reduction, whereas the diuretic alone was ineffective. The morphology of the aortic intima improved dramatically in response to captopril and hydralazine and, to a lesser extent, hydrochlorothiazide alone. This effect becomes apparent within 6 weeks of treatment, and the only evidence of preexisting disease is the persistence of collagen in the subendothelium. Captopril and hydralazine, but not hydrochlorothiazide alone, reduce the thickness of the aortic media below that of normotensive controls. In addition, captopril and hydralazine improve the structure of small intrarenal vessels. There was a strong correlation between the relative effectiveness of the three pharmacologic agents in lowering blood pressure and in improving the changes of intrarenal vessels. These results highlight the capacity of antihypertensive therapy to arrest or reverse the structural sequelae of hypertension. In addition, they underscore the heterogeneity in the response of different components of the cardiovascular system, which, in part, reflects selectivity in the action of antihypertensive agents.
Animals↗
Ectopic hamartomatous thymoma. A distinctive benign lesion of lower neck.
Five cases of a distinctive tumor located in the soft tissues of the lower neck in adults are described. The lesion is characterized microscopically by the presence of four components: cellular areas made up of spindle elements; epithelial islands composed of solid nests, trabeculae and cysts; mature adipose tissue; and lymphocytes, sometimes arranged in a Hassall's corpuscle-like fashion. Electron microscopy and immunostaining for keratin showed that the spindle cell component was of epithelial nature. These tumors were supraclavicular or suprasternal in location, and no local recurrence has developed in any case following local resection. We interpret these lesions as benign tumors arising on the basis of a developmental defect. We think that they are derived from the third branchial arch and that they are composed of abnormal thymic tissue.
Adult↗
Involvement of microtubules in the isoproterenol-induced 'down'-regulation of myocardial beta-adrenergic receptors.
The number of cardiac beta-adrenergic receptors identified by [3H]dihydroalprenolol binding decreases in a concentration-dependent manner during prolonged administration of isoproterenol. Loss of membrane beta-receptors is paralleled by the appearance of [3H]dihydroalprenolol binding activity in the cytosol. This redistribution of receptors is prevented by colchicine and vinblastine but not lumicolchicine. Cardiac receptor desensitization is, therefore, dependent on microtubules and may be influenced by agents interfering with tubulin polymerization.
Animals↗
Phospholipid metabolism in the rat renal inner medulla.
In view of the importance of phospholipids as a source of precursor fatty acids for the high prostaglandin synthesis in the renal inner medulla, we studied pathways of phospholipid esterification and degradation in the rat inner medulla. De novo acylation of [14C]arachidonate occurred predominantly in position 2 of phosphatidylcholine in the microsomal fraction. This newly esterified [14C]arachidonate was accessible to deacylation by a microsomal phospholipase A2 (EC 3.1.1.4) with alkaline optimum which was Ca2+-dependent and resistant to 0.1% deoxycholate. No phospholipase A1 (EC 3.1.1.32) activity against endogenous labeled phosphatidylcholine could be demonstrated in the microsomal fraction. When exogenous phosphatidylcholine labeled at position 2 was deacylated by renomedullary homogenates, labeled free fatty acid but no labeled lysophosphatidylcholine was recovered in the reaction products. This could be attributed to further degradation of generated lysophosphatidylcholine by a cytosolic lysophospholipase (EC 3.1.1.5). Sodium deoxycholate at a concentration of 0.1% or higher inhibited the lysophospholipase and allowed the demonstration of both A2 and A1 alkaline phospholipase activities in the homogenate. The major in vitro pathway of lysophosphatidylcholine disposition is further degradation by a cytosolic lysophospholipase, while reutilization for phosphatidylcholine synthesis through the action of a predominantly microsomal acyltransferase appears to be a minor pathway. In the presence of several acyl-CoAs, reutilization of lysophosphatidylcholine is significantly increased by an acyl-CoA:lysophosphatidylcholine acyltransferase (EC 2.3.1.23) but there is no preferential transfer of arachidonyl-CoA compared to other acyl-CoAs.
1-Acylglycerophosphocholine O-Acyltransferase↗
Effect of antihypertensive therapy on the vascular changes of spontaneously hypertensive rats.
The effect of antihypertensive therapy on vascular morphologic characteristics was studied in spontaneously hypertensive rats (SHRs). Starting at either 7 or 22 weeks of age, SHRs were given a combination of hydralazine, chlorothiazide, and reserpine, which reduced the blood pressure significantly below the level of untreated animals. Rats were sacrificed at either the 22nd or the 42nd week of age along with age-matched untreated SHRs and normotensive Wistar-Kyoto controls. The following treatment groups were thus obtained: a) treated from the 7th to the 22nd or 42nd week, b) treated from the 22nd to the 42nd week, and c) treated from the 7th to the 22nd and left untreated until the 42nd week. Ultrastructural and morphometric studies were carried out on the aorta and intrarenal vessels. The expansion of the subendothelial space and medial thickening in the aorta as well as the increase in external to luminal diameter ratios and wall thickness of intrarenal vessels were prevented in SHRs treated continuously from the 7th week on. The severity of vascular lesions was markedly reduced in animals treated from the 22nd to 42nd week. Discontinuation of therapy resulted in rapid reestablishment and progression of both aortic and renal vascular disease to a degree identical to that of untreated SHRs. The results indicate that hypertensive vascular changes are preventable by early treatment and, depending on their nature, can be arrested or reversed by delayed treatment.
Animals↗
Age-dependency of vascular phospholipid deacylation-reacylation in spontaneously hypertensive rats.
We have studied the temporal relation of phospholipid turnover and prostaglandin synthesis to the evolution of hypertensive vascular disease in the spontaneously hypertensive rat. The incorporation of arachidonate into aortic phospholipids, its release by phospholipase A2 and its utilization for prostaglandin synthesis were compared in spontaneously hypertensive and Wistar-Kyoto rats aged 7, 20 and 42 weeks. When expressed per mg of protein in the assay medium, arachidonate incorporation into aortic phospholipids decreased, while prostaglandin synthesis increased, with age in both rat strains. No significant differences were noted between hypertensive and normotensive animals at 7 weeks of age whereas both enhanced phospholipid turnover and prostaglandin synthesis was demonstrated in hypertensive rats at 20 and 42 weeks of age. The higher phospholipase activity in hypertensive aortas was associated with a significant increase in the capacity for exogenous lysophosphatide hydrolysis. Transacylation and reacylation of lysolecithin, however, were not significantly enhanced in hypertensive aortas. These biochemical changes accompany, and may be related to, structural modifications of the aortic wall in the course of hypertension.
Acylation↗
A, B, H antigen detectability in normal and neoplastic urothelium. Influence of methodologic factors.
Markedly reduced or absent reactivity for the normally expressed A B H antigens in transitional cell carcinomas (TCCs) of the human urinary bladder appears to correlate with an aggressive clinical course. To evaluate the clinical applicability of this observation, the authors investigated the influence of methodologic variants as well as certain patient characteristics on urothelial A, B, H reactivity. Biopsy-obtained TTCs and/or normal mucosae from 104 patients were examined for the effect of fixation, paraffinization, and alcohol treatment. Variability due to the secretor status and blood group of the patient was evaluated in conjunction with methodologic factors. In the fresh-frozen state, the expected antigen was always detectable in normal mucosas but only in 69% of TCCs regardless of patient's secretor status and blood group (BG). Few normal mucosae (12%) but a large number of TTCs (46%) converted to negative after paraffin processing. Similar reduction in A, B, H reactivity was also noted when the tissues were treated with concentrations of alcohol comparable to those used in the paraffin procedure. Tumor antigens were more sensitive to alcohol. This suggested that in neoplastic cells ABH determinants are not only fewer but also disproportionately represented in polar (alcohol-soluble) molecules. Alcohol more profoundly affected tissues from nonsecretors probably because the proportion of alcohol-soluble A, B, H substances differs in secretors and nonsecretors. In the fresh-frozen state, the H antigen was detectable with the Ulex Europeus lectin in the majority of TCCs from BGO patients (79%) as well as in most tumors from BGA or B patients (90%) even in the absence of the expected A or B antigen. Alcohol treatment, however, more potently reduced reactivity for H rather than the other antigens, a phenomenon that also points to the significance of glycolipid extraction and explains the marked differences in the detectability of this antigen between fresh-frozen and paraffin-processed TCCs.
ABO Blood-Group System↗
Prognostic significance of morphologic parameters in renal cell carcinoma.
The prognostic significance of morphologic parameters was evaluated in 103 patients with renal cell carcinoma diagnosed during 1961--1974. Pathologic material was classified as to pathologic stage, tumor size, cell arrangement, cell type and nuclear grade. Four nuclear grades (1--4) were defined in order of increasing nuclear size, irregularity and nucleolar prominence. Nuclear grade was more effective than each of the other parameters in predicting development of distant metastasis following nephrectomy. Among 45 patients who presented in Stage I, tumors classified as nuclear grade 1 did not metastasize for at least 5 years, whereas 50% of the higher grade tumors did so. Moreover, among Stage I tumors there was a significant difference in subsequent metastatic rate between nuclear grades 1 and 2. There was an apparent positive relationship between cell type and metastatic rate; clear cell tumors were less aggressive than predominantly granular cell tumors (metastatic rate 38% versus 71%). This relationship in part a function of the nuclear grade: only 5% of grade 3 and 4 tumors consisted of clear cells, whereas such high grades were seen in 57% of granular cell tumors. The size of the primary correlated well with the stage at the time of surgery. However, with the exception of extremely large and small tumors, the size was not useful in predicting the subsequent course of patients treated for Stage I tumors. Nuclear grade was the most significant prognostic criterion for the outcome of Stage I renal cell carcinoma.
Adenocarcinoma↗
Aortic morphology in salt-dependent genetic hypertension.
Excessive salt intake is an important determinant of human essential hypertension. Hypertension resulting from genetically determined salt sensitivity can be studied by the used of the salt-sensitive (S) and -resistant (R) rat strains developed by Dahl. A longitudinal morphometric and ultrastructural study of S and R Dahl rats fed different amounts of salt (0.6%, 4.0%, and 8.0% NaCl) for 2-14 weeks was undertaken. Only S rats responded to high-salt (4.0% and 8.0%) diets with an increase in blood pressure, and the rate of hypertension development was proportional to the daily amount of salt consumed. Likewise, S but not R rats fed high-salt diets showed thickening of the aortic media which paralleled the rise of blood pressure. Intimal lesions were characterized by the accumulation of an amorphous, electron-dense substance in the subendothelial space (SES), adherence or penetration of lymphoid cells, and subendothelial fibrin deposition. The extent and severity of SES expansion correlated more closely with the duration of salt feeding than with the level of blood pressure. Fibrin deposition was noted only in severely hypertensive animals and was not related to the salt concentration in the diet. Morphologic abnormalities in endothelial cells were noted in hypertensive animals by transmission and scanning electron microscopy as well as by en face preparation, but endothelial denudation and junctional disruptions were notably absent. In contrast to the large numbers of lymphoid cells, neither platelets nor fibrin were seen adherent on the endothelium. These results, in conjunction with previous studies in other hypertensive models, indicate that the nature and extent of vascular lesions depend not only on the severity of hypertension but also on its rate of development, duration, and pathophysiologic characteristics.
Age Factors↗
Aortic phospholipid deacylation-reacylation cycle in spontaneously hypertensive rats.
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Acylation↗
Altered reactivity for A, B, H antigens in transitional cell carcinomas of the urinary bladder. A study of the mechanisms involved.
Transitional cell carcinomas (TCCs) of the urinary bladder show variable blood group (BG) antigen reactivity even in the non-invasive stage. A correlation exists between the tumor reactivity and subsequent clinical course: when the expected BG antigen(s) is retained, the clinical course is favorable; absence of the expected antigen(s) denotes an aggressive potential. In the present study we investigated some of the possible mechanisms of altered BG antigen reactivity in TCCs. It was found that the "loss" of A, B, H reactivity is a quantitative phenomenon and the threshold for positive reactions depends on the method of tissue processing and the titer of the antisera. Thus, in the 35 cases studied, paraffin processing resulted in reduced reactivity compared to fresh-frozen tissue sections. The reactivity of tumors that appeared positive when tested with undiluted antisera was found reduced when quantitatively compared to that of normal mucosa from the same individual. Excessive or inappropriate sialylation does not appear to be responsible for the reduced BG antigen reactivity of the tumors. In fact, TCCs (9 cases) had significantly reduced sialic acid content compared to normal bladder mucosae (6 cases) regardless of their A, B, H reactivity and neuraminidase did not change their reactions for BG antigens. In addition, spontaneous unmasking of the Thomsen-Friedenreich (T) antigen was observed in invasive tumors that were negative for the expected BG antigen(s). Tumors from patients of blood group A or B often showed increased reactivity for the H antigen, although their A or B antigen was reduced or absent. In view of the known biosynthetic sequence from H to A and B substances, these observations suggest a specific biochemical defect in the tumors.
ABO Blood-Group System↗
Tissue blood group antigen testing in transitional cell carcinoma of the bladder.
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Carcinoma, Transitional Cell↗
Progressive myocardial dysfunction associated with increased vascular resistance.
To study heart failure from a myocardial lesion, we injected glass beads into the circumflex coronary artery of 11 conscious dogs and followed hemodynamics for 10 mo. Heart rate remained unchanged. Control mean arterial pressure of 112.3 +/- 3.0 (SE) mmHg was unchanged at 1 and 3 mo, but rose to 127.2 +/- 8.5 to 84.0 +/- 7.6 ml . kg-1 . min-1 at 10 mo (P < 0.02), but was unchanged at 1 and 3 mo. Left ventricular end-diastolic pressure (LVEDP) averaged 4.6 +/- 0.8 mmHg at control and rose to 11.8 +/- 1.4 mmHg at 1 mo and 14.9 +/- 2.5 mmHg at 10 mo (both P < 0.01). Systemic vascular resistance rose significantly by 10 mo. The ratio of stroke work to LVEDP fell from 13.1 +/- 0.1 at control to 3.8 +/- 0.5 by 10 mo (P < 0.01). In this dog model, left ventricular dysfunction is manifest early by increased LVEDP and later by high systemic vascular resistance with low cardiac output, thus suggesting a role of the peripheral circulation in the progression of heart failure.
Animals↗
The evolution of vascular changes in the spontaneously hypertensive rat.
A longitudinal study on the development of vascular lesions was carried out in the spontaneously hypertensive rat (SHR) of the Aoki-Okamoto strain. The aorta and intrarenal arterial vessels were examined at different ages, from 5 to 48 weeks, by light and electron microscopy. Endothelial permeability to injected horseradish peroxidase (HRP) was evaluated in 20-week-old animals. Morphologic differences between vessels of SHRs and age-matched normotensive controls (Wistar-Kyoto strain) were first noted at 10 weeks of age and became more pronounced with time. Vascular pathology involved both intima and media. Medial thickening was seen in both aorta and peripheral arteries and, in the latter, was associated with decreased luminal diameters. These medial changes may contribute to the maintenance of the elevated blood pressure. Intimal lesions affected predominantly the aorta and were characterized by an expansion of the subendothelial space with deposition of acid mucopolysaccharides. There was increased accumulation of tracer HRP in the expanded subendothelium, which suggested enhanced permeability and/or retention of the tracer. In animal species susceptible to atherosclerosis, these intimal changes could serve as the structural basis for the higher propensity for atheromatous lesions in hypertensive individuals. In the SHR, despite stabilization of systolic blood pressure at about 20 weeks of age, both intimal and medial lesions continue to progress and become more extensive and severe; this suggests that not only the severity of hypertension but also its duration are significant determinants of the degree of vascular damage.
Animals↗
Decreased number of beta-adrenergic receptors in hypertensive vessels.
Responsiveness to inotropic agents is altered in hypertension and may contribute to its initiation and maintenance. A biochemical basis for this change was provided by the observation that the number of beta-adrenergic receptors, as reflected in specific [3H]dihydroalprenolol binding, was diminished in both arteries and veins of spontaneously hypertensive rats. There was no change in the affinity of dihydroalprenolol for the binding sites or in the capacity of isoproterenol to displace dihydroalprenolol. The decline in beta-adrenergic receptor numbers is not secondary to blood pressure elevation but may, instead, contribute to the pathogenesis of hypertension.
Alprenolol↗
A, B, H antigens in transitional cell tumors of the urinary bladder: correlation with the clinical course.
The A, B, H blood group antigens can be detected in normal transitional epithelium of the urinary bladder by the red cell adherence (RCA) test. We examined the possibility that the reactivity for these antigens is lost or decreased in transitional cell carcinomas and that such a change may reflect the future evolution of these tumors. We studied several bladder biopsies from 60 patients who presented with noninvasive transitional cell carcinomas and were followed for at least 5 years or until muscle invasion was histologically demonstrated. Eighty-one percent of patients whose tumors were RCA positive in the initial biopsy did not subsequently develop invasive tumors and 27% of these patients had no recurrences. All 34 patients whose tumors were negative in the initial biopsy experienced recurrences and 62% of them developed invasive lesions. In 81% of patients, the recurrent tumors retained the same pattern of RCA reactivity for blood group antigens on serial biopsies. These results suggest that the presence of readily detectable A, B, B antigens correlates with a favorable prognosis whereas their absence denotes an aggressive potential.
ABO Blood-Group System↗