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Biomedical subjects

K T Weber

Publications and source records attributed to K T Weber.

At least 145 records · Page 8Linked to original sources
PubMed1994

Angiotensin-converting enzyme, bradykinin, and angiotensin II receptor binding in rat skin, tendon, and heart valves: an in vitro, quantitative autoradiographic study.

Angiotensin converting enzyme (ACE), an ectoenzyme bound to vascular endothelial cells, is also found at tissue sites (TACE) normally composed of fibrillar collagen and fibroblasts. For example, TACE is present in the adventitia of intramural coronary arteries and matrix of heart valves, as well as the fibrous tissue that follows the chronic administration of angiotensin II (AII) or aldosterone. At these sites bradykinin (BK) receptor but not AII receptor binding has been observed, suggesting that in fibrous tissue TACE uses BK as substrate. Dermis, subcutaneous tissue, and skeletal muscle tendon likewise are sites that are rich in fibrillar collagen but are different in their cellularity. Accordingly, we tested the hypothesis that TACE is normally present at sites of fibrous tissue and that BK--not AIK--receptor binding is anatomically coincident with TACE in keeping with its role as a kininase II. TACE and receptors for BK and AII were localized by quantitative in vitro autoradiography with [125I]351A, 125I[Tyr8]BK, and 125I[Sar1, Ile8]AII, respectively. Skin morphology was examined in serial full thickness sections obtained from the dorsum of Sprague-Dawley rats. We found the following: (1) high TACE binding occurred in subcutaneous connective tissue and heart valves that was displaced by lisinopril or 351A in a dose-dependent manner; (2) BK receptor binding and low density AII receptor binding were seen at these sites, where AII receptor binding was totally displaced by a type 1 (DuP753) but not a type 2 (PD123177) receptor antagonist; (3) ACE, BK, and AII receptor binding was not evident in epidermis, dermis, skeletal muscle, or tendon.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Influence of collagen network on left ventricular systolic and diastolic function in aortic valve disease.

OBJECTIVES: The purpose of this study was to evaluate left ventricular structure-function interplay in aortic valve disease. BACKGROUND: An increase in myocardial fibrosis has been demonstrated in aortic valve disease, but changes in the collagen network and their effect on ventricular function have not been defined. METHODS: Left ventricular structure was assessed from left ventricular endomyocardial biopsy specimens obtained in 32 patients with aortic valve disease (aortic stenosis in 25, aortic regurgitation in 7). Total collagen volume fraction, orthogonal collagen fiber meshwork (cross-hatching), endocardial fibrosis, muscle fiber diameter and volume fraction of myofibrils were determined by morphologic-morphometric evaluation. Control biopsy data were obtained from six donor hearts before transplantation. Eleven other patients with normal left ventricular function served as hemodynamic status control subjects. Left ventricular biplane cineangiography and high fidelity pressure measurements were carried out in all patients. Systolic function was assessed from ejection fraction. Diastolic function was evaluated by the time constant of relaxation, early and late peak filling rates and the constant of passive myocardial stiffness. Patients were assigned to three groups according to increasing severity of nonmyocyte tissue alterations. Group 1 comprised 10 patients with elevated total collagen volume fraction. Group 2 comprised 6 patients with normal total collagen volume fraction and the presence of increased cross-hatching or endocardial fibrosis, or both. Group 3 comprised 16 patients with elevated total collagen volume fraction and the presence of cross-hatching or endocardial fibrosis, or both. RESULTS: Muscle fiber diameter was increased in the three groups with aortic valve disease, whereas the volume fraction of myofibrils was comparable in all four study groups. Ejection fraction was depressed in groups 2 and 3 compared with the control group. The time constant of relaxation was prolonged in the three groups with aortic valve disease. No differences in early and late peak filling rate were observed in the four study groups, but the constant of myocardial stiffness increased in groups 2 and 3. CONCLUSIONS: In aortic valve disease, changes in collagen architecture are associated with altered systolic function and passive diastolic properties. The sole increase in total collagen volume fraction without a change in architecture leaves systolic and passive diastolic function unaltered.

Adult↗
PubMed1993

Myocardial matrix metalloproteinase(s): localization and activation.

Matrix metalloproteinases (MMPs) and neutrophil elastase (NE) may each contribute to fibrillar collagen degradation in various disease states. Little, however, is known about the activation and localization of MMP in the heart. Accordingly, we extracted MMP and examined mechanisms of proMMP activation in whole tissue extracts of the adult rat myocardium. Incubation of extracts with serine proteases (i.e., trypsin or neutrophil elastase) at 37 degrees C resulted in a time-dependent activation of proMMPs. Based on immunoblot and measurements of MMP activity by zymography, the molecular weight of active MMP was deduced to be 52 kDa. The second-order rate constant for activation of proMMP by serine protease was 5.5 +/- 0.2 x 10(5) M-1min-1 and for oxidized glutathione (GSSG) 1.5 +/- 0.1 M-1min-1. Incubation of the extract with both serine protease and GSSG increased the rate of activation 30-fold. Based on reverse zymographic analysis of collagenase inhibition, tissue inhibitors of metalloproteinases were identified. Indirect immunofluorescence localized proMMPs/MMPs to the endothelium and subendothelial space of the endocardium and throughout the interstitial space found between groups of muscle fibers. These results suggest that the mechanism of activation of MMPs by either a serine protease and by oxidizing, thiol-modifying reagents are mechanistically different and the presence of either a serine protease or GSSG synergistically increase the rate of activation of proMMPs. Our results also suggest that MMPs may be regulated by its own endogenous inhibitors. The contribution of this proteolytic enzyme to tissue remodeling and wound healing responses that occur in various diseases states remains to be established.

Animals↗
PubMed1993

Aldosterone and antialdosterone therapy in congestive heart failure.

The pathophysiologic cycle that links myocardial failure with the appearance of congestive heart failure is not fully understood. It is clear, however, that an activation of several neurohormonal systems and the interplay between kidneys, adrenal glands, and heart contribute to abnormal sodium and water homeostasis. Aldosterone, the body's most potent mineralocorticoid hormone, contributes to intravascular and extravascular volume expansion, and thus to the appearance of symptomatic failure. Antialdosterone therapy in patients with secondary hyperaldosteronism due to heart failure must achieve one or more of the following goals: reduce or, preferably, normalize plasma aldosterone levels by limiting synthesis; antagonize the renal and systemic effects of aldosterone at its receptor sites; and eliminate or minimize the multiple stimuli to aldosterone secretion.

Aldosterone↗
PubMed1993

Antifibrotic effects of spironolactone in preventing myocardial fibrosis in systemic arterial hypertension.

Activation of the renin-angiotensin-aldosterone system in arterial hypertension can lead to remodeling of the myocardial collagen network, with progressive collagen accumulation in the cardiac interstitium. This reactive myocardial fibrosis, which is not secondary to myocyte necrosis, appears to be an important determinant of diastolic dysfunction and thus of pathologic hypertrophy. To examine the effects of the aldosterone antagonist spironolactone on myocardial fibrosis, we analyzed interstitial fibrosis in 7 different models of arterial hypertension in rats: 2 kidney, 1 clip model of renovascular hypertension (RHT); continuous subcutaneous aldosterone (0.75 micrograms/hr) infusion; RHT and aldosterone models treated with 20 mg/kg per day of subcutaneous spironolactone; uninephrectomized rats on a high sodium diet; and age- and sex-matched controls with or without spironolactone treatment. Systolic arterial pressure was comparably elevated in RHT and aldosterone models; it was modestly lowered but not normalized by 8 weeks of spironolactone treatment at the low doses used. Such treatment also failed to prevent left ventricular hypertrophy (LVH) in all experimental groups with hypertension. Spironolactone, however, was able to prevent myocardial fibrosis in RHT and aldosterone models of acquired arterial hypertension irrespective of the development of LVH and the presence of hypertension. These findings provide further evidence that elevated aldosterone levels play an important role in the adverse remodeling of the myocardium in arterial hypertension. The antifibrotic effects of spironolactone, if confirmed in human studies, may be a valuable strategy in treating hypertensive heart disease.

Aldosterone↗
PubMed1993

Structural basis for pathologic left ventricular hypertrophy.

Left ventricular hypertrophy (LVH) is a major risk factor associated with the emergence of symptomatic congestive heart failure. Cardiac myocyte excitation-contraction coupling has been the biochemical focus in the search for insights into the impaired contractility, relaxation, and stiffness of the hypertrophied myocardium. Although hypertrophied myocytes are the hallmark of LVH, other aspects of myocardial structure may be altered to impair pump function--specifically an abnormal accumulation of connective tissue (interstitial fibrosis). Cardiac fibroblasts, which are nonmyocyte cells of the cardiac interstitium, synthesize and degrade collagen and, therefore, represent an important determinant of pathologic LVH. Significantly, this reactive fibrosis has been found not only in the pressure-overloaded hypertrophied left ventricle but also in the normotensive, nonhypertrophied right ventricle of animals with experimental hypertension. These findings suggest the involvement of a circulating substance that has access to the coronary circulation common to both ventricles. Based on in vivo studies that examined this hypothesis, it can be concluded that chronic elevation of circulating aldosterone, relative to sodium intake, is associated with myocardial fibrosis, which initially adversely alters diastolic function and ultimately systolic ventricular function. The mechanisms by which fibroblast collagen metabolism is invoked in this setting are under investigation. Elucidation of these mechanisms may prepare the way to the prevention as well as the reversal of myocardial fibrosis and, in turn, of pathologic LVH.

Animals↗
PubMed1993

Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism.

In arterial hypertension associated with primary or secondary hyperaldosteronism myocardial fibrosis is an important determinant of pathologic hypertrophy. To further examine the relationship between elevations in plasma aldosterone (ALDO) and myocardial fibrosis, we analysed perivascular collagen area (PVCA) and interstitial collagen volume fraction (CVF) by videodensitometry and hydroxyproline concentration (HPro) by high-performance liquid chromatography. We examined both the left (LV) and right (RV) ventricles in the following rats models of primary or secondary hyperaldosteronism of eight weeks duration: unilateral renal ischemia (RHT); continuous ALDO administration via osmotic minipumps (0.75 microgram/h s.c.) and enhanced dietary sodium following uninephrectomy (AL); in RHT and AL after pre- and continuous treatment with either 20 (S) or 200 (SS) mg/kg/day s.c. of the aldosterone receptor antagonist, spironolactone; in AL after pre- and continuous treatment with 50 mg/kg/day oral captopril (AL + CAP); as well as in age and sex matched controls (C). Systolic arterial pressure was comparably elevated in RHT and AL (202 +/- 12 and 193 +/- 7 mmHg, respectively; P < 0.0005 vs C); it remained elevated with low dose spironolactone in either model of arterial hypertension, but was normalized with high dose spironolactone or captopril in AL. Left ventricular hypertrophy (LVH), expressed as significantly elevated LV/RV weight or LV/BW ratios, was present in all experimental groups, excluding AL + SS and AL + CAP, when compared with C (P < 0.005). In each ventricle, CVF and PVCA were increased (P < 0.005) in either model of hypertension and in AL + CAP, but were no different from C in all groups receiving either dose of spironolactone. Similar findings were observed for HPro. Thus, myocardial fibrosis was comparable in primary or secondary hyperaldosteronism, wherein elevations in plasma aldosterone, relative to increased sodium intake, are associated with arterial hypertension. The competitive ALDO receptor antagonist, spironolactone, was able to prevent fibrosis in either model irrespective of the development of LVH and the presence of hypertension. Captopril prevented hypertension and LVH, but not unexpectedly it did not prevent myocardial fibrosis in primary hyperaldosteronism. These findings provide further evidence that in these rat models increased plasma ALDO, relative to dietary sodium, plays a major role in the adverse accumulation of collagen that appears in the myocardium.

Angiotensin II↗
PubMed1993

Myocardial fibrosis: role of angiotensin II and aldosterone.

In this report we review the replacement (i.e., scarring) and reactive (i.e., perivascular and interstitial fibrosis) fibrous tissue responses found in the myocardium in response to effector hormones of the renin-angiotensin-aldosterone system. Experimental data are presented to indicate: a) endogenous or exogenous elevations in plasma angiotensin II are associated with acute cardiac myocyte necrosis and subsequent microscopic scarring; b) chronic elevations in plasma aldosterone (ALDO), relative to Na+ intake, are associated with a perivascular and interstitial fibrosis of the coronary and systemic circulations and are also seen in response to chronic administration of the mineralocorticoid hormone deoxycorticosterone (DOC); and c) chronic mineralocorticoid excess, due to ALDO or DOC, is associated with enhanced urinary K+ excretion, cardiac myocyte necrosis and scarring. Pharmacologic agents which interfere with these effector hormones (e.g., ACE inhibition and ALDO receptor antagonism) protect the myocardium against this pathologic structural remodeling created by the reactive and replacement (reparative) fibrosis. Evidence is also presented to indicate that chronic ACE inhibition is associated with a regression in reactive myocardial fibrosis. Based on these experimental findings we would suggest that clinical trials are indicated to address the prevention and regression of myocardial fibrosis--an important determinant of pathologic structural remodeling and abnormal myocardial stiffness.

Aldosterone↗
PubMed1993

Renin-angiotensin system and myocardial collagen matrix remodeling in hypertensive heart disease: in vivo and in vitro studies on collagen matrix regulation.

The interstitial space of the myocardium is composed of nonmyocyte cells and a highly organized collagen network which serves to maintain the architecture and mechanical behavior of the myocardial walls. It is the myocardial collagen matrix that determines myocardial stiffness in the normal and structurally remodeled myocardium. In hypertensive heart disease, the heterogeneity in myocardial structure, created by the altered behavior of nonmyocyte cells, particularly cardiac fibroblasts which are responsible for collagen synthesis and degradation, explains the appearance of diastolic and/or systolic dysfunction of the left ventricle that leads to symptomatic heart failure. Several lines of evidence suggest that circulating and myocardial renin-angiotensin systems (RAS) are involved in the regulation of the structural remodeling of the nonmyocyte compartment, including the cardioprotective effects of angiotensin converting enzyme (ACE) inhibition that was found to prevent myocardial fibrosis in the rat with renovascular hypertension. In cultured adult rat cardiac fibroblasts angiotensin II was shown to directly stimulate collagen synthesis and to inhibit collagenase activity, which is the key enzyme for collagen degradation, that would lead to collagen accumulation. In the spontaneously hypertensive rat, an appropriate experimental model for primary hypertension in man, left ventricular hypertrophy could be regressed and abnormal myocardial diastolic stiffness due to interstitial fibrosis could be restored to normal by inhibition of the myocardial RAS. These antifibrotic or cardioreparative effects of ACE inhibition that occurred irrespective of blood pressure normalization may be valuable in reversing left ventricular diastolic dysfunction in hypertensive heart disease.

Collagen↗
PubMed1993

Direct extraction and estimation of collagenase(s) activity by zymography in microquantities of rat myocardium and uterus.

Measurement of collagenolytic activity is of interest to a wide variety of investigators using mammalian tissue. In order to develop a method that would quantitate active collagenase from microquantities of human tissue, we employed zymography to the heart and uterus of neonatal, adult, and postpartum rats. Collagenase rapidly cleaves native collagen into two fragments, which at 37 degrees C form gelatin. Gelatin can also be hydrolyzed by collagenase, but at a slower rate, and therefore we used gelatin to quantitate the amount of collagenase present in heart and uterine tissue and developed a method for the direct extraction of collagenase from small quantities of rat myocardium. Our method was found to be comparable with the chemical method reported by Masui et al. (Anal Biochem 1977; 17:215-21). The enzyme, which was not detected in normal adult rat cardiac tissue, was found to exist entirely in latent form and demonstrated typical properties of a mammalian collagenase/gelatinase after activation by trypsin and plasmin. We observed a 60-80% increase in collagenase activity after activation by these proteases and estimated that there is approximately 5 +/- 2 pg of procollagenase per microgram of normal adult rat left ventricle. Collagenolytic activity in the postpartum rat heart was found to be slightly (approximately 2-5%) reduced when compared to the adult heart but it was increased in the neonatal heart and postpartum uterus. This method allows for the rapid quantitative and qualitative measurement of collagenase activity in a variety of tissues containing collagenase/gelatinase activity. Our results indicate that most collagenase in the myocardium exists in latent form.

Amino Acid Sequence↗
PubMed1993

Role of aldosterone in congestive heart failure.

Antialdosterone therapy in patients with secondary hyperaldosteronism due to myocardial failure must accomplish the following: (1) reduce or preferably normalize plasma aldosterone levels by blockade of excessive synthesis, (2) antagonize the renal and systemic effects of aldosterone at its receptor sites, and (3) minimize the presence of multiple stimuli to aldosterone secretion. Fulfillment of these goals likely requires the blockade of angiotensin II-induced aldosterone secretion (ie, angiotensin-converting enzyme inhibition) with an antagonist of aldosterone receptors (ie, spironolactone [Aldactone]). Despite the potential for hyperkalemia with this combined use of medications, particularly in patients with impaired renal function, such therapy is likely to attenuate the salt-acquisitive state that is characteristic of myocardial failure.

Aldosterone↗
PubMed1993

Myocardial fibrosis in the rat with mineralocorticoid excess. Prevention of scarring by amiloride.

In both humans and experimental animals, mineralocorticoid (MC)-induced hypertension is associated with myocardial fibrosis. We have shown that this fibrous tissue response includes a reactive interstitial fibrosis not initiated by parenchymal cell loss, and a reparative fibrosis or scarring, occurring in response to cardiac myocyte necrosis. The reactive fibrosis is thought to be related to MC excess, while cell loss and microscopic scarring may be secondary to enhanced potassium excretion or a cytotoxic effect of aldosterone. This histologic study was undertaken to determine whether or not the potassium sparing diuretic amiloride would be effective in preventing the appearance of either form of fibrosis. Uninephrectomized male Sprague Dawley rats received either aldosterone (AL; 0.75 microgram/h), amiloride (AMC; 1 mg/kg/day), aldosterone+amiloride (ALAM), or vehicle (ALC) alone via subcutaneous osmotic minipumps for 8 weeks. All rats received 1% NaCl in their drinking water. Hearts were recovered, immersion-fixed, and tissue sections from both left and right ventricles stained with the collagen specific stain Sirius Red F3BA were morphometrically analyzed. The interstitial collagen volume fraction was elevated in AL and ALAM groups compared to ALC and AMC, but did not differ between AL and ALAM. Microscopic scarring, found in both ventricles, was evident in AL animals, but was not found in the ALAM, AMC, or ALC groups. These data suggest that chronic elevations in plasma aldosterone, relative to dietary sodium intake, do not have a direct cytotoxic effect on cardiac myocytes, but they are associated with a reactive interstitial fibrosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1993

Endothelin receptors in cultured adult rat cardiac fibroblasts.

OBJECTIVES: Endothelins, released by vascular endothelial cells, are known growth promoters of various mesenchymal cells that contribute to stromal protein accumulation. Whether endothelins could contribute to myocardial fibrosis depends, in part on whether cardiac fibroblasts have endothelin receptors. The identification and binding characteristics of endothelin-1 and endothelin-3 and their ETA and ETB receptor subtypes in cultured adult rat cardiac fibroblasts represented study objectives. METHODS: Cultured rat cardiac fibroblasts (passages 5-10) grown until confluence were used to study radioligand binding assays, receptor subtypes, association and dissociation, effects of agonist and antagonist on binding kinetics, and affinity cross linking. RESULTS: Binding association of 125I-endothelin-1 and 125I-endothelin-3 was rapid, specific, and saturable within 60 minutes. The dissociation of receptor bound 125I-endothelin-1 was slow and partially reversible (30%-40%), suggesting more than one class of endothelin receptors, whereas the dissociation of 125I-endothelin-3 was time dependent and reversible. Competitive displacement with unlabeled endothelin-1, endothelin-3, endothelin-receptor nonselective sarafotoxin (S6b), and ETA receptor selective antagonist PED-3512-PI were used to identify receptor subtypes. Displacement of 125I-endothelin-1 by cold endothelin-1, resulted in a low affinity, high binding site (IC50 5.4 x 10(-9) M; 3.6 x 10(4) binding sites.cell-1) and a high affinity, low binding site (IC50 4.2 x 10(-4) M; 11,830 binding sites.cell-1). With 125I-endothelin-1 the IC50 s for sarafotoxin, endothelin-3, and PED-3512-PI were 1.8 x 10(-10), 1.7 x 10(-9), and 3.7 x 10(-9) M, respectively; for 125I-endothelin-3 these IC50s were 2.28 x 10(-11), 1.9 x 10(-10), and 1.7 x 10(-9) M, respectively. Endothelin receptor subunits of 53, 37, 34, and 24 kDa were identified by affinity cross linking. CONCLUSION: Endothelin-1 and endothelin-3 binding and ETA and ETB receptor subtypes are present in cardiac fibroblasts with ETB predominant. The presence of these receptors support the hypothesis that endothelins may regulate cardiac fibroblast function.

Animals↗
PubMed1993

Effects of endothelins on collagen turnover in cardiac fibroblasts.

OBJECTIVES: Endothelins (ET-1 and ET-3) may be promoters of tissue remodeling, including fibrillar collagen accumulation. The hypothesis that ET-1 and ET-3 each modify cardiac fibroblast collagen turnover was tested. METHODS: Confluent adult rat cardiac fibroblasts were maintained for 24 hours in medium with 0.4% fetal calf serum, and varying concentrations of ET-1 or ET-3. Collagen synthesis was measured by 3H-proline incorporation. The synthesis of type I and III collagens was measured by enzyme linked immunosorbent assay (ELISA). The effects of endothelins on collagenase activity were estimated by zymography. RESULTS: ET-1 and ET-3 increased collagen synthesis in a concentration-dependent manner with a maximal 1.7-fold increase (p < 0.001 v control cells). The effects of ET-1 or ET-3 on collagen synthesis were not blocked by PED-3512-PI (10(-6) M), an ETA receptor antagonist. ET-1 and ET-3 each significantly (p < 0.01) increased the synthesis of both type I and III collagens. ET-1 caused a 5.8-fold decrease in collagenase activity (p < 0.01 v control), and this effect was blocked by PED-3512-PI (10(-6) M). ET-3 did not alter collagenase activity. CONCLUSION: ET-1 and ET-3 increased the synthesis of type I and III collagens, whereas ET-1, but not ET-3, reduced collagenase activity. The effects of endothelins on collagen synthesis in cardiac fibroblasts seem to be mediated through ETA and ETB receptors, whereas their effects on collagenase seem to be mediated by ETA receptors.

Animals↗
PubMed1993

Endothelial cell induced modulation of cardiac fibroblast collagen metabolism.

OBJECTIVE: The aim was to examine the influence of vascular endothelial cells on rat cardiac fibroblast collagen synthesis and collagenase activity under co-culture conditions, and to determine whether angiotensin II or aldosterone influence endothelial cell induced modulation of fibroblast collagen metabolism. METHODS: Bovine aortic endothelial cells were grown to confluence on microporous membrane inserts and then co-cultured with cardiac fibroblasts obtained from adult rats, previously grown to confluence in 35 mm dishes supplemented with 0.4% fetal bovine serum. Collagen synthesis was measured by 3H-proline incorporation. Experiments were also conducted under similar conditions to quantitate collagenase activity by zymography in conditioned medium from fibroblasts co-cultured with endothelial cells. RESULTS: After 48 h co-culture, there was a 1.9-fold increase in fibroblast collagen synthesis when compared to fibroblasts alone (p < 0.001). Aldosterone (10(-8) M) or angiotensin II (10(-7) M) added to endothelial cells did not increase fibroblast collagen synthesis over co-cultures alone. Neither the aldosterone receptor antagonist spironolactone (10(-8) M) nor type I (DuP 753, 10(-8) M) or type II (PD 123319, 10(-8) M) angiotensin II receptor antagonists altered fibroblast collagen synthesis in co-cultures. A significant increment in collagenase activity was observed in co-cultured fibroblasts relative to collagenase activity of fibroblasts alone. CONCLUSIONS: Endothelial cells modulate both cardiac fibroblast collagen synthesis and degradation. The nature of the responsible signal(s) remains to be defined, but does not appear to be mediated or regulated by angiotensin II or aldosterone.

Aldosterone↗
PubMed1993

Cardioreparation and the concept of modulating cardiovascular structure and function.

Hypertension and atherosclerotic cardiovascular disease represent major global health problems. Practising physicians are challenged daily by patients suffering adverse cardiovascular events, such as myocardial infarction, stroke, heart failure and sudden cardiac death. Major risk factors have been identified of which the most important is left ventricular hypertrophy. In recent years, growth factors, regulatory peptides and effector hormones of the renin-angiotensin-aldosterone system have been identified as important modulators of cell growth and behaviour. It therefore follows that a major emphasis has been placed on the importance of abnormalities in organ structure as the primary basis for impaired function of the heart and vasculature, including large and medium sized arteries and resistance vessels, or arterioles. The concept of reparation recognizes the importance of abnormalities in tissue structure to the functional basis of disease. It suggests that the structurally remodelled heart and vasculature can be restored to, or toward, normal structure and function by suitable therapy. Experimental and clinical trials which address this premise are reviewed herein.

Animals↗