Biomedical subjects

C G Brilla

Publications and source records attributed to C G Brilla.

At least 19 recordsLinked to original sources

PubMed1998

Angiotensin II and intracellular calcium of adult cardiac fibroblasts.

In various cardiovascular disorders, circulating or myocardial angiotensin II (Ang II) levels are increased, leading to excess collagen synthesis of cardiac fibroblasts. To characterize signal transduction mechanisms of Ang II, we examined changes in intracellular Ca2+ concentration ([Ca2+]i) of fura-2-loaded cultured adult rat cardiac fibroblasts by fluorescence photometry. [Ca2+]i was increased by Ang II via AT1 receptors in a dose-dependent manner (EC50 = 2.4 x 10(-8) mol/l) involving two distinct phases, an initial Ca2+ peak and a sustained elevated plateau phase. The initial Ca2+ peak occurred transiently and independently of the duration of Ang II application. While the magnitude of the transient Ca2+ peak did not differ in a nominally Ca(2+)-free (3 mmol/l EGTA) solution, the Ang II-mediated sustained plateau phase of [Ca2+]i was dependent on extracellular Ca2+. Thus, the initial transient Ca2+ peak appears to arise from intracellular Ca2+ stores, whereas the plateau phase involves an external Ca2+ influx. Since collagen synthesis of cardiac fibroblasts is maximally stimulated by Ang II or by fetal bovine serum (FBS), the effects of Ang II and FBS on [Ca2+]i were compared. The magnitude of the transient Ca2+ peak induced by 10(-7) mol/l Ang II was comparable to that of 10% FBS indicating that the rise in [Ca2+]i might be involved in the signal transduction pathway of Ang II-mediated collagen synthesis of cardiac fibroblasts.

Angiotensin II↗

PubMed1997

[Heart failure after myocardial infarct in decompensated diabetes mellitus. Acute therapy with catecholamines--long-term therapy with ACE inhibitor-loop diuretic combination].

In a 63-year-old woman with longstanding type I diabetes mellitus, CAD and chronic heart failure, a subacute myocardial infarction developed, together with decompensation of cardiac function and diabetes and concurrent pneumonia. Acute heart failure with acute renal failure on top of diabetic nephropathy, and interstitial pulmonary edema was initially treated with hemofiltration and catechol amines together with antibiotic and perfusor-regulated insulin therapy, and systemic heparinization. Subsequent chronic treatment with digitalis, acetyl salicylic acid, insulin and a combination of an ACE inhibitor and a loop diuretic resulted in an improvement of heart failure to NYHA functional class II where PTCA of coronary multi-vessel disease could be performed with low risk.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

[Spironolactone: renaissance of anti-aldosterone therapy in heart failure?].

Mortality of patients with severe congestive heart failure (CHF) is still high despite combined treatment with angiotensin-converting enzyme (ACE) inhibitors, diuretics, and digitalis. Further therapeutic regimens are needed which include reversal of adverse myocardial remodeling and subsequent ventricular dysfunction. One third of all patients with CHF have diastolic left ventricular (LV) dysfunction with preserved systolic function. In these patients myocardial collagen matrix is the major determinant of myocardial stiffness and therefore diastolic function. Cardiac fibroblasts, expressing mRNA for types I and III collagens which are the major fibrillar proteins of the myocardial collagen network and for matrix metalloproteinase (MMP) 1 which is the key enzyme for interstitial collagen degradation, are controlled by the renin-angiotensin-aldosterone (RAAS) system irrespective of hemodynamics and cardiac myocyte growth. In the rat with primary or secondary hyperaldosteronism, myocardial fibrosis occurs in the pressure overloaded, hypertrophied left and in the normotensive, nonhypertrophic right ventricle. In contrast, no fibrosis is found in either ventricle of rats with infrarenal aortic banding, when the RAAS is not activated, despite comparable systemic hypertension and LV hypertrophy. In cultured cardiac fibroblasts, either effector hormone of the RAAS, angiotensin (Ang) II and aldosterone (Aldo) stimulate collagen synthesis measured by 3H-proline incorporation under serum-free conditions. Aldo is able to stimulate collagen synthesis normalized per total protein synthesis in a dose-dependent manner and at concentrations (10(-9) M) which are comparable to stimulated states in vivo (e.g., CHF). While Aldo does not affect collagen degradation AngII significantly inhibits, MMP 1 activity that would lead to further accumulation of collagen in the myocardium. Specific AngII type I or Aldo receptor antagonists are able to abolish the AngII or Aldo-mediated increase in collagen synthesis, respectively. In vivo in rats with primary or secondary hyperaldosteronism, the Aldo antagonist spironolactone has been shown to prevent myocardial fibrosis in both ventricles irrespective of the development of LV hypertrophy and hypertension. Thus, in vivo and in vitro evidence could be provided that the mineralocorticoid. Aldo, plays a pivotal role in promoting myocardial fibrosis and can be antagonized by its competitive receptor blocker, spironolactone. This may be of particular clinical relevance in treating patients with CHF where the RAAS is activated leading to myocardial fibrosis with subsequent deterioration of myocardial function. Clinical trials are needed to confirm these experimental data. If the ongoing RALES mortality study will prove that survival and/or morbidity of patients with CHF are improved by combined ACE inhibitor/spironolactone treatment a renaissance of anti-aldosterone therapy in patients with CHF would occur.

Animals↗

PubMed1997

Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease.

In hypertensive heart disease, reactive myocardial fibrosis represents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium. The fact, that the myocardium of both ventricles is involved, irrespective of ventricular loading conditions, suggests that circulating factors, and not the hemodynamic load are primary responsible for this adverse response of the myocardial fibrous tissue. In various experimental in vivo models, it has been shown that myocardial fibrosis is always associated with activation of circulating or local renin-angiotensin-aldosterone systems (RAAS). Cardiac collagen metabolism is regulated by cardiac fibroblasts which express mRNAs for types I and III collagens, the major fibrillar collagens in the heart, and for interstitial collagenase or matrix metalloproteinase (MMP) 1 which is the key enzyme for interstitial collagen degradation. In order to elucidate the role of the RAAS effector hormones, angiotensin II (AngII) and aldosterone (ALDO), in the regulation of collagen synthesis or inhibition of MMP 1 production, adult human cardiac fibroblasts were cultured. Collagen synthesis was determined by 3H-proline incorporation, and MMP 1 activity by degradation of 14C-collagen measured under serum-free conditions in confluent fibroblasts after 24 hour-incubation with either AngII or ALDO over a wide range of concentrations (10(-11)-10(-6)M). In addition, the effects of the mineralocorticoid, deoxycorticosterone (DOC), and prostaglandin E2 (PGE2) on cardiac fibroblast function were determined. Compared with untreated control fibroblasts, collagen synthesis, normalized per total protein synthesis, showed a significant and dose-dependent increase after incubation with either mineralocorticoid hormone, ALDO or DOC, or after incubation with AngII. In contrast, collagen synthesis of cardiac fibroblasts was significantly decreased by PGE2 treatment. AngII type 1 or mineralocorticoid receptor antagonists, respectively, were able to completely inhibit the AngII- or mineralocorticoid-mediated increase of collagen synthesis. Furthermore, AngII significantly decreased MMP 1 activity while ALDO or DOC had no effect on cardiac fibroblast-mediated collagen degradation. In contrast, PGE2 significantly increased MMP 1 activity. Thus cardiac fibroblast function is modulated by either effector hormone of the RAAS, AngII and ALDO, via specific receptors that lead to progressive myocardial fibrosis in disease states where circulating or local RAAS is activated, i.e., in hypertensive heart disease. In contrast, PGE2, which would be elevated in myocardial tissue after angiotensin-converting enzyme inhibition, counteracts the fibrotic effects of the RAAS on myocardial tissue.

Adult↗

PubMed1997

[Transmyocardial laser revascularization--an innovative pathophysiologic concept].

In patients with coronary artery disease where standard revascularization procedures are not appropriate, transmyocardial laser revascularization (TMLR) represents an innovative technique which is currently validated worldwide. Initially, it has been assumed that myocardial perfusion of ischemic regions could be instantly improved by inducing TMLR channels, which, however, might not be confirmed in ongoing studies. Indeed, the gain in O2 diffusion surface obtained by 20 patent TMLR channels is only 6 cm2 which accounts for just 0.01% of the total capillary surface (47000 cm2) of the myocardium. Instead, a chronic structural remodeling of myocardial regions, adjacent to TMLR channels and mediated by TMLR-induced expression of vascular endothelial growth factor (VEGF), may occur leading to neocapillarization of ischemic myocardium irrespective of the long-term patency of TMLR channels and, thereby, would improve myocardial perfusion (Figure 1). Six weeks following TMLR in the pig, patent TMLR channels were not observed. Instead, a marked degree of reparative fibrosis was found at the site of TMLR-treated myocardial regions (Figure 2). It is, however, not known, whether ischemic conditions would affect chronic channel patency. TMLR combined with intramyocardial administration of 0.5 microgram VEGF between the laser-induced channels resulted in few patent channels (Figure 3). The apparently low efficacy of VEGF applied as protein could be attributed to degradation of VEGF by local peptidases. In addition to VEGF, other growth factors and the interaction of endothelial cells and the extracellular matrix need to be considered. Of particular relevance appears alpha v beta 3-integrin which is needed for adhesion of endothelial cells to extracellular matrix components and is, therefore, required for neocapillarization. Among various other growth factors associated with neoangiogenesis, TGF-beta 1 and PDGF-BB are involved in the formation of extracellular matrix anchoring newly formed vessels. Thus, the expression of VEGF and alpha V beta 3-integrin in myocardial regions surrounding TMLR channels appears to be of major importance for the development of neoangiogenesis within the ischemic myocardium. Whether concomitant therapeutical strategies, i. e., gene transfer leading to over-expression of VEGF, will optimize the TMLR procedure by improving neoangiogenesis remains to be elucidated in future experimental studies.

Animals↗

PubMed1997

Schedule-induced psychological stress and molecular structures of cardiomyocytes.

To establish a psychological stress model, we characterized in rats the effects of chronic (5-6 wk) scheduled food pellet feeding (35 mg/80 s for 8 h/day). Because the scheduled intake of pellets required that rats have access to 80% of ad libitum intake, the effect of food restriction was also examined by withholding food intermittently for 24 or 48 h each, followed by 24 h free access to food. Cardiac norepinephrine concentration was significantly increased (1,076 +/- 169 vs. 693 +/- 107 ng/g, P < 0.05) in rats subjected to pellet feeding compared with pair-fed rats (same amount of pellets in one portion) or 24- or 48-h intermittently fasted rats; similarly, the epinephrine content of adrenal glands was increased (P < 0.05). Left ventricular rate of sarcoplasmic reticulum Ca2+ uptake was decreased (P < 0.05) compared with pair-fed rats, reaching values observed for 24-h fasted rats, whereas the proportion of alpha-myosin heavy chains was only slightly reduced. Thus the schedule-induced stress arising from pellet feeding exhibits features of stress models involving physical pain and appears to stimulate the adrenergic system with subsequent impairment of Ca2+ cycling that is typical of various heart diseases.

Animals↗

PubMed1997

Renin-angiotensin system and myocardial collagen matrix: modulation of cardiac fibroblast function by angiotensin II type 1 receptor antagonism.

BACKGROUND: Left ventricular hypertrophy is an adaptive process to increased loading of the left ventricle. This condition becomes pathologic with impaired myocardial function if the various tissue compartments of the myocardium (myocyte, interstitial and vascular compartments) are inhomogeneously altered, particularly if myocardial fibrosis occurs. In arterial hypertension, myocardial fibrosis is known to occur in association with activated circulating or local renin-angiotensin systems and includes reactive perivascular and interstitial fibrosis in both the pressure-overloaded hypertrophied left ventricle and the normotensive non-hypertrophied right ventricle. Therefore, it appears that hemodynamics are not primarily responsible for the adverse myocardial collagen matrix remodeling in hypertensive heart disease. Accordingly, we studied the interaction between cultured adult rat cardiac fibroblasts, which express messenger (m)RNAs for types I and III collagens, the major fibrillar collagens in the heart, and angiotensin II (Ang II), the effector hormone of the renin-angiotensin system. OBJECTIVES: Specifically, we sought to determine whether Ang II stimulates total collagen synthesis and the expression of type I collagen mRNA in cultured adult rat cardiac fibroblasts, and to investigate the effects of Ang II on intracellular Ca2+ levels. MATERIALS AND METHODS: Adult rat cardiac fibroblasts were cultured in Dulbecco's Modified Eagle's Medium + 10% fetal calf serum and incubated for 24 h with Ang II with or without specific Ang II type 1 or type 2 receptor antagonists. Collagen synthesis was measured using a 3H-proline incorporation assay, and type I collagen mRNA was determined using reverse-transcriptase polymerase chain reaction. Intracellular Ca2+ transients were measured by fast fluorescence photometry using the fluorescent dye fura-2-acetoxymethylester. RESULTS: We found a 76% increase in type I collagen mRNA in cultured cardiac fibroblasts after a 24-h incubation with Ang II, and this was abolished by simultaneous incubation with the Ang II type 1 (AT1)-receptor antagonist candesartan. Likewise, total collagen synthesis was stimulated by Ang II in a dose-dependent manner, and this stimulation was also counteracted by candesartan. Additionally, incubation with Ang II resulted in a significant dose-dependent increase in intracellular Ca2+ transients which was also abolished by treatment with candesartan. CONCLUSIONS: Ang II stimulates collagen synthesis in cultured adult rat cardiac fibroblasts via AT1 receptors, most likely using Ca2+ as a second messenger. These findings suggest a direct interaction between Ang II and cardiac fibroblasts in mediating myocardial fibrosis in arterial hypertension, leading to pathologic left ventricular hypertrophy with initially impaired diastolic and ultimately reduced systolic function of the left ventricle. The AT1-receptor antagonist candesartan cilexetil, which is the prodrug of the active compound candesartan, may prove valuable in preventing or regressing myocardial fibrosis in hypertensive heart disease.

Angiotensin II↗

PubMed1996

Dietary linolenic acid-mediated increase in vascular prostacyclin formation.

To define vascular effects of an enhanced dietary alpha-linolenic acid intake, 28 spontaneously hypertensive rats were fed a 3% sunflowerseed oil (44% linoleic acid) diet; in 3 groups (7 rats each), the diet was supplemented with 1, 2.5 or 5% linseed oil containing 62% alpha-linolenic acid. alpha-Linolenic acid was incorporated up to 12% in the aorta of the 5% linseed oil group. The eicosapentaenoic acid content was not significantly increased. The content of arachidonic acid and docosatetraenoic acid was moderately reduced in rats fed 5% linseed oil. The generation of 6-keto-PGF1 alpha (degradation product of prostacyclin) assessed by HPLC/electrochemical detection was, however, markedly increased (p < 0.05) in rats fed 2.5 and 5% linseed oil. The minor prostanoids TXB2, PGE2 and PGF2 alpha were not significantly altered. The high systolic and diastolic blood pressure of SHR monitored by radio telemetry was more effectively reduced (p < 0.05) in the light, i.e. sleep, cycle. An increased prostacyclin formation and lowered vascular arachidonic acid content associated with enhanced dietary alpha-linolenic acid intake would thus be expected to prove beneficial in the prevention of vascular disorders.

6-Ketoprostaglandin F1 alpha↗

PubMed1996

Drug withdrawal and rebound hypertension: differential action of the central antihypertensive drugs moxonidine and clonidine.

To examine the antihypertensive action of the centrally acting antiadrenergic drugs moxonidine and clonidine, systolic and diastolic blood pressure as well as heart rate were monitored by radio telemetry in spontaneously hypertensive rats (SHR) with established high blood pressure. Increasing doses were administered with regular rat chow for 6-8 day periods. Moxonidine reduced (p < 0.05) diastolic blood pressure at a dose of 8 mg/kg/day and systolic blood pressure at 13 mg/kg/day. Heart rate was reduced during high activity of rats corresponding to an antitachycardiac action. After withdrawal of 18 mg/kg administered for only 1 day, blood pressure returned to pretreatment values within 8 days. Clonidine reduced systolic and diastolic blood pressure at 0.3 mg/kg/day. At 0.8 and 1.3 mg/kg/day, systolic blood pressure reduction was less pronounced, although heart rate was reduced further, reaching values that were below those of untreated sleeping rats. When 1.3 mg/kg/day clonidine was discontinued, systolic as well as diastolic blood pressure increased above pretreatment values within 1 day. A rebound was also observed in heart rate, which increased by 150 beats/ min. A comparable rebound in blood pressure was observed after withdrawal of 0.3 mg/kg/day. Since a blood pressure rebound occurred also after withdrawal of 0.3 mg/kg/day clonidine in normotensive rats, the rebound phenomenon was independent of the presence of high blood pressure. No blood pressure rebound was observed when moxonidine (8 mg/kg/ day) was administered (chow or gavage) in normotensive rats. These findings in unanesthetized undisturbed rats demonstrate distinct differences in the mode of action of moxonidine and clonidine, which can be accounted for by specific interactions of moxonidine with imidazoline I1-receptors, whereas clonidine would interact not only with I1-receptors but also with alpha2-adrenoceptors, and most probably also with the vagal activity. In view of our previous studies demonstrating a rise in blood pressure and heart rate after a hypercaloric dietary intake, the selective I1-receptor agonist moxonidine appears particularly appropriate for treating overweight hypertension associated with an enhanced sympathetic outflow of the brain. Of importance in this respect is that a moxonidine-induced reduction in sympathetic outflow was not associated with a gain in body weight but resulted in reduced caloric intake.

Animals↗

PubMed1996

Effect of the renin-angiotensin-aldosterone system on the cardiac interstitium in heart failure.

The interaction of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth is of great interest in chronic heart failure. The pressure or volume overloaded heart shows a hypertrophic growth of the myocardium, i.e., an enlargement of cardiac myocytes. In addition, cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. This remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure. The growth of cardiac fibroblasts is not primarily regulated by the hemodynamic load. In vivo and in vitro studies suggest that the effector hormones, angiotensin II and aldosterone, of the RAAS are primarily involved in regulating the structural remodeling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, angiotensin II and aldosterone has been shown to stimulate collagen synthesis while angiotensin II additionally inhibits matrix metalloproteinase I activity, which is the key enzyme for interstitial collagen degradation in the myocardium. These findings may serve as rationale for a remedial therapy with angiotensin converting enzyme inhibition or blockage of the RAAS in congestive heart failure in patients with hypertensive heart disease, post myocardial infarction or with dilated cardiomyopathy.

Animals↗

PubMed1996

Advanced hypertensive heart disease in spontaneously hypertensive rats. Lisinopril-mediated regression of myocardial fibrosis.

Left ventricular hypertrophy (LVH) in spontaneously hypertensive rats (SHR) is accompanied by a structural remodeling of the myocardium that includes myocyte hypertrophy and interstitial and perivascular fibrosis of intramyocardial coronary arteries. The structural abnormalities related to fibrous tissue accumulation lead to increased myocardial diastolic stiffness and ultimately impaired systolic function of the left ventricle. It has been shown in 14-week-old SHR with early hypertensive heart disease that myocardial fibrosis could be reversed and myocardial diastolic stiffness normalized by 12-week treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether such functional defects of the myocardium, based on adverse structural changes, are also reversible in advanced hypertensive heart disease has been questioned. Therefore, we treated 78-week-old male SHR that had chronic hypertension and advanced LVH with severe myocardial fibrosis and age- and sex-matched normotensive Wistar-Kyoto rats (WKY) with 20 mg/kg per day oral lisinopril for 8 months. Compared with untreated SHR or WKY, we found the following: (1) Systolic arterial pressure was normalized (P < .025) and LVH completely reversed (P < .025) in SHR, with no significant reduction in systolic arterial pressure or left ventricular mass in WKY; (2) morphometrically determined myocardial fibrosis in SHR was significantly reversed (P < .025) and associated with improved diastolic stiffness (P < .05), which was measured in the isolated heart by calculation of the stiffness constant of the myocardium; no significant changes occurred in WKY; (3) reversal of myocardial fibrosis was accompanied by an increase (P < .025) in myocardial matrix metalloproteinase 1 activity determined by degradation of [14C]collagen with myocardial tissue extracts after trypsin activation of myocardial promatrix metalloproteinase 1; matrix metalloproteinase 1 activity remained unchanged in WKY treated with lisinopril; and (4) systolic dysfunction, measured by a significantly (P < .025) diminished slope of the systolic stress-strain relation under isovolumic conditions of the left ventricle, was found in 110-week-old SHR, and it could be prevented by lisinopril treatment. Thus, long-term angiotensin-converting enzyme inhibition with lisinopril normalized arterial pressure and LVH, reversed myocardial fibrosis, and improved abnormal myocardial diastolic stiffness in advanced hypertensive heart disease in SHR. In addition, systolic dysfunction of the left ventricle could be prevented. The fibrolytic response to lisinopril was at least partly due to enhanced collagen degradation by activation of tissue matrix metalloproteinase 1.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

[Hypertension and alcohol: central and peripheral mechanisms].

Despite intense research efforts, the etiology of primary hypertension remains ill-defined. During our work on molecular influences of lifestyle factors on hypertension, the question arose to what extent cellular and molecular events could be involved in alcohol-induced hypertension. There is increasing evidence that alcohol initiates central as well as peripheral reactions which in a synergistic manner have a hypertensive action. Thus, alcohol diminishes the baro (presso) reflex by interacting with receptors in the brain stem, i.e. nucleus tractus solitarii and rostral ventrolateral medulla. In addition, alcohol induces an increased sympathetic outflow, most probably linked to secretion of corticotropin-releasing hormone. The increased sympathetic outflow is expected not only to induce adrenoceptor-mediated reactions (vasoconstriction, heart rate increase) but to stimulate oxidation reactions. Deleterious peripheral actions result from acetaldehyde which binds to macromolecules if the abundance of cysteine and glutathione is limited. This acetaldehyde induced reduction of low molecular weight thiol compounds can be interpreted as "oxidative stress" which has various unfavourable consequences. The hypertensive action of alcohol should be taken into account when discussing its potential protective influence on coronary risk.

Acetaldehyde↗

PubMed1996

The concept of cardioreparation: Part 1. Pathophysiology of remodelling.

PURPOSE: Left ventricular hypertrophy is common in patients with hypertension or congestive heart failure and in survivors of myocardial infarction. It is associated with increased risks of adverse cardiovascular events, including angina, myocardial infarction and congestive heart failure. We aimed to explain these observations in terms of changes in the structure of the heart, collectively described as remodelling. DATA EXTRACTION: Laboratory investigations of animal models of cardiovascular diseases were reviewed. The most prominent features of remodelling are myocyte hypertrophy, excessive accumulation of collagen in the heart (myocardial fibrosis) and pathological changes in the coronary blood vessels. Remodelling disrupts the structure of the heart and impairs its pumping function and blood supply. The reversal of remodelling, termed cardioreparation, could restore cardiac structure and function towards normal and improve the prognosis of patients with cardiovascular diseases. CONCLUSIONS: Cardioreparation implies the regression of myocyte hypertrophy and myocardial fibrosis. Myocyte hypertrophy is primarily a response to chronic pressure or volume overload of the ventricles, whereas myocardial fibrosis depends on activation of circulating and tissue renin-angiotensin-aldosterone systems. Angiotensin converting enzyme inhibitors reduce blood pressure and inhibit these systems. They might therefore induce cardioreparation.

Cardiovascular Diseases↗

PubMed1995

Role of angiotensin II and prostaglandin E2 in regulating cardiac fibroblast collagen turnover.

In hypertensive heart disease, after myocardial infarction or in congestive heart failure, myocardial fibrosis presenting as a diffuse perivascular and interstitial accumulation of fibrillar collagens within the normal connective tissue structures of the myocardium is associated with an activated renin-angiotensin system (RAS). This reactive fibrosis occurs in the overloaded left ventricle and the nonoverloaded right ventricle irrespective of myocyte necrosis or the development of myocyte hypertrophy. Therefore, it appears that hemodynamic factors or the load of the ventricle are not primarily responsible for the adverse fibrous tissue response in the myocardium, and humoral factors may play a key role in regulating the myocardial collagen matrix. The neurohumoral response in hypertensive heart disease, after myocardial infarction with overall deterioration of left ventricular function or congestive heart failure leads to an activation of either the cardiac or the circulating RAS, which closely interacts with the bradykinin-prostaglandin system. To ascertain whether the RAS modulates collagen fibroblasts that express mRNAs for types I and III collagens (the major fibrillar collagens in the heart) and matrix metalloproteinase 1 (MMP1; the key enzyme for collagen degradation), collagen synthesis was measured by [3H]proline incorporation normalized to total protein synthesis and MMP1 activity was determined by degradation of [14C]collagen in cultured fibroblasts after 24-hour incubation with various concentrations of angiotensin II or PGE2 (10(-11)-10(-3) M) under serum-free conditions. In addition, effects of angiotensin II were evaluated in the presence or absence of either type 1 (ICI D8731) or type 2 (PD 123177) angiotensin II (AT1 or PGE2 (10(-11)-10(-3) M) under serum-free conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Hormonal regulation of cardiac fibroblast function.

In arterial hypertension or congestive heart failure, myocardial fibrosis is associated with an activated renin-angiotensin-aldosterone system (RAAS). This reactive fibrosis presents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium in either ventricle, irrespective of its haemodynamic load. It therefore would appear that circulating (hormonal) and not haemodynamic factors are responsible for this adverse fibrous tissue response. The cardiac fibroblast expresses mRNA for types I and III collagens, the major fibrillar collagens in the heart, and for collagenase or matrix metalloproteinase 1 (MMP 1), the key enzyme for interstitial collagen degradation. Therefore, adult rat cardiac fibroblasts were cultured to ascertain whether the RAAS effector hormones angiotensin II (Ang II) or aldosterone (Aldo) directly stimulate collagen synthesis or inhibit MMP 1 production. Collagen synthesis, determined by 3H-proline incorporation and MMP 1 activity determined by degradation of 14C-collagen, were measured under serum-free conditions in confluent, quiescent fibroblasts after 24 h incubation with Ang II or Aldo over a wide range of concentrations (10(-11) -10(-6) M). In addition, collagen synthesis was measured after incubation with the mineralocorticoid, dexoycorticosterone (DOC), or the prostaglandin, PGE2. Collagen synthesis, normalized per total protein synthesis, increased significantly in a dose-dependent manner after incubation with either mineralocorticoid hormone, Aldo or DOC, or after incubation with Ang II compared with untreated control cells. In contrast, collagen synthesis was significantly decreased with PGE2 treatment. This increase in collagen synthesis in Ang II or mineralocorticoid-stimulated fibroblasts could be completely abolished by Ang II type 1 or mineralocorticoid receptor antagonists, respectively. (ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

The renin-angiotensin-aldosterone system and myocardial collagen matrix remodelling in congestive heart failure.

In chronic heart failure, various regulatory systems including the Frank-Starling mechanism, the neuro-hormonal response, cardiac growth and peripheral oxygen delivery may be operative. Recently, the inter-relationship of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth has drawn clinical interest. In the pressure-or volume-overloaded heart, the development of myocyte growth is primarily dependent on ventricular loading. Non-myocyte cell growth involving cardiac fibroblasts may also occur but this is not primarily regulated by the haemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. In addition to relaxation abnormalities due to impairment of sarcoplasmic Ca(2+)-ATPase activity, this remodelling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the progression of symptomatic heart failure. The effector hormones of the RAAS, angiotensin II (AngII) and aldosterone (Aldo), appear to be primarily involved in promoting the adverse structural remodelling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, AngII and Aldo have been shown to stimulate collagen synthesis while AngII additionally inhibits matrix metalloproteinase I activity, which is the key enzyme for degradation of fibrillar collagen in the cardiac interstitium, leading to excessive collagen accumulation. These findings may serve as rationale as to why angiotensin converting enzyme inhibition or blockade of the RAAS represents such remedial therapy beyond the effect of simply unloading the heart in patients with congestive heart failure.

Adult↗

PubMed1995

[Experimental types of hypertension--models for essential hypertension in the human?].

Since the pathogenesis of essential hypertension is multifactorial, the causal therapy of primary arterial hypertension remains a great challenge. At a given genetic predisposition, the manifestation of hypertension depends critically on lifestyle factors. It is thus essential to study the molecular consequences of various deleterious lifestyle factors. We demonstrated by radiotelemetric measurements that an increased caloric intake raises both systolic and diastolic blood pressure as well as heart rate in spontaneously hypertensive rats (SHR). This model is comparable to hyperkinetic hypertension in hypertensive persons which, if it persists, will lead to established hypertension. Overfeeding also results in the characteristic metabolic derangements (hyperinsulinemia, hypertriglyceridemia) of insulin resistant hypertensive persons. The enhanced sympathetic outflow of the brain can be potentiated by lifestyle factors such as high sodium intake and psychological stress. In contrast to sodium intake, psychological stress (e.g. schedule-induced stress) is difficult to mimic in animal experiments. In view of the recent progress in the characterization of imidazoline receptors in the rostral ventrolateral medulla and the development of antihypertensive drugs with a high selectivity (moxonidine) for imidazoline receptors, efforts should be made to elucidate key regulatory mechanisms involved in brain insulin sensitivity and appetite regulation. Such an approach could help in pharmacologically reducing the influence of deleterious lifestyle factors at a given genetic predisposition.

Animals↗

PubMed1995

[Cardiac structure-function relationship and the renin-angiotensin-aldosterone system in hypertensive heart disease].

Based on the epidemiologic data of the Framingham heart study, arterial hypertension and coronary artery disease are the most frequent etiologic factors for the development of heart failure. In the pressure overloaded heart, hypertrophic growth of the myocardium includes the enlargement of cardiac myocytes stimulated by ventricular loading. Non-myocyte cell growth involving cardiac fibroblasts may also occur but is not primarily regulated by the hemodynamic load. Cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium while vascular smooth muscle cell growth accounts for the medial thickening of resistance vessels. This remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness and impaired coronary vasodilator reserve, leading to ventricular diastolic and systolic dysfunction and ultimately to the appearance of symptomatic heart failure. Several lines of evidence suggest that the renin-angiotensin-aldosterone system is involved in regulating 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 rats with genetic hypertension, established left ventricular hypertrophy, abnormal diastolic stiffness due to interstitial fibrosis, and reduced coronary vasodilator reserve associated with medial wall thickening of intramyocardial resistance vessels, the ACE inhibitor lisinopril was able to restore myocardial structure and function to normal. These cardioreparative properties of ACE inhibition may be valuable in reversing left ventricular dysfunction in hypertensive heart disease.

Animals↗