Pharmacological and histopathological aspects of 1-methyl-4-phenyl-4-hydroxy-piperidine (MPIP)

The inhibitory effects of Radix Astragali (RA) on hypoxic structural remodeling of intra-acinar pulmonary arteries (IAPA) and pulmonary hypertension (PHT) were studied in rats, which were fed in hypoxic environment under normal atmospheric pressure (10% O2 10 hours/day). 60 rats were divided into 3 groups; hypoxia group, hypoxia+RA group and control group. On the 15th and 30th day of hypoxia, right ventricular systolic pressure (RVSP) and right ventricle hypertrophy index (RVHI) were measured and pulmonary vessel changes were studies under light and electronic microscopes and morphometric analysis. Compared with the hypoxia+RA group, RA could prevent IAPA wall cell damage and dilate the constricted IPIA induced by hypoxia. RA could also inhibit hypertrophic changes in the tunica media and proliferation of adventitial cells of the IAPA and muscularization of non-muscular arteries. Therefore, preserving the IAPA wall cells and dilating IAPA by RA may play an important role in inhibiting structural remodeling of IAPA and pulmonary hypertension.     

Effects of ginkgolide B on isobaric hypoxic pulmonary hypertension in rats

We examined the effects of ginkgolide B (BN52021), a specific platelet activating factor (PAF) antagonist, on hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling. Chronic hypoxia can cause pulmonary hypertension and pulmonary vascular remodeling in rats. Treated with BN52021, the rat's pulmonary hypertension, pulmonary vascular remodeling and right ventricular hypertrophy at 3 weeks of hypoxic exposure (FiO2 = 0,10) could be reduced. The results suggest that PAF contributes to the development of chronic hypoxic pulmonary hypertension and pulmonary vascular remodeling, and PAF antagonist may be an useful agent for preventing hypoxic pulmonary hypertension.     

Angiotensin-converting enzyme inhibition delays pulmonary vascular neointimal formation

Primary pulmonary hypertension (PPH) is a disease characterized pathologically by pulmonary artery medial hypertrophy, adventitial thickening, and neointimal proliferation. Increasing recognition of the importance of remodeling to the pathogenesis of PPH suggests new therapeutic possibilities, but it will be necessary to (1) identify essential mediators of remodeling, and (2) demonstrate that inhibiting those mediators suppresses remodeling before new antiremodeling therapies can be considered feasible. The effect of angiotensin-converting enzyme (ACE) inhibition on pulmonary vascular remodeling was studied in a newly developed rat model in which neointimal lesions develop between 3 and 5 wk after monocrotaline injury is coupled with increased pulmonary artery blood flow after contralateral pneumonectomy. Neointimal formation was significantly suppressed at 5 wk by ACE inhibition whether it was started 10 d before or 3 wk after remodeling was initiated, although medial hypertrophy and adventitial thickening still developed. By 11 wk, the extent of neointimal formation in rats treated with ACE inhibition was similar to rats without ACE inhibition at 5 wk. Pulmonary artery pressures and right ventricular weights correlated with the extent of neointimal formation. Northern blot analysis and in situ hybridization demonstrated marked suppression of lung tropoelastin and type I procollagen gene expression in the presence of ACE inhibition. An angiotensin II type I receptor antagonist partially, but not completely, replicated the effects of ACE inhibition. These data suggest that the tissue angiotensin system may be a target for therapeutic efforts to suppress the vascular remodeling that is characteristic of primary pulmonary hypertension.     

Lectin histochemistry of fallopian tube epithelial cells. Relation to ovum transport and ovum pickup

BACKGROUND: This study was designed to investigate whether collagen type I degradation is altered in patients with essential hypertension and whether this alteration could be related to disturbances in the serum matrix metalloproteinase pathway of collagen degradation. A second aim of the study was to assess whether some relation exists between serum markers of collagen type I degradation and left ventricular hypertrophy in hypertensive patients. METHODS AND RESULTS: We measured serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) as a marker of extracellular collagen type I degradation, of total matrix metalloproteinase-1 (MMP-1), or collagenase, of total tissue inhibitor of metalloproteinases 1 (TIMP-1), and of MMP-1/TIMP-1 complex in 37 patients with never-treated essential hypertension and in 23 normotensive control subjects. Serum concentrations of free MMP-1 and free TIMP-1 were calculated by subtracting the values of MMP-1/TIMP-1 complex from the values of total MMP-1 and total TIMP-1, respectively. Measurements were repeated in 26 hypertensive patients after 1 year of treatment with the ACE inhibitor lisinopril. Baseline free MMP-1 was decreased (P<0.001) and baseline free TIMP-1 was increased (P<0.001) in hypertensives compared with normotensives. No significant differences were observed in the baseline values of CITP between the 2 groups of subjects. Hypertensive patients with baseline left ventricular hypertrophy exhibited lower values of free MMP-1 (P<0.01) and CITP (P<0.05) and higher (P<0.001) values of free TIMP-1 than hypertensive patients without baseline left ventricular hypertrophy. Treated patients attained an increase (P<0.001) in free MMP-1 and a decrease (P<0.05) in free TIMP-1. In addition, serum CITP was increased (P<0.05) in treated hypertensives compared with normotensive subjects. CONCLUSIONS: These findings suggest that systemic extracellular degradation of collagen type I is depressed in patients with essential hypertension and can be normalized by treatment with lisinopril. A depressed degradation of collagen type I may facilitate organ fibrosis in hypertensive patients, namely, in those with left ventricular hypertrophy.     

Quantifying the bias associated with use of discrepant analysis

In rats, monocrotaline causes pulmonary vascular damage leading to pulmonary hypertension, right ventricular hypertrophy, and eventually heart failure. This study determined the inotropic and chronotropic responses in isolated cardiac tissues from pulmonary hypertensive rats (single treatment with monocrotaline, 105 mg/kg) to noradrenaline, forskolin, EMD 57033 (calcium sensitizer), and calcium chloride. Further, vasoconstrictor responses to noradrenaline, 5-hydroxytryptamine (5-HT), and KCl were measured in isolated pulmonary artery and thoracic aortic rings. Marked right ventricular hypertrophy was evident 4 weeks after treatment; at 6 weeks, treated rats additionally showed symptoms of severe heart failure. Pulmonary hypertension led to marked increases in pulmonary artery responses to 5-HT and to decreases in positive inotropic responses in right ventricular papillary muscles to all compounds except calcium chloride. The development of heart failure maintained or increased these changes. Positive chronotropic responses were unchanged. In the right ventricle, beta1-adrenoceptor density decreased only in heart failure; beta2-adrenoceptor density was unchanged. The densities of both beta-adrenoceptor subtypes were decreased in the lungs but increased in the liver of pulmonary hypertensive rats. The functional changes in the failing human heart are similar to those in rats with monocrotaline-induced right ventricular hypertrophy. This may be a useful model to define adequate therapy in human right ventricular failure.     

Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.     

Thromboendarterectomy in chronic thromboembolic pulmonary hypertension. Hemodynamics and right-heart function over the long term

OBJECTIVE: To find out whether pulmonary thromboendarterectomy (PTE) can achieve lasting reduction of pulmonary vascular resistance in patients with pulmonary arterial hypertension due to chronic thromboembolism. PATIENTS AND METHODS: 45 patients (25 women, 20 men; mean age 45 +/- 24 [19-67] years) were re-investigated a mean of 21 (13-32) months after successful PTE. Two patients had then been in New York Heart Association (NYHA) stage II, 26 in stage III, and 17 in stage IV. In addition to clinical examination and chest radiogram 36 patients had right heart catheterization, 28 pulmonary angiography and 44 echocardiography. RESULTS: Definite improvement of symptoms had occurred in all. 34 were now in NYHA stage I, nine in stage II, and two in stage III. The pulmonary vascular resistance was significantly lower than before and immediately after PTE (pre-PTE: 1052 +/- 472 dyn.s.cm-5; post-PTE: 293 +/- 175 dyn.s.cm-5; at follow-up: 187 +/- 92 dyn.s.cm-5; P < 0.001 for follow-up vs pre-PTE; P < 0.05 for follow-up vs post-PTE). Correspondingly, cardiac index had significantly increased (3.0 +/- 0.5 vs 2.0 +/- 0.7 l/min.m2; P < 0.001). Radiological and echocardiographic examinations showed a definite decrease in right ventricular dimensions and improvement in right ventricular function. CONCLUSION: In patients with pulmonary arterial hypertension due to chronic pulmonary thromboembolism PTE can achieve a reduction in pulmonary vascular resistance with lasting improvement in right heart function and clinical symptoms.     

The orally active nonpeptide endothelin A-receptor antagonist A-127722 prevents and reverses hypoxia-induced pulmonary hypertension and pulmonary vascular remodeling in Sprague-Dawley rats

Exposure to hypoxia is associated with increased pulmonary artery pressure and plasma endothelin (ET-1) levels and with selective enhancement of ET-1 peptide and messenger RNA (mRNA) and endothelin-A (ET-A) receptor mRNA in rat lung. Our study tested the hypothesis that A-127722, an orally active antagonist of the ET-A receptor, can prevent hypoxia-induced pulmonary hypertension and vascular remodeling in the rat. Pretreatment with A-127722 (3, 10, and 30 mg/kg/day in drinking water for 2 days) caused dose-dependent inhibition of the pulmonary vasoconstrictor response to short-term hypoxia (10% O2, 90 min). Long-term A-127722 treatment (10 mg/kg/day in drinking water for 2 weeks) instituted 48 h before hypoxic exposure attenuated the subsequent development of pulmonary hypertension, the associated right atrial hypertrophy, and pulmonary vascular remodeling. Institution of A-127722 treatment (10 mg/kg/day in drinking water for 4 weeks) after 2 weeks of hypoxia retarded the progression of established hypoxia-induced pulmonary hypertension and right atrial hypertrophy and reversed the pulmonary vascular remodeling despite continuing hypoxic exposure. These findings support the hypothesis that endogenous ET-1 plays a major role in hypoxic pulmonary vasoconstriction/hypertension, right heart hypertrophy, and pulmonary vascular remodeling and suggest that ET-A receptor blockers may be useful in the treatment and prevention of hypoxic pulmonary hypertension in humans.     

Importance of Doppler analysis of transmitted atrial waveforms prior to placement of central venous access catheters

Cardiac fibrosis is linked to aldosterone-induced hypertension, but the effects on in vivo left ventricular (LV) function are not established. We studied the relations between in vivo LV function and aldosterone/salt cardiac fibrosis. Adult guinea pigs (GPs) were treated for 3 months with an aldosterone infusion and high-salt diet. This treatment induced arterial hypertension (+35%) and moderate LV hypertrophy (LVH; +60%) without right ventricular (RV) hypertrophy. Echo-Doppler LV assessment demonstrated unaltered cardiac output, stroke volume, or LV relaxation. Type I collagen messenger RNA (mRNA) was significantly increased in both ventricles (LV, +48%; RV, +77%) and accompanied by a significant increase in total collagen deposition (LV, from 0.52% in controls to 4.4% in treated GPs; RV, from 0.82 to 5.5% in treated GPs). Plasma norepinephrine levels increased 2.6-fold (p < 0.01) and correlated with the increase in collagen deposition in both ventricles. Collagen content was not correlated with hypertension or LVH. We conclude that aldosterone administration induces cardiac collagen accumulation and a sympathetic stimulation, which might preserve systolic and diastolic function.     

Alleviation of monocrotaline-induced pulmonary hypertension by antibodies to monocyte chemotactic and activating factor/monocyte chemoattractant protein-1

Administration of monocrotaline (MCT) causes pulmonary vascular lesions consisting of monocyte/macrophage infiltration in the early phase and medial thickening in pulmonary arteries and arterioles associated with pulmonary hypertension (PH) in the later phase. However, the molecular mechanism of monocyte/macrophage infiltration and its roles remain elusive. Herein, we have evaluated the role of a potent monocyte chemotactic and activating chemokine/monocyte chemoattractant protein-1 (MCAF/MCP-1) in MCT-induced PH in rats. A single injection of MCT induced PH at Day 21, as evidenced by increases in the ratio of right ventricular to left ventricular and septum weights (RV/LV+S) and right ventricular systolic pressure (RVSP). A significant increase in macrophage number in lungs started at Day 14, reaching a maximum at Day 21. MCAF/MCP-1 levels in bronchoalveolar lavage fluids were elevated significantly at Day 14 and remained high until Day 28, whereas plasma MCAF/MCP-1 levels increased at Day 7, returning to normal levels by Day 21. Immunoreactive MCAF/MCP-1 proteins were mainly detected in macrophages in alveoli and in perivascular regions of pulmonary arterioles and venules. Intravenous administration of anti-MCAF/MCP-1 antibodies with MCT significantly decreased macrophage infiltration and eventually reduced the increases in RV/LV+S and RVSP, as well as medial thickening of pulmonary arterioles. Thus, MCAF/MCP-1 is essentially involved in MCT-induced PH by recruiting and activating macrophages.     

Regulation of extracellular matrix proteins in pressure-overload cardiac hypertrophy: effects of angiotensin converting enzyme inhibition

OBJECTIVE: Left ventricular hypertrophy (LVH) is characterized by remodeling of both myocyte and interstitial compartments of the heart. The aim of this investigation was to study the effects of angiotensin converting enzyme (ACE) inhibition on alterations in the composition of the interstitium in chronic pressure-overload hypertrophy. DESIGN: LVH was induced in weanling rats by banding the ascending aorta. Animals with aortic banding received either vehicle (n = 20), hydralazine (20 mg/kg per day, n = 20), or the ACE inhibitor ramipril (10 mg/kg per day, n = 20) during weeks 6-12 after banding. RESULTS: Compared with sham-operated, untreated rats (n = 20), aortic-banded vehicle and hydralazine-treated rats displayed substantially increased left ventricular weights and myocyte diameters whereas ramipril significantly blunted the hypertrophic response at the myocyte level (each P < 0.001) as well as the increase in left ventricular weight (each P < 0.01). In addition, image analysis revealed a significant induction of perivascular and interstitial tissue accumulation in vehicle- and hydralazine-treated rats (2.5-fold, each P < 0.0001). In contrast, ramipril-treated rats displayed attenuated interstitial and perivascular fibrosis, both being significantly diminished compared with vehicle- and hydralazine-treated rats (each P< 0.001). Further, vehicle- and hydralazine-treated rats were characterized by elevated steady-state messenger (m)RNA levels of fibronectin (2.7- and 2.8-fold, P< 0.005), collagen I (2.0- and 1.8-fold, P < 0.0005), collagen III (both 2.2-fold, P < 0.001) and laminin B (1.6- and 1.6-fold, P < 0.005). In parallel, the corresponding immunohistochemical signals were markedly enhanced in these groups. In comparison, ramipril significantly blunted the induction of collagen I and III, laminin B and fibronectin at both the mRNA and protein levels. These morphological and molecular differences between the hydralazine and ramipril groups could not be attributed to differences in left ventricular-pressures, which were markedly elevated in all aortic stenosis rats (1.9-fold, each P < 0.001 versus sham). In fact, given that ramipril but not hydralazine blunted the hypertrophic response to pressure overload, the echocardiographic measurements revealed that left ventricular systolic wall stress was higher in the ramipril group (70 +/- 1 versus 34 +/- 0.7 kdyn/cm2; P < 0.02). CONCLUSIONS: ACE inhibition may limit both myocyte and interstitial remodeling despite ongoing cardiac pressure overload.     

Pulmonary responses to 5-hydroxytryptamine and endothelin-1 in a rabbit model of left ventricular dysfunction

OBJECTIVE: To determine whether pulmonary hypertension developed in a coronary artery-ligated rabbit model of left ventricular dysfunction (LVD) and to examine the effects of i.v. 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) on pulmonary arterial pressure (PAP). METHODS: Eight weeks after experimental coronary artery ligation or sham operation, ejection fractions were assessed by echocardiography. The rabbits were later anaesthetised and pulmonary arterial pressure was measured via a catheter inserted into the pulmonary artery via the right external jugular vein. 5-HT (1-400 micrograms/kg) and ET-1 (0.001-4 nmol/kg) were administered i.v. RESULTS: Ejection fraction was significantly decreased from 76.6 +/- 1.4% in sham-operated to 42.2 +/- 1.3% in coronary artery-ligated rabbits (n = 9 in each group; P < 0.001), consistent with LVD. Baseline mean pulmonary arterial pressure was significantly increased in the coronary artery-ligated group compared to the shams, (16.5 +/- 0.5 vs. 11.5 +/- 0.8 mmHg; P < 0.001). A significant degree of right ventricular hypertrophy was found in the coronary artery-ligated rabbits (0.70 +/- 0.04 g/kg final body weight (f.b.wt.), n = 8 cf. 0.48 +/- 0.02 g/kg f.b.wt. in sham-operated controls, n = 8; P < 0.001). There was a significant increase in the percentage of muscularised pulmonary vessels adjacent to alveolar ducts and alveoli < 60 microns i.d. in the LVD rabbits compared with their sham-operated controls (8.5 +/- 0.4 cf. 20 +/- 0.5%; P < 0.0005). 5-HT produced a greater response in the coronary artery-ligated rabbits (a maximum increase of 8.7 +/- 1.0 mmHg in mean pulmonary artery pressure vs. 4.6 +/- 1.5 mmHg for sham-operated controls; P < 0.05). ET-1 did not have any effect on pulmonary arterial pressure in either group. CONCLUSION: In the rabbit, LVD secondary to coronary artery ligation, causes right ventricular hypertrophy, pulmonary vascular remodelling, and an increased PAP consistent with the onset of pulmonary hypertension (PHT). The greater PAP response to i.v. 5-HT in the PHT group supports the hypothesis that this substance could be involved in the development of PHT. A role for ET-1 cannot be excluded, despite its lack of effect on PAP when intravenously administered in either group.     

Markedly different effects on ventricular remodeling result in a decrease in inducibility of ventricular arrhythmias

OBJECTIVES: The purpose of this study was to determine whether the type and extent of ventricular remodeling after infarction influence inducibility of ventricular arrhythmias after infarction. BACKGROUND: Although serious ventricular arrhythmias after infarction are related to ventricular dysfunction, the relation between inducibility of ventricular arrhythmias and ventricular remodeling remains incompletely understood. METHODS: Rats that survived ligation of the left anterior descending coronary artery (n = 218) were randomized to receive placebo (saline solution) or captopril or propranolol therapy and were followed up for 5 weeks. Hemodynamic and neurohumoral blood measurements were obtained, and therapy was stopped. Two days later, susceptibility to ventricular arrhythmias was assessed by programmed electrical stimulation, and hearts were prepared for pathologic studies. RESULTS: Placebo-treated rats with a large myocardial infarction had ventricular dysfunction, marked neurohumoral activation, ventricular enlargement (endocardial circumference 16 +/- 3 [mean +/- SD] to 20 +/- 4 mm, p < 0.05) and increased cardiac fibrosis (volume density of collagen 2.3 +/- 0.8% to 5.6 +/- 2.4%, p < 0.05). In many rats this resulted in easily inducible ventricular arrhythmias (inducibility quotient 4.9 +/- 2.2). Captopril attenuated the development of ventricular dysfunction, neurohumoral activation, ventricular hypertrophy and dilation (endocardial circumference 18 +/- 3 mm) and cardiac fibrosis (3.1 +/- 0.8%, p < 0.05). These modifications were accompanied by decreased inducibility of ventricular arrhythmias (inducibility quotient 1.1 +/- 2.0, p < 0.05). Propranolol did not prevent ventricular dysfunction, had variable effects on neurohumoral activation and led to increased ventricular dilation (endocardial circumference 25 +/- 4 mm, p < 0.05) and cardiac fibrosis (7.7 +/- 1.2%, p < 0.05). Nevertheless, these morphologic changes led to decreased inducibility of ventricular arrhythmias (inducibility quotient 2.2 +/- 2.5%, p < 0.05). CONCLUSIONS: This study indicates that the inducibility of ventricular arrhythmias can be reduced as a result of markedly different effects on ventricular remodeling, indicating that the relation between ventricular remodeling, arrhythmias and survival is more complex than previously thought.     

Evidence for load-dependent and load-independent determinants of cardiac natriuretic peptide production

BACKGROUND: In hypertension with cardiac hypertrophy, the specific contributions to increased production of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) by load and the hypertrophic process are not known. In the present work we determine ANF and BNP synthesis and secretion in the aortic-banded rat treated with dosage schedules of the ACE inhibitor ramipril that result in the prevention or regression of both hypertension and hypertrophy (high dosage) or in the prevention or regression of hypertrophy alone with persistent hypertension (low dosage). Myosin heavy chain (MHC) isoform switch was studied as an indicator of ventricular cardiocyte hypertrophy as well as the levels of collagen III mRNA as a measure of changes in extracellular matrix. METHODS AND RESULTS: Ramipril was administered for 6 weeks just after suprarenal aortic banding, or rats were banded for 6 weeks, after which ramipril was administered during the following 6 weeks. Banding caused an increase in blood pressure, left ventricular weight-to-body weight ratio, plasma and ventricular NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA. Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10 micrograms/kg normalized left ventricular weight-to-body weight ratio but not blood pressure. Plasma and ventricular NP content and mRNA levels were partially normalized by ramipril (10 micrograms/kg). Ramipril (10 micrograms/kg) prevented increased collagen III mRNA levels but did not affect beta-MHC mRNA levels. CONCLUSIONS: (1) NP production and secretion in aortic-banded rats are independently related to increased blood pressure and hypertrophy. (2) A load-dependent component is more important than a load-independent component in regulating left ventricular NP production. (3) ANF production is more sensitive than BNP production to the load-independent component. (4) Low-dose ramipril treatment reverses hypertrophy and the increased collagen III expression but does not reverse the increased beta-MHC isoform expression, suggesting that these are independently regulated processes. (5) Aortic banding and ACE inhibition do not affect atrial NP production and content.     

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.     

Survey of echinococcosis in Hokkaido and measure against it

Exposure to hyperoxia results in lung injury and a decrease in lung collagen. Retinol is known to influence collagen gene expression, and retinol deficiency has been shown to potentiate hyperoxic lung injury. To investigate the combined effects of retinol deficiency and hyperoxia on lung collagen expression, retinol-deficient rats were exposed to acute hyperoxia, and expression of the alpha-1 chains of type I procollagen [pro alpha 1 (I)] and type III procollagen [pro alpha 1 (III)] were determined using Northern hybridization analyses and immunohistochemical staining. Hyperoxia alone reduced pro alpha 1 (I) mRNA by 60 +/- 4% (p < .05) and pro alpha 1 (III) mRNA by 30 +/- 5% (p < .05), and retinol deficiency alone reduced pro alpha 1 (I) mRNA abundance by 49 +/- 8.8% (p < .05) and pro alpha 1 (III) mRNA abundance by 14 +/- 7.5% (p = not significant), respectively. Retinol deficiency plus hyperoxia did not cause any further reduction in procollagen mRNA than that seen with oxygen exposure alone. Immunohistochemical staining demonstrated decreased staining for type I collagen in retinol-deficient animals. Hyperoxic exposure resulted in decreased connective tissue staining and increased alveolar wall staining for type I collagen. Retinol deficiency and hyperoxia together resulted in a marked increase in alveolar exudates staining for type I collagen. No changes in type III collagen staining were seen. These findings demonstrate that while retinol deficiency does not potentiate hyperoxia-induced reductions in procollagen mRNA, it is associated with alterations in collagen staining in distal lung and immunohistologic evidence of collagen fragments in alveolar exudates.     

Placental protein 14 functions as a direct T-cell inhibitor

Morphological changes in the myocardium after left ventricular hypertrophy, due to chronic experimental hypertension, require an understanding of the quantitative relationship between myocyte and nonmyocyte compartments forming the structural framework of the myocardium. Hypertension was induced by long-term low-dosage inhibition of nitric oxide synthesis by NG-nitro-L-arginine methyl ester (L-NAME) in rats. L-NAME (12 mg/kg) was given to animals in water ad libitum during 15 weeks. After this period, systolic blood pressure increased almost 50% as compared with that in the control group. Morphological changes in control and L-NAME animals were investigated with stereology and immunohistochemistry. Comparing control and L-NAME animals, the surface density of myocytes decreased 73.7% while the mean cross-sectional area increased 97.6% in L-NAME rats. The volume density of myocytes decreased 45.9% and the volume density of the interstitium increased 71.7% in L-NAME rats. No stereological difference was found in blood vessels comparing the two groups. Remodeling of the cardiac interstitium occurred with increased deposition of both fibronectin and type III collagen. Fibronectin was seen in both early and latter responses to infarction while type III collagen was seen mainly in areas of incomplete healing among myocytes and around intramyocardial branches of the coronary arteries. The long-term low-dosage administration of an inhibitor of the NO synthase such as L-NAME causes myocyte hypertrophy and early interstitial and perivascular fibrosis without important quantitative changes in microcirculation.