Coronary Artery Ligation In Rats Research Articles

Myocardial Heat Shock Proteins during the Development of Heart Failure

When cardiomyocytes are exposed to stresses, production of heat shock proteins (HSPs) in the cells is enhanced. Such increase in cellular HSP production is considered to bring about tolerance against stress-induced cell damage. The exact role of the cellular HSPs remains unclear. In the present study, HSPs in the viable left ventricular myocardium were determined during the development of heart failure following coronary artery ligation (CAL). The rats after CAL showed symptoms of chronic heart failure (CHF) at the 8th week, but not at the 1st and 2nd weeks. Myocardial HSP27, which may bind to cytoskeletal protein, at the 1st, 2nd, and 8th weeks after CAL was approximately 180, 160, and 125% of the control, respectively. Myocardial HSP60, one of mitochondrial proteins, at the 8th week increased to 140% of the control, whereas those at the 1st and 2nd weeks did not change. Myocardial HSP72, an inducible form of HSP70 family, at the 1st week after CAL increased to 180% of the control, whereas that at the 2nd or 8th week was similar to control. Myocardial heat shock constitutive protein 73 (HSC73), a constitutively expressed form of HSP70 family, and HSP90, which may bind to steroid hormone receptor and actin fiber, of CAL rats did not alter throughout the experiment. These findings show that diverse changes in the production of myocardial HSPs occur during the development of heart failure. Only the increase in myocardial HSP60 production was associated with the development of CHF.

Insulin-like growth factor-binding protein-3 induces fetalization in neonatal rat cardiomyocytes.

We employed cDNA microarrays representing 4000 distinct sequences to profile changes in gene expression in a rodent model of heart disease, namely, progression to heart failure after myocardial infarction. Differential gene expression in the left ventricle was examined at 4-week intervals over a 12-week period after coronary artery ligation in rats. Over this time course, insulin-like growth factor-binding protein-3 (IGFBP-3) was found to have a greater expression than in nondiseased tissues. We then employed quantitative real-time PCR to analyze gene expression in neonatal rat cardiac myocytes that had been treated with recombinantly expressed IGFBP-3 to examine a number of transcriptional responses designed to reflect the heart failure phenotype. The IGFBP-3 protein was shown to induce transcription of atrial natriuretic factor (ANF) and beta-myosin heavy chain (B-MHC). Analysis of conditioned media taken from IGFBP-3-treated cardiac myocyte cultures demonstrated an increase in ANF protein as well as in protein synthesis, as determined by metabolic incorporation of a radiolabeled amino acid. However, transcriptional changes of troponin-1, endothelin-1, or angiotensin-II by IGFBP-3 were not observed.

At2 Receptor-Mediated Vasodilation in the Heart: Effect of Myocardial Infarction.

P64 To investigate the functional consequences of the changes in AT 2 receptor density that have been reported following myocardial infarction (MI; Matsubara, Circ Res, 1998), three consecutive 10 min intravenous infusions of angiotensin (Ang) II (100, 300 and 1000 ng/kg/min) were given to 19 sham-operated and 16 coronary artery-ligated rats, at four weeks after surgery, pretreated with either saline, the AT 1 receptor antagonist irbesartan (100 μg/kg/min for 30 min), or the AT 2 receptor antagonist PD123319 (20 μg/kg/min for 30 min, followed by continuous infusion). Systemic and regional hemodynamic effects were studied using the radioactive microsphere method. Ang II induced comparable changes in sham and MI rats in mean arterial pressure (MAP; maximally +30±10% and +30±8%, resp., mean±SEM) and systemic vascular conductance (cardiac output/MAP, -27±8% and -32±5%, resp.). Cardiac output decreased in MI (-20±5%) but not in sham rats. Irbesartan decreased MAP by 34% (sham) and 22% (MI), increased SVC by 41% (sham) and 24% (MI), and blocked the Ang II-mediated systemic hemodynamic effects in both sham and MI rats, while PD123319 did not affect these parameters. Myocardial conductance at baseline was diminished in MI vs. sham rats (41±3 vs. 55±6 μl/min/mmHg, resp.), while renal conductance was comparable in both groups (168±9 vs. 156±18 μl/min/mmHg, resp.). Ang II increased myocardial conductance maximally to 56±3 (MI) and 72±3 (sham) μl/min/mmHg, and decreased renal conductance to 67±4 (MI) and 74±8 (sham) μl/min/mmHg. Irbesartan increased renal, but not myocardial, conductance in both groups and blocked the Ang II-mediated renal vasoconstriction. PD123319 did not affect renal or myocardial conductance and blocked the Ang II-mediated myocardial vasodilation in sham but not in MI rats. PD123319 did not affect the Ang II-mediated renal responses. In conclusion, Ang II increases myocardial, but not renal, conductance (i.e., induces vasodilation) via AT 2 receptor stimulation. The inability of PD123319 to block this response in MI rats suggests either an upregulation of AT 2 receptors or a role for non-AT 1 , non-AT 2 receptors in the infarcted heart.

At 2 Receptor-Mediated Vasodilation in the Heart: Effect of Myocardial Infarction.

P64 To investigate the functional consequences of the changes in AT 2 receptor density that have been reported following myocardial infarction (MI; Matsubara, Circ Res, 1998), three consecutive 10 min intravenous infusions of angiotensin (Ang) II (100, 300 and 1000 ng/kg/min) were given to 19 sham-operated and 16 coronary artery-ligated rats, at four weeks after surgery, pretreated with either saline, the AT 1 receptor antagonist irbesartan (100 μg/kg/min for 30 min), or the AT 2 receptor antagonist PD123319 (20 μg/kg/min for 30 min, followed by continuous infusion). Systemic and regional hemodynamic effects were studied using the radioactive microsphere method. Ang II induced comparable changes in sham and MI rats in mean arterial pressure (MAP; maximally +30±10% and +30±8%, resp., mean±SEM) and systemic vascular conductance (cardiac output/MAP, -27±8% and -32±5%, resp.). Cardiac output decreased in MI (-20±5%) but not in sham rats. Irbesartan decreased MAP by 34% (sham) and 22% (MI), increased SVC by 41% (sham) and 24% (MI), and blocked the Ang II-mediated systemic hemodynamic effects in both sham and MI rats, while PD123319 did not affect these parameters. Myocardial conductance at baseline was diminished in MI vs. sham rats (41±3 vs. 55±6 μl/min/mmHg, resp.), while renal conductance was comparable in both groups (168±9 vs. 156±18 μl/min/mmHg, resp.). Ang II increased myocardial conductance maximally to 56±3 (MI) and 72±3 (sham) μl/min/mmHg, and decreased renal conductance to 67±4 (MI) and 74±8 (sham) μl/min/mmHg. Irbesartan increased renal, but not myocardial, conductance in both groups and blocked the Ang II-mediated renal vasoconstriction. PD123319 did not affect renal or myocardial conductance and blocked the Ang II-mediated myocardial vasodilation in sham but not in MI rats. PD123319 did not affect the Ang II-mediated renal responses. In conclusion, Ang II increases myocardial, but not renal, conductance (i.e., induces vasodilation) via AT 2 receptor stimulation. The inability of PD123319 to block this response in MI rats suggests either an upregulation of AT 2 receptors or a role for non-AT 1 , non-AT 2 receptors in the infarcted heart.

Inducible nitric oxide synthase-derived superoxide contributes to hypereactivity in small mesenteric arteries from a rat model of chronic heart failure.

The aims of this study were to (a) determine whether inducible nitric oxide synthase (iNOS) is expressed in small mesenteric arteries from rats with chronic heart failure (CHF), (b) investigate the functional significance of this potential source of nitric oxide (NO) on vascular responsiveness and (c) investigate the role that superoxide plays in modulating vascular function in these arteries. CHF was induced in male Wistar rats by coronary artery ligation (CAL). In sham-operated rats the ligature was not tied but pulled under the artery. Six weeks after surgery CAL rats had left ventricular (LV) infarctions and elevated LV end-diastolic pressures. Immunoreactive iNOS was found in endothelial cells, vascular smooth muscle cells and in the adventitia of small mesenteric arteries from CAL rats but not those from sham-operated rats. Third order mesenteric arteries (300-350 microm) were mounted in a small vessel pressure myograph. Endothelium-intact arteries from CAL rats were more responsive to phenylephrine (PE) than arteries from sham-operated rats (pD(2) value, CAL, 6.2+/-0.1; sham-operated, 5.9+/-0.1, P<0.05). Both the selective iNOS inhibitor, N-(3-(Aminomethyl) benzyl) acetamidine dihydrochloride (1400W; 10(-6) M) and the superoxide dismutase mimetic, Mn [III] tetrakis [1-methyl-4-pyridyl] porphyrin, (MnTMPyP; 10(-4) M) reversed the hyperesponsiveness (pD(2) values, 1400W, 5.9+/-0.1; MnTMPyP, 5.81+/-0.1, P<0.05). The NOS substrate, L-arginine (10(-3) M), reduced responsiveness of endothelium-denuded small mesenteric arteries from CAL rats (P<0.01). None of these drugs altered responses to PE in arteries from sham-operated rats. In summary, this study demonstrates that iNOS is expressed in mesenteric arteries from rats with CHF. However, instead of generating large quantities of NO, iNOS appears to be generating superoxide, perhaps because of a deficiency in its substrate, L-arginine. Increased superoxide generation from iNOS contributes to the hyperesponsive nature of endothelium-intact small mesenteric arteries from rats with CHF.

Beneficial effects of MET-88, a γ-butyrobetaine hydroxylase inhibitor in rats with heart failure following myocardial infarction

Myocardial ischemia can cause myocardial infarction and as a consequence, heart failure. 3-(2,2,2-trimethylhydrazinium) propionate (MET-88) inhibits γ-butyrobetaine hydroxylase and has cardioprotective effects on the ischemic heart. We now examined the effects of MET-88 in rats with congestive heart failure following myocardial infarction. Congestive heart failure was produced by left coronary artery ligation in rats. MET-88 at 100 mg/kg/day was orally administered from the 2nd day after surgery. We performed a survival study for 181 days, and measured ventricular remodeling, cardiac function, and myocardial high-energy phosphate levels after treatment for 20 days. MET-88 prolonged survival with a median 50% survival of 103 days compared to 79 days for the heart-failure control rats. The expansion of the left ventricular cavity (ventricular remodeling) in heart-failure rats was prevented by treatment with MET-88, and the effect of MET-88 was similar to that of captopril at 20 mg/kg. MET-88 attenuated the rise in right atrial pressure in heart-failure rats and augmented cardiac functional adaptability against an increased load. Also, MET-88 improved the myocardial energy state in heart-failure rats. The present results indicate that MET-88 improves the pathosis in rats with heart failure induced by myocardial infarction.

Combined neutral endopeptidase and angiotensin-converting enzyme inhibition attenuates left ventricular remodeling without hypotension in a rat coronary artery ligation model of heart failure

Combined neutral endopeptidase and angiotensin-converting enzyme inhibition attenuates left ventricular remodeling without hypotension in a rat coronary artery ligation model of heart failure

Induction of Cardiac β -adrenergic Receptor Kinase 1 in Rat Heart Failure Caused by Coronary Ligation

β -adrenergic receptor kinase 1 (β ARK1) participates in the desensitization of β -adrenergic receptors by uncoupling the signal transduction. The present study was designed to examine whether neurohumoral increase is crucial for the activation of β ARK1in heart failure. Four weeks after the ligation of rat coronary artery, LV dP/d t max was reduced, cardiac response to isoproterenol was impaired, and ratio of right ventricular weight to body weight, an index of cardiac hypertrophy, was increased. At the same time,β ARK1expression and activity were augmented in the hypertrophied hearts. In addition, plasma norepinephrine content was enhanced in accordance with cardiac hypertrophy, cardiac β ARK1expression, LV dP/d t max, and LVEDP. These results of the present study suggest that β ARK1is augmented in concert with circulating norepinephrine level and that β ARK1may account for, at least in part, the cardiac dysfunction in rat with myocardial infarction.

Induction of cardiac β-adrenergic receptor kinase 1 in rat heart failure caused by coronary ligation.

Beta-adrenergic receptor kinase 1 (beta ARK1) participates in the desensitization of beta-adrenergic receptors by uncoupling the signal transduction. The present study was designed to examine whether neurohumoral increase is crucial for the activation of beta ARK1 in heart failure. Four weeks after the ligation of rat coronary artery, LV dP/d t max was reduced, cardiac response to isoproterenol was impaired, and ratio of right ventricular weight to body weight, an index of cardiac hypertrophy, was increased. At the same time, beta ARK1 expression and activity were augmented in the hypertrophied hearts. In addition, plasma norepinephrine content was enhanced in accordance with cardiac hypertrophy, cardiac beta ARK1 expression, LV dP/d t max, and LVEDP. These results of the present study suggest that beta ARK1 is augmented in concert with circulating norepinephrine level and that beta ARK1 may account for, at least in part, the cardiac dysfunction in rat with myocardial infarction.

Effect of chronic neutral endopeptidase inhibition on cardiac hypertrophy after experimental myocardial infarction.

Candoxatril is an inhibitor of neutral endopeptidase, a membrane-bound enzyme that degrades atrial natriuretic peptide. The effects of candoxatril on hemodynamic parameters and cardiovascular hypertrophy were evaluated in the rat model of myocardial infarction. Myocardial infarction was induced by left coronary artery ligation in rats and they were treated either with candoxatril (10mg/kg per day) or a vehicle for up to 4 weeks. Systolic blood pressure and body weight did not change for up to 4 weeks between the 2 groups. At the end of treatment, hemodynamic parameters were measured, and then plasma, heart, lungs and kidneys were collected. Kidney neutral endopeptidase, as measured by the quantitative autoradiographic method, was significantly inhibited in candoxatril-treated rats compared with that in controls (66.6+/-3.2% of control, p<0.001). On the contrary, there were no significant differences in right atrial pressure, left ventricular end-diastolic pressure, systemic pressure, and plasma level of atrial natriuretic peptide between the 2 groups. There were also no significant differences in cardiac weight and lung weight. These data indicate that inhibition of neutral endopeptidase by candoxatril at a dose of 10 mg/kg per day did not oppose cardiac hypertrophy in the rat model of myocardial infarction in spite of significant neutral endopeptidase inhibition.

Effects of long‐term treatment with trandolapril on sarcoplasmic reticulum function of cardiac muscle in rats with chronic heart failure following myocardial infarction

1 Calcium transport activity of isolated cardiac sarcoplasmic reticulum (SR) including Ca2+ uptake and release is decreased in animals with chronic heart failure (CHF) following myocardial infarction. The present study was undertaken to determine whether an angiotensin converting enzyme (ACE) inhibitor, trandolapril, improves cardiac sarcoplasmic reticular function in animals with CHF following myocardial infarction. 2 CHF was induced by left coronary artery ligation in rats, which resulted in an infarction of approximately 45% of the left ventricle. Aortic flow and cardiac output index were decreased, and left ventricular end-diastolic pressure was increased 8 weeks after the operation, suggesting the development of CHF. 3 The developed force transients of cardiac skinned fibres of the rats with CHF were decreased when the skinned fibre was preloaded for 0.25-1 min with 10(-5) M Ca2+ (48-88%) and when preloaded with 10(-6) M Ca2+ and then exposed to 0.1-1 mM caffeine (45-93%). 4 The [3H]-ryanodine-binding activity in SR-enriched fractions was reduced by 23% in the CHF group. These results suggest that the amount of Ca2+ released from SR is decreased due to a reduced rate of SR Ca2+ uptake and a downregulation of the SR Ca2+-release channel. 5 Rats were treated orally with 3 mg kg(-1) day(-1) trandolapril from the 2nd to the 8th week after the coronary artery ligation. Treatment with trandolapril attenuated the reduction in aortic flow and cardiac output index and the increase in left ventricular end-diastolic pressure, and improved the developed force transients of the skinned fibre of the animal with CHF without causing a reduction of infarct size. Treatment with trandolapril also attenuated the reduction in ryanodine receptor density in the viable left ventricle of the rat with CHF. 6 It is concluded that long-term treatment with trandolapril attenuates cardiac SR dysfunction in rats with CHF and that the mechanism underlying this effect is, at least in part, attributed to prevention of downregulation of Ca2+ release channel.

Endothelin-converting enzyme and angiotensin-converting enzyme in failing hearts of rats with myocardial infarction.

We have previously reported that production of endothelin (ET)-1 is markedly increased in failing hearts of rats with chronic heart failure (CHF). It was also reported that the production of angiotensin II (Ang II) is increased in the failing heart. In this study we investigated both converting enzymes of the ET-1 system and the angiotensin system. We used left coronary artery-ligated rats as a model of CHF. The peptide level of ET-1 in the left ventricle (LV) was markedly higher in CHF rats than in control rats. In the LV, expression of preproET-1 mRNA was also markedly higher in CHF rats than in controls. The expression of endothelin-converting enzyme (ECE)-1 mRNA in the rats with CHF was similar to that in controls. Therefore, we believed that the increase in ET-1 production in the failing heart originated from an increase in preproET-1 production rather than increase in ECE. The expression of angiotensin-converting enzyme (ACE) mRNA in failing hearts of CHF rats was significantly higher than that of the sham-operated rats. The expression of angiotensinogen mRNA in failing hearts of these CHF rats was slightly higher than that of the sham-operated rats. This study suggests that there is a difference in the role of peptide synthesis between the ECE system and the ACE system in rats with CHF.

Cardiac Sarcoplasmic Reticular Function in Rats with Chronic Heart Failure Following Myocardial Infarction

Sarcoplasmic reticular function of rats with chronic heart failure (CHF) following coronary artery ligation was examined. The coronary artery ligation produced 43% infarction of the left ventricle and increased left ventricular end-diastolic pressure 8 weeks after the operation, suggesting the development of CHF by this period. The developed force transients of the skinned fiber of coronary artery-ligated rats were decreased when the skinned fiber was preloaded for 0.25–0.5 min with 10−5mCa2+(53–70%) and when preloaded with 10−6mCa2+and then exposed to 0.1–1mmcaffeine (39–87%). The results suggest that the rate of Ca2+uptake by the sarcoplasmic reticulum (SR) and its ability to release Ca2+were reduced in the failing heart. [3H]Ryanodine binding activities in homogenates and SR-enriched fractions were significantly reduced in the coronary artery-ligated group (32% and 21%, respectively). The results suggest that the amount of Ca2+released from SR decreased due to decreased Ca2+uptake rate of SR and down-regulation of the SR Ca2+-release channel, which contributes to cardiac dysfunction in failing hearts following acute myocardial infarction.

Pulmonary hypertension caused by congestive heart failure is ameliorated by long-term application of an endothelin receptor antagonist Increased expression of endothelin-1 messenger ribonucleic acid and endothelin-1-like immunoreactivity in the lung in congestive heart failure in rats

Objectives. The purpose of this study was to investigate whether 1) endothelin-1, a potent vasoconstrictor peptide, is involved in progression of pulmonary hypertension caused by congestive heart failure (CHF); and 2) whether long-term treatment with BQ-123, an endothelin receptor antagonist, ameliorates pulmonary hypertension caused by CHF.Background. Congestive heart failure accompanies pulmonary hypertension, and the severity of pulmonary hypertension is an important determinant of prognosis. Although we reported that production of endothelin-1 is increased in the failing heart in rats with CHF, it is not known whether production of endothelin-1 in the lung is altered by CHF.Methods. Congestive heart failure was induced by coronary artery ligation in rats. Expression of preproendothelin-1 messenger ribonucleic acid (mRNA) in the lung and kidney was determined. Endothelin-1 staining (immunoreactivity) in the lung was studied by immunohistochemical analysis. Effects of long-term BQ-123 treatment on the rats were studied.Results. Two weeks postoperatively, CHF accompanied by pulmonary hypertension developed in the rats (CHF rats). Expression of preproendothelin-1 mRNA in the lung was markedly higher in the CHF rats than in the sham-operated rats, whereas that in the kidney did not differ between the two groups. Endothelin-1 staining on the pulmonary vascular endothelial cells was more intense in the CHF rats. BQ-123 treatment over a 2-week period in the CHF rats greatly reduced right ventricular systolic pressure and central venous pressure, but it did not affect blood pressure or left ventricular contractility (peak positive first derivative of left ventricular pressure) in these rats.Conclusions. Long-term BQ-123 treatment greatly ameliorated pulmonary hypertension in the CHF rats. The present study suggests that endothelin-1 plays an important role in the progression of pulmonary hypertension caused by CHF and that an endothelin receptor antagonist may be a new therapeutic agent for CHF-induced pulmonary hypertension.

The effect of AT1 receptor antagonist on chronic cardiac response to coronary artery ligation in rats

The aim was to study the effect of the AT1 receptor antagonist losartan on hemodynamic and morphometric changes following experimental infarction. Experimental infarction was produced in adult male rats by ligating the coronary artery. Treatment with losartan was compared to untreated controls, in rats with experimental infarction and sham-operated animals. Infarcted hearts were characterized by significant decreases in left ventricular developed pressure, as well as positive and negative (dP/dt)max, whereas left ventricular end-diastolic pressure (LVEDP), relaxation constant tau and right ventricular systolic pressure (RVSP) significantly increased. Treatment with losartan decreased the LVEDP, the relaxation constant tau and RVSP in the infarcted hearts. Right ventricular weight significantly increased in rats with infarction; this was attenuated by losartan. Infarct size was not significantly influenced by losartan treatment. Morphometric data revealed decreased capillary supply in infarcted hearts, especially in regions close to infarction; the decrease was less pronounced after losartan treatment. Capillary density in near infarct region decreased from 2826/mm2 to 1471/mm2 in untreated animals but in the treated animals it decreased from 2982/mm2 to only 2037/mm2. Simultaneous significant decrease in myocyte-to-capillary ratio in treated animals compared to untreated rats (0.87 to 0.67) seems to indicate formation of new capillary channels after losartan treatment. LVEDP was dependent on the size of infarction in untreated but not in treated animals. A close correlation between LVEDP and capillary density was found. Decreased ventricular contractility, prolonged relaxation and decreased coronary capillary density in rat experimental cardiac infarction confirm and amplify previous reports dealing with this experimental model. Moreover, we have found evidence of improved hemodynamics and coronary angiogenesis after losartan treatment.

The effect of AT1 receptor antagonist on chronic cardiac response to coronary artery ligation in rats

The effect of AT1 receptor antagonist on chronic cardiac response to coronary artery ligation in rats

Comparative Effects of Idazoxan, Prazosin, and Yohimbine on Coronary Ligation-Induced Arrhythmias in Spontaneously Hypertensive Rats

We investigated whether certain drugs with alpha-adrenergic antagonist activity display anti-arrhythmic effects in hypertensive animals subjected to acute coronary artery ligation. The left anterior descending coronary artery (LAD) was ligated in open-chest pentobarbital-anesthetized spontaneously hypertensive rats (SHR); arrhythmias were subsequently recorded for 30 min. Drugs were administered intravenously, (i.v.) 5 min before ligation. The effects of yohimbine and idazoxan were compared with those of prazosin. Prazosin (100 mu g/kg) increased the occurrence of ventricular tachycardia (VT). In contrast, yohimbine 1.6 mg/kg decreased both the occurrence and the duration of VT and the occurrence and the duration of ventricular fibrillation, (VF). The results obtained with idazoxan 1 mg/kg were similar to those with yohimbine. The ECG alterations induced by coronary artery ligation in rats treated with yohimbine and idazoxan were more pronounced than in controls and in rats treated with prazosin, suggesting that the antiarrhythmic effects observed were not mediated by antiischemic activity. The protective effects against ligation-induced arrhythmias were preceded by a hypotensive effect and a decrease in the rate-pressure product in yohimbine-treated but not in idazoxan-treated animals. In rats treated with prazosin, more arrhythmic events were observed, although hemodynamics were similar to those in rats treated with yohimbine. Our results suggest that the yohimbine-induced antiarrhythmic action is not due to an alteration of conduction or repolarization rates. In this model, yohimbine and idazoxan appear to protect against ligation-induced arrhythmias. These data suggest that drugs with alpha-adrenergic properties might influence the nervous drive to the heart in SHR with cardiac ischemia. However, further investigations are needed to ascertain whether the alpha-adrenoceptor blockade participates in this effect.

Long-term treatment with angiotensin I-converting enzyme inhibitors attenuates the loss of cardiac beta-adrenoceptor responses in rats with chronic heart failure.

Cardiac contractile force in response to beta-adrenoceptor agonists and beta-adrenergic receptor density are decreased in failing human hearts. The effects of angiotensin I-converting enzyme (ACE) inhibitor on cardiac responsiveness to beta-adrenergic stimulation in failing hearts are not established. The present study was undertaken to determine whether ACE inhibitor may improve cardiac beta-adrenergic responsiveness in animals with chronic heart failure (CHF). CHF was induced by left coronary artery ligation in rats. Cardiac output and stroke volume indices decreased 12 weeks after the operation. In sham-operated rats, dobutamine and isoprenaline increased cardiac output and stroke volume indices. In contrast, cardiac output and stroke volume responses to dobutamine and isoprenaline were severely blunted in the CHF rat. Cardiac beta 1-adrenergic receptor density was decreased while its dissociation constant (Kd) was not altered in the viable tissue of the left ventricle of the CHF rat, which is consistent with beta-adrenergic receptor downregulation. Cardiac norepinephrine content decreased in the CHF rats. Rats were treated orally with ACE inhibitors, 3 mg/kg trandolapril or 10 mg/kg enalapril once daily, or 5 mg/kg captopril twice daily from the 2nd to the 12th weeks after the operation. Treatment with ACE inhibitors attenuated the reduction in cardiac output and stroke volume indices and improved the inotropic response to dobutamine and isoprenaline and reversed partially the cardiac norepinephrine content in the CHF rat. ACE inhibitor treatment also attenuated the reduction in beta 1-adrenergic receptor density in the viable tissue of the left ventricle of the CHF rat. The results suggest that ACE inhibitor treatment attenuates the blunting of cardiac responses to beta-adrenergic agonists in the CHF rat and that one of the mechanisms underlying this effect is prevention of cardiac beta 1-adrenergic receptor downregulation.

An extra-adrenal sodium-retaining factor in congestive heart failure

The extra-adrenal sodium-retaining factor was first described in Circulation Research in 1964. This factor increases the responsiveness of the renal tubules to aldosterone in heart failure, and marked sodium retention occurs with resultant edema or ascites. Evidence for the extra-adrenal sodium-retaining factor is presented in two models of experimental heart failure in dogs and in dogs with thoracic caval constriction and a low cardiac output. Since the nature of this sodium-retaining factor remains unknown, several of the recently discovered factors that influence kidney function and that might alter the responsiveness of the renal tubules to a mineralocorticoid are described. These factors include atrial natriuretic peptide, nitric oxide, 11β-hydroxysteroid dehydrogenase activity, the endothelins, and the intrarenal tissue renin-angiotensin system. It is suggested that the nature and action of the sodium-retaining factor be reinvestigated in lieu of the new knowledge of kidney function. The applicability of newly developed experimental models of heart failure for study of the extra-adrenal factor is discussed; these include coronary artery ligation in rats, cardiac pacing in the dog, and application of transmyocardial direct current shock to local myocardial areas in dogs.

Lack of correlation of hypotensive effects with prevention of cardiac hypertrophy by perindopril after ligation of rat coronary artery.

1. The present study was designed to test the hypothesis that beneficial effects of angiotensin converting enzyme (ACE)inhibitors are independent of a fall in blood pressure in rat experimental heart failure following coronary ligation. 2. The animals were assigned randomly to six groups; sham operation, controls subjected to coronary ligation (control), coronary ligation plus chronic treatment with ACE inhibitors at non- and hypotensive doses; perindopril (0.2 or 2 mg kg-1 day-1) or enalapril (2 or 20 mg kg-1 day-1) for three weeks starting one week after the ligation. 3. Systemic blood pressure was measured every week during the experiments. At the end of the treatments, cardiac function and heart weight (an index of myocardial hypertrophy) were determined. In the other animals, ACE activities in plasma and tissues including heart, kidney, lung and blood vessels were measured. 4. In the controls, cardiac ACE activity, weight of right ventricle and left ventricular end-diastolic pressure (LVEDP) were higher compared to those in the sham-operated animals four weeks after the coronary ligation. However, ACE activities were not changed in plasma, kidney, lung and aorta by ligation of the coronary artery. 5. The chronic treatment with perindopril at a dose of 0.2 mg kg-1 day-1 inhibited the increase in ACE activity in cardiac tissue and suppressed the right ventricular hypertrophy without affecting systemic haemodynamics. In contrast, enalapril at a dose of 20 mg kg-1 day-1, but not 2 mg kg-1 day-1, prevented the development of the right ventricular hypertrophy. Enalapril at 20 mg kg-1 day-1 also lowered systemic blood pressure. 6. There is no significant correlation between systemic blood pressure and right ventricular hypertrophy at the end of the treatment with perindopril (r = 0.06) or enalapril (r = 0.1).7. These findings demonstrate that perindopril, an ACE inhibitor, prevents cardiac hypertrophy without affecting systemic blood pressure in the rat with heart failure after coronary ligation, and suggest that selective augmentation of ACE activity in cardiac tissue is involved in the progression of hypertrophy in this model.