Role of the renin-angiotensin system in the development of congestive heart failure in the dog as assessed by chronic converting-enzyme blockade

Riegger, Günter A.J.; Liebau, G.; Holzschuh, M.; Witkowski, Dorothea; Steilner, H.; Kochsiek, K

doi:10.1016/0002-9149(84)90040-7

Cited by 91 publications

(48 citation statements)

References 28 publications

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“…The relation between baseline concentrations and mortality seen in the group of patients receiving placebo was absent in the patients receiving enalapril. Furthermore, the entire effect on mortality was observed among those patients who had concentrations above median shown experimentally by Riegger et al 25 Recently, it has been demonstrated by Tan et a14 that angiotensin II may induce direct myocardial toxicity.…”

Section: Mortality Versus Hormone Concentrationsmentioning

confidence: 81%

Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group.

et al. 1990

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There is a varying hormonal activation in heart failure. To be able to evaluate this activation and relate it to prognosis, we took blood samples at baseline and after 6 weeks from 239 patients with severe heart failure (all in New York Heart Association class IV) randomized to additional treatment with enalapril or placebo. In this study (CONSENSUS), which has previously been reported, there was a significant reduction in mortality among patients treated with enalapril. The present data show in the placebo group a significant positive relation between mortality and levels of angiotensin II (p<0.05), aldosterone (p=0.003), noradrenaline (p<0.001), adrenaline (p=0.001), and atrial natriuretic factor (p=0.003). A similar relation was not observed among the patients treated with enalapril. Significant reductions in mortality in the groups of patients treated with enalapril were consistently found among patients with baseline hormone levels above median values. There were significant reductions in hormone levels from baseline to 6 weeks in the group of patients treated with enalapril for all hormones except adrenaline. There were no correlations between these changes in hormone levels. Summarily, there is a pronounced but variable neurohormonal activation in heart failure even in patients with similar clinical findings. This activation is reduced by enalapril therapy. The results suggest that the effect of enalapril on mortality is related to hormonal activation in general and the renin-angiotensin system in particular. (Circulation 1990;82:1730-1736 T he long-term prognosis for patients with severe congestive heart failure has been very poor.1 In severe congestive heart failure, compensatory activation of neurohormonal mechanisms,2 the importance of which is unclear, takes place. The increased sympathetic activity may even induce myocardial deterioration in certain types of congestive heart failure.3 The neurohormonal activation may increase myocardial oxygen consumption by elevating heart rate and afterload and may also induce coronary vasoconstriction. A direct cardiotoxic effect of angiotensin II has also been recently

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Section: Mortality Versus Hormone Concentrationsmentioning

confidence: 81%

Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group.

et al. 1990

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“…A subsequent paper by Coleman et al (2), 9 yr later, established that rapid ventricular pacing in dogs was associated with marked abnormalities in left ventricular (LV)' systolic function. After a 15-yr dormancy, this model resurfaced (3)(4)(5). This resurrection was due in part to the burgeoning interest in molecular and biochemical alterations associated with heart failure, but also reflected the simplicity and consistency of this model in comparison to others.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

Urasawa¹,

Helmer²,

Hammond³

1993

J. Clin. Invest.

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The extent to which congestive heart failure (CHF) is dependent upon increased levels of the cardiac inhibitory GTP-binding protein (Gi), and the impact of CHF on the cardiac stimulatory GTP-binding protein (Gs) and mechanisms by which Gs may change remain unexplored. We have addressed these unsettled issues using pacing-induced CHF in pigs to examine physiological, biochemical, and molecular features of the right atrium (RA) and left ventricle (LV). CHF was associated with an 85±20% decrease in LV segment shortening (P < 0.001) and a 3.5-fold increase (P = 0.006) in the ED5, for isoproterenol-stimulated heart rate responsiveness. Myocardialfg-adrenergic receptor number was decreased 54% in RA (P = 0.004) and 57% in LV (P < 0.001), and multiple measures of adenylyl cyclase activity were depressed 49±8% in RA (P < 0.005), and 44±9% in LV (P < 0.001). Quantitative immunoblotting established that Gi and Gs were decreased in RA (Gi: 59% reduction; P < 0.0001; Gs: 28% reduction; P < 0.007) and LV (Gi: 35% reduction; P < 0.008; Gs: 28% reduction; P < 0.01 ) after onset of CHF. Reduced levels of Gi and Gs were confirmed by ADP ribosylation studies, and diminished function of Gs was established in reconstitution studies. Steady state levels for Gsa mRNA were increased in RA and unchanged in LV, and significantly more GSa was found in the supernatant (presumably cytosolic) fraction in RA and LV membrane homogenates after CHF, suggesting that increased Gs degradation, rather than decreased Gs synthesis, is the mechanism by which Gs is downregulated. We conclude that cardiac Gi content poorly predicts adrenergic responsiveness or contractile function, that decreased Gs is caused by increased degradation rather than decreased synthesis, and that alterations in fI-adrenergic receptors, adenylyl cyclase, and GTP-binding proteins are uniform in RA and LV in this model of congestive heart failure. (J. Clin. Invest. 1993. 91:939-949.)

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“…The systolic blood pressure was significantly decreased after 3 hr with 0.25, 0.5 and 1.0 mg/ kg s.i.d. When given twice a day, systolic blood pressure was significantly decreased after 3 and 15 hr at all doses.Activation of the renin angiotensin aldosterone system and sympathetic tone as compensatory mechanisms is observed in congestive heart failure [9,15]. Congestive heart failure resulting from chronic valvular disease, dilated cardiomyopathy, and hypertrophic cardiomyopathy in dogs is treated pharmacologically with vasodilating agents, such as hydralazine [17].…”

mentioning

confidence: 99%

“…The interval of each dose was taken at least 3 days. Blood for measuring plasma ACE activity was drawn from the jugular vein before administration at baseline and after administration at 3, 6, 12, and 24 hr in the once a day protocol, or at baseline and after administration at 3,6,12,15,18, and 24 hr in the twice a day protocol. Blood was immediately heparinized and centrifuged at 1,000 g, and the supernatant was kept at -80°C.…”

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confidence: 99%

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Dose-Dependent Inhibition of Angiotensin Converting Enzyme by Enalapril in Cats.

Uechi

Imamoto

Ishikawa

2002

The Journal of Veterinary Medical Science

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ABSTRACT. Although heart failure in cats is treated with angiotensin converting enzyme (ACE) inhibitors, data on the effects of different doses of enalapril on hemodynamics and the inhibition of ACE activity have not been published. To evaluate the effect of enalapril, 0.25, 0.5, or 1.0 mg/kg was given once (s.i.d., p.o.) or twice (b.i.d., p.o.) a day, and plasma ACE activity, indirect blood pressure, and heart rate were measured. Plasma ACE activity and blood pressure fell dose-dependently. There was a biphasic effect on blood pressure with twice daily administration. Enalapril 0.25 mg/kg b.i.d. inhibited plasma ACE activity by 40% after 24 hr, which was almost the same as the effect of 0.5 and 1.0 mg/kg s.i.d., and 0.5 and 1.0 mg/kg b.i.d., while 0.25 mg/kg s.i.d. inhibited it by 23%. Thus, enalapril with a daily dose exceeding 0.5 mg/kg may provide similar efficacy of ACE inhibition in cats. KEY WORDS: angiotensin converting enzyme, enalapril, feline.J. Vet. Med. Sci. 64(4): 385-387, 2002 Angiotensin converting enzyme (ACE) inhibitors have been used to treat mild to severe heart failure in humans and dogs [1, 4, 6-8, 14, 19]. In cats, there are several clinical reports of treating dilated and hypertrophic cardiomyopathy with ACE inhibitors [5,12,13,16]. Although the current recommended treatment for cardiac hypertrophy in cats is to use diltiazem first and then switch to a β blocker if the clinical response is not optimal [11], a plasma ACE inhibitor may also be useful for treating certain feline diseases, notably congestive heart failure, hypertension, and chronic renal disease. However, the depressor or ACE inhibitory effects of ACE inhibitors such as enalapril in cats have not been published. The objective of this study was to determine the dose response of enalapril on hemodynamics and plasma ACE activity. To evaluate the effect of enalapril, cats were given 0.25, 0.5, or 1.0 mg/kg once or twice daily, and the plasma ACE activity, indirect blood pressure, and heart rate were measured. This study followed the Guidelines for Institutional Laboratory Animal Care and Use of the School of Veterinary Medicine and Animal Science at Kitasato University.This study used 8 clinically healthy cats (4 males, 4 females), weighing 3.5-5.3 kg, for which routine laboratory tests, including hematological examinations and urinalysis, were normal. The cats were housed in cages and fed with commercial cat food twice a day (Hill's Colgate, Tokyo, Japan) at 10:00 and 22:00. Water was given ad libitum. Placebo or enalapril (0.25, 0.5, or 1.0 mg/kg, Enacard ® , Merial Japan, Tokyo, Japan) was orally administered once a day at 10:00 or twice a day at 10:00 and 22:00. The interval of each dose was taken at least 3 days. Blood for measuring plasma ACE activity was drawn from the jugular vein before administration at baseline and after administration at 3, 6, 12, and 24 hr in the once a day protocol, or at baseline and after administration at 3, 6, 12, 15, 18, and 24 hr in the twice a day protocol. Blood was immediately heparinize...

show abstract

Role of the renin-angiotensin system in the development of congestive heart failure in the dog as assessed by chronic converting-enzyme blockade

Cited by 91 publications

References 28 publications

Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group.

Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group.

Downregulation of cardiac guanosine 5'-triphosphate-binding proteins in right atrium and left ventricle in pacing-induced congestive heart failure.

Dose-Dependent Inhibition of Angiotensin Converting Enzyme by Enalapril in Cats.

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