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Angiotensin-converting enzyme inhibitors promise to make important therapeutic contributions to the control of hypertension and congestive heart failure. The nonapeptide teprotide was the first of these inhibitors to be tested clinically. It was followed by orally active inhibitors, captopril in 1977 and enalapril in 1980. The latter is representative of a new design for the inhibition of metallopeptidases and is the subject of this review. The best of the N-carboxyalkyldipeptide inhibitors inhibits angiotensin-converting enzyme with a Ki of 7.6 X 10(-11) M. This compound is the most potent competitive inhibitor of a metallopeptidase yet to have been reported. The basis of this high potency is beginning to be understood and in part is considered to involve precisely arranged multiple interactions within the enzyme active site. X-ray crystallography of a thermolysin-inhibitor complex has been achieved. Assuming that similar interactions within the active site of angiotensin-converting enzyme are mechanistically probable, the authors hypothesize the binding of enalaprilat to converting enzyme as shown in Figure 24. Such interactions are consistent with kinetic studies (Section V) with the understanding that binding to the enzyme is not sensitive to the inhibitor's state of NH protonation. The reason for this surprising conclusion has not been established. Perhaps counterbalancing factors are involved in the energetics of binding or there may be compensating adjustments made in the enzyme which permit NH protonated and nonprotonated inhibitor to bind equally well. Figure 24 also summarizes present understanding of the conformation of enalaprilat when bound to angiotensin-converting enzyme. From studies on conformationally defined analogs of enalaprilat, it seems likely that the Ala-Pro segment of enalaprilat binds in a conformation that is close to a minimum energy conformer. This situation no doubt contributes to the potency of enalaprilat, since little binding energy would be needed to induce conformational changes in this part-structure of enalaprilat when it is bound to the enzyme. The phenethyl group of enalaprilat is believed to be near the alpha-hydrogen of the L-Ala residue in the enzyme-inhibitor complex. However, the synthesis of conformationally restricted analogs to establish this point has not yet been reached. The N-carboxyalkylpeptide design was developed from Wolfenden's collected product inhibitors of carboxypeptidase-A. Whether or not N-carboxyalkyldipeptides should be classified as collected product or transition state inhibitors is unclear.(ABSTRACT TRUNCATED AT 400 WORDS)
Adv Enzymol Relat Areas Mol Biol 1985
PMID:The design and properties of N-carboxyalkyldipeptide inhibitors of angiotensin-converting enzyme. 299 4

Some biochemical and pharmacological properties of a novel, potent inhibitor of cyclic AMP phosphodiesterase, N-cyclohexyl-N-methyl-4-(7-oxy-1,2,3,5-tetrahydroimidazo[2,1-b] quinazolin-2-one) butyramide (RS-82856), were investigated. RS-82856 selectively inhibits the high affinity form of cyclic AMP phosphodiesterase (type IV) isolated from human platelets (Ki = 0.5 nM) with only weak effects on both the nonspecific and cyclic GMP-sensitive phosphodiesterases. The inhibitor reduces both maximum velocity and substrate affinity of the type IV enzyme. This mixed pattern of partial competitive and noncompetitive inhibition was also obtained with one of the two high affinity forms of phosphodiesterase found in dog heart (Ki = 0.75 nM). Of several human and dog tissues examined, RS-82856 exhibits marked selectively for the platelet high affinity enzyme. It also has significant inhibitory effects on cardiac membrane-bound phosphodiesterase. RS-82856 inhibits the aggregation of human platelets in response to adenosine 5'-diphosphate (IC50 = 0.11 microM) in vitro and is active ex vivo for at least 2 hr following oral administration (10 mg/kg) to rhesus monkeys. Administration of RS-82856 to instrumented, anesthetized dogs by either intravenous or intraduodenal routes increases cardiac contractile force and reduces afterload. These data suggest that RS-82856 may be useful as an agent to increase cardiac output in the treatment of congestive heart failure.
Mol Pharmacol 1986 Jun
PMID:A potent and selective inhibitor of cyclic AMP phosphodiesterase with potential cardiotonic and antithrombotic properties. 301 20

The hamster hereditary cardiomyopathy provides a unique model for the study of membrane abnormalities during chronic congestive heart failure. It is associated with intracellular calcium accumulation, mitochondrial calcification and cell necrosis. Previous studies have shown a decrease in Na,K-ATPase activity purified from ventricle sarcolemma. The present study demonstrates a decrease in K-dependent 3-O-methylfluorescein phosphatase (3-O-MFPase) activity from 1.93 to 1.30 mumol/g wet wt. or 33% in crude homogenates from the left ventricle of 7-months-old cardiomyopathic hamsters as compared to control animals. This represents an equivalent decrease in Na, K-ATPase activity. The values are several times higher than previously published for membrane fractions of myocardium from the hamster. Concomitantly, there was an increase in intracellular Na-concentration of the myocardium of 42% whereas the K-concentration was unchanged. The decrease in Na,K-pump concentration may be of importance for the increase in intracellular sodium and ensuing calcifying necrosis observed in the myocardium of cardiomyopathic hamsters. It is emphasized that quantification of the Na,K-ATPase or Na,K-pump should preferably be performed using crude homogenates.
J Mol Cell Cardiol 1987 Jun
PMID:Heart Na,K-ATPase activity in cardiomyopathic hamsters as estimated from K-dependent 3-O-MFPase activity in crude homogenates. 304 Oct 9

Functional states of cardiac contractile apparatus and mitochondria were studied in hereditary cardiomyopathic hamsters (CHF 146) and control golden hamsters using cardiac fibers skinned by two different techniques. The Triton X-100 skinned fibers obtained from diseased animals of 175 to 200 days old, or from control animals, demonstrated the same resting and maximal Ca-activated tensions, the same stiffness, the same rate of tension recovery after quick stretch; the fibers from cardiomyopathic animals differed only by a slightly increased calcium sensitivity. Functional activity of myofibrillar creatine kinase in cardiomyopathy was decreased as indicated by a smaller shift in the pMgATP/rigor tension curve to lower [MgATP] in the presence of phosphocreatine and by a slower rate of the tension recovery after quick stretch in the presence of phosphocreatine and ADP (without ATP). The saponin-skinned fibers allow evaluation of the respiration properties of the total tissue mitochondria. Data obtained in the preparations isolated from diseased animals of two ages (75 to 100 and 175 to 200 days) showed that the ratio of maximal ADP-stimulated respiration rate to the respiration rate in the absence of ADP (an analog of respiration control index) was unchanged in myopathy as compared with age-matched controls. However stimulation of respiration after an addition of creatine at submaximal ADP concentration was observed to be respectively 1.45 times and 3.5 times less in the preparations from younger and older myopathic animals as compared with their respective controls, thus indicating the impairment of functional coupling between mitochondrial creatine kinase reaction and oxidative phosphorylation. These results suggest that hereditary cardiomyopathy is associated with alterations in myocardial creatine kinase system, while myofilaments and mitochondria preserve their basic functional properties.
J Mol Cell Cardiol 1988 Apr
PMID:Functional state of myofibrils, mitochondria and bound creatine kinase in skinned ventricular fibers of cardiomyopathic hamsters. 326 69

The effect of therapeutic doses of digitalis in modifying neural activity has been the subject of considerable controversy. In earlier studies we reported an increase both in serotonergic activity in the posterior hypothalamus and pons-medulla and in cardiac sympathetic tone in the failing cardiomyopathic hamster. In this study we examine the effects of doses of digitoxin, known to be therapeutic for hamster heart failure, on monoamine neurotransmitter metabolism in the brain and heart during the cardiomyopathy. Both digitoxin and ASI-222, a polar amino-glycoside which does not cross the blood-brain barrier, given either acutely (6 mg/kg ip) or chronically (2 mg/kg/day ip for 10 days), normalized the failure-induced increase in serotonin turnover in the pons-medulla but had no effect on the changes in the posterior hypothalamus. Digitoxin therapy also reduced cardiac and adrenal sympathetic activity partially restoring cardiac catecholamine stores. In order to more clearly define the pathways involved we measured serotonin (microgram/g protein) in 18 brain nuclei after 10 days of digitoxin or vehicle treatment. Heart failure was associated with an increase in serotonin in five nuclei: the mammillary; bodies, ventromedial, periventricular and paraventricular nuclei of the hypothalamus, and the centralis superior nucleus of the raphe. Digitoxin therapy completely normalized the changes in the centralis superior and ventromedialis nuclei; neither congestive heart failure nor digitoxin affected serotonin levels in other nuclei. We conclude that there is an increase in activity in specific brain serotonergic nuclei in congestive heart failure. Digitalis reduces cardiac sympathetic tone and restores the changes in two of these nuclei: the ventromedial and the centralis superior.+2
J Mol Cell Cardiol 1985 Nov
PMID:Digitoxin therapy partially restores cardiac catecholamine and brain serotonin metabolism in congestive heart failure. 407 5

Control ( F1B ) and cardiomyopathic (Bio 14.6) hamsters have been studied over an 11 month time interval, in an attempt to relate alterations in liver function with the onset of progressive heart damage. In most instances the parameters measured (e.g., liver weight, liver polysome content, in vitro polysome driven protein synthesis) were similar for both groups of animals. The exceptions appeared to be two Bio 14.6 animals that had liver hypertrophy, coupled with severe necrosis and liver damage. These livers had very low levels of virtually inactive polysomes and depicted many of the histopathological characteristics of hepatic ischemic injury known in humans to be associated with congestive heart failure. Our biochemical and histological data suggests that for the Bio 14.6 hamsters, progressive cardiomyopathy is associated with severe liver damage for only a few animals.
Virchows Arch B Cell Pathol Incl Mol Pathol 1984
PMID:Changes in hamster liver albumin synthesis during the development of cardiomyopathy. 614 43

Volume overload congestive heart failure in dogs is associated with a reduced myocardial inotropic responsiveness to the exogenous administration of beta-adrenergic agonists [10, 11]. This same blunted inotropic responsiveness to beta-agonists has now been identified in the failing human myocardium [2]. Volume overload congestive heart failure in dogs is also associated with a reduced resting coronary vascular resistance [7, 12] suggesting the possibility of increased myocardial production of a metabolic vasodilator in the failing heart. Adenosine is a metabolic coronary vasodilator [1] and also has recently been shown to antagonize the inotropic action of beta-adrenergic agonists through a mechanism involving action on the sarcolemmal adenylate cyclase system [4, 13]. Given the findings of blunted inotropic responsiveness of the failing myocardium to beta-adrenergic agonists and reduced coronary vascular resistance in heart failure, we hypothesized that heart failure was associated with elevated myocardial production of adenosine. Accordingly we measured myocardial adenosine release in normal dogs and dogs with volume overload heart failure. Basal levels of myocardial adenosine release were found to be elevated three-fold above normal in dogs with heart failure. It is possible that elevated adenosine release in the failing myocardium contributes both to abnormalities of coronary blood flow and to the blunted inotropic responsiveness of the failing heart to catecholamines.
J Mol Cell Cardiol 1984 Jun
PMID:Increased myocardial adenosine release in heart failure. 674 93

The Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue. Variable and pleiotropic clinical features are observed in the skeletal, ocular, and cardiovascular systems. The most severe end of the phenotypic spectrum of this disorder comprises a group of patients usually diagnosed at birth, who have a life expectancy of little more than a year. To distinguish this group of patients from those with classical MFS, we refer to them as neonatal Marfan syndrome (nMFS). These infants usually die of congestive heart failure rather than aortic aneurysmal disease, the most frequent cause of morbidity and mortality in classical MFS. Defects in fibrillin, an elastin-associated microfibrillar glycoprotein, are now known to cause both the classical and neonatal forms of MFS. Here we report the recurrent mis-splicing of fibrillin (FBN1) exon 32, a precursor EGF-like calcium binding domain, in two unrelated infants with nMFS. The mis-splicing, in one patient, was due to an A-->T transversion at the -2 position of the consensus acceptor splice site; while that in the second patient was caused by a G-->A transition at the +1 position of the donor splice site. Characterization of FBN1 mutations in individuals at the most severe end of the Marfan syndrome spectrum should provide greater understanding of the multiple domains and regions of fibrillin.
Hum Mol Genet 1995 Apr
PMID:Recurrent mis-splicing of fibrillin exon 32 in two patients with neonatal Marfan syndrome. 763 9

Digitalis, diuretics and vasodilators are considered the standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of Coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2664 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing study in 173 Italian centers. The daily dosage of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two-to seven-point scales. The results show a low incidence of side effects: 38 adverse effects were reported in 36 patients (1.5%) of which 22 events were considered as correlated to the test treatment. After three months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 78.1%, oedema 78.6%, pulmonary rales 77.8%, enlargement of liver area 49.3%, jugular reflux 71.81%, dyspnoea 52.7%, palpitations 75.4%, sweating 79.8%, subjective arrhytmia 63.4%, insomnia 662.8%, vertigo 73.1% and nocturia 53.6%. Moreover we observed a contemporary improvement of at least three symptoms in 54% of patients; this could be interpreted as an index of improved quality of life.
Mol Aspects Med 1994
PMID:Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators. 775 41

The present investigation was designed to evaluate whether end-stage cardiac failure in patients affected by dilated cardiomyopathy (DC) was dependent upon extensive myocyte cell death with reduction in muscle mass or was the consequence of collagen accumulation in the myocardium independently from myocyte cell loss. In addition, the mechanisms of ventricular dilation were analysed in order to determine whether the changes in cardiac anatomy were important variables in the development of intractable congestive heart failure. DC is characterized by chamber dilation, myocardial scarring and myocyte hypertrophy in the absence of significant coronary atherosclerosis. However, the relative contribution of each of these factors to the remodeling of the ventricle is currently unknown. Moreover, no information is available concerning the potential etiology of collagen deposition in the myocardium and the changes in number and size of ventricular myocytes with this disease. Morphometric methodologies were applied to the analysis of 10 DC hearts obtained from patients undergoing cardiac transplantation. An identical number of control hearts was collected from individuals who died from causes other than cardiovascular diseases. DC produced a 2.2-fold and 4.2-fold increase in left ventricular weight and chamber volume resulting in a 48% reduction in mass-to-volume ratio. In the right ventricle, tissue weight and chamber size were both nearly doubled. Left ventricular dilation was the result of a 59% lengthening of myocytes and a 20% increase in the transverse circumference due to slippage of myocytes within the wall. Myocardial scarring represented by segmental, replacement and interstitial fibrosis occupied approximately 20% of each ventricle, and was indicative of extensive myocyte cell loss. However, myocyte number was not reduced and average cell volume increased 2-fold in both ventricles. In conclusion, reactive growth processes in myocytes and architectural rearrangement of the muscle compartment of the myocardium appear to be the major determinants of ventricular remodeling and the occurrence of cardiac failure in DC.
J Mol Cell Cardiol 1995 Jan
PMID:The cellular basis of dilated cardiomyopathy in humans. 776 Mar 53


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