Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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The effects of neutral endopeptidase inhibition (NEP-I) were studied in 6 conscious sheep with heart failure (HF) induced by rapid ventricular pacing for 7 days. Measurements were performed 1 h before and for 6 h after intravenous (i.v.) bolus administration of vehicle and SCH 39370 (1.25 and 5 mg/kg) on separate days. After the higher dose, an index of serum NEP activity decreased from 0.83 +/- 0.05 to 0.13 +/- 0.07 nmol/ml/min (p less than 0.001) at 1 h and then returned to control levels at 6 h. Plasma atrial natriuretic peptide (ANP) and cyclic GMP rose from 328 +/- 28 and 20.2 +/- 4.3 to a peak of 570 +/- 65 pmol/L (p less than 0.001) and 28.7 +/- 6.3 nmol/L (p less than 0.05) respectively. Natriuresis and diuresis were significant and left atrial pressure (LAP) decreased from 21.9 +/- 1.1 to 20.1 +/- 0.8 mm Hg (p less than 0.05). Despite high endogenous ANP levels in HF, NEP-I further increases both ANP and its "second messenger." Its natriuretic and hemodynamic effects are consistent with enhanced ANP activity in renal and vascular tissues, suggesting that NEP-I may be useful for treating HF.
J Cardiovasc Pharmacol 1992 Apr
PMID:Acute hemodynamic, hormonal, and renal effects of neutral endopeptidase inhibition in ovine heart failure. 138 Jun 8

Cellular and mitochondrial swelling are regarded as typical intra-ischemic alterations ("IIA"), contraction band lesions (CBL), in contrast, as products of post-ischemic reperfusion. The occurrence of both types of structural deterioration was investigated in Purkinje fibres and subendocardial and intramural working myocardium: initially after St. Thomas- or HTK cardioplegia, then during ensuing global ischemia up to the "practical limit of resuscitability", and following post-ischemic reperfusion. Generally, Purkinje fibres are not better preserved than neighbouring working myocardium. Comparing St. Thomas- and HTK cardioplegia, considerable quantitative, but not qualitative differences in the reaction patterns of different cell types or layers arise. Immediately after cardioplegia, CBL are completely lacking in both cell types. During ischemia, CBL occur occasionally in Purkinje fibres and seldom in subendocardial working myocardium, "IIA" predominate. During post-ischemic reperfusion "IIA" tend to reverse in all layers, whereas CBL are found to remain in the subendocardial cell types. In intramural layers, CBL occur only during reperfusion. Thus, we deduce that cardioplegia only modulates the severity of "IIA" and the frequency of CBL, but cannot abolish the particular sensitivity of subendocardial Purkinje fibres to global ischemia. Prerequisites for the development of irreversible CBL are on the one hand ischemic metabolic alterations and corresponding energy deficits, and, on the other hand, a supply of oxygen. The oxygen may be inadequately supplied via diffusion during ischemia or may be subsequently provided by reperfusion.
Thorac Cardiovasc Surg 1991 Aug
PMID:Patterns of structural deterioration due to ischemia in Purkinje fibres and different layers of the working myocardium. 194 65

Cardiovascular disease in all its clinical manifestations progresses significantly as age advances and takes its heaviest toll in the elderly. Hypertension becomes the dominant risk factor for cardiovascular disease in this age group because of its high incidence. Traditionally, diastolic rather than systolic blood pressure has been regarded as the main risk factor for cardiovascular complications in hypertension, although it is becoming clearer that the risk of cardiovascular complications is likely to be associated mainly with systolic pressure in the elderly. Various intervention drug trials in elderly patients seem to indicate that hypotensive drug treatment can decrease cardiovascular mortality, mainly by decreasing cerebrovascular mortality. The EWPHE used a diuretic combination with methyldopa, and the HEP study used atenolol with a thiazide diuretic. The multicenter Systolic Hypertension in the Elderly Program (SHEPS) currently underway in the United States is likely to also provide some answers. The place of newer agents such as ACE inhibitors or calcium antagonists is still undetermined. Calcium antagonist drugs have been reported to be effective, and possibly more so in the elderly than in a younger population, although this assumption is not proven and may not be valid. Pharmacokinetic studies in the elderly are very few, although the studies reported indicate a reduced clearance. Studies also indicate that Nifedipine Retard tablets are effective, with a low incidence of adverse effects. There are no trials, however, looking at the long-term benefit of treating elderly hypertensive patients with either nifedipine tablets or other calcium-channel blockers.
Cardiovasc Drugs Ther 1990 Aug
PMID:Hypertension in the elderly. 207 5

Intracellular pH (pHi) has been measured in human or cat ventricular muscle during 60, 120 and 180 minutes of cardiac arrest by Bretschneider's cardioplegic solution HTK or St. Thomas solution with and without procaine. In 319 control measurements in modified Tyrode's solution pHi (mean, S.D.) was 7.38 +/- 0.02 (n = 128) during the first hour, 7.36 +/- 0.03 (n = 112) during the second hour and 7.35 +/- 0.03 (n = 79) in the third hour. The pHi in right ventricular muscle of the cat and left ventricular human muscle did not differ significantly during the time of measurements (Bretschneider HTK). The values (human/cat) in the first hour were 6.85 +/- 0.03 for both groups, 6.72 +/- 0.04/6.68 +/- 0.04 during the second hour and 6.70 +/- 0.03/6.67 +/- 0.05 in the third hour of measurement. The values for the St. Thomas solution with/without procaine were 6.83 +/- 0.02/6.74 +/- 0.03 in the first hour, 6.79 +/- 0.02/6.82 +/- 0.04 during the second hour and 6.68 +/- 0.03/6.82 +/- 0.02 in the third hour. An important difference to all other solutions was the observation made under the St. Thomas solution with procaine, that after recovery to normal values pHi decreased between the 2.-5. minute to values of 6.39-6.48 when the preparations were superfused with Tyrode's solution again. No recovery within 1 hour was observed. This fall in pHi was accompanied by a contracture.
Thorac Cardiovasc Surg 1987 Feb
PMID:Intracellular pH measurement during cardiac arrest in ventricular myocardium by Bretschneider's cardioplegic solution HTK and St. Thomas Hospital solution with and without procaine. 243 44

Clinically applied methods of cardioplegia show very different effects on the rapidity of decay of energy-rich phosphates as well as on kind and progression of ultrastructural alterations of the ischemic myocardium. Comparing the methods of cardioplegia according to Kirklin, St. Thomas's Hospital and Bretschneider (solution HTK) with pure ischemia at 25 degrees C (model A) and Kirklin's or St. Thomas's cardioplegia and subsequent 210 min or HTK cardioplegia and 300 min ischemia at 22 degrees C plus 20 min subsequent reperfusion (model B) leads to the following results: Model A: Compared with pure ischemia cardioplegia according to Kirklin and the St. Thomas's Hospital slows down the decay of the left ventricular ATP-concentration by a mean factor of 3 and the progression of structural alterations of the left ventricular subendocardium by a factor of 2. HTK retards the ATP-decay by a factor of 6, the alterations of ultrastructure by a factor of 6.5. St. Thomas's solution, in contrast to all other methods of cardioplegia, at the onset of ischemia already causes a cellular edema of myocytes; the edema increases during ischemia, and at the ATP-concentration of 4 mumol per gram myocardium is more pronounced than with pure ischemia, Kirklin or HTK. After application of Kirklin's solution, in contrast, a cellular edema of capillary endothelia develops during ischemia, which at 4 mumol ATP is more pronounced than with each of the other methods. Model B: After global ischemia until the ATP-concentration of left ventricular myocardium is 4 mumol/g and a subsequent 20 minutes post-ischemic recovery the ultrastructural alterations in principle resemble those occurring during ischemia (model A).(ABSTRACT TRUNCATED AT 250 WORDS)
Thorac Cardiovasc Surg 1987 Jun
PMID:Myocardial protection: left ventricular ultrastructure after different forms of cardiac arrest. 244 33

To evaluate the hypothesis of alpha-antagonism as a contributing factor to the vascular action of calcium entry blockade (CEB) in man, we have compared the action of verapamil, a CEB, on nonselective (norepinephrine, NE) and selective alpha 1-(methoxamine, MET) and alpha 2-(B-HT 933, BHT) adrenergic agonists in human forearm vasculature. All drugs were infused into the brachial artery at systemically ineffective rates. Blood pressure and heart rate were continuously monitored; forearm blood flow was measured through strain gauge plethysmography. Sixteen mild, untreated hypertensive patients were studied. Cumulative forearm blood flow dose-response curves to three cumulative infusion rates (3 min each) of NE (0.015, 0.05, 0.15 micrograms/100 ml tissue/min), MET (0.06, 0.6, 6 micrograms/100 ml tissue), and BHT (3, 10, 30 micrograms/100 ml tissue/min) were obtained during saline and after verapamil (0.9 micrograms/100 ml tissue/min X 15 min) infusion. Verapamil did not modify to any significant extent NE-mediated vasoconstriction, but clearly blunted the vascular action of either MET or BHT. Because NE is the physiological neurotransmitter, the data cast doubts about the relevance of alpha-antagonism as a mechanism of action of calcium entry blockade through verapamil. Besides, the data caution against generalizing by using data obtained through several compounds, including CEBs, of alpha-adrenergic stimuli.
J Cardiovasc Pharmacol 1987
PMID:Verapamil and alpha-mediated vasoconstriction in human forearm: a comparison between norepinephrine and selective alpha 1- and alpha 2-adrenergic agonists. 245 39

Several processes participate in the clearance of atrial natriuretic peptide (ANP) from the circulation, one of which is enzymatic degradation. Endoprotease EC 3.4.24.11 (NEP 24.11), present within the kidney in high concentration, has been shown in vitro to degrade ANP. Phosphoramidon and thiorphan, two potent NEP 24.11 inhibitors, have been shown to prevent the enzymatic degradation of ANP. The purpose of the present study was to determine if phosphoramidon or thiorphan would alter the in vivo time course of the pharmacologic effects of ANP. The magnitude and duration of the ANP-induced increase in urine output and sodium and cyclic GMP excretion were examined with and without either thiorphan or phosphoramidon. Six separate groups of anesthetized rats received either a low, medium, or high infusion rate of thiorphan or phosphoramidon. Renal responses to ANP were potentiated and prolonged during the low phosphoramidon infusion (3 Ki) and the medium thiorphan infusion (150 Ki). At high inhibitor infusion rates in the anesthetized rat, ANP elicited a marked depressor response. In the conscious spontaneously hypertensive rat (SHR), a 15-min intravenous (i.v.) infusion of ANP (1 microgram/kg/min) lowered mean arterial pressure (MAP 23 +/- 6 mm Hg), with an approximately 35-min duration of action. A simultaneous i.v. infusion of phosphoramidon (high dose) produced both a potentiation (33 +/- 3 mm Hg) and a prolongation (greater than 65 min to return to baseline) of the depressor response. These data lend support to the hypothesis that enzymatic breakdown of ANP may play an important role in regulating the actions of atrial natriuretic peptide.
J Cardiovasc Pharmacol 1989 Aug
PMID:Degradation of atrial natriuretic peptide: pharmacologic effects of protease EC 24.11 inhibition. 247 3

Accurate use and interpretation of exercise test results depend on an understanding of physiologic principles, meticulous attention to proper methodology, and realization of the appropriate applications and limitations of testing. Understanding the relationship between myocardial and ventilatory oxygen consumption and exercise test variables will aid in the diagnosis and prognostic evaluation. Use of proper methodology in preparing the patient, performing the examination, and interpreting the results is critical to obtaining the maximum information with maximum safety for each individual patient. Improvements in methodology including the use of the Borg scale to estimate individual effort, abandonment of the predicted maximum heart rate, and the increased use of ventilatory oxygen uptake measurements should be applied. Exercise capacity should not be reported in total time but rather as the VO2 or MET equivalent of the workload achieved. This permits the comparison of the results of many different exercise testing protocols. The most useful exercise ECG variable for the diagnosis of coronary artery disease remains the ST segment shift. Unfortunately, it is not as helpful in localizing myocardial ischemia. Diagnostic accuracy can be improved by adjusting ST depressions for exercise-induced heart rate increase. Accuracy can be further increased by combining ECG, clinical, and radionuclide variables in probabilistic formulas that retain the independent diagnostic information from each variable and accurately predict disease probability. To avoid errors in clinical decision making, care must be used to insure that the mathematical formula used was derived from a population of patients that is similar to those being tested. The clinical applications for exercise testing include diagnosis of patients with chest pain syndromes, determination of disease severity, and prognosis in patients with known coronary artery disease, evaluation of arrhythmias, screening of asymptomatic patients, and evaluation of medical, surgical, and angioplastic therapy for coronary disease. In spite of studies involving thousands of patients, controversy exists regarding the diagnostic power of exercise testing. The large differences in reported accuracies are largely due to methodologic problems that have been encountered by various investigators. Clinicians should be made aware of these problems when reading the literature on ECG and radionuclide exercise testing. Such awareness will help them understand the limitations of these noninvasive procedures.(ABSTRACT TRUNCATED AT 400 WORDS)
Prog Cardiovasc Dis
PMID:Exercise testing: uses and limitations considering recent studies. 305 66

A prospective consecutive study was undertaken to compare the hemodynamic effect of two cardioplegic solutions in CABG patients after bypass, and in relation to aorta occlusion time with the support of a automatic datalogging database. A total of 249 patients were randomized. One group received Bretschneider cardioplegic HTK solution (132 patients, group I) the other group received St. Thomas cardioplegic solution (117 patients, group II). The data was divided in four periods of aortic clamp time: less than or equal to 40 min (group I 26 patients, group II 32 patients); 41-60 min (group I 49 patients, group II 47 patients); 61-80 min (group I 30 patients, group II 29 patients); and greater than 80 minutes (group I 27 pts, group II 9 patients). Anesthesia regime and therapeutic drugs and infusions were given in both groups in similar dosages. Within both groups HR, CO, PAP, PCWP increased after bypass in relation to prebypass values. SVR decreased in both groups by 30%, MAP and PVR decreased only in group I. Between group I and II differences were found in the CI (3.0 vs. 3.3 l/min/m2), MAP (70 vs. 76 mmHg), PMAR (18 vs. 16 mHg), and SVR (827 vs. 954 dyn.sec.cm-5). In significantly more of the patients in group I, sinus rhythm started spontaneously after the release of the aorta clamp (39.5% vs. 20.4%, p less than 0.005). Patients in group I needed temporarily a pacemaker after bypass in 6.3% cases (in 1.1% of patients in group II,). There was no relation of the hemodynamic data in relation to aorta occlusion time within the groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Thorac Cardiovasc Surg 1988 Jun
PMID:Clinical effect of Bretschneider-HTK and St. Thomas cardioplegia on hemodynamic performance after bypass measured using an automatic datalogging database system. 314 85

Although exact definitions of exercise requirements for primary and secondary prevention of coronary disease cannot be stated with certainty on the basis of currently available information, we can make some general conclusions. The characteristics associated with lowered risk from coronary disease in apparently normal populations are: 8 MET-hours of activity during leisure time or job: walking briskly during leisure time (1 hour = 1 MET-hour) walking at job (same as above) jogging during leisure time (30 minutes of activity = 1 MET-hour) walking to and from work (same as walking above) performing very heavy work in occupational pursuits (few jobs today have those energy requirements) regularly climbing 5 flights or more of stairs (10 steps per flight) regularly walking 5 city blocks per day (12 blocks per mile) regularly engaging in strenuous sports (basketball, running, mountaineering, skiing, swimming, or tennis) accumulating activities that use 2000 or more kcal per week Conclusions concerning the prevention of reinfarction in patients who are recovering from a first heart attack include: Exercise is helpful in hastening the recovery process after myocardial infarction and should be started early in the recovery period. Exercise helps to reduce mortality when used in conjunction with a multifactorial program.
Cardiovasc Clin 1985
PMID:The role of exercise in the primary and secondary prevention of atherosclerotic coronary artery disease. 391 44


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