Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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1. Beta-Recptor-blocking drugs are rapidly and completely absorbed after oral administration. Systemic availability is nevertheless incomplete for propranolol, alprenolol and oxprenolol, owing to "first-pass' extraction by the liver. 2. Plasma half-life is between 2 and 4 h, except for sotalol (10-12 h). Plasma elimination of propranolol is reduced with decreased liver blood flow observed in congestive heart failure or during chronic propranolol therapy itself. 3. beta-Receptor blockade is usually achieved in these concentration ranges: propranolol and alprenolol, 50-100 ng/ml; oxprenolol, 500-1000 ng/ml; pindolol, 10-30 ng/ml; sotalol, 2-6 microng/ml. Higher concentrations are often found with high doses administered to hypertensive patients.
Clin Sci Mol Med Suppl 1976 Dec
PMID:Pharmacokinetics of beta-receptor-blocking agents in relation to their anti-hypertensive effect. 1 58

1. The kinetics of plasma noradrenaline have been determined in normal and essential hypertensive patients by intravenous injection of tritiated noradrenaline and serial mixed venous sampling. 2. The metabolic clearance rate of plasma noradrenaline in normal subjects was approximately 1 1 min-1 m-2, whereas in essential hypertensive patients it was significantly reduced to approximately 0.6 1 min-1 m-2. 3. Metabolic clearance rate was negatively correlated to mean arterial blood pressure and total peripheral resistances. 4. Particularly low values of metabolic clearance rate were found in two patients with congestive heart failure and one with phaeochromocytoma. 5. We propose that the access of plasma noradrenaline to the main removal mechanisms takes place in competition with the flow of unlabelled endogenous noradrenaline directly released by nerve endings. The slower removal of plasma noradrenaline in essential hypertension could then express a larger release of endogenous noradrenaline in this condition.
Clin Sci Mol Med Suppl 1978 Dec
PMID:The kinetics of plasma noradrenaline in normal and hypertensive subjects. 28 6

1. We investigated the haemodynamic effects of intravenously administered hydrallazine, diazoxide and nitroprusside and orally administered minoxidil to determine whether vasodilators (such as nitroprusside) which do not increase cardiac output might be better treatment for hypertensive complications associated with, or caused by, myocardial failure than those that do. 2. Hydrallazine and diazoxide caused increases in heart rate, cardiac output, cardiopulmonary blood volume, the ratio of cardiac output to cardiopulmonary volume, and pulmonary artery pressure. Nitroprusside, although decreasing pressure and vascular resistance, caused no significant change in the other functions except for reducing pulmonary artery pressure. Minoxidil, when given orally, had the potential for causing pulmonary hypertension. This seemed explained by increased flow (hyperdynamic type) in some but by congestive cardiac failure in others; the latter condition was probably intensified by the marked fluid retention that the drug can cause. 3. On the basis of these results a classification of vasodilators was constructed which depends on the presence or absence of a venodilating effect. Vasodilators which produce no (or little) venodilatation, increase heart rate, cardiac output, cardiopulmonary blood volume and pulmonary artery pressure. In this class are diazoxide, hydrallazine and minoxidil. Those that cause venodilatation do not stimulate the heart nor do they cause pulmonary hypertension. Nitroprusside and nitroglycerine are drugs of this type. 4. These results suggest that drugs producing both venodilatation and arteriolar dilatation may be more specific therapy for hypertensive complications associated with cardiac failure than those that cause only arteriolar dilatation.
Clin Sci Mol Med Suppl 1976 Dec
PMID:Vasodilating drugs: contrasting haemodynamic effects. 107 83

1. The chronic administration of minoxidil, 0-024-0-212 mmol (5-40 mg) daily, to fifty-two severely hypertensive patients resulted in an average reduction of mean arterial pressure from 170 to 111 mmHg. 2. Haemodynamic studies in twelve of these patients indicated that the rise in pulmonary arterial pressure in patients without heart failure appears to be a direct result of a disproportionately large increase in cardiac output with respect to a relatively small decrease in pulmonary vascular resistance. Anti-hypertensive treatment of patients with congestive heart failure resulted in a decrease in mean pulmonary arterial pressure.
Clin Sci Mol Med Suppl 1976 Dec
PMID:Treatment of severe hypertension with minoxidil and its effects on systemic and pulmonary haemodynamics. 107 85

1. Body weight was measured through forty consecutive illnesses in seventeen patients with oedema in association with chronic bronchitis and hypoxia. All patients were taking diuretic drugs at the time. 2. Body weight increased little as peripheral oedema and a raised jugular venous pressure appeared. The subsequent weight-loss during treatment was usually greater than the pre-treatment weight-gain. Body weight increased slowly in convalescence to equal or exceed hospital admission weight without a deterioration of general health or reappearance of oedema. 3. Total body water, exchangeable sodium and exchangeable potassium were measured in patients after treatment of the acute illness and clearance of oedema and again in six patients of the group 2-3 months later in convalescence. Total exchangeable sodium was normal or slightly reduced after treatment of oedema and in convalescence between recurrent acute illnesses. Even when gross oedema was present exchangeable sodium was substantially increased in only one of three patients studied at this stage. Total exchangeable potassium was invariably severely depressed. 4. Large changes of body tissue weight without comparable change in exchangeable sodium support previous evidence that oedema in hypoxic bronchitis is not simply a further form of congestive cardiac failure. 5. It is suggested that at least some of the tissue loss in acute exacerbations is a direct result of hypoxaemia and similar to that observed at high altitude. Part of the oedema fluid is thought to be derived from intracellular water released during dissolution of tissue matrix.
Clin Sci Mol Med 1975 Oct
PMID:Body weight and body water in chronic cor pulmonale. 119 92

Na+,K(+)-ATPase is a major determinant of myocyte homeostasis and excitation-contraction. Cardiac glycosides such as digitalis and ouabain increase the inotropic state of the heart through the inhibition of Na+,K(+)-ATPase. While cardiac glycosides are commonly used in the setting of congestive heart failure, optimal therapy would depend upon an intact Na+,K(+)-ATPase system. Changes in Na+,K(+)-ATPase activity and glycoside receptor density with the development of cardiomyopathy have not been well defined. Accordingly, left ventricular (LV) function and Na+,K(+)-ATPase activity and glycoside binding were examined in 7 pigs with dilated cardiomyopathy and in 7 controls. Dilated cardiomyopathy was produced by pacing induced supraventricular tachycardia (SVT) for 3 weeks at 240 bpm. Left ventricular function was examined by simultaneous echocardiography and catheterization. Left ventricular fractional shortening significantly decreased with SVT (34 +/- 2 vs. 10 +/- 2%, P less than 0.05) and LV diastolic dimension and pressure significantly increased (3.8 +/- 0.3 vs. 5.1 +/- 0.4 cm, and 8 +/- 2 vs. 27 +/- 2 mmHg, respectively, P less than 0.05) as compared to controls. Na+,K(+)-ATPase activity was assayed as potassium dependent p-nitrophenol-phosphatase activity. Glycoside receptor density (Bmax) and affinity (KD) was determined using [3H]-ouabain binding assays. Na+,K(+)-ATPase activity, Bmax, and KD all significantly fell from control values with SVT induced cardiomyopathy (0.64 +/- 0.06 vs. 0.45 +/- 0.12 micrograms pNP/mg/h, 5.5 +/- 0.4 vs. 1.9 +/- 0.4 pmol/mg, and 15 +/- 3 vs. 9 +/- 3 nM, respectively, P less than 0.05). The distribution of Na+,K(+)-ATPase in LV sections taken from control and SVT hearts were examined using immunohistochemical techniques. A patchy distribution of Na+,K(+)-ATPase along the sarcolemma in SVT sections was observed as opposed to a more uniform distribution in control myocytes. There was no observable change in the relative content and distribution of the Na+,K(+)-ATPase isoforms alpha 2 and alpha 3 in the SVT sections as compared to controls. In an additional set of experiments, changes in LV as well as isolated myocyte responsiveness to ouabain were examined. Left ventricular fractional shortening and peak dP/dt were measured following administration of 20-60 micrograms/Kg of ouabain in control (n = 3) and SVT (n = 3) pigs. In the control group, 40 micrograms/Kg caused a 25% in LV fractional shortening and a 60% increase in peak dP/dt from baseline. Cumulative doses of 60 micrograms/Kg in the control pigs resulted in over a 75% increase in peak dP/dt from baseline values.(ABSTRACT TRUNCATED AT 400 WORDS)
J Mol Cell Cardiol 1992 Mar
PMID:Myocardial Na+,K(+)-ATPase in tachycardia induced cardiomyopathy. 132 Jul 3

Myoglobin is known to protect the mechanical function of the heart from hypoxia by acting as a sarcoplasmic oxygen reservoir and shuttle. We postulated a role for myoglobin in the pathogenesis of congestive heart failure. Several models of congestive heart failure were employed to test the hypothesis, including spontaneous inherited dilated cardiomyopathy in Doberman Pinschers, and heart failure produced by rapid ventricular pacing in dogs, volume overload in chickens and furazolidone toxicity in turkeys. Myocardial myoglobin was decreased by approximately 50% for all models (P less than 0.05). In Doberman Pinschers dogs which are predisposed to the development of dilated cardiomyopathy and have mild subclinical depression of cardiac performance, myocardial myoglobin (1.05 +/- 0.22 mg/g) is approximately 50% decreased compared to healthy mongrel dogs (2.15 +/- 0.52 mg/g), approximately twice as much as dobermans with heart failure (0.47 +/- 0.25 mg/g) but similar to the concentration found in dogs paced to heart failure (1.09 +/- 0.34 mg/g). Myocardium from poultry had remarkably decreased myoglobin compared to mammals (34 +/- 4 micrograms/g) with heart failure produced either by furazolidone or salt toxicity causing a further 50% reduction. In the canine models of heart failure, myocardial myoglobin concentration was demonstrated to be correlated with biochemical and physiological indicators of myocardial performance, namely, mitochondrial and sarcoplasmic reticular ATPase activities, and cardiac output, systemic vascular resistance, pulmonary capillary wedge pressure and mean arterial pressure, respectively. Our data implicates a role for myoglobin deficiency in the pathogenesis of congestive heart failure and in the predisposition of doberman pinschers to dilated cardiomyopathy.
J Mol Cell Cardiol 1992 Jul
PMID:Myocardial myoglobin deficiency in various animal models of congestive heart failure. 140 11

Moderate and severe stages of congestive heart failure due to the loss of myocardium upon coronary occlusion in rats was associated with an increase in alpha-adrenergic receptors and a decrease in beta-adrenergic receptors in the viable left ventricle. However, at early stages of heart failure the number of beta-adrenergic receptors was decreased without any changes in the number of alpha-adrenergic receptors. The affinities of these receptors to alpha receptor antagonist (3H-prazosin) and beta receptor antagonist (3H-dihydroalprenolol) were not altered in the failing hearts. On the other hand, the pattern of changes in both alpha- and beta-adrenergic receptors in heart membranes treated with oxygen free radical generating system was different from that seen in the failing hearts. In particular, the affinities for these receptors were decreased whereas the number of beta-receptors was increased and the number of alpha-receptors was decreased or unchanged. These results indicate that alterations in the adrenergic receptors in heart failure are not due to the formation of oxygen free radicals.
Mol Cell Biochem 1992 Sep 08
PMID:Changes in adrenergic receptors during the development of heart failure. 146 Dec 61

Contractility, lusitropy and responsiveness to the increase of external Ca2+ concentration were studied in left ventricular papillary muscles of normal and cardiomyopathic Syrian hamsters (SCH) from the UM-X 7.1 strain, both at the onset of myolysis (50-day-old animals) and at the cardiac hypertrophy stage (180-day-old animals) in the absence of congestive heart failure. A marked decrease in all indices of systolic performance was observed in 180-day-old myopathic hamsters as compared to age-matched controls. This was associated with (1) an impairment of the relaxation phase, (2) a loss of the load sensitivity of relaxation, and (3) a decrease in the inotropic and lusitropic responsiveness to Ca2+. On the other hand, when some indices of contraction and the inotropic response to Ca2+ were impaired in 50-day-old myopathic hamsters as compared to age-matched controls, relaxation phase and the lusitropic response to Ca2+ did not alter. This study shows that, in the UM-X 7.1 myopathic hamsters at the earlier stage of the disease, alterations in calcium homeostasis and contraction seem to be the first determinant factors of the development of heart failure when relaxation is not impaired. Conversely, when cardiac hypertrophy has developed, impaired relaxation may worsen heart failure.
J Mol Cell Cardiol 1992 Oct
PMID:Myocardial contractility, lusitropy and calcium responsiveness in young (50 days) and hypertrophied (180 days) cardiomyopathic hamsters. 147 11

We studied post-extrasystolic potentiation (PESP) and frequency potentiation (FP) of human working myocardium isolated from the ventricles of 10 patients with end-stage heart failure (CHF) and 17 non-failing controls (CTL). The contractility index was peak isometric tension developed in vitro by trabeculae carneae (CTL n = 34, CHF n = 31); programmed electrical stimulation was used to initiate as well as alter the timing relationship of the contractile events. While holding constant the total number of contractions per unit of time, we compared the augmentation of contractile performance that occurred upon doubling the stimulation frequency (FP) to that of changing the stimulation pattern (PESP). In the CTL group we found that FP and PESP differed in their ability to augment cardiac contractile performance, PESP being more effective; 105 +/- 13% for PESP vs. 34 +/- 11% (mean +/- S.E.M.) for FP. In the CHF group, the inotropic response to PESP was similar to CTL; in contrast, the relative efficacy of FP (3 +/- 3%) compared to PESP (81 +/- 14%) was markedly diminished. Studies with positive inotropic agents revealed that the percent change in contractility induced by FP and PESP depends upon the relative inotropic state of the heart; however, the contractile response to PESP always equaled or exceeded those produced by clinically relevant concentrations of inotropic agents, particularly in CHF muscles. Agents that increase intracellular levels of adenosine 3',5'-cyclic monophosphate reversed the FP abnormalities seen in the CHF group, suggesting that deficient production of this second messenger in heart failure may cause the abnormal force-frequency relationship in failing myocardium. We conclude that the differential responses of myopathic muscle to PESP and FP may be caused by abnormal restitution processes during diastole. Our results suggest that PESP may be an effective therapeutic modality for patients with severe heart failure who have failed to adequately respond to inotropic drugs, and may serve as a useful indicator of cardiac contractile reserve in these patients.
J Mol Cell Cardiol 1990 Jan
PMID:Post-extrasystolic potentiation and the force-frequency relationship: differential augmentation of myocardial contractility in working myocardium from patients with end-stage heart failure. 169


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