Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Ca2+-dependent regulation of contractile protein interactions in cardiac and vascular smooth muscle involves structurally related but distinct Ca2+ binding proteins. In vascular smooth muscle, Ca2+ binds to calmodulin, and Ca2+-calmodulin activates myosin light chain (MLC) kinase with ultimate stimulation of MLC phosphorylation and actin-myosin interactions. The largest class of inhibitors of vascular contractile protein interactions are the calmodulin antagonists which include certain Ca2+ entry blockers. Pharmacologically, some of these agents can be distinguished from pure Ca2+ entry blockers by being more effective vs. vasoconstrictor agents in vitro, less cardiac depressant, and more effective as platelet aggregation inhibitors. An even greater distinction from Ca2+ entry blockers is evident with another series of agents, isoquinolinesulfonamides, which directly inhibit protein kinase activity. Cardiac muscle myofibrillar regulation involves Ca2+ binding to troponin C (TnC). Some cardiotonics, such as Vardax and APP 201-533, increase the Ca2+ sensitivity of cardiac myofibrillar ATPase activity with a concomitant increase in Ca2+ binding to TnC. Several calmodulin antagonists, Ca2+ blockers, and structurally related agents differentially affect cardiac myofibrillar ATPase activity. Potency and efficacy of some of these stimulating agents is markedly greater than Vardax or APP 201-533. Mechanistically, all agents do not affect cardiac MLC phosphorylation, but directly enhance the Ca2+ sensitivity of ATPase activity. However, differential effects on basal and maximum ATPase activity by some agents suggest more complex or additional effects which are related to the type of agent as well as the species (dog vs. hamster). A major subcellular defect in congestive heart failure in various small animal models is a depressed maximum ATPase activity. Thus, a desired goal would be a pharmacological modulator which increases maximum ATPase activity, not necessarily Ca2+ sensitivity. In sum, it is possible to identify agents, Ca2+ binding protein modulators, which directly inhibit vascular smooth muscle and stimulate cardiac muscle contractile protein interactions. The potential advantages/disadvantages of this approach for vasodilator/cardiotonic drug development will have to await future development of novel compounds targeted specifically for these cellular regulatory processes.
J Cardiovasc Pharmacol 1986
PMID:Pharmacological modulation of cardiac and vascular contractile protein function. 243 41

The purpose of this paper is to review very briefly how our understanding of the control of muscle contraction by calcium has developed, and to give an overview of the different regulatory systems that have been shown so far. It should provide a background for some of the more specific presentations that appear later in the symposium. Three different molecular mechanisms for calcium regulation of actin-activated myosin Mg-ATPase activity have been identified. Control of contraction and relaxation in different types of muscle is dominated by one or the other of these regulatory mechanisms. The troponin-tropomyosin system associated with the actin filaments is the best known of the calcium control systems. It operates, for instance, in vertebrate skeletal and cardiac muscles. Direct binding of Ca2+ to myosin controls contraction in muscles of certain invertebrates such as the scallop. This calcium binding is dependent on the presence of the regulatory light chains on the myosin molecules. In vertebrate smooth muscle, calcium in conjunction with calmodulin activates an enzyme, myosin light chain kinase, which phosphorylates the regulatory light chains of the myosin, and this phosphorylation triggers contraction. Relaxation is brought about by dephosphorylation of the light chains through the action of phosphatase(s). Additional regulatory mechanisms, not yet fully identified, appear to operate in smooth muscles.
J Cardiovasc Pharmacol 1987
PMID:Calcium and regulation of contraction: a short review. 244 27

The influence of nicorandil, a potent antianginal drug, on cellular calcium in vascular smooth muscle cells (VSMC) was investigated by studying its effects on the cytosolic free calcium concentration ([Ca2+]i) and calcium-stimulated magnesium-dependent ATPase [(Ca2+ + Mg2+)-ATPase] in the cells. VSMC were prepared from rat aorta, and their [Ca2+]i level was determined by measuring the fluorescence of the free calcium indicator, fura 2. Preincubation with nicorandil for 5 min significantly decreased the rise in [Ca2+]i evoked by addition of either angiotensin II in control solution or prostaglandin F2 alpha, the latter in either the presence or absence of extracellular calcium. The effect of nicorandil on (Ca2+ + Mg2+)-ATPase activity in the microsomal fraction of porcine coronary artery smooth muscle, which is rich in plasma membranes and sarcoplasmic reticulum, was also investigated. Nicorandil at concentrations of 10(-6) and 10(-5) M increased the activity of (Ca2+ + Mg2+)-ATPase significantly at a free calcium concentration of 0.3 microM. At 10(-6) M, nicorandil significantly decreased the Kd for calcium of this enzyme without significantly changing its Vmax. These data suggest that nicorandil suppressed increase of [Ca2+]i, possibly by stimulating (Ca2+ + Mg2+)-ATPase, thereby inhibiting contraction of vascular smooth muscle.
J Cardiovasc Pharmacol 1987
PMID:Effect of nicorandil on the cytosolic free calcium concentration and microsomal (Ca2+ + Mg2+)-ATPase activity of vascular smooth muscle cells. 244 22

The effect of canrenone, an antialdosterone and partial ouabain-agonist drug, was studied in rats that developed volume expansion and hypertension after renal mass reduction and excess Na+ intake (RRM-salt). The RRM-salt was characterized by: (1) increased endogenous "digitalis-like" compounds in plasma [cross reactivity with digoxin-antibodies (57.5 +/- 5.0 vs. 42.1 +/- 3.8 pg/ml, p less than 0.02); inhibition of kidney Na+, K+-ATPase activity (135 +/- 5 vs. 154 +/- 5 mumol/mg/h, p less than 0.01); and inhibition of Na+ extrusion from normal erythrocytes (5.96 +/- 0.40 vs. 7.68 +/- 0.34 mmol/L cells/h, p less than 0.01)]; (2) reduced Na+, K+-pump activity (7.34 +/- 0.29 vs. 10.88 +/- 0.41 mmol/L cells/h, p less than 0.001) and increased Na+ content (4.66 +/- .08 vs. 4.16 +/- 0.11 mmol/L cells, p less than 0.01) in erythrocytes; and (3) low plasma renin activity (2.1 +/- 0.9 vs. 12.6 +/- 1.6 ng/ml/h). Ninety minutes after the administration to RRM-salt of a single oral dose of 60 mg/kg of canrenone, the systolic blood pressure decreased by 36 +/- 4 mm Hg (mean +/- SEM). Chronic canrenone administration (60 mg/kg/day) resulted in a marked antihypertensive effect associated to a correction of volume expansion, a decrease in endogenous "digitalis-like" compounds, and a partial recovery of Na+, K+-pump activity and Na+ content in erythrocytes. Our results suggest that the antihypertensive effect in RRM-salt rats results, at least in part, from antagonism with endogenous "digitalis-like" compounds.
J Cardiovasc Pharmacol 1988 Jan
PMID:Antihypertensive effect of canrenone in a model where endogenous ouabain-like factors are present. 245 Feb 60

Rings of canine basilar arteries with and without endothelium were suspended for isometric tension recording in modified Krebs-Ringer bicarbonate solution. Increased extracellular concentrations of potassium (3-20 mM) caused rhythmic activity in rings with endothelium. This activity was reduced by the removal of the endothelium and by exposure to indomethacin, meclofenamate, diltiazem, or ouabain; it was not affected by tetrodotoxin, bretylium tosylate, phentolamine, propranolol, atropine, methiothepin, and cimetidine. Prostaglandin F2 alpha and E2 caused concentration-dependent increases in the frequency and the amplitude of this rhythmic activity and reversed the inhibitory effect of indomethacin and meclofenamate. Prostacyclin abolished the activity. These results suggest that increasing the concentration of extracellular potassium causes rhythmic activity in canine basilar arteries because of the production and/or release by the endothelium of products of cyclooxygenase such as prostaglandin F2 alpha and E2. These may initiate the contraction while prostacyclin triggers the relaxation phase of the rhythmic activity, possibly by activating Na+, K+-ATPase of the vascular smooth muscle.
J Cardiovasc Pharmacol 1988 Jul
PMID:Potassium-induced endothelium-dependent rhythmic activity in the canine basilar artery. 245 32

In normotensive humans with a positive family history of essential hypertension (FHH), blood pressure (BP) is often dysregulated. Resting BP already tends to be slightly higher than in age-matched control groups with negative FHH; BP responses to high sodium intake and perhaps to psychological and/or physical stress may also be exaggerated. Considering BP regulating factors, total exchangeable body sodium, whole blood volume, and their responses to low or high sodium intakes are normal in normotensive subjects with positive FHH; this does not exclude an existing although fully compensated regulatory disturbance. The response of plasma immunoreactive atrial natriuretic peptide levels to a high sodium intake seems to be impaired. On the other hand, a tendency for high ouabain-like Na+/K+-ATPase activity was reported in some normotensive subjects with positive FHH; data on central blood volume are lacking. Basal plasma renin, angiotensin II (AngII), and aldosterone levels, the reactivity of BP to acute increases in circulating AngII, and the responses of these variables to changes in sodium intake did not differe significantly between normotensive groups with a negative or positive FHH; this does not exclude a tendency for low renin-angiotensin activity in certain hypertension-prone families. The responsiveness of plasma aldosterone to acute rises in circulating AngII appeared to be largely unaltered when normotensive subjects with positive FHH were on moderate or high sodium intakes, but aldosterone responses may be blunted on a low sodium diet. Although a familial occurrence of subtle disturbances in AngII-dependent control of aldosterone and renal hemodynamics appears possible, BP regulation by the renin-angiotensin system is probably often intact at the stage of prehypertension. The finding of unaltered basal peripheral venous plasma norepinephrine (NE) and epinephrine levels and NE responses to changes in sodium intake, posture, or physical exercise in normotensive subjects with positive FHH has so far provided no evidence for enhanced sympathetic activity; nevertheless, direct analysis of regional nerve activity or NE release will be required to resolve this question. Regardless of the level of sympathetic activity, an exaggerated pressor responsiveness to NE occurs as a common disturbance in normotensive subjects with a positive FHH.(ABSTRACT TRUNCATED AT 400 WORDS)
J Cardiovasc Pharmacol 1988
PMID:Dysregulation of blood pressure in normotensive offspring of hypertensive parents. 246 99

Alterations in cellular calcium metabolism are presumed to be the basis of the vasoconstrictive process that sustains elevations in arterial pressure. Altered membrane sodium transport can effect changes in intracellular free calcium concentration through changes in transmembrane sodium gradients and membrane depolarization. Thus, changes in membrane sodium transport could produce calcium accumulation in vascular smooth muscle, resulting in vasoconstriction and arterial hypertension. Multiple sodium transport abnormalities exist in tissues of genetically hypertensive rats, and blood cells of human essential hypertensives. Na+-K+ cotransport and Na+-Li+ countertransport abnormalities appear to be primary membrane defects, but a direct physiologic link of these to vasoconstriction remains to be established. Evidence for circulating Na,K-ATPase inhibitors in hypertension is now widely reported, and Na,K-ATPase inhibition provides a rationale for vasoconstriction through altered calcium and/or neurotransmitter metabolism. Na,K-ATPase inhibition in hypertensive disease appears to arise not as a primary abnormality in membrane transport, nor as a phenomenon secondary to hypertension per se, but as a physiological response to compensate for excess extracellular fluid volume accumulation.
J Cardiovasc Pharmacol 1988
PMID:Circulating inhibitors of sodium transport at the prehypertensive stage of essential hypertension. 246 9

The cardiovascular properties of MS-857 [4-acetyl-1-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydro-3(2H)-isoquinolinone ], a novel cardiotonic agent, were investigated in anesthetized and conscious dogs. MS-857 (1-100 micrograms/kg i.v.) produced a significant and dose-dependent increase in cardiac contractility with relatively small changes in heart rate and blood pressure. This indicates a sizable separation between positive inotropic and other effects of MS-857. Oral administration of MS-857 to conscious dogs (0.1-1 mg/kg) also produced a sustained increase in cardiac contractility in a dose-dependent manner. The total duration of action was longer than 7 h at a dose of 1 mg/kg p.o. There occurred no arrhythmias and no changes in animal behavior. After chronic oral administration, MS-857 completely retained its activities, indicating the lack of tachyphylaxis. In the acute heart failure models induced by either propranolol or pentobarbital, MS-857 reversed the cardiac depressant effects of these drugs. Moreover, MS-857 also significantly improved the pentobarbital-induced heart failure in the heart-lung preparation. MS-857 did not inhibit the Na+, K+-ATPase, but inhibited the phosphodiesterase (PDE) III selectively, both of which were prepared from the dog ventricular muscle. Thus, MS-857 can be characterized as a potent nonsympathomimetic, nonglycoside cardiotonic drug with a selective inhibitory activity on PDE III. The cardiovascular properties revealed by this study strongly suggest that MS-857 will exert a beneficial effect in the treatment of congestive heart failure.
J Cardiovasc Pharmacol 1988
PMID:Cardiovascular properties of MS-857, a new and potent cardiotonic agent, on normal and failing hearts. 246 58

We tested the effect of dietary potassium (KCl, 20 mEq three times daily), calcium (Ca, 500 mg twice daily), sodium-potassium-dependent ATPase inhibition (digoxin), calcium channel blockade (nifedipine), and placebo on acute natriuresis in 14 normal subjects who received 2 L normal saline intravenously over 4 h. Plasma renin activity (PRA) was increased in subjects receiving nifedipine, while plasma aldosterone (PA) concentrations were not different among the regimens. Only KCl and nifedipine affected sodium excretion compared to controls. KCl and nifedipine increased the amount of sodium excreted after the infusion was terminated. In the case of nifedipine, this natriuresis was sufficient to increase the 24 h sodium excretion on that day to above that of the other regimens.
J Cardiovasc Pharmacol 1988
PMID:Facilitation of natriuresis with nifedipine in normal humans. 246 94

Rat kidney glomeruli and cortical tubules were obtained by a combination of sieving and differential centrifugation technique. [3H]Prazosin and [3H]rauwolscine were used to identify and quantify the alpha 1- and alpha 2-adrenergic receptors, respectively. In the glomeruli, the alpha 1-adrenoceptor concentration was 27% and alpha 2-adrenoceptor concentration was 33% of the corresponding values in the tubules. Further localization of the tubular alpha-adrenoceptors was undertaken by studies in the isolated basolateral membrane and comparison with values in the crude plasma membrane. alpha 1-Adrenoceptors were enriched 1.54 +/- 0.1 times and alpha 2-adrenoceptors were enriched 1.73 +/- 0.04 times in the basolateral membrane as compared to crude plasma membrane. However, these values were significantly (p less than 0.05) less than the enrichment value of 2.77 +/- 0.3 obtained for the basolateral membrane marker (Na+ + K+)-ATPase. These results suggested the possibility that alpha 1- and alpha 2-adrenoceptors may also be distributed in the brush border membrane. Direct-binding studies in the purified renal brush border membrane indicated alpha 1-adrenoceptor concentration of 82.1 +/- 3.8 and alpha 2-adrenoceptor concentration of 108.2 +/- 9.3 fmol/mg protein. These values were 32 and 17% of the corresponding values in the basolateral membrane. Overall, our results suggest that alpha 1- and alpha 2-adrenoceptors are present both in the basolateral and brush border membranes analogous to what has been reported for angiotensin and insulin receptors; their primary concentration, however, is in the basolateral membranes.
J Cardiovasc Pharmacol 1989 Jan
PMID:Glomerular and tubular alpha 1- and alpha 2-adrenoceptors in the rat kidney: distribution in basolateral and brush border membranes of tubular cells. 246 28


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