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Query: HUMANGGP:009336 (ATPase)
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The evidence in favor of a direct role of active Na transport in the regulation of excitation-contraction coupling in vascular smooth muscle has been examined. The observations in vivo and those obtained in isolated tissues do not always lead to the same conclusions. The changes of the membrane potential obtained in vitro by slight reductions in, or increases of [K]o do not modify the resting potential of the cells sufficiently to make them contract. Applying K-free or Na-free medium on isolated tissues is a much more vigorous procedure than the limited changes of [K]o that can occur in vascular beds in situ. The Na-Ca exchange-mechanism does not seem to play a major role in those smooth-muscle cells that have been analyzed in detail, but even here the experimental procedures have neither given precise information about the composition of the intracellular compartment nor allowed sufficient control of the parameters studied. The comparison of membrane vesicles from smooth muscle and from cardiac muscle indicates that important differences exist in Na-Ca exchange and in activities of Na+-K+ ATPase and Ca2+-Mg2+ ATPase. These findings suggest a poor development of Na-Ca exchange in smooth muscle as compared to cardiac muscle. Finally, the changes in the Na metabolism of erythrocytes from hypertensives are mentioned, and the present difficulties of linking those changes to an increased reactivity of vascular smooth-muscle cells are briefly discussed.
J Cardiovasc Pharmacol 1985
PMID:Na+-K+ ATPase, Na-Ca exchange, and excitation-contraction coupling in smooth muscle. 240 82

To obtain a better understanding of the mechanism of action of the cardiac glycosides, we examined inotropic and biochemical effects of digitoxin in myocardium from cats chronically exposed to the drug. The mechanical function of papillary muscles was tested isometrically and left ventricular tissue was analyzed for Na+,K+-dependent adenosine triphosphatase ATPase activity. Muscles from control cat hearts developed tension at 2.5 +/- 0.7 g/mm2; muscles from cats that received subcutaneous digitoxin--100 micrograms/kg on day 1, followed by 40 micrograms/kg/day for 4 days (group A), and 75 micrograms/kg on day 1, followed by 25 micrograms/kg/day for 9 days (group B)--developed significantly greater (p less than 0.05) tension of 4.8 +/- 0.3 and 3.6 +/- 0.6 g/mm2, respectively. Further, in vitro maximal responsiveness to digitoxin was greater in the muscles from digitalized groups than in controls (p less than 0.05): Muscles from control cats had a maximal response to in vitro addition of digitoxin of 3.5 +/- 0.1 g/mm2; muscles from cats in group A reached 4.9 +/- 0.3 g/mm2, and those from group B, 4.5 +/- 0.7 g/mm2. Specific activity of microsomal Na+,K+-ATPase from hearts of digitalized groups A and B was inhibited by 50-70% (p less than 0.01). Developed tension, specific Na+,K+-ATPase activity, and in vitro maximal responsiveness to digitoxin in a third group (C) of cats receiving the least daily digitoxin (75 micrograms/kg on day 1, followed by 15 micrograms/kg/day for 29 days) were not different from controls. Mean plasma digitoxin concentrations were 33, 16, and 3 ng/ml in groups A, B, and C, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol
PMID:Relationship of cardiac muscle tension to Na+,K+-adenosine triphosphatase activity after chronic digitoxin administration in cats. 241 Jun 68

In isolated rat tail arteries perfused with Krebs-Henseleit solution, ouabain, in concentrations of less than 10(-5) M, caused a concentration-dependent, noncompetitive inhibition of the vasoconstrictor response to phenylephrine. Concentrations of 10(-8) and 10(-6) M caused 30 and 61% inhibition, respectively. The inhibition was gradual in onset, with a maximal effect at 45 min. In concentrations greater than 10(-5) M, ouabain caused a parallel shift to the left of the phenylephrine dose-response curve, indicating potentiation. The potentiation was rapid in onset (within 1 min), and was approximately 1.4-fold. The cutoff point between inhibition and potentiation of vasoconstrictors occurred at a ouabain concentration of 10(-5) M. Ouabain-induced potentiation was nonspecific in regard to the vasoconstrictor used. Phenylephrine, clonidine, and serotonin were each potentiated. Potentiation probably resulted from a reduction in the smooth muscle membrane potential as a consequence of inhibition of Na-K ATPase. The mechanism of the inhibitory effect of ouabain on vasoconstrictors was not resolved but may operate via stimulation of Na-K ATPase. The results are consistent with a "partial agonist" action of ouabain on Na-K ATPase.
J Cardiovasc Pharmacol
PMID:Effect of ouabain on the responses to vasoconstrictor agents in isolated perfused rat tail arteries. 241 Jul 10

Time-dependent alterations in integrated cardiovascular function were assessed in the streptozotocin-diabetic rat. Hemodynamic measurements in the intact, anesthetized animal revealed significant and progressive reduction in heart rate after 2, 4, and 8 weeks of diabetes. Myocardial contractility (+ dP/dt) and rate of relaxation (-dP/dt) were preserved at 2 weeks, but progressively declined thereafter. Integrative mechanisms maintained mean arterial blood pressure within normal limits at all time points. Pressure was regulated by minimizing cardiac output reduction via slight increases in stroke volume (Starling mechanism) and concomitant small increases in total peripheral resistance. In response to graded isoproterenol infusion and brief, total aortic occlusion, percent increase of heart rate and + dP/dt was maintained despite decrements in absolute values. Reduced peripheral vasodilation resulted in elevated sensitivity of the heart rate-blood pressure relationship during isoproterenol challenge. The -dP/dt was uniformly impaired in diabetic rats during isoproterenol infusion. When given a rapid saline infusion, diabetic hearts appropriately augmented volume output via the Starling mechanism. Initial hemodynamic abnormalities observed in the intact, diabetic rat are consistent with known defects in cardiac adrenergic receptor density, contractile protein ATPase activity, and sarcoplasmic reticulum calcium uptake. However, many cellular and subcellular defects are compensated by integrative hemodynamic mechanisms while latent alterations are observed only in the intact cardiovascular system.
J Cardiovasc Pharmacol
PMID:Integrative nature and time course of cardiovascular alterations in the diabetic rat. 242 82

Milrinone is a new inotropic agent for the treatment of refractory congestive heart failure. Our understanding of the mechanisms(s) of action of this synthetic cardiotonic drug is incomplete. We examined the effects of milrinone and the parent compound amrinone on sarcoplasmic reticulum function (45Ca-uptake and Ca-ATPase); radioligand binding to adenosine, beta-adrenergic, and cholinergic muscarinic receptors; cyclic AMP accumulation; and inhibition of various forms of cyclic AMP phosphodiesterases. Comparisons were made to observe how these effects correlate with the inotropic response of heart. Milrinone was shown to be a potent phosphodiesterase inhibitor that was 40 times more potent than amrinone and 10 times more potent at inhibiting the high-affinity (Km = 0.23 microM) form (Ki = 22 microM) than the low-affinity (Km = 140 microM) form (Ki = 225 microM) of cyclic AMP phosphodiesterase in heart. The potency of milrinone as a phosphodiesterase inhibitor was the same in the presence and absence of calcium. Concentrations of milrinone that increased cyclic AMP accumulation also produced positive inotropy. A comparison of milrinone with amrinone and methylxanthines revealed the order of potency to be isobutylmethylxanthine greater than milrinone greater than theophylline greater than caffeine greater than amrinone. Milrinone and amrinone had no effect on 45Ca-uptake or Ca-ATPase activity in myocyte sarcoplasmic reticulum. However, milrinone did bind weakly to adenosine receptors (KD = 466 microM) but not to cholinergic muscarinic or beta-adrenergic receptors. Also, in combination with isoproterenol high concentrations of milrinone blocked the negative inotropic response to the adenosine agonist phenylisopropyladenosine.(ABSTRACT TRUNCATED AT 250 WORDS)
J Cardiovasc Pharmacol
PMID:Biochemical mechanisms for the inotropic effect of the cardiotonic drug milrinone. 242 30

Results concerning kidney and red blood cell (RBC) function of Milan hypertensive rats (MHS), and of their age- and body weight-matched normotensive controls (MNS), are summarized. Our data suggest a biochemical and physiological link between RBC abnormalities and the renal mechanisms causing hypertension in MHS, and therefore the possibility of using the former as a tool for studying the genetic biochemical mechanisms of hypertension. In particular, the following results are discussed: a positive correlation between blood pressure and RBC Na+-K+ cotransport found in the F2 generation, obtained by crossing F1 (MHS X MNS) hybrids; bone marrow transplantation from MHS and MNS into F1 hybrids, causing a parallel change in recipient RBC characteristics; and similarities between erythrocytes and renal tubular cells in Na+ content, cell volume, and Na+ transport. Ca2+ ATPase or Ca2+ pump at Vmax are lower in MHS renal tubular cells and MHS erythrocytes than in MNS cells. Moreover, isolated kidneys of MHS and MNS, perfused in vitro with media at different Ca2+ concentrations, showed that the function of MNS kidney remained stable over a range of Ca2+ from 0.75 to 1.25 mM, while the function of MS kidney deteriorated at a Ca2+ concentration of 1.25 mM.
J Cardiovasc Pharmacol 1986
PMID:Renal mechanisms and calcium in the pathogenesis of a type of genetic hypertension. 243 13

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


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