Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

An extensive investigation of the cardiac actions of phorbol esters and the potential role of the Na(+)-H+ exchanger in those actions was carried out using isolated rat hearts. Sixty minutes of perfusion with 10(-9) M phorbol 12-myristate 13-acetate (PMA) or 10(-8) M phorbol 12,13-dibutyrate (PDBu) produced marked cardiac dysfunction associated with depressed contractility, coronary constriction, and elevated resting tension, the latter being particularly evident with PMA. These effects were also associated with disturbances in tissue levels of energy metabolites manifested primarily by a reduction in ATP and an elevation in lactate. Furthermore, both phorbols produced a sustained stimulation of the release of 6-ketoprostaglandin F1 alpha (6-keto PGF1 alpha), the hydrolysis product of prostacyclin (prostaglandin I2). Amiloride, an inhibitor of the Na(+)-H+ exchanger, significantly attenuated the loss in contractility and elevation in coronary pressure as well as the stimulated release of 6-keto PGF1 alpha but was without effect on elevations in resting tension or on changes in energy metabolites. Increasing concentrations of PMA or PDBu 10-fold resulted in a much more rapid and severe (greater than 80% loss in contractile function after 30 minutes) effect that was nonetheless qualitatively identical to that seen with the lower concentrations of phorbol. However, the effects were not prevented by amiloride. Surprisingly, 4 alpha-phorbol 12,13-didecanoate (alpha-PDD, 10(-6) M), which does not activate protein kinase C, was found to be a potent inhibitor of cardiac function (greater than 80% loss in contractility and 50% increase in resting tension) after 30 minutes of perfusion, although these effects were not associated with changes in levels of energy metabolites or with elevations in coronary pressure. Similarly, none of the actions of this compound were attenuated by amiloride. In contrast to the sustained effects of other phorbols on 6-keto PGF1 alpha release, the effect of alpha-PDD was transient (less than 10 minutes). In all hearts studied, the marked depression in contractile function caused by all phorbol esters occurred in the absence of any ultrastructural changes. 4 alpha-Phorbol (10(-6) M), which does not activate protein kinase C, was without effect on any parameter studied. Our results demonstrate very complex effects of phorbol esters on numerous parameters of cardiac function, including an amiloride-sensitive component that occurs at low concentrations. The latter observation suggests the involvement of Na(+)-H+ exchange activation, possibly occurring as a consequence of protein kinase C stimulation, in mediation of the effects of phorbol esters at low concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Concentration-dependent effects of protein kinase C-activating and -nonactivating phorbol esters on myocardial contractility, coronary resistance, energy metabolism, prostacyclin synthesis, and ultrastructure in isolated rat hearts. Effects of amiloride. 193 40

Myocardial recovery after hypoxia may be determined not only by the extent of metabolic depression during the hypoxic period but also by changes in cation contents as well. Calcium overload during reoxygenation, mediated in part by Na-Ca exchange and supported by the rise in cell sodium during hypoxia, may be one factor. The effects of amiloride (0.1 mM), a diuretic that inhibits Na(+)-H+ and Na-Ca exchanges in cardiac sarcolemma and mitochondria preparations, were studied during hypoxia-reoxygenation in the isovolumic, isolated rat heart. During hypoxia, cell sodium, measured using potassium ethylenediamine tetraacetate cobaltate as an extracellular marker, increased in amiloride and amiloride-free hearts, but there was no increase in cell calcium (3.3 +/- 0.3 vs. 3.6 +/- 0.9 mumol/g dry wt; p = NS). Amiloride did not alter developed pressure (DP), end-diastolic pressure (EDP), pH, or integrated areas of adenosine triphosphate (ATP) and phosphocreatine (PCr) (determined by phosphorus-31-nuclear magnetic resonance spectroscopy) during hypoxia or normal perfusion conditions. Forty minutes after reoxygenation, however, cell calcium was significantly lower in the amiloride (5.1 +/- 1.3 mumol/g dry wt) than in the amiloride-free group (10.4 +/- 1.8 mumol/g dry wt; p less than 0.001), and there was improved recovery of DP (percent of initial) (72 +/- 12% vs. 41 +/- 12%; p less than 0.001), PCr (99 +/- 9% vs. 70 +/- 14%; p less than 0.001), and pH (7.17 +/- 0.17 vs. 6.88 +/- 0.16; p less than 0.001) in the amiloride group. To determine whether this dose of amiloride inhibits the manifestations of sodium-mediated calcium gain in the same model during normoxia, the metabolic and functional sequelae of lithium-substituted low sodium (50 mM) perfusion were studied. Amiloride significantly limited the manifestations of sodium-mediated calcium gain as indexed (all expressed as percent of control) by a lower peak DP (221 +/- 25% vs. 284 +/- 20%) at 3 minutes, improved preservation of PCr (85 +/- 10% vs. 68 +/- 9%) and ATP (104 +/- 12% vs. 84 +/- 9%), lower rise in inorganic phosphate (201 +/- 74% vs. 332 +/- 106%), and a smaller fall in intracellular pH (7.01 +/- 0.04 vs. 6.70 +/- 0.15, p less than 0.05) for all metabolic parameters during a 20-minute period.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effects of amiloride on metabolism and contractility during reoxygenation in perfused rat hearts. 231 84

The role of protein kinases in renal noradrenergic stimulation was examined using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), using sphingosine, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperizine (H7), or staurosporine to inhibit the responses to norepinephrine (NE, 60 nM) in isolated perfused rat kidneys. Sphingosine (20 mumol/L) increased the noradrenergic vasoconstrictor response. H7 (10 mumol/L) partially blocked the immediate vasoconstrictor response and completely inhibited it after 2 min without altering the antinatriuretic and antilithuretic responses. H7 also blocked the increase in free water produced by NE, which is consistent with the inhibition of protein kinase A linked to beta-adrenergic stimulation. Staurosporine (10 nmol/L) partially inhibited noradrenergic vasoconstriction and antinatriuresis, and it completely blocked the depression of gluconeogenic responses to NE in pyruvate-perfused kidneys. To examine the role of diacylglycerol and protein kinase C in the renal responses to NE, we used oleoyl-acetyl-glycerol (OAG, 50-100 microM) or phorbol-12-myristyl-13-acetate (TPA, 5-50 nM). TPA slowly vasoconstricted the kidney and reduced GFR and fractional Na+, Li+, and free water excretion. Amiloride (1 mM) prevented the TPA responses. OAG mimicked the effects of TPA except that vasoconstriction occurred more rapidly and was brief. Both TPA and OAG acted like alpha 1-adrenergic agonists. These results indicate that diaclyglycerol and protein kinase are involved in the prolonged effects of NE on vasoconstriction. GFR, and proximal tubular reabsorption.
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PMID:Diacylglycerol and protein kinase mediated noradrenergic responses in perfused rat kidneys. 239 Jul 42

1. Excitatory postsynaptic potentials (e.p.s.ps) were recorded from the submandibular parasympathetic ganglia of newborn rats (10-20 days old), by intracellular microelectrode recording and a suction electrode to deliver stimulus trains to the lingual nerve (15 stimuli at 0.1, 0.3, 1, 3, and 10 Hz, 22 degrees C). Only evoked responses without voltage-dependent action potentials were analyzed (observed at membrane potentials negative to -70 mV), and e.p.s.p. amplitudes were determined for the plateau responses during each train (5-15th response). 2. Cadmium, an inorganic calcium channel antagonist, reduced e.p.s.p. amplitudes in a dose-dependent manner (Kd 74 microM, P less than 0.01). Nickel (1-300 microM) did not attenuate the amplitude of evoked responses. 3. Verapamil (0.1-30 microM), a phenylamine, had no significant effects upon e.p.s.p. amplitudes at any frequency examined. Higher concentrations of verapamil (100 microM) blocked neurally evoked responses in a manner consistent with the antagonism of voltage-sensitive sodium currents. 4. Diltiazem, a benzothiazepine, reduced e.p.s.p. amplitudes in a dose-dependent manner, the depression being accentuated at high stimulation frequencies (80% block at 30 microM and 10 Hz). The pure (-)-cis enantiomer of diltiazem (10-30 microM) was without effect. 5. Amlodipine, a 1,4-dihydropyridine, did not antagonize synaptic transmission at any stimulus frequency examined (10-30 microM, 0.1-10 Hz, n = 3). 6. Amiloride, a potassium-sparing diuretic, depressed the amplitudes of evoked responses in a dose-dependent manner (one-site Kd 31 microM, P less than 0.005), although the extent of the block was alleviated with high stimulus frequencies. The effects of 30 microM amiloride were unlikely to be of post-synaptic origin as both the amplitudes of miniature e.p.s.ps, and the iontophoretic potentials induced by exogenous acetylcholine, were not attenuated by treatment with this compound. The amiloride derivative, 3',4'-dichlorobenzamil was ineffective in reducing the amplitude of e.p.s.ps (30-100 microM). 7. omega-Conotoxin GVIA, a marine neurotoxin, which depressed whole cell calcium currents recorded from cultured rat parasympathetic cardiac neurones (up to 90% block at 10 nM), was ineffective at blocking synaptic transmission in submandibular ganglia (0.1-1 microM). 8. The differential effects of these calcium channel antagonists upon synaptic transmission in rat parasympathetic ganglia, suggest that either more than one type of calcium channel may be involved in transmitter release, or that the presynaptic calcium channels possess pharmacological sensitivities different from those of channel types described in ne
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PMID:Inhibition of neurally-evoked transmitter release by calcium channel antagonists in rat parasympathetic ganglia. 257 81

1. Intracellular pH (pHi) and Na+ activity were recorded (ion-selective microelectrodes) in guinea-pig papillary muscle and the sheep cardiac Purkinje fibre while simultaneously recording twitch tension. The effects of intracellular acidosis and alkalosis upon contraction were investigated. 2. A fall of pHi produced by reducing pHo was associated with a fall of twitch tension. Similarly, a rise of pHi produced by raising pHo produced a rise of twitch tension. The time course of the changes in tension correlated with the time course of changes of pHi rather than pHo. These results are consistent with previous work showing that acidosis inhibits contraction and that the inhibition depends upon a fall of pHi. 3. Changes of pHi were produced while maintaining pHo constant at 7.4. Removal of NH4Cl or addition of sodium acetate (pHo 7.4) reduced pHi but this gave either an increase of tension (papillary muscle) or an initial fall followed by a subsequent recovery of tension (Purkinje fibre). The increase or recovery of tension occurred despite the fact that there was an intracellular acid load. Thus, reducing pHi at constant pHo can increase tension whereas reducing pHi at low pHo (6.4, see paragraph 2) inhibits tension. 4. The increase of recovery of tension during intracellular acidosis produced at a constant pHo (7.4) was associated with a rise of intracellular sodium activity (aiNa). Amiloride (1.5 mmol/l), an inhibitor of Na(+)-H+ exchange, prevented the rise of aiNa during intracellular acidosis and also prevented the recovery of tension. It is concluded that the increase or recovery of tension at low pHi is secondary to a rise of aiNa caused by stimulation of Na(+)-H+ exchange. A rise of aiNa will elevate Ca2+ via sarcolemmal Na(+)-Ca2+ exchange and thus will elevate tension. 5. An intracellular acidosis produced by reducing pHo (6.4) does not elevate aiNa in the Purkinje fibre. In papillary muscle, aiNa rises but this occurs slowly and the rise is 50% smaller than that seen when the same intracellular acidosis is induced at normal pHo (7.4). The net depression of tension under these conditions thus correlates with the lack of a large rise of aiNa. 6. Knowing the quantitative dependence of tension upon both aiNa and pHi in the two tissues it is possible to predict the recovery of twitch tension during intracellular acidosis at constant pHo (7.4), using the changes of pHi and aiNa measured under these conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of intracellular and extracellular pH on contraction in isolated, mammalian cardiac muscle. 262 16

Increasing [K+] from 2.5 mmol/l to 115 mmol/l on the serosal side of the frog skin produces a rapid decrease of short-circuit current (Isc) that is followed, within a few minutes, by a recovery of Isc to near or above its control value. After isolation of the epithelium by a procedure involving collagenase treatment and physical removal of the corium, increasing serosal [K+] still produced a depression of Isc but no significant recovery phase. By itself, collagenase treatment reduced but did not eliminate the recovery phase. The recovery phase was also markedly depressed by the beta-adrenergic blocker oxprenolol, but not by propranolol, atropine or indomethacin. Amiloride, given during the recovery phase, caused Isc to reverse to a small outward value. These results suggest that the recovery phase of Isc seen in the response to increased serosal [K+] represents an increase in Na+ influx through amiloride-sensitive channels which is triggered by the release of an intermediary agent, possibly a beta-adrenergic agonist, from some structure in the corium.
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PMID:K+ -stimulated Na+ transport in frog-skin epithelia. 287 69

The Ca2+ transport mechanism between endolymph and perilymph was evaluated by the effects of vanadate and amiloride on the endocochlear potential (EP) and the Ca2+ concentration in endolymph using Ca2+-selective microelectrodes. Under normal conditions, the EP was 81.8 +/- 0.9 mV, and the Ca2+ concentrations in endolymph and perilymph were 16.6 +/- 1.3 microM and 1.85 +/- 0.11 mM (N = 12), respectively. Therefore, the uphill electrochemical potential gradient for Ca2+ from perilymph to endolymph, 20.2 +/- 2.0 mV, indicates the existence of an active uptake of Ca2+ into endolymph. Vanadate, the inhibitor of Ca2+-ATPase, topically applied to the round window membrane caused biphasic changes of the EP and the endolymph Ca2+ concentration; the former in a transient increase followed by a consistent decrease and the latter in a slow decrease followed by a slow increase. Amiloride induced a slight EP depression and a concomitantly slight elevation of the Ca2+ concentration in endolymph. The electrochemical potential gradient for Ca2+ between endolymph and perilymph vanished with the use of vanadate but was not affected by amiloride. These results suggest that Ca2+-ATPase, sensitive to vanadate, maintained the bulk of active Ca2+ transport in the cochlea and that the participation of Na+-Ca2+ exchange is negligible.
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PMID:Calcium transport mechanism in the endolymph of the chinchilla. 297 41

Amiloride and 5-N,N-dimethylamiloride (DMA) inhibit the choline uptake of Ehrlich ascites tumor cells. The inhibition by DMA is competitive with a KI value of 20 microM. The apparent KM value for choline was determined as 15 microM. Amiloride is approximately three times less potent. Amiloride uptake is not antagonized by choline or impaired in cells characterized by a deficient choline carrier. This indicates that amiloride is not transported into the cell by the choline carrier. The inhibition of the choline uptake by DMA cannot be attributed to a depression of choline kinase (EC 2.7.1.32) and is therefore considered to be due to a direct interaction between DMA and the choline carrier. DMA does not compete with sodium ions for its effect on the choline carrier. It is suggested that the choline carrier of Ehrlich ascites tumor cells exhibits a binding site for DMA similar to the one on the Na+/H+ antiporter.
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PMID:Amiloride and 5-N,N-dimethylamiloride inhibit the carrier mediated uptake of choline in Ehrlich ascites tumor cells. 359 91

Potassium and magnesium deficiency have been reported as risk factors for experimental gentamicin nephrotoxicity. Amiloride, a potassium-sparing diuretic, also leads to increased renal magnesium reabsorption. Amiloride, 2 mg/kg/day, was given to groups of 8-12 Fischer 344 rats receiving gentamicin, 20 mg/kg b.i.d., for 3, 7, 10 and 14 days. Control animals received the vehicle for gentamicin, amiloride alone or gentamicin alone. The degree of renal failure and weight loss were similar in gentamicin and gentamicin + amiloride groups at all time points despite increases in serum potassium and magnesium in the amiloride-treated animals. Tubular dysfunction as assessed by depression of renal cortical slice uptake of p-aminohippurate and N-methylnicotinamide was not improved by the addition of amiloride. In addition, a comparable degree of tubular necrosis and regeneration was observed in all gentamicin-treated groups. Maximum gentamicin concentrations in the renal cortex did not differ. Thus, despite reduction of urinary losses of potassium and magnesium with resultant increased serum values, amiloride did not protect against experimental gentamicin nephrotoxicity. The tubular electrolyte wasting noted clinically is likely to be a result, rather than a cause of proximal tubular cell damage.
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PMID:Effect of amiloride on experimental gentamicin nephrotoxicity. 400 Mar 46

Manipulations of pH and electrical gradients in a perfused preparation were used to analyze the factors controlling ammonia distribution and flux in trout white muscle after exercise. Trout were exercised to exhaustion, and then an isolated-perfused white muscle preparation with discrete arterial inflow and venous outflow was made from the posterior portion of the tail. The tail-trunks were perfused with low (7.4)-, medium (7.9)-, and high (8.4)-pH saline, achieved by varying HCO3- concentration ([HCO3-]) at constant Pco2. Intracellular and extracellular pH, ammonia, CO2, K+, Na+, and Cl- were measured. Muscle intracellular pH was not affected by changes in extracellular pH. Increasing extracellular pH caused a decrease in the transmembrane NH3 partial pressure (PNH3) gradient and a decrease in ammonia efflux. When extracellular K+ concentration was increased from 3.5 to 15 mM in the medium-pH group, a depolarization of the muscle cell membrane potential from -92 to -60 mV and a 0.1-unit depression in intracellular pH occurred. Ammonia efflux increased despite a marked reduction in the PNH3 gradient. Amiloride (10(-4) M) had no effect, indicating that Na+/H(+)-NH4+ exchange does not participate in ammonia transport in this system. A comparison of observed intracellular-to-extracellular ammonia distribution ratios with those modeled according to either pH or Nernst potential distributions supports a model in which ammonia distribution across white muscle cell membranes is affected by both pH and electrical gradients, indicating that the membranes are permeable to both NH3 and NH4+. Membrane potential, acting to retain high levels of NH4+ in the intracellular compartment, appears to have the dominant influence during the postexercise period. However, at rest, the pH gradient may be more important, resulting in much lower intracellular ammonia levels and distribution ratios. We speculate that the muscle cell membrane NH3-to-NH4+ permeability ratio in trout may change between the rest and postexercise condition.
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PMID:Ammonia movement and distribution after exercise across white muscle cell membranes in rainbow trout. 885 99


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