Further evidence that prostaglandins inhibit the release of noradrenaline from adrenergic nerve terminals by restriction of availability of calcium.
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1 Guinea-pig vasa deferentia were continuously superfused after labelling the transmitter stores with [3H](-)-noradrenaline. Release of [3H]-(-)-noradrenaline was induced by transmural nerve stimulation. 2 Prostglandin E2 (14 nM) drastically reduced the release of [3H]-(-)-noradrenaline, while tetraethylammonium (2 mM), rubidium (6 mM), phenoxybenzamine (3 muM) each in the presence or absence of Uptake 1 or 2 blockade, and prolonged pulse duration (from 0.5 to 2.0 ms) all significantly increased the release of [3H]-(-)-noradrenaline per nerve impulse. 3 The inhibitory effect of prostaglandin E2 on evoked release of [3H]-(-)-noradrenaline was significantly reduced by tetraethylammonium, rubidium and prolonged pulse duration, whilst it was actually enhanced by phenoxybenzamine. This indicates that increased release of noradrenaline per nerve impulse does not per se counteract the inhibitory effect of prostaglandin E2. 4 It is concluded that tetraethylammonium, rubidium and prolonged pulse duration counteracted the inhibitory effect of prostaglandin E2 on T3H]-(-)-noradrenaline release by promoting calcium influx during the nerve action potential. The results are consistent with, and add more weight to the view that prostaglandins inhibit the release of noradrenaline by restriction of calcium availability. (+info)
Abnormal calcium metabolism in normocalcaemic sarcoidosis.
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In studies of calcium metabolism in 13 unselected patients with untreated sarcoidosis all were normocalcaemic but five had hypercalcuria. All had normal renal function. Calcium absorption was indexed by a double isotope test. 45Ca hyperabsorption occurred in six patients. Ten kinetic studies were carried out with 47Ca and in six bone turnover was increased. 45Ca absorption correlated well with the calculated bone uptake rate of calcium, and with urine calcium excretion. These results suggest that in sarcoidosis abnormalities in calcium metabolism are fairly common although they rarely result in sustained hypercalcaemia. (+info)
Automatic activity in depolarized guinea pig ventricular myocardium. Characteristics and mechanisms.
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Membrane potential was changed uniformly in segments, 0.7-1.0 mm long, of guinea pig papillary muscles excised from the right ventricle by using extracellular polarizing current pulses applied across two electrically insulated cf preparations superfused with Tyrode's solution at maximum diastolic membrane potentials ranging from-35.2+/-7.5 (threshold) to +4.0+/-9.2 mV. The average maximum dV/dt of RAD ranged from 17.1 to 18.0 V/sec within a membrane potential range of -40 to +20 mV. Raising extracellular Ca2+ concentration [Ca2+]0 from 1.8 to 6.8 mM, or application of isoproterenol (10(-6)g/ml) enhanced the rate of RAD, but lowering [Ca2+]0 to 0.4 mM or exposure to MnCl2 (6 mM) abolished RAD. RAD were enhanced by lowering extracellular K+ concentration [K+]0 from 5.4 to 1.5 mM. RAD were suppressed in 40% of fibers by raising [K+]0 to 15.4 mM, and in all fibers by raising [K+]0 to 40.4 mM. This suppression was due to increased [K+]0 and not to K-induced depolarization because it persisted when membrane potential was held by means of a conditioning hyperpolarizing puled gradually after maximum repolarization. These observations suggest that the development of RAD in depolarized myocardium is associated with a time-dependent decrease in outward current (probably K current) and with increase in the background inward current, presumably flowing through the slow cha-nel carrying Ca or Na ions, or both. (+info)
Intrarenal site of action of calcium on renin secretion in dogs.
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We studied the effects of intrarenal calcium infusion on renin secretion in sodium-depleted dogs in an attempt to elucidate the major site of calcium-induced inhibition of renin release. Both calcium chloride and calcium gluconate reduced renal blood flow and renin secretion while renal perfusion pressure was unchanged. These data indicate that calcium inhibition of renin secretion did not occur primarily at the renal vascular receptor; decreased renal blood flow is usually associated with increased renin secretion. Calcium chloride infusion increased urinary chloride excretion without affecting sodium excretion, and calcium gluconate failed to increase either sodium or chloride excretion. Also, the filtered loads of sodium and chloride were unchanged during the calcium infusions. These results give no indication that calcium inhibited renin secretion by increasing the sodium or chloride load at the macula densa. The effects of intrarenal calcium infusion on renin release were also assessed in dogs with a nonfiltering kidney in which renal tubular mechanisms could not influence renin secretion. The observation that calcium still suppressed renin release in these dogs provides additional evidence that the the major effect of calcium involved nontubular mechanisms. Thus, it appears likely that calcium acted directly on the juxtaglomerular cells to inhibit renin secretion. (+info)
Structural and functional changes in acute liver injury.
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Carbon tetrachloride produces liver cell injury in a variety of animal species. The first structurally recognizable changes occur in the endoplasmic reticulum, with alteration in ribosome-membrane interactions. Later there is an increase in intracellular fat, and the formation of tangled nets of the ergastoplasm. At no time are there changes in mitochondria or single membrane limited bodies in cells with intact plasmalemma, although a relative increase in cell sap may appear. In dead cells (those with plasmalemma discontinuties) crystalline deposits of calcium phosphatase may be noted. Functional changes are related to the endoplasmic reticulum and the plasma membrane. An early decrease in protein synthesis takes place; an accumulation of neutral lipid is related to this change. Later alterations in the ergastoplasmic functions (e.g., mixed function oxidation) occurs. Carbon tetrachloride is not the active agent; rather, a product of its metabolism, probably the CC1, free radical, is. The mechanisms of injury include macromolecular adduction and peroxide propagation. A third possibility includes a cascade effect with the production of secondary and tertiary products, also toxic in nature, with the ability to produce more widespread damage to intracellular structures. (+info)
Nonbehavioral selection for pawns, mutants of Paramecium aurelia with decreased excitability.
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The reversal response in Paramecium aurelia is mediated by calcium which carries the inward current during excitation. Electrophysiological studies indicate that strontium and barium can also carry the inward current. Exposure to high concentrations of barium rapidly paralyzes and later kills wild-type paramecia. Following mutagenesis with nitrosoguanidine, seven mutants which continued to swim in the ;high-barium' solution were selected. All of the mutants show decreased reversal behavior, with phenotypes ranging from extremely non-reversing (;extreme' pawns) to nearly wild-type reversal behavior (;partial' pawns). The mutations fall into three complementation groups, identical to the pwA, pwB, and pwC genes of Kunget al. (1975). All of the pwA and pwB mutants withstand longer exposure to barium, the pwB mutants surviving longer than the pwA mutants. Among mutants of each gene, survival is correlated with loss of reversal behavior. Double mutants (A-B, A-C, B-C), identified in the exautogamous progeny of crosses between ;partial' mutants, exhibited a more extreme non-reversing phenotype than either of their single-mutant (;partial' pawn) parents.---Inability to reverse could be expected from an alteration in the calcium-activated reversal mechanism or in excitation. A normal calcium-activated structure was demonstrated in all pawns by chlorpromazine treatment. In a separate report (Schein, Bennett and Katz 1976) the results of electrophysiological investigations directly demonstrate decreased excitability in all of the mutants, a decrease due to an altered calcium activation. The studies of the genetics, the survival in barium and the electro-physiology of the pawns demonstrate that the pwA and pwB genes have different effects on calcium activation. (+info)
Dopamine stimulates salivary duct cells in the cockroach Periplaneta americana.
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This study examines whether the salivary duct cells of the cockroach Periplaneta americana can be stimulated by the neurotransmitters dopamine and serotonin. We have carried out digital Ca2+-imaging experiments using the Ca2+-sensitive dye fura-2 and conventional intracellular recordings from isolated salivary glands. Dopamine evokes a slow, almost tonic, and reversible dose-dependent elevation in [Ca2+]i in the duct cells. Upon stimulation with 10(-)6 mol l-1 dopamine, [Ca2+]i rises from 48+/-4 nmol l-1 to 311+/-43 nmol l-1 (mean +/- s.e.m., N=18) within 200-300 s. The dopamine-induced elevation in [Ca2+]i is absent in Ca2+-free saline and is blocked by 10(-)4 mol l-1 La3+, indicating that dopamine induces an influx of Ca2+ across the basolateral membrane of the duct cells. Stimulation with 10(-)6 mol l-1 dopamine causes the basolateral membrane to depolarize from -67+/-1 to -41+/-2 mV (N=10). This depolarization is also blocked by La3+ and is abolished when Na+ in the bath solution is reduced to 10 mmol l-1. Serotonin affects neither [Ca2+]i nor the basolateral membrane potential of the duct cells. These data indicate that the neurotransmitter dopamine, which has previously been shown to stimulate fluid secretion from the glands, also stimulates the salivary duct cells, suggesting that dopamine controls their most probable function, the modification of primary saliva. (+info)
PKCdelta acts as a growth and tumor suppressor in rat colonic epithelial cells.
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We have analysed the expression of three calcium-independent isoforms of protein kinase C (PKC), PKCdelta, PKCepsilon and PKCzeta, in an in vitro model of colon carcinogenesis consisting of the nontumorigenic rat colonic epithelial cell line D/WT, and a derivative src-transformed line D/src. While PKCzeta and PKCepsilon showed similar protein levels, PKCdelta was markedly decreased in D/src cells when compared to the D/WT line. To assess whether down-regulation of PKCdelta was causally involved in the neoplastic phenotype in D/src cells, we prepared a kinase-defective mutant of PKCdelta. Stable transfection of this sequence caused morphological and growth changes characteristic of partial transformation in D/WT cells. Moreover, to test whether PKCdelta was involved in growth control and transformation in this model, we overexpressed PKCdelta in D/src cells. Transfected cells underwent marked growth and morphological modifications toward the D/WT phenotype. In a late stage in culture, transfected cells ceased to proliferate, rounded up and degenerated into multinucleated, giant-like cells. We conclude that PKCdelta can reverse the transformed phenotype and act as a suppressor of cell growth in D/src cells. Moreover, our data show that downregulation of this isoenzyme of PKC may cooperate in the neoplastic transformation induced by the src oncogene in D/WT cells. (+info)