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PubMed1998

Antinociceptive effects of intrathecal L-type calcium channel blockers on visceral and somatic stimuli in the rat.

UNLABELLED: L-type calcium channels can modulate neuronal transduction in the spinal cord. However, their role in noxious information processing in animals that are physiologically intact has not been elucidated. We evaluated the effects of L-type calcium channel blockers diltiazem and verapamil on somatic and visceral nociception at the level of the spinal cord. Intrathecal catheters were inserted at the L4-5 level in Sprague-Dawley rats. The tail flick (TF) test and colorectal distension (CD) test were used to assess somatic and visceral antinociceptive effects, respectively. Motor function was assessed by posture and muscle tone in the limbs. TF latency and CD threshold were measured before and for 180 min after the intrathecal administration of verapamil (50, 100, 300, and 500 microg), diltiazem (100, 300, 500, and 1000 microg), or isotonic sodium chloride solution. The percent maximal possible effect (%MPE) was calculated by transforming response threshold in TF and CD tests. Intrathecally administered diltiazem or verapamil increased both TF latency and CD threshold in a dose-dependent fashion. Isotonic sodium chloride solution, diltiazem 100 microg, and verapamil 50 microg did not increase %MPE in either test. Diltiazem 300 or 500 microg or verapamil 300 or 500 microg significantly (P < 0.05) increased %MPE, with the peak effects 5 min after administration and short-duration antinociception. %MPE was 100% until 15 min after the administration of diltiazem 1000 microg, and significant antinociception continued until 180 min in the TF test. Motor paralysis was observed after the administration of the larger dose of each drug. We demonstrated that intrathecally administered L-type calcium channel blockers diltiazem or verapamil produced both somatic and visceral antinociception and motor block dose-dependently. IMPLICATIONS: We examined the effects of intrathecally administered L-type calcium channel blockers diltiazem and verapamil on somatic and visceral nociception in rats. L-type calcium channel blockers produced antinociceptive effects, suggesting a possible clinical application to control pain.

Analgesics↗

PubMed1997

Comparison of N- and P/Q-type voltage-gated calcium channel current inhibition.

Activation of N- and P/Q-type voltage-gated calcium channels triggers neurotransmitter release at central and peripheral synapses. These channels are targets for regulatory mechanisms, including inhibition by G-protein-linked receptors. Inhibition of P/Q-type channels has been less well studied than the extensively characterized inhibition of N-type channels, but it is thought that they are inhibited by similar mechanisms although possibly to a lesser extent than N-type channels. The aim of this study was to compare the inhibition of the two channel types. Calcium currents were recorded from adrenal chromaffin cells and isolated by the selective blockers omega-conotoxin GVIA (1 microM) and omega-agatoxin IVA (400 nM). The inhibition was elicited by ATP (100 microM) or intracellular application of GTP-gamma-S. It was classified as voltage-sensitive (relieved by a conditioning prepulse) or voltage-insensitive (present after a conditioning prepulse). The voltage-insensitive inhibition accounted for a 20% reduction of both currents, whereas the voltage-sensitive inhibition reduced the N-type current by 45% but the P/Q-type current by 18%. However, the voltage dependence of the inhibition, the time course of relief from inhibition during a conditioning prepulse, and the time course of reinhibition after such a prepulse showed few differences between the N- and P/Q-type channels. Assuming a simple bimolecular reaction, our data suggest that changes in the kinetics of the G-protein/channel interaction alone cannot explain the differences in the inhibition of the N- and P/Q-type calcium channels. The subtle differences in inhibition may facilitate the selective regulation of neurotransmitter release.

Adenosine Triphosphate↗

PubMed1992

Selective inhibitory effects of calcium channel antagonists on the two components of the neurogenic response of guinea pig vas deferens.

The effects of L-type calcium channel antagonists and omega-conotoxin on the contractile responses of guinea pig vas deferens were examined in vitro. Electrical stimulation of the postganglionic hypogastric nerve induced biphasic contraction consisting of rapid phasic and delayed tonic components. L-type calcium channel antagonists, such as diltiazem, verapamil and nicardipine, mainly inhibited the delayed tonic component, whereas omega-conotoxin mainly inhibited the rapid phasic component. Stimulations in the presence of prazosin and alpha, beta-methylene ATP induced rapid transient and delayed contraction, respectively, which were inhibited by omega-conotoxin and L-type calcium channel antagonists, respectively. Short-term stimulation with five pulses induced a small fast phasic contraction. This contraction, which could be desensitized by alpha, beta-methylene ATP, was inhibited by omega-conotoxin, but not by L-type calcium channel antagonists. At the concentrations used in the present study, none of the calcium channel antagonists inhibited the contractions induced by exogenously added ATP or norepinephrine. These findings suggest that L-type calcium channel antagonists and omega-conotoxin inhibit the neurotransmissions mediated by norepinephrine and ATP, respectively, from the postganglionic nerve to the vas deferens of the guinea pig. Inhibition of the voltage-dependent calcium channel is discussed in relation to the mechanism of cotransmission in this preparation.

Adenosine Triphosphate↗

PubMed1985

Calcium channel blockade and asthma--the current position.

Calcium has a central role coupling stimulus to cellular activities such as secretion and contraction. Because calcium is critical for airway smooth muscle contraction, degranulation of mast cells and secretion of mucus, there has been great interest and hope in the use of calcium channel blockers in the treatment of asthma. We here discuss the effects of calcium channel blockers and also review clinical studies of these drugs in asthma, focusing on recent findings. There have been several recent reviews on this topic (1,2) and it is now possible to evaluate the role of these drugs in the management of asthma.

Asthma↗

PubMed1998

Randomised controlled double-blind trial of the calcium channel antagonist amlodipine in the treatment of acute alcoholic hepatitis.

BACKGROUND/AIMS: Calcium channel blockers have a hepatoprotective action in animal models of alcohol-induced liver injury but their effect in alcoholic liver disease in humans has not been previously investigated. We have conducted a randomised, placebo-controlled trial to investigate the possible benefit of the calcium channel blocker amlodipine in terms of 4-week survival in hospitalised patients with severe acute alcoholic hepatitis. METHODS: Sixty-two patients with acute alcoholic hepatitis were randomised to receive 5-10 mg amlodipine each day for 1 year or an identical capsule containing placebo. In 36 (58%), acute alcoholic hepatitis was confirmed on biopsy and in the remainder on clinical and laboratory criteria. There were no statistically significant differences in clinical characteristics and disease severity in the treated and placebo groups. RESULTS: Of the 32 patients receiving amlodipine, there were six deaths (19%) in the first 4 weeks compared with seven (23%) of the placebo patients (p=0.329). Causes of death were similar in the amlodipine and control groups, with liver failure predominant. Analysis by the Cox proportional hazards model after adjustment for other prognostic factors showed survival was not significantly influenced by active treatment (p=0.07). One patient in each group was withdrawn because of the development of hypotension, but this did not recur on reintroduction of the capsules. CONCLUSIONS: This study shows that calcium channel blockers are well tolerated with few side effects in advanced alcoholic liver disease, but there is no conclusive evidence from this study that calcium channel blockers are helpful in the treatment of alcoholic hepatitis.

Acute Disease↗

PubMed1993

Voltage-operated calcium channels in fresh and cultured rat retinal pigment epithelial cells.

PURPOSE: There is little known about the membrane properties of retinal pigment epithelial (RPE) cells with respect to calcium. The authors attempted to characterize membrane calcium channels from solitary fresh and cultured RPE cells from normal and dystrophic rat retinas. METHODS: RPE cells were enzymatically dissociated from eyes of neonatal rats of several strains, including dystrophic RCS strains. Membrane currents were recorded using the whole-cell version of the patch-clamp technique from either fresh or cultured cells. RESULTS: The authors observed sustained high-voltage-activated calcium channels that were dihydropyridine sensitive and closely resembled neuronal L-type calcium channels. The RCS-rdy+p+ strain was mainly investigated, but high-voltage-activated calcium channels were also recorded from fresh RPE cells of other rats regardless of age or strain, including RCS p+, RCS rdy+, Long Evans, Sprague Dawley, and also cultured RPE cells taken from a neonatal Long Evans strain. Low-voltage-activated calcium channels were not observed in any of these cells. CONCLUSION: Voltage-operated calcium channels of the L-type are the main calcium channels present in rat RPE cells. Cultured cells retained the identical channels. The dystrophic RCS strains (studied until 17 days postnatal) also exhibited these channels.

Animals↗

PubMed1994

Beta-blocker and calcium channel blocker toxicity.

Toxicity from beta-blocker and calcium channel blocker drugs is a challenging medical emergency with steadily increasing incidence. Clinical manifestations of intoxication with these drugs are presented in light of known pharmacologic and pharmacokinetic properties, as well as the physiology of the beta-adrenoreceptor and calcium channel. Review of clinical and basic science literature provides the basis for specific management guidelines for beta-blocker and calcium channel blocker toxicity.

Adrenergic beta-Antagonists↗

PubMed1986

Selective enhancement of angiotensin II- and potassium-stimulated aldosterone secretion by the calcium channel agonist BAY K 8644.

Recent studies with dihydropyridine calcium channel antagonists have indicated that voltage-sensitive calcium channels (VSCC) play a major role in the control of aldosterone secretion. The modulation of VSCC by physiological regulators of zona glomerulosa function was further evaluated by analysis of the actions of the dihydropyridine calcium channel agonist BAY K 8644 (BK 8644) on basal and stimulated aldosterone production in isolated rat glomerulosa cells. In the presence of normal K+ concentrations (3.5-4.5 mM), only high concentrations of BK 8644 (greater than or equal to 100 nM) stimulated aldosterone secretion. However, addition of 10 nM BK 8644 markedly enhanced steroid production (70% over control) in cells stimulated by incubation in 7.5 mM K+ or 0.1 nM angiotensin II (AII). Greater enhancement was achieved with 1 microM BK 8644, with aldosterone secretion 150% and 300% above control levels for K+ and AII, respectively. In AII-stimulated cells, 30 nM BK 8644 enhanced aldosterone secretion at all peptide concentrations studied, including a 70% increase in the maximum steroid response, with no change in sensitivity to AII. In K+-stimulated cells, the effects of BK 8644 were dependent on the medium concentration of K+. At submaximally stimulating K+ concentrations (less than 9 mM), 30 nM BK 8644 increased the sensitivity of glomerulosa cells to K+ with no change in the maximal aldosterone response. However, at supramaximally stimulating concentrations of K+ (greater than 10 mM), BK 8644 reduced aldosterone production by 50%. In contrast to the effects of BK 8644 on cells stimulated with K+ or AII, the channel agonist had no effect on the action of ACTH. The ability of BK 8644 to enhance the maximum aldosterone response to AII suggests that AII, unlike K+, does not fully activate the Ca2+ influx pathway that leads to aldosterone secretion. Since BK 8644 is believed to facilitate Ca2+ influx primarily through previously activated channels, these results suggest that VSCC in the rat glomerulosa cell are partially operative under basal conditions, and that the same types of channels are further activated by AII and K+.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1997

Low-voltage-activated calcium channels in the lamprey locomotor network: simulation and experiment.

To evaluate the role of low-voltage-activated (LVA) calcium channels in the lamprey spinal locomotor network, a previous computer simulation model has been extended to include LVA calcium channels. It is also of interest to explore the consequences of a LVA conductance for the electrical behavior of the single neuron. The LVA calcium channel was modeled with voltage-dependent activation and inactivation using the m3h form, following a Hodgkin-Huxley paradigm. Experimental data from lamprey neurons was used to provide parameter values of the single cell model. The presence of a LVA calcium conductance in the model could account for the occurrence of a rebound depolarization in the simulation model. The influence of holding potential on the occurrence of a rebound as well the latency at which it is elicited was investigated and compared with previous experiments. The probability of a rebound increased at a more depolarized holding potential and the latency was also reduced under these conditions. Furthermore, the effect of changing the holding potential and the reversal potential of the calcium dependent potassium conductance were tested to determine under which conditions several rebound spikes could be elicited after a single inhibitory pulse in the simulation model. A reduction of the slow afterhyperpolarization (sAHP) after the action potential reduced the tendency for a train of rebound spikes. The experimental effects of gamma-aminobutyric acid-B (GABA(B)) receptor activation were simulated by reducing the maximal LVA calcium conductance. A reduced tendency for rebound firing and a slower rising phase with sinusoidal current stimulation was observed, in accordance with earlier experiments. The effect of reducing the slow afterhyperpolarization and reducing the LVA calcium current was tested experimentally in the lamprey spinal cord, during N-methyl-D-aspartate (NMDA)-induced fictive locomotion. The reduction of burst frequency was more pronounced with GABA(B) agonists than with apamin (inhibitor of K(Ca) current) when using high NMDA concentration (high burst frequency). The burst frequency increased after the addition of a LVA calcium current to the simulated segmental network, due to a faster recovery during the inhibitory phase as the activity switches between the sides. This result is consistent with earlier experimental findings because GABA(B) receptor agonists reduce the locomotor frequency. These results taken together suggest that the LVA calcium channels contribute to a larger degree with respect to the burst frequency regulation than the sAHP mechanism at higher burst frequencies. The range in which a regular burst pattern can be simulated is extended in the lower range by the addition of LVA calcium channels, which leads to more stable activity at low locomotor frequencies. We conclude that the present model can account for rebound firing and trains of rebound spikes in lamprey neurons. The effects of GABA(B) receptor activation on the network level is consistent with a reduction of the calcium current through LVA calcium channels even though GABA(B) receptor activation will affect the sAHP indirectly and also presynaptic inhibition.

Animals↗

PubMed2002

Single-channel pharmacology of mibefradil in human native T-type and recombinant Ca(v)3.2 calcium channels.

To study the molecular pharmacology of low-voltage-activated calcium channels in biophysical detail, human medullary thyroid carcinoma (hMTC) cells were investigated using the single-channel technique. These cells had been reported to express T-type whole-cell currents and a Ca(v)3.2 (or alpha 1H) channel subunit. We observed two types of single-channel activity that were easily distinguished based on single-channel conductance, voltage dependence of activation, time course of inactivation, rapid gating kinetics, and the response to the calcium agonist (S)-Bay K 8644. Type II channels had biophysical properties (activation, inactivation, conductance) typical for high-voltage-activated calcium channels. They were markedly stimulated by 1 microM (S)-Bay K 8644, allowing to identify them as L-type channels. The channel termed type I is a low-voltage-activated, small-conductance (7.2 pS) channel that inactivates rapidly and is not modulated by (S)-Bay K 8644. Type I channels are therefore classified as T-type channels. They were strongly inhibited by 10 microM mibefradil. Mibefradil block was caused by changes in two gating parameters: a pronounced reduction in fraction of active sweeps and a slight shortening of the open-state duration. Single recombinant low-voltage-activated T-type calcium channels were studied in comparison, using human embryonic kidney 293 cells overexpressing the pore-forming Ca(v)3.2 subunit. Along all criteria examined (mechanisms of block, extent of block), recombinant Ca(v)3.2 interact with mibefradil in the same way as their native counterparts expressed in hMTC cells. In conclusion, the pharmacologic phenotype of these native human T-type channels--as probed by mibefradil--is similar to recombinant human Ca(v)3.2.

Calcium Channel Blockers↗

PubMed1993

Chlordiazepoxide block of two types of calcium channels in neuroblastoma cells.

Chlordiazepoxide is a benzodiazepine that is widely used as a minor tranquilizer. It is also effective in the treatment of acute alcohol withdrawal. In this setting, chlordiazepoxide acts as a sedative and prevents the development of epileptiform activity. Although benzodiazepines are known to augment gamma-aminobutyric acid-activated chloride channels, an action which at least partially accounts for their anticonvulsant properties, there is some evidence to suggest that voltage-activated calcium channels may also be the target of these agents. We therefore studied the effect of chlordiazepoxide in blocking two distinct types of voltage-activated calcium channels in N1E-115 neuroblastoma cells. Chlordiazepoxide reversibly blocked calcium channels in both closed and open configurations. It was slightly more potent in blocking the transient (T-type or type I) than the long-lasting (L-type or type II) type of calcium channels with apparent Ki values of 311 and 398 microM, respectively. In the presence of chlordiazepoxide, the currents of both types of calcium channel currents decayed more quickly than control, an observation that suggests open channel block. Chlordiazepoxide-induced block of T-type calcium channels was use dependent, increasing with an increase in stimulus frequency. This was due primarily to the acceleration of current decay and slowing of recovery from inactivation by chlordiazepoxide. These calcium channel blocking actions could contribute some to the sedative and anticonvulsant properties of chlordiazepoxide in patients suffering from acute alcohol withdrawal and in electric shock-induced seizures in animal models.

Animals↗

PubMed1990

Biochemical analysis of L-type calcium channels from skeletal and cardiac muscle.

The development of specific pharmacological agents that modulate different types of ion channels has prompted an extensive effort to elucidate the molecular structure of these important molecules. The calcium channel blockers that specifically modulate the L-type calcium channel activity have aided in the purification and reconstitution of this channel from skeletal muscle transverse tubules. The L-type calcium channel from skeletal muscle is composed of five subunits designated alpha 1, alpha 2, beta, gamma, and sigma. The alpha 1-subunit is the pore-forming polypeptide and contains the ligand binding and phosphorylation sites through which channel activity can be modulated. The role of the other subunits in channel function remains to be studied. The calcium channel components have also been partially purified from cardiac muscle. The channel consists of at least three subunits that have properties related to the subunits of the calcium channel from skeletal muscle. A core polypeptide that can form a channel and contains ligand binding and phosphorylation sites has been identified in cardiac preparations. Here we summarize recent biochemical and molecular studies describing the structural features of these important ion channels.

Animals↗

PubMed1988

Noradrenaline contracts arteries by activating voltage-dependent calcium channels.

Noradrenaline (NA) regulates arterial smooth muscle tone and hence blood vessel diameter and blood flow. NA apparently increases tone by causing a calcium influx through the cell membrane. Two calcium influx pathways have been proposed: voltage-activated calcium channels and NA-activated calcium-permeable channels that are voltage-insensitive. Although voltage-activated calcium channels have been identified in arterial smooth muscle, voltage-insensitive calcium channels activated by NA have not. We show here that NA contractions of rabbit mesenteric arteries increase with depolarization. The increase parallels the elevation of open-state probability (P0) of single, voltage-dependent calcium channels. The action of noradrenaline can be explained by NA-activating voltage-dependent calcium channels, rather than by opening a second type of channel. We show directly that NA increases the open-state probability of single calcium channels. Thus, in the presence of NA, calcium entry through voltage-dependent calcium channels can regulate smooth muscle tone at physiological membrane potentials. These results may have relevance to pathophysiological conditions such as hypertension.

Animals↗

PubMed1997

Pharmacologic and pharmacokinetic profile of mibefradil, a T- and L-type calcium channel antagonist.

Mibefradil is a recently introduced calcium antagonist that, as a tetralol derivative, is chemically distinct from previous calcium antagonists. This article will review pertinent results from in vitro, animal, and clinical investigations to report the pharmacologic properties that distinguish mibefradil from all of the calcium channel antagonists in use today, all of which operate on the "L-type" calcium channel. Mibefradil's pharmacokinetic profile indicates it can be used as a once-daily oral treatment for hypertension and chronic stable angina pectoris.

Animals↗

PubMed1986

Reconstitution of the voltage-sensitive calcium channel purified from skeletal muscle transverse tubules.

The purified calcium antagonist receptor of the voltage-sensitive calcium channel from skeletal muscle transverse tubule membrane consists of three subunits: alpha with Mr 135 000, beta with Mr 50 000, and gamma with Mr 33 000. Purified receptor preparations were incorporated into phosphatidylcholine (PC) vesicles by addition of PC in 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate and removal of detergent by molecular sieve chromatography. Forty-five percent of the alpha, beta, and gamma polypeptides and the [3H]dihydropyridine/receptor complex were recovered in association with PC vesicles. The rate of dissociation of the purified and reconstituted dihydropyridine/receptor complex was identical with that in T-tubule membranes, and allosteric modulation by verapamil and diltiazem was retained. The reconstituted calcium antagonist receptor, when occupied by the calcium channel activator BAY K 8644, mediated specific 45Ca2+ and 133Ba2+ transport into the reconstituted vesicles. 45Ca2+ influx was blocked by the organic calcium antagonists PN200-110 (K0.5 = 0.2 microM), D600 (K0.5 = 1.0 microM), and verapamil (K0.5 = 1.5 microM) and by inorganic calcium channel antagonists (La3+ greater than Cd2+ greater than Ni2+ greater than Mg2+) as in intact T-tubules. A close quantitative correlation was observed between the presence of the alpha, beta, and gamma subunits of the calcium antagonist receptor and the ability to mediate 45Ca2+ or 133Ba2+ flux into reconstituted vesicles. Comparison of the number of reconstituted calcium antagonist receptors and functional channels supports the conclusion that only a few percent of the purified calcium antagonist receptor polypeptides are capable of mediating calcium transport as previously demonstrated for calcium antagonist receptors in intact T-tubules.

Animals↗

PubMed1991

Calcium-channel drugs: structure-function relationships and selectivity of action.

Calcium channels are ubiquitously distributed in excitable cells. The calcium-channel antagonists interact specifically at the L subclass of channels to mediate cardiovascular effects. These channels may be considered as pharmacologic receptors with specific drug binding sites and subject to a variety of regulatory influences. Each site is specific for agents of the three principal structural classes--the phenylalkylamines, the 1,4-dihydropyridines, and the benzothiazepines--and each exhibits defined structure-activity relationships. The 1,4-dihydropyridine structure exhibits both potent antagonistic and activator properties. The calcium channel antagonists exhibit considerable selectivity of action in the cardiovascular system, both between and within structural groups. This selectivity has a variety of causes including voltage dependence of the interaction, whereby the apparent affinity of the antagonist is determined by the membrane potential and stimulus pattern. Experimental evidence underlying the structure-activity relationships and the voltage-dependent behavior of 1,4-dihydropyridines is reviewed.

Calcium↗

PubMed2002

Use of a purified and functional recombinant calcium-channel beta4 subunit in surface-plasmon resonance studies.

Native high-voltage-gated calcium channels are multi-subunit complexes comprising a pore-forming subunit Ca(v) and at least two auxiliary subunits alpha(2)delta and beta. The beta subunit facilitates cell-surface expression of the channel and contributes significantly to its biophysical properties. In spite of its importance, detailed structural and functional studies are hampered by the limited availability of native beta subunit. Here, we report the purification of a recombinant calcium-channel beta(4) subunit from bacterial extracts by using a polyhistidine tag. The purified protein is fully functional since it binds on the alpha1 interaction domain, its main Ca(v)-binding site, and regulates the activity of P/Q calcium channel expressed in Xenopus oocytes in a similar way to the beta(4) subunit produced by cRNA injection. We took advantage of the functionality of the purified material to (i) develop an efficient surface-plasmon resonance assay of the interaction between two calcium channel subunits and (ii) measure, for the first time, the affinity of the recombinant His-beta(4) subunit for the full-length Ca(v)2.1 channel. The availability of this purified material and the development of a surface-plasmon resonance assay opens two immediate research perspectives: (i) drug screening programmes applied to the Ca(v)/beta interaction and (ii) crystallographic studies of the calcium-channel beta(4) subunit.

Animals↗

PubMed1988

Regulation of relaxin release from monodispersed porcine luteal cells: effect of calcium ionophore A23187 and calcium channel blockers.

The role of calcium ion mobilization in modulation of secretion of the ovarian protein hormone relaxin by porcine luteal cells was examined by use of a reverse hemolytic plaque assay. In this assay, luteal cells were cocultured in monolayers with protein-A-coupled ovine erythrocytes. In the presence of porcine relaxin antiserum and complement, a zone of hemolysis, a plaque, developed around relaxin-releasing luteal cells. The rate of development of plaques in time-course experiments was used in this study as an index of the rate of relaxin release. Exposure of luteal cell-containing monolayers to the calcium-mobilizing agent A23187 (40 nM to 5 microM) resulted in a dose-related increase in the rate of relaxin-plaque formation. This effect [and the influence of a stimulatory secretagogue, prostaglandin E2 (PGE2; 1 microM)] was suppressed by coculture with Co2+ (5 mM), a calcium channel blocker. These results are consistent with the view that calcium ion redistribution within porcine luteal cells forms a pathway that subserves, at least in part, the rates of basal and stimulated relaxin release in vitro. However, A23187 was equally effective in enhancing the rate of plaque formation when the monolayers were bathed in a low calcium medium (mean +/- SEM, 6.61 +/- 0.92 microM Ca2+), rather than a calcium-replete medium (1.56 +/- 0.09 mM Ca2+). Likewise, neither basal nor PGE2-stimulated (1 microM) relaxin secretion was abrogated by culture of monolayers in low calcium medium. These data suggest that the stimulatory effect of A23187 (and perhaps PGE2) arose predominantly through redistribution of calcium stored within intracellular sites in luteal cells, rather than entrance of calcium into the cell from the extracellular medium. Yet, incompatible with this interpretation, we observed that TMB-8 [8-(N,N-diethylamino)octyl 3,4,5-trimethoxybenzoate hydrochloride; a putative inhibitor of intracellular calcium redistribution] enhanced rather than blocked A23187- or PGE2-stimulated relaxin release. This result is consistent with the possibility that TMB-8 mobilized (rather than blocked) calcium in this cell system or that it acted via calcium-independent mechanisms. We conclude that calcium mobilization has the potential to act as a molecular pathway that transduces secretion of an ovarian peptide hormone, relaxin. However, the exact nature and physiological role(s) of the Ca2+ pathway in the control of relaxin secretion and the interrelationships of this mechanism with other intracellular messengers that may also modulate ovarian peptide secretion remain to be more clearly defined.

Animals↗