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At least 343 records · Page 19Linked to original sources
PubMed2001

Effects of amlodipine on unitary non-L-type high voltage-activated Ca2+ channel currents in differentiated PC12 cells.

Effects of amlodipine on unitary non-L-type high voltage-activated Ca2+ channels (Cav2 channels) were investigated in cell-attached patches of nerve growth factor (NGF)-differentiated PC12 cells. Cav2 channels, mainly composed of N-type channel in our experimental condition, were defined in this study as high voltage-activated Ca2+ channels obtained after selection of patches without L-type channel "mode 2" activity in the presence of 1 microM BayK8644, or L-type channel block by 5 microM nifedipine. At a test potential of +20 mV, they had a unitary current amplitude of approximately 0.5 pA and open time constants of approximately 0.4 ms and approximately 1.1 ms when fit assuming double exponential components. As bath application of amlodipine was ineffective to modify Cav2 channels in the sealed patch, we analyzed the channel activity when giga-seal formation was obtained in the presence of amlodipine (10 microM both in the pipette and bath solution). Amlodipine did not modify the unitary current amplitude but suppressed the channel open probability (NPo) when holding potential was depolarized, shifting the voltage-dependent inactivation curve towards negative potentials by 25mV. Amlodipine-induced suppression of NPo was mainly due to the decreased ratio of sweeps with channel openings (availability) and was not associated with changes in open time constants. These results were consistent with the view that amlodipine prevented channel openings through the high-affinity binding to the inactivated state, as often observed when dihydropyridines block L-type Ca2+ channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Two types of pharmacologically distinct Ca(2+) currents with voltage-dependent similarities in zona fasciculata cells isolated from bovine adrenal gland.

Voltage-activated Ca(2+) currents, in zona fasciculata cells isolated from calf adrenal gland, were characterized using perforated patch-clamp recording. In control solution (Ca(2+): 2.5 mm) a transient inward current was followed, in 40% of the cells, by a sustained one. In 20 mm Ba(2+), 61% of the cells displayed an inward current, which consisted of transient and sustained components. The other cells produced either a sustained or a transient inward current. These different patterns were dependent upon time in culture. Current-voltage relationships show that both the transient and sustained components activated, peaked and reversed at similar potentials: -40, 0 and +60 mV, respectively. The two components, fully inactivated at -10 mV, were separated by double-pulse protocols from different holding potentials where the transient component could be inactivated or reactivated. The decaying phase of the sustained component was fitted by a double exponential (time constants: 1.9 and 20 sec at +10 mV); that of the transient component was fitted by a single exponential (time constant: 19 msec at +10 mV). Steady-state activation and inactivation curves of the two components were superimposed. Their half activation and inactivation potentials were similar, about -15 and -34 mV, respectively. The sustained component was larger in Ba(2+) than in Sr(2+) and Ca(2+). Ni(2+) (20 microm) selectively blocked the transient component while Cd(2+) (10 microm) selectively blocked the sustained one. (+/-)Bay K 8644 (0.5 microm) increased the sustained component and nitrendipine (0.5-1 microm) blocked it selectively. The sustained component was inhibited by calciseptine (1 microm). Both components were unaffected by omega-conotoxin GVIA and MVIIC (0.5 microm). These results show that two distinct populations of Ca(2+) channels coexist in this cell type. Although the voltage dependence of their activation and inactivation are comparable, these two components of the inward current are similar to T- and L-type currents described in other cells.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

An L-type calcium channel in renal epithelial cells.

A voltage-activated Ca++ channel has been identified in the apical membranes of cultured rabbit proximal tubule cells using the patch-clamp technique. With 105 mm CaCl2 solution in the pipette and 180 NaAsp in the bath, the channel had a conductance of 10.4 +/- 1.0 pS (n = 8) in on-cell patches, and 9.8 +/- 1.1 pS (n = 8) in inside-out patches. In both on-cell and inside-out patches, the channel is active by membrane depolarization. For this channel, the permeation to Ba++ and Ca++ is highly selective over Na+ and K+ (PCa(Ba):PNa(K) >200:1). The sensitivity to dihydropyridines is similar to that for L-type channels where the channel was blocked by nifedipine (10 microM), and activated by Bay K 8644 (5 microM). When activated by Bay K 8644, the channel showed subconductance levels. Treatment with forskolin (12.5 microM), phorbol ester (1 microM), or stretching (40 cm water) did not activate this channel. These results indicate that this Ca++ channel is mostly regulated by membrane voltage, and appears to be an epithelial class of L-type Ca++ channel. As such, it may participate in calcium reabsorption during periods of enhanced sodium reabsorption, or calcium signaling in volume regulation, where membrane depolarization occurs for prolonged periods.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1998

Ca2+ uptake through voltage-gated L-type Ca2+ channels by polarized enterocytes from Atlantic cod Gadus morhua.

The presence and localization of voltage-gated Ca2+ channels of L-type were investigated in intestinal cells of the Atlantic cod. Enterocytes were loaded with the fluorescent Ca2+ probe, fure-2/AM and changes in intracellular Ca2+ concentrations ([Ca2+]i) were measured, in cell suspensions, in the presence of high potassium levels (100 mm), BAY K-8644 (5 microM), nifedipine (5 microM) or omega-conotoxin (1 microM). L-type Ca2+ channels were visualized on intestinal sections using the fluorescent dihydropyridine (-)-STBodipy. Depolarization of the plasma membrane produced a rapid (within 5 sec) and transient (at basal levels after 21 sec) increase in [Ca2+]i. BAY K-8644 increased the [Ca2+]i by 7.2%. Cells in a Ca2+-free buffer increased [Ca2+]i after addition of 10 mm Ca2+, and this increase was abolished by nifedipine in both depolarizing and normal medium but not by omega-conotoxin. Single cell experiments using video microscopy revealed that enterocytes remained polarized several hours after preparation and that the Ca2+ entry and extrusion occurred at specific and different regions of the enterocyte outer membrane. Fluorescent staining of L-type Ca2+ channels in the intestinal mucosa showed the most intense staining at the brushborder membrane. These results demonstrate the presence of voltage gated L-type Ca2+ channels in enterocytes from the Atlantic cod. The channels are mainly located at the apical side of the cells, and there is a polarized uptake of Ca2+ into the enterocytes. This suggests that the L-type Ca2+ channels are involved in the transcellular Ca2+ entry into the enterocytes.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2003

L-type Ca2+ channel and Ca2+-permeable nonselective cation channel as a Ca2+ conducting pathway in myocytes isolated from the cricket lateral oviduct.

The Ca2+-conducting pathway of myocytes isolated from the cricket lateral oviduct was investigated by means of the whole-cell patch clamp technique. In voltage-clamp configuration, two types of whole cell inward currents were identified. One was voltage-dependent, initially activated at -40 mV and reaching a maximum at 10 mV with the use of 140 mM Cs2+-aspartate in the patch pipette and normal saline in the bath solution. Replacement of the external Ca2+ with Ba2+ slowed the current decay. Increasing the external Ca2+ or Ba2+ concentration increased the amplitude of the inward current and the current-voltage (I-V) relationship was shifted as expected from a screening effect on negative surface charges. The inward current could be carried by Na+ in the absence of extracellular Ca2+. Current carried by Na+ (INa) was almost completely blocked by the dihydropyridine Ca2+ channel antagonist, nifedipine, suggesting that the INa is through voltage-dependent L-type Ca2+ channels. The other inward current is voltage-independent and its I-V relationship was linear between -100 mV to 0 mV with a slight inward rectification at more hyperpolarizing membrane potentials when 140 mM Cs+-aspartate and 140 mM Na+-gluconate were used in the patch pipette and in the bath solution, respectively. A similar current was observed even when the external Na+ was replaced with an equimolar amount of K+ or Cs+, or 50 mM Ca2+ or Ba2+. When the osmolarity of the bath solution was reduced by removing mannitol from the bath solution, the inward current became larger at negative potentials. The I-V relationship for the current evoked by the hypotonic solution also showed a linear relationship between -100 mV to 0 mV. Bath application of Gd3+ (10 microM) decreased the inward current activated by membrane hyperpolarization. These results clearly indicate that the majority of current activated by a membrane hyperpolarization is through a stretch-activated Ca2+-permeable nonselective cation channel (NSCC). Here, for the first time, we have identified voltage-dependent L-type Ca2+ channel and stretch-activated Ca2+-permeable NSCCs from enzymatically isolated muscle cells of the cricket using the whole-cell patch clamp recording technique.

Animals↗
PubMed2000

The absorption of calcium ions from the ovine reticulo-rumen.

Net Ca2+ and Mg2+ absorption rates were measured in vivo from buffer solutions placed in the washed reticulo-rumen, isolated in situ in 30 conscious, trained sheep. An increase in concentration of short chain fatty acids (SCFA) in the buffer, over the range 0-50 mM, was shown to stimulate the net rates of absorption of Ca2+ and Mg2+ ions from the rumen. Similarly, the results of in vitro experiments, carried out with ovine rumen epithelium mounted in short-circuited Ussing chambers, showed that the absence of SCFA from the chamber fluid resulted in a reduction in Jnet Ca2+ caused by reduced flux of Ca2+ ions in the mucosal to serosal direction (Jms Ca2+). The addition of 1 mM acetazolamide, an inhibitor of carbonic anhydrase, to the ruminal buffer used in the in vivo experiments led to significant reductions in the net absorption rates of Ca2+ and Mg2+ ions in the presence of SCFA (50 mmol x l(-1)) but not in the absence of SCFA. However, in the in vitro experiments, the addition of 60 microM ethoxyzolamide had no significant effect on Jnet Ca2+. A reduction in pH of the intraruminal buffer in vivo from 6.8 to 5.4 led to significant increases in the net absorption rates of Ca2+ and Mg2+ ions, an effect which was duplicated for Ca2+ in preliminary in vitro experiments in which the pH of the mucosal buffer was reduced from 7.4 to 5.4. This stimulatory effect was confined to Jms Ca2+ and Jnet Ca2+. Ussing chambers were also used to demonstrate that Jnet Ca2+ was reduced by a high transmural potential difference (PD), caused by voltage clamping, independently of the mucosal K+ concentration. Both unidirectional Ca2+ fluxes consisted of a PD-dependent and a K+-insensitive PD-independent component. The latter may be represented by a Ca2+/ 2H+ antiporter. It is postulated that SCFA, and to a lesser extent H2CO3, can stimulate Jms Ca2+ by activation of an apical Ca2+/2H+ antiporter through the provision of protons within the ruminal epithelial cell. A mild reduction in ruminal pH may also lead to a similar stimulation of this putative electroneutral exchange.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

The force-frequency relationship is dependent on Ca(2+)-influx via L-type- and SR-Ca(2+)-channels in human heart.

UNLABELLED: The present study investigated the influence of Bay K 8644 and nifedipine (Nif) on the force-frequency relationship and on tetanic tension and force of contraction of failing human myocardium (PAP, n = 12). In addition, ryanodine (Rya) was studied on the force-frequency relationship. Bay K 8644 (0.1 microM) increased, but Nif (0.01 microM) reduced isometric force of contraction significantly. However, both, Bay K 8644 (2 Hz vs. 0.5 Hz: CONTROL: -31.6 +/- 7.8%; +Bay K 8644: +103 +/- 30% (% basal); p < 0.005) as well as Nif (2 Hz vs. 0.5 Hz: CONTROL: -8.8 +/- 9.7%; +Nif: +90.9 +/- 31.5% (% basal); p < 0.05), were able to restore a positive FFR in PAP. By measurement of tetanic tension and posttetanic potentiation in the presence of the 1,4-dihydropyridines, we support the hypothesis of the existence and functional relevance of a dihydropyridin-ryanodine receptor junctional complex. In skinned fiber preparations, Bay K 8644 showed no effect on Ca(2+)-sensitivity or caffeine induced Ca(2+)-release. Rya (10 microM) decreased force of contraction in PAP and was effective in restoring a positive FFR (2 Hz vs. 0.5 Hz: CONTROL: -7.3 +/- 5.1%; +Rya: +98.0 +/- 31.9% (% basal); p < 0.05). Thus, the altered FFR and Ca(2+)-homeostasis in failing human myocardium may result from changes in sarcolemmal Ca(2+)-influx and/or from altered SR-Ca(2+)-load.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2001

L-type calcium currents in atrial myocytes from patients with persistent and non-persistent atrial fibrillation.

OBJECTIVE: In patients with persistent atrial fibrillation (AF), the atrial myocardium is characterized by a reduced contractile force, by a shortened duration of the action potential and a recently demonstrated reduction of the L-type Ca2+ currents. We analyzed potential effects on L-type Ca2+ currents of the patients' medication and of the duration of AF. METHODS AND RESULTS: Human atrial myocytes were prepared from the right auricles of patients undergoing open-heart surgery. Three groups of patients were studied: a control group with sinus rhythm (SR, n = 26 patients) and a group with persistent AF (> 3 months duration; n = 10), a group with non-persistent AF (3 patients with SR but with documented episodes of AF in their history). L-type Ca2+ currents were measured during depolarizing pulses from a holding potential of -70 mV to a test potential of +10 mV and are given as mean +/- SEM of current densities (currents normalized to the cell capacitance). Ca2+ current densities were significantly (p < 0.0001) smaller in cells from patients with persistent AF than in control cells (0.54 +/- 0.08 pA/pF vs. 1.96 +/- 0.12 pA/pF). No indication was found that these changes were caused by medication with Ca2+ channel antagonists, beta blockers, or digitalis. Stimulation with the dihydropyridine Bay K 8644 (1 microM) or with isoproterenol (0.1 microM) increased Ca2+ currents in control cells 3.5 +/- 0.2 and 3.5 +/- 0.3-fold. In persistent AF, this increase was significantly larger (6.0 +/- 0.5 and 5.2 +/- 0.6-fold) but stimulated currents were still significantly lower than in control cells. Patients with non-persistent AF exhibited Ca2+ currents well within the control range. CONCLUSION: A reduction in Ca2+ currents, due to a reduction in number as well as a depression of L-type channels, is a characteristic and pathophysiologically important part of the myocardial remodeling during long-lasting atrial fibrillation. It is not present in patients with non-persistent AF and not caused by medication.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2002

Kinetics and Gbetagamma modulation of Ca(v)2.2 channels with different auxiliary beta subunits.

Modulation of calcium channels by both auxiliary subunits and G proteins was studied in cell-attached patches from COS-7 cells transfected with Ca(v)2.2 channel subunits (N-type, alpha(1)B and either beta(1b) or beta(2a)). These were co-expressed with either Gbeta(1)gamma(2) or the Gbetagamma-binding domain of beta-adrenergic-receptor kinase-1 to sequester endogenous Gbetagamma. Since G protein modulation of Ca(v) channels may affect both inactivation and activation, we examined Gbetagamma modulation of Ca(v)2.2 channels in the presence of two different beta-subunits that affect inactivation differently and compared in detail the single-channel characteristics of N-type channels expressed with either of these beta-subunit isoforms. The single-channel mean amplitude and mean open time were not influenced by the transfection combination. However, the mean closed time at +40 mV was increased for both beta(1b) and beta(2a)-subunits by co-transfection with Gbeta(1)gamma(2). This effect was absent at lower voltages as examined for channels with the beta(1b)-subunit. The distribution of latency-to-first-opening of Ca(v)2.2 channels was similar for both beta-subunit isoforms. However, the inclusion of the beta(2a) subunit resulted in channels with an additional, prominent, slow activation phase. Co-transfection of Gbeta(1)gamma(2) with Ca(v)2.2 channels markedly reduced the ensemble current amplitude and slowed the first latency. The inhibition imposed by Gbeta(1)gamma(2) was largely independent of the beta-subunit species. Facilitation of Gbetagamma-modulated currents (the channel response following a large and brief depolarising prepulse) was observed for channels with both beta-subunits and involved mainly enhancement of the activation, as assessed by the faster first latency. The inactivation process was strongly dependent on the beta-subunit species, with beta(1b) supporting inactivation and beta(2a) reducing this process. This difference was assessed by estimation of both steady-state inactivation (prepulse influence on test pulse responses) and the inactivation time course during depolarisation. At +40 mV, channels with the beta(1b)-subunit had a fast component of inactivation (time constant ~180 ms, 50%) and a slow phase with time constant of approximately 1 s, while the beta(2a)-subunit supported only a very slow inactivation process with time constant of approximately 5 s. Co-transfection of Gbeta(1)gamma(2) with the Ca(v)2.2 channel had no effect on the inactivation properties with either beta-subunit. In summary, we show that the inactivation properties of expressed Ca(v)2.2 channels depend largely on the beta-subunit species and to a minor extent only on the presence or absence of the Gbetagamma modulator. Furthermore, the activation, amplitude, mean open and closed times and G protein modulation of N-type channels were similar for both beta(1b)- and beta(2a)-subunits.

Algorithms↗
PubMed1996

The role of sarcoplasmic reticulum and sarcoplasmic reticulum Ca2+-ATPase in the smooth muscle tone of the cat gastric fundus.

Circular smooth muscle strips isolated from cat gastric fundus were studied in order to understand whether the sarcoplasmic reticulum (SR) and SR Ca2+-ATPase could play a role in the regulation of the muscle tone. Cyclopiazonic acid (CPA), a specific inhibitor of SR Ca2+-ATPase, caused a significant and sustained increase in muscle tone, depending on the presence of extracellular Ca2+. Nifedipine and cinnarizin only partially suppressed the CPA-induced tonic contraction. Bay K 8644 antagonized the relaxant effect of nifedipine in CPA-contracted fundus. Nitric-oxide-releasing agents sodium nitroprusside and 3-morpholino-sydnonimine completely suppressed the CPA-induced tonic contraction. The blockers of Ca2+-activated K+ channels, tetraethylammonium, charybdotoxin and/or apamin, decreased the contractile effect of CPA. Vanadate increased the tone but did not change significantly the effect of CPA. CPA exerted its contractile effect even when Ca2+ influx was triggered through the Na+/Ca2+ exchanger and the other Ca2+ entry pathways were blocked. Thapsigargin, another specific SR Ca2+-ATPase inhibitor, also increased the muscle tone. The effect of thapsigargin was completely suppressed by sodium nitroprusside and 3-morpholino-sydnonimine and partially by nifedipine. In conclusion, under conditions when the SR Ca2+-ATPase is inhibited, the tissue develops a strong tonic contraction and a large part of this is mediated by Ca2+ influx presumably via nifedipine-sensitive Ca2+ channels. This study suggests the important role of SR Ca2+-ATPase in the modulation of the muscle tone and the function of SR as a "buffer barrier" to Ca2+ entry in the cat gastric fundus smooth muscle.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Functional role of low-voltage-activated dihydropyridine-sensitive Ca channels during the action potential in adult rat sensory neurones.

Neuronal cell firing is crucial to nerve-nerve communication. The ability to produce consecutive action potentials is related to the activation of inward currents after each upstroke. If fast Na current is indeed responsible for the overshoot, it is still unclear which current drives membrane voltage to the Na threshold. In this study we present evidence that in adult rat sensory neurones a dihydropyridine-sensitive Ca channel exists in addition to the well characterized L-type, or high-threshold Ca channel. During stimulated action potential trains, L-type Ca channels open during the excitation wave, whereas activity of the other dihydropyridine-sensitive Ca channel was observed primarily between action potentials. This second Ca pathway shows remarkably long openings at negative potentials after a series of positive prepulses. The nerve action potential and the repetitive firing work as a physiological Ca channel facilitation mechanism. Therefore, we suggest that this novel Ca conductance provides inward current, between two consecutive action potentials, able to modulate the frequency of neuronal bursts.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1995

Alterations in L-type calcium channels in the brain and spinal cord of acutely treated and morphine-tolerant mice.

Opiate tolerance has been associated with changes in neuronal intracellular calcium levels. In vivo studies have indicated the involvement of dihydropyridine (DHP)-sensitive ('L-type') voltage-gated calcium channels in the morphine-tolerant state. In this study, we assessed how the morphine-tolerant state would affect the antinociception produced by intrathecal administration of two agents (Bay K 8644 and thapsigargin) that increase intracellular calcium. Morphine-tolerant mice displayed a 7-fold greater ED50 for Bay K 8644 antinociception than placebo-treated animals; no difference was found in the dose-response curve for thapsigargin. To further explore the role of the L-type channel in morphine tolerance development, we performed radiolabeled nitrendipine binding studies in the spinal cord and brain regions associated with pain modulation from acutely treated, tolerant, and control mice. Our treatment protocol produced a 4-fold shift in the ED50 for s.c. morphine antinociception, as determined by the tail-flick procedure. Binding site number and affinity were determined using Scatchard analysis for the following timepoints: 20 min and 60 min after s.c. injection of morphine or vehicle, as well as after 4 days of chronic administration, and after naloxone-precipitated withdrawal. Although some changes were observed in the affinity of nitrendipine for its receptor, a significant change in these measures was found only following naloxone administration, which produced increases in Bmax in both placebo- and morphine-treated mice.

Analgesics, Opioid↗
PubMed1996

Calcium modulates circadian variation in cAMP-stimulated melatonin in chick pineal cells.

In chick pineal cells, melatonin synthesis is regulated by both calcium and cAMP. Calcium-dependent regulation of melatonin is suggested by the monotonic decrease in melatonin observed with decreasing extracellular calcium ion concentrations ([Ca2+]0), the stimulation of melatonin with Bay K8644, and the inhibition of nocturnal melatonin by several calmodulin antagonists. At submicromolar [Ca2+]0, a stimulation of melatonin was observed in the presence of 8-Br cAMP, but not with Bay K8644, suggesting that this amount of stimulation of melatonin by 8-Br cAMP is independent of Ca2+ influx through dihydropyridine-sensitive Ca2+ channels. At micromolar [Ca2+]0, there was a further increase in the stimulation of melatonin by 8-Br cAMP that was not blocked by nifedipine, a dihydropyridine-sensitive Ca2+ channel antagonist. Micromolar [Ca2+]0 is required for the greater stimulation of melatonin by 8-Br cAMP during the night than during the day. Melatonin was stimulated by 8-Br cAMP to higher levels during the night than during the subjective day under normal [Ca2+]0 (1.3 mM). This difference in the amount of melatonin stimulated by 8-Br cAMP during the subjective night versus the subjective day was blocked by lowering [Ca2+]0 to a submicromolar concentration (0.2 microM). Both nifedipine and calmidazolium partially blocked nocturnal increases in melatonin, but were ineffective during the day. These results suggest that Ca2+ plays an important role in the differential ability of cAMP to stimulate melatonin during the night versus the day.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1990

Two subtypes of dihydropyridine-sensitive calcium channels in rat ventricular muscle.

Two opposite inotropic effects of the dihydropyridine activators, CGP 28392 and Bay K 8644, given at the same concentration (1-2 microM) were found in rat papillary muscles: a positive effect in polarized tissue (4 mM KCl) and a negative one during partial depolarization. The depressive effect found at a low rate or after a short rest was associated with marked prolongation of the Ca2(+)-mediated action potential, indicating that the drugs behave as Ca channel stimulators. The depressive effect of the activation on the resting state contraction was antagonized by nifedipine (2 microM) and high Mg2+ (5 mM). It was suggested that at least two subtypes of the L-type, dihydropyridine-sensitive channels underlie the opposite inotropic responses of the activators. The positive effect is apparently caused by conventional stimulation of Ca2+ entry through the cell membrane, whereas the negative effect is probably due to the stimulation of Ca2+ efflux from the sarcoplasmic reticulum, leading to depletion of intracellular stores. The effect was proposed to be mediated by activation of junctional channels linked to sarcoplasmic reticulum Ca2+ release. An important role for these channels in triggering the sarcoplasmic reticulum Ca2+ release and regulation of force-frequency relation is proposed.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1991

Inhibitory effect of 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) in vascular smooth muscle.

The inhibitory effects of 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) on vascular smooth muscle contraction and cytosolic Ca2+ level ([Ca2+]i) were examined using isolated rabbit aorta loaded with a fluorescent Ca2+ indicator, fura-2. TMB-8 (100 microM) decreased the high K(+)-induced increase in muscle tension, and [Ca2+]i and 45Ca2+ influx to their respective resting levels. TMB-8 (100 microM) almost completely inhibited the increase in [Ca2+]i and 45Ca2+ influx due to norepinephrine although muscle tension was only partially decreased. A higher concentration of TMB-8 (300 microM) inhibited the remaining portion of the contraction without additional decrease in [Ca2+]i. The inhibitory effect of TMB-8 on high K(+)-induced contraction, but not on the norepinephrine-induced contraction, was antagonized by the increase in external Ca2+ concentrations or by the Ca2+ channel activators, CGP 28,392 and by Bay K8644. In Ca(2+)-free solution, norepinephrine-induced transient increases in [Ca2+]i and muscle tension and 100 microM TMB-8 inhibited these changes. The caffeine-induced transient increases in [Ca2+]i and muscle tension were also inhibited by TMB-8 at concentrations higher than those needed to inhibit the norepinephrine-induced transient changes. In permeabilized smooth muscle, TMB-8 (300 microM) did not inhibit the Ca(2+)-induced contraction. These results suggest that TMB-8 inhibits vascular smooth muscle contractility by inhibiting Ca2+ influx, Ca2+ release and Ca2+ sensitization of contractile elements.

Animals↗
PubMed1993

Pharmacological characterization of effects of verapamil and GS 283 on isolated guinea pig and rat trachealis.

The pharmacological effects of verapamil and GS 283, 1-(4'-methoxybenzyl)-6,7-dihydroxy-3,4-dihydroxyisoquinoline, were investigated using isolated rat and guinea pig trachealis. Both verapamil and GS 283 inhibited carbachol-, histamine (only guinea pig)-, and high-K(+)-induced contraction in a dose-dependent manner. GS 283 acted as a weak histamine H1 and muscarinic receptor antagonist in guinea pig and rat trachealis with respective pKB values in the range of 5.60 approximately 6.12 and 5.17 approximately 5.83. On the other hand, pyrilamine and atropine showed a typical competitive antagonism on histamine (guinea pig) and on muscarinic receptors (rat trachea) with pKB values of 9.25 +/- 0.21 and 9.37 +/- 0.32, respectively. GS 283 inhibited Ca(2+)-induced contraction on guinea pig trachealis in Ca(2+)-free media. Furthermore, very high concentrations of GS 283 and verapamil completely abolished a phasic contraction induced by carbachol in Ca(2+)-free media, suggesting that verapamil and GS 283 can enter into the cytoplasm, where they may exert secondary actions on internal sites of the muscle, such as the sarcoplasmic reticulum. It is concluded that GS 283 has a Ca2+ antagonistic action along with weak histamine and muscarinic receptor blocking activity in isolated rat and guinea pig tracheal smooth muscle and its mode of action is likely inhibition of Ca2+ influx from plasma membrane and also release from the sarcoplasmic reticulum.

Animals↗
PubMed1993

Age-related changes in Ca2+ channel antagonist receptors in rabbit lower urinary tract.

(+)-[3H]PN 200-110 and [3H]nitrendipine binding sites were studied in 1 day, 6 week, 6 month and 4.5-5 year rabbit urethra, bladder base and bladder dome. In all age groups, the density of these Ca2+ channel antagonist binding sites was significantly greater in the urethra than in the bladder base or bladder dome, except that the density of [3H]nitrendipine binding sites in the 1 day rabbit was similar in all three regions. In the urethra the maximum number of binding sites for (+)-[3H]PN 200-110 was twice that for [3H]nitrendipine. In the bladder base and bladder dome both Ca2+ channel antagonists labelled a similar number of binding sites. For both ligands, the Bmax values for the Ca2+ channel antagonists in the urethra increased from 1 day to 6 weeks and then decreased. In the bladder base and dome, however, the receptor density decreased gradually or was unchanged with aging. The pharmacological profiles of these binding sites in 1 day and 6 month urethra and bladder dome showed K1 values with the following rank order: nitrendipine < niguldipine < BAY K 8644. These data demonstrate the presence of regional- and age-dependent changes in the density of Ca2+ channel antagonist binding sites in the lower urinary tract of the rabbit.

Aging↗