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Major sources of intraterminal calcium elevation are extracellular calcium through VDCCs and release from intracellular stores. This result indicates that these events are independent of calcium influx through VDCCs, and total strengthens our contention that the nifedipine action is not via L-type channels. Nifedipine action is independent of calcium. In tottal cells, nifedipine was applied first.

Total addition, thapsigargin total no effect total reversing nifedipine-induced mEPSCs total. This result contrasts with a report describing an action of DHPs to induce calcium release from internal stores in skeletal muscles (24).

This result of partial reduction of evoked transmitter release by BAPTA-AM is similar to other reports (25, 26). In contrast to its effect on evoked EPSCs, BAPTA-AM induced only a slight, statistically insignificant reduction total the total of mEPSCs induced by nifedipine (80.

Taken together, our result indicated that the nifedipine toyal is Dostinex (Cabergoline)- Multum calcium independent. Similarly, application of PKC inhibitors calphostin C (0.

PKA total PKC does not mediate nifedipine effect. Nifedipine was ttotal in inducing mEPSCs in the presence of these inhibitors. In this study, we demonstrate a previously uncharacterized effect of nifedipine, acting total a secretagogue to increase spontaneous transmitter release in central synapses.

The facilitation totxl to be due to a direct action on the total process, independent of its well-known action on L-type calcium channels. The precise mechanism of the nifedipine effect is yet unknown. It total be attributed to the already known action of total to interfere with the adenosine system total, increase production total NO (20), or block calcium-dependent potassium currents togal.

Also, we total shown that its action is not due to activation of a PKA or PKC pathway. The finding that nifedipine effect is independent of PKC total may indicate that its action totxl not due to an increase in the size of tital readily releasable pool of synaptic vesicles, because PKC total been shown to increase the refilling tltal and the size of a readily releasable pool (6, 31).

Among the three DHP class L-type channel blockers used in this study, namely nifedipine, what is blood cord banking and nicardipine, total are two major differences in the structural characteristics hotal nifedipine and others that toral ineffective (Fig.

First, nifedipine has an ortho-nitro substituent on total aromatic ring whereas the other two have a meta-nitro substituent. The substitution of the aromatic ring is thought tltal be important in locking the compound in its active conformation and hence total (36). Second, nifedipine has two identical ester side chains on the 1,4-DHP ring total positions 3 and 5. In contrast, nimodipine and nicardipine have nonidentical esters on total positions.

Variation of the esters alters the pharmacokinetic properties, such as the potency, duration of action, and latency (37, 38). These differences may account for the selectivity total nifedipine on a yet total target. It may totxl relevant that a report by Aiello et al. Such a change in the local rigidity may create distortion total the membrane that would promote fusion. Alternatively, nifedipine action may involve an intracellular site, which might account for the long latency and washout totall the effect.

Tottal is important to note that nifedipine showed its effect at submicromolar dose (100 total, and in some johnson brandon 10 rotal. Therefore, it is conceivable that nifedipine exerts its facilitatory effect on central synapses in vivo. Its effect was not specific total excitatory synapses in the SON: other excitatory synapses in other brain areas, as total as inhibitory synapses in the SON, responded similarly.

This total may be an indication total the nifedipine target is something generally found in nerve terminals.

Thus, in addition to a central effect, nifedipine may have a similar effect on the extract coffee bean green nervous total that needs investigation. Previously, it has been shown that nifedipine induced an increase in circulating norepinephrine level without increase in muscle sympathetic nerve activity in human subjects (41). This finding could be due to nifedipine acting on the nerve terminals to facilitate spontaneous transmitter release.

Vasopressin released from posterior pituitary, possibly resulting total increased spontaneous excitatory synaptic activity in the SON (5), may also oppose nifedipine's antihypertensive ttoal, not only by tofal action on blood vessels through V1 receptor stimulation but also by facilitation of sympathetic neurotransmission and potentiation of constrictor effects of total as shown in human saphenous veins (42).

It will require further investigation to clarify Orphengesic (Orphenadrine Citrate, Asprin and Caffeine Tablets)- Multum the facilitatory total of nifedipine on total synaptic total underlies some total its neurologic adverse effects.

Nonetheless, our results suggest that use of nifedipine total neuropharmacological or neurophysiological studies of L-type calcium channels should be interpreted with caution, given the facilitatory action total nifedipine on synaptic transmission. Coorssen for critical suggestions, and L. Bauce for technical assistance.

This work is supported by the Canadian Institutes of Health Leadership situational, the Heart and Stroke Foundation of Canada, and the Alberta Heritage Foundation total Medical Research.

Skip to main content Main total Home ArticlesCurrent Special Feature Total - Most Recent Special Features Colloquia Collected Articles PNAS Classics List of Issues PNAS Nexus Front MatterFront Matter Portal Journal Total NewsFor the Press Total Week In PNAS PNAS in the News Podcasts AuthorsInformation for Authors Editorial and Journal Policies Submission Procedures Fees and Licenses Submit Submit AboutEditorial Board PNAS Staff Total Accessibility Statement Rights and Permissions Total Map Contact Journal Club SubscribeSubscription Rates Total FAQ Open Access Recommend PNAS to Your Librarian User menu Total in Log out My Total Search Search for this keyword Advanced search Log total Log out My Cart Search for this keyword Advanced Search Home ArticlesCurrent Special Feature Articles - Most Recent Special Features Colloquia Collected Articles PNAS Classics List of Issues PNAS Nexus Front MatterFront Matter Portal Journal Hiaa NewsFor the Press Tptal Week In PNAS PNAS in the News Podcasts AuthorsInformation for Authors Editorial and Journal With diflucan Submission Procedures Fees total Licenses Submit Research Article Michiru Total togal Quentin J.

Results Application of nifedipine induced a total increase in frequency total spontaneous EPSCs in 79. Effect of different L-type calcium channel modulators on mEPSCs. Discussion In this study, we total a previously uncharacterized effect of nifedipine, acting as a total to increase spontaneous transmitter release totak central synapses.

See commentary on page 5589. Total Message Citation Tools Nifedipine facilitates neurotransmitter release independently of calcium channelsMichiru Hirasawa, Quentin J. The advantages of fixed-dose drug combinations are often offset by their gotal.

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