The multiple 5-hydroxytryptamine (5-HT, serotonin) receptor subtypes are distinguished. In this article, we described mainly the 5-HT4 receptor of four subtypes of functional 5-HT receptors, 5-HT1, 5-HT2, 5-HT3, and 5-HT4, recognized in the gastrointestinal tract. In-vivo microdialysis experiments determined that activation of the 5-HT4 receptor stimulated intestinal motor activity associated with a local increase in acetylcholine (ACh) release from the intestinal cholinergic neurons in the whole body of dogs. The 5-HT4 receptor-mediated response of ACh release in the antral, corporal, and fundic strips isolated from guinea pig stomach corresponds to the presence of 5-HT4 receptor in the myenteric plexus. In-vitro receptor autoradiograms of the stomach and colon indicate that the distribution of 5-HT4 receptors in human tissues is similar to that in the guinea pig, although density of 5-HT4 receptors in the myenteric plexus of human tissues is lower than that in guinea pig tissues. The 5-HT4 receptors located in the myenteric plexus may participate in gastrointestinal motility, and thus the 5-HT4 agonists and antagonists may be available for treatment of dysfunction of gastrointestinal motility.
We investigated the inactivation process of macroscopic cardiac L-type Ca(2+) channel currents using the whole cell patch-clamp technique with Na(+) as the current carrier. The inactivation process of the inward currents carried by Na(+) through the channel consisted of two components >0 mV. The time constant of the faster inactivating component (30.6 +/- 2.2 ms at 0 mV) decreased with depolarization, but the time constant of the slower inactivating component (489 +/- 21 ms at 0 mV) was not significantly influenced by the membrane potential. The inactivation process in the presence of isoproterenol (100 nM) consisted of a single component (538 +/- 60 ms at 0 mV). A protein kinase inhibitor, H-89, decreased the currents and attenuated the effects of isoproterenol. In the presence of cAMP (500 microM), the inactivation process consisted of a single slow component. We propose that the faster inactivating component represents a kinetic of the dephosphorylated or partially phosphorylated channel, and phosphorylation converts the kinetics into one with a different voltage dependency.
The relationship between abnormal atrial electrograms (AAE) recorded during sinus rhythm by endocardial catheter mapping of the right atrium and the atrial conduction defects of sinus impulses or single atrial extrastimuli was investigated in 44 patients with sick sinus syndrome. The patients were divided into two groups on the basis of the presence (n = 29) or absence (n = 15) of AAE recorded during sinus rhythm. The P wave duration in the AAE (+) Group patients was 137 +/- 14 msec, and 125 +/- 15 msec in the AAE (-) Group; P < 0.02. The intraatrial conduction time of sinus impulses in the AAE (+) Group was 54 +/- 12 msec, and 39 +/- 9 msec in the AAE (-) Group; P < 0.001. The interatrial conduction time in the AAE (+) Group was 101 +/- 14 msec, and 78 +/- 16 msec in the AAE (-) Group; P < 0.001. In the AAE (+) Group, 11 (38%) patients had a sinus node recovery time > 4 seconds, whereas in the AAE (-) Group there was only one (6%) patient; P < 0.03. AAE showed a specificity of 93% and a positive predictive accuracy of 91% in predicting inducibility of atrial fibrillation. The sensitivity was 35% and the negative predictive accuracy was 42%. Sustained atrial fibrillation was induced in ten (35%) patients of the AAE (+) Group, and in one (7%) patient of the AAE (-) Group; P < 0.05. These data suggest that in patients with sick sinus syndrome who possess abnormal endocardial electrograms in sinus rhythm within the right atrium have: (1) a significantly longer P wave duration; (2) a significantly longer intraatrial and interatrial conduction time of sinus impulses; and (3) a significantly greater sinus node dysfunction and higher incidence of induction of sustained atrial fibrillation. It is concluded that there are significantly greater atrial conduction defects in patients with sick sinus syndrome who possess AAE within the right atrium during sinus rhythm.
SUMMARY1. Intracellular mechanism(s) for controlling the opening of muscarinic K+ channels in the absence of an applied muscarinic agonist were studied in rabbit atrium by applying the patch clamp technique to isolated single myocytes.2. In the cell-attached patch configuration, currents due to the activity of both the muscarinic K+ channel and the inward rectifying K+ channel were recorded. However, while the inward rectifying K+ channel currents were observed in only ten patches of 211 examined, spontaneous opening (i.e. in the absence of a muscarinic agonist) of the muscarinic K+ channel currents was observed in all patches examined in these atrial cells.3. The single-channel currents due to spontaneous opening of muscarinic K+ channels were identified on the basis of their very similar conductance and gating properties to the unitary events which have been recorded when 05 sm-acetylcholine is included in the pipette and 10 /,cM-GTP is present in the internal side of the patch membrane.4. Although the spontaneous opening of the muscarinic K+ channels disappeared soon after excision of the patch membrane, this type of channel activity reappeared following application of ATP and MgCl2 to the internal side of the torn-off patch, as expected from previous publications.5. The K+ channel activity induced by the ATP and Mg2+ (measured as the product of the number of channels, N, times the probability of opening, P.) was strongly dependent upon concentration of free Mg2+; it was half-maximal at 2-2 x 10-4 M [Mg2+]i. However, after the muscarinic K+ channels had been activated by 100 ,sM-guanosine 5'-0-3-thiotriphosphate (GTPyS) together with ATP and Mg2+, an increase in the Mg2+ concentration from 5.5 x 10-5 to 2 x 10-3 M failed to enhance this channel activity. 8. This Mg2+-ATP-dependent phosphorylation does not appear to involve activation of protein kinase C since 12-O-tetradecanoylphorbol-13-acetate (TPA, 10 nM), an activator of protein kinase C, did not increase the spontaneous opening of this muscarinic K+ channel in the cell-attached patch configuration; and this channel activity was not inhibited by 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine (H-7, 20/tm).9. To assess the possibility that the phosphorylation reaction required for channel activation may involve a membrane-bound nucleotide diphosphate kinase (NDPK) we applied nucleotide triphosphates which are known to be able to substitute for ATP as substrates for the NDPK. Consistent with this possibility, uridine 5'-triphosphate (UTP) (1 mM), thymidine 5'-triphosphate (TTP) (1 mM) and guanosine 5'-triphosphate (GTP) (1 mM) were able to activate these K+ channels in the presence of 2 mM-MgCl2; however GTP was much less effective than ATP.10. Additional evidence for the involvement of NDPK in the spontaneous activation of these K+ channels was obtained by applying nucleotides known to be non-specific inhibitors of this enzyme. Adenosine 5'-diphosphate (ADP, 500 /tm), guanosine 5'-O-(2-thiodiphosphate) (GDP/JS, 100l,um) and guanosine 5'-diposphate (GDP,...
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