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This Article Full Text Full Text (PDF) All Versions of this Article: 295/5/H1989    most recent 00007.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by von der Weid, P.-Y. Articles by van Helden, D. F. PubMed PubMed Citation Articles by von der Weid, P.-Y. Articles by van Helden, D. F.

Spontaneous transient depolarizations in lymphatic vessels of the guinea pig mesentery: pharmacology and implication for spontaneous contractility

¹Inflammation Research Network and Smooth Muscle Research Group, Department of Pharmacology and Therapeutics and Department of Physiology and Biophysics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; and ²The Neuroscience Group, School of Biomedical Sciences, Faculty of Health, The University of Newcastle, Callaghan, New South Wales, Australia

Submitted 3 January 2008 ; accepted in final form 8 September 2008

Guinea pig mesenteric lymphatic vessels exhibit rhythmic constrictions induced by action potential (AP)-like spikes and initiated by entrainment of spontaneous transient depolarizations (STDs). To characterize STDs and the signaling mechanisms responsible for their occurrence, we used intracellular microelectrodes, Ca²⁺ imaging, and pharmacological agents. In our investigation of the role of intracellular Ca²⁺ released from Ca²⁺ stores, we observed that intracellular Ca²⁺ transients accompanied some STDs, although there were many exceptions where Ca²⁺ transients occurred without accompanying STDs. STD frequency and amplitude were markedly affected by activators/inhibitors of inositol 1,4,5-trisphosphate receptors (IP₃Rs) but not by treatments known to alter Ca²⁺ release via ryanodine receptors. A role for Ca²⁺-activated Cl^– (Cl_Ca) channels was indicated, as STDs were dependent on the Cl^– but not Na⁺ concentration of the superfusing solution and were inhibited by the Cl_Ca channel blockers niflumic acid (NFA), anthracene 9-carboxylic acid, and 5-nitro-2-(3-phenylpropylamino)benzoic acid but not by the volume-regulated Cl^– blocker DIDS. Increases in STD frequency and amplitude induced by agonist stimulation were also inhibited by NFA. Nifedipine, the hyperpolarization-activated inward current blocker ZD-7288, and the nonselective cation/store-operated channel blockers SKF-96365, Gd³⁺, and Ni²⁺ had no or marginal effects on STD activity. However, nifedipine, 2-aminoethoxydiphenyl borate, NFA, SKF-96365, Gd³⁺, and Ni²⁺ altered the occurrence of spontaneous APs. Our findings support a role for Ca²⁺ release through IP₃Rs and a resultant opening of Cl_Ca channels in STD generation and confirm the importance of these events in the initiation of lymphatic spontaneous APs and subsequent contractions. The abolition of spontaneous APs by blockers of other excitatory ion channels suggests a contribution of these conductances to lymphatic pacemaking.

lymphatic pacemaking; membrane potential; calcium transients; inositol 1,4,5-trisphosphate receptors; calcium-activated chloride channels