Relative roles of protein kinase A and protein kinase C in modulation of transient receptor potential vanilloid type 1 receptor responsiveness in rat sensory neurons in vitro and peripheral nociceptors in vivo.

The function of the transient receptor potential vanilloid type 1 capsaicin receptor is subject to modulation by phosphorylation catalyzed by various enzymes including protein kinase C and cAMP-dependent protein kinase. The aim of this study was to compare the significance of the basal and stimulated activity of protein kinase C and cAMP-dependent protein kinase in transient receptor potential vanilloid type 1 receptor responsiveness in the rat in vitro by measurement of the intracellular calcium concentration in cultured trigeminal ganglion neurons and in vivo by determination of the behavioral noxious heat threshold. KT5720, a selective inhibitor of cAMP-dependent protein kinase, reduced the calcium transients induced by capsaicin or the other, much more potent transient receptor potential vanilloid type 1 receptor agonist resiniferatoxin in trigeminal sensory neurons and diminished the drop of the noxious heat threshold (heat allodynia) evoked by intraplantar resiniferatoxin injection. Chelerythrine chloride, a selective inhibitor of protein kinase C, failed to alter either of these responses, although it inhibited the effect of phorbol 12-myristate 13-acetate in the in vitro assay. Staurosporine, a rather nonselective protein kinase inhibitor, failed to reduce the capsaicin- and resiniferatoxin-induced calcium transients but inhibited the resiniferatoxin-evoked heat allodynia. Dibutyryl-cAMP and phorbol 12-myristate 13-acetate, activator(s) of cAMP-dependent protein kinase and protein kinase C, respectively, enhanced the effect of capsaicin in the calcium uptake assay while forskolin, an activator of adenylyl cyclase, augmented that of resiniferatoxin in the heat allodynia model. None of the protein kinase inhibitors or activators altered the calcium transients evoked by high potassium, a nonspecific depolarizing stimulus. It is concluded that basal activity of cAMP-dependent protein kinase, unlike protein kinase C, is involved in the maintenance of transient receptor potential vanilloid type 1 receptor function in somata of trigeminal sensory neurons but stimulation of either cAMP-dependent protein kinase or protein kinase C above the resting level can lead to an enhanced transient receptor potential vanilloid type 1 receptor responsiveness. Similar mechanisms are likely to operate in vivo in peripheral terminals of nociceptive dorsal root ganglion neurons.

Direct evidence for activation and desensitization of the capsaicin receptor by N-oleoyldopamine on TRPV1-transfected cell, line in gene deleted mice and in the rat.

Effects of the endogenous lipid N-oleoyldopamine (OLDA) were analyzed on the rTRPV1-expressing HT1080 human fibrosarcoma cell line (HT5-1), on cultured rat trigeminal neurons, on the noxious heat threshold of rats and on nocifensive behavior of TRPV1 knockout mice. The EC(50) of capsaicin and OLDA on (45)Ca accumulation of rTRPV1-expressing HT5-1 cells was 36 nM and 1.8 microM, respectively. The efficacy of OLDA was 60% as compared to the maximum response of capsaicin. OLDA (330 nM to 3.3 microM) caused a transient increase in fluorescence of fura-2 loaded cultured small trigeminal neurons of the rat and rTRPV1-transfected HT5-1 cells measured with a ratiometric technique. Repeated application of OLDA and capsaicin caused similar desensitization in the Ca(2+) transients both in cultured neurons and rTRPV1-transfected HT5-1 cells. In the rat intraplantar injection of OLDA (5 nmol) decreased the noxious heat threshold by 6-9 degrees C and this response was strongly inhibited by the TRPV1 antagonist iodoresiniferatoxin (0.05 nmol intraplantarly (i.pl.)). In wild-type mice OLDA (50 nmol i.pl.) evoked paw lifting/licking which was significantly less sustained in TRPV1 knockout mice. It is concluded that on TRPV1 capsaicin receptors OLDA is 50 times less potent than capsaicin and it might serve as an endogenous ligand for TRPV1 in the rat, but more likely in humans.

[Cardiogenic shock and ventricular fibrillation induced by prajmalium and metoprolol poisoning]. / Kardiogén shock és kamrafibrilláció kialakulása prajmalin és metoprolol mérgezés következtében.

Prajmaline is not a relatively well known and frequently used antiarrhythmic belonging to Class IA group of antiarrhythmics, which was administered to a young male with metoprolol for the treatment of parasystole. The patient took in 120 mgs prajmaline and 600 mgs metoprolol during the day of the case, which leads to cardiogenic shock, ventricular tachycardia and ventricular fibrillation. The patient's parameters were normalized after successful resuscitation, temporary pacemaker and two days long Dopamin therapy. Therapy was not regarded to be necessary for a few ventricular premature beats detected during a week observation period. The patient is without complaints now, and significant ventricular arrhythmias, or malignant ventricular ectopy hasn't been proved with ECG tests and Holter monitoring for more than three months. Due to adverse effect profile of prajmaline, even at commonly used doses it should be administered carefully and other agents should probably be considered first before beginning long term treatment with prajmaline.