The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Sep 2005
(+)-Norfenfluramine-induced arterial contraction is not dependent on endogenous 5-hydroxytryptamine or 5-hydroxytryptamine transporter.
(+)-Norfenfluramine, the major metabolite of fenfluramine, causes vasoconstriction dependence on the 5-hydroxytryptamine (5-HT)(2A) receptor in rat. (+)-Norfenfluramine was reported as a 5-hydroxytryptamine transporter (5-HTT) substrate and 5-HT releaser. Because the arterial 5-HTT exists and is functional in the rat, we hypothesized that (+)-norfenfluramine causes vasoconstriction by releasing 5-HT from vascular smooth muscle via 5-HTT. The released 5-HT, in turn, activates the 5-HT(2A) receptor. ⋯ To further test the role of 5-HTT in (+)-norfenfluramine-induced aortic contraction, the 5-HTT-targeted mutation mouse was used. (+)-Norfenfluramine induced similar aortic contraction in wild-type and 5-HTT-targeted mutation mice, and these contractions were inhibited by fluoxetine (1 microM). Thus, (+)-norfenfluramine vasoconstriction is not dependent on 5-HTT-mediated release of endogenous 5-HT but by activating membrane 5-HT(2A) receptors directly. Understanding of the mechanism by which (+)-norfenfluramine induces vasoconstriction is important to characterize and understand the function of the serotonergic system in peripheral arterial vasculature.
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J. Pharmacol. Exp. Ther. · Sep 2005
5-Iodoresiniferatoxin evokes hypothermia in mice and is a partial transient receptor potential vanilloid 1 agonist in vitro.
Transient receptor potential vanilloid 1 (TRPV1) is a capsaicin- and heat-gated ion channel required for normal in vivo responses to these painful stimuli. However, growing evidence suggests that TRPV1 also participates in thermoregulation. ⋯ In response to I-RTX in vitro, HEK293 cells expressing rat TRPV1 exhibited increases in intracellular Ca(2+) (biphasic, EC(50) = 56.7 nM and 9.9 microM) that depended on Ca(2+) influx and outwardly rectifying, capsazepine-sensitive currents that were smaller than those evoked by 1 microM capsaicin. Thus, I-RTX induces TRPV1-dependent hypothermia in vivo and is a partial TRPV1 agonist in vitro.
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J. Pharmacol. Exp. Ther. · Sep 2005
Tertiapin-Q blocks recombinant and native large conductance K+ channels in a use-dependent manner.
Tertiapin, a short peptide from honey bee venom, has been reported to specifically block the inwardly rectifying K(+) (Kir) channels, including G protein-coupled inwardly rectifying potassium channel (GIRK) 1+GIRK4 heteromultimers and ROMK1 homomultimers. In the present study, the effects of a stable and functionally similar derivative of tertiapin, tertiapin-Q, were examined on recombinant human voltage-dependent Ca(2+)-activated large conductance K(+) channel (BK or MaxiK; alpha-subunit or hSlo1 homomultimers) and mouse inwardly rectifying GIRK1+GIRK2 (i.e., Kir3.1 and Kir3.2) heteromultimeric K(+) channels expressed in Xenopus oocytes and in cultured newborn mouse dorsal root ganglion (DRG) neurons. In two-electrode voltage-clamped oocytes, tertiapin-Q (1-100 nM) inhibited BK-type K(+) channels in a use- and concentration-dependent manner. ⋯ Under current-clamp conditions, tertiapin-Q blocked the action potential after hyperpolarization (AHP) and increased action potential duration in DRG neurons. Taken together, these results demonstrate that the blocking actions of tertiapin-Q are not specific to Kir channels and that the blockade of recombinant BK channels and native neuronal AHP currents is use-dependent. Inhibition of specific types of Kir and voltage-dependent Ca(2+)-activated K(+) channels by tertiapin-Q at nanomolar range via different mechanisms may have implications in pain physiology and therapy.
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J. Pharmacol. Exp. Ther. · Sep 2005
Inhibition of the A-type K+ channels of dorsal root ganglion neurons by the long-duration anesthetic butamben.
n-Butyl-p-aminobenzoate (BAB; butamben) is a long-duration anesthetic used for the treatment of chronic pain. Epidural administration of BAB is thought to reduce the electrical excitability of dorsal root nociceptor fibers by inhibiting voltage-gated ion channels. To further investigate this mechanism, we examined the effects of BAB on the potassium currents of acutely dissociated neurons from the rat dorsal root ganglion (DRG). ⋯ Substituting polar threonines for conserved hydrophobic residues of the S6 segment weakened BAB binding but did not alter the voltage-dependent gating of the Kv4.2 channel. At physiological pH, BAB is uncharged, suggesting that hydrophobic interactions may contribute to drug binding. The data support a mechanism in which BAB binds near the narrow cytoplasmic entrance of Kv4 channels and inhibits current by a pore blocking mechanism.
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J. Pharmacol. Exp. Ther. · Sep 2005
Protection against cisplatin-induced toxicities by N-acetylcysteine and sodium thiosulfate as assessed at the molecular, cellular, and in vivo levels.
Cisplatin (CDDP) is a common, highly toxic chemotherapeutic agent. This study investigates chemoprotective effects of N-acetylcysteine (NAC) and sodium thiosulfate (STS) on in vitro and in vivo CDDP toxicities. For ototoxicity studies, CDDP (6 mg/kg) was administered to rats via a retrograde carotid artery infusion. ⋯ Delayed STS treatment was not consistently protective against nephrotoxicity. STS administration fully protected against the in vitro cytotoxic and apoptotic effects of CDDP if added within 2 h of CDDP, but chemoprotection decreased if STS administration was 4 h, and was minimal by 6 h, after CDDP. Thus, the chemoprotection route and timing of administration can be manipulated to maintain CDDP antitumor efficacy while protecting against toxicities.