Angiotensin II produces nociceptive behavior through spinal AT1 receptor-mediated p38 mitogen-activated protein kinase activation in mice

Background: It has been demonstrated that angiotensin II (Ang II) participates in either the inhibition or the facilitation of nociceptive transmission depending on the brain area. Neuronal Ang II is locally synthesized not only in the brain, but also in the spinal cord. Though the spinal cord is an important area for the modulation of nociception, the role of spinal Ang II in nociceptive transmission remains unclear. Therefore, in order to elucidate the role of Ang II in nociceptive transmission in the spinal cord, we examined the effect of intrathecal (i.t.) administration of Ang II into mice.Results: I.t. administration of Ang II produced a behavioral response in mice mainly consisting of biting and/or licking of the hindpaw and the tail along with slight hindlimb scratching directed toward the flank. The behavior induced by Ang II (3 pmol) was dose-dependently inhibited by intraperitoneal injection of morphine (0.1-0.3 mg/kg), suggesting that the behavioral response is related to nociception. The nociceptive behavior was also inhibited dose-dependently by i.t. co-administration of losartan (0.3-3 nmol), an Ang II type 1 (AT1) receptor antagonist, and SB203580 (0.1-1 nmol), a p38 MAPK inhibitor. However, the Ang II type 2 (AT2) receptor antagonist PD123319, the upstream inhibitor of ERK1/2 phosphorylation U0126, and the JNK inhibitor SP600125 had no effect on Ang II-induced nociceptive behavior. Western blot analysis showed that the i.t. injection of Ang II induced phosphorylation of p38 MAPK in the lumbar dorsal spinal cord, which was inhibited by losartan, without affecting ERK1/2 and JNK. Furthermore, we found that AT1 receptor expression was relatively high in the lumbar superficial dorsal horn.Conclusions: Our data show that i.t. administration of Ang II induces nociceptive behavior accompanied by the activation of p38 MAPK signaling mediated through AT1 receptors. This observation indicates that Ang II may act as a neurotransmitter and/or neuromodulator in the spinal transmission of nociceptive information. © 2013 Nemoto et al.; licensee BioMed Central Ltd

Determination of the Antibacterial and Lipopolysaccharide-Neutralizing Regions of Guinea Pig Neutrophil Cathelicidin Peptide CAP11

Previously, we revealed that a cationic antibacterial polypeptide of 11 kDa (CAP11), a member of the cathelicidins isolated from guinea pig neutrophils, exhibits not only potent antibacterial activity but also lipopolysaccharide (LPS)-neutralizing activity. In this study, to determine the biologically active regions of CAP11, we isolated or synthesized the partial peptides of CAP11 and evaluated their antibacterial and LPS-neutralizing activities. Although CAP11 has a unique homodimeric structure with a disulfide bridge, the biological activities of dimeric and monomeric forms of CAP11 were almost the same. Moreover, the G(1)-E(33) peptide of CAP11 showed the same activities as CAP11, whereas the C-terminal region (Y(34) to I(43)) possessed no biological activities. In addition, the three 18-mer peptides (G(1)-R(18), T(9)-K(26), and L(16)-E(33)) with overlapping sequences were synthesized, and their activities were determined. The three 18-mer peptides retained the antibacterial activities, and G(1)-R(18) was the most potent. In contrast, the LPS-neutralizing activities of these peptides were markedly reduced. Together, these observations indicate that the active region with antibacterial activity is localized at G(1) to R(18) of CAP11, whereas longer sequences (such as G(1) to E(33)) would be required for the expression of LPS-neutralizing activity. Furthermore, the C-terminal region (Y(34) to I(43)) and a disulfide bridge are not essential for the antibacterial and LPS-neutralizing activities of CAP11

Efficacy of Long-term Flecainide Therapy in Patients with Paroxysmal Atrial Fibrillation —Analysis Based on Time of Onset—

This study sought to evaluate the efficacy of long-term flecainide therapy in maintaining sinus rhythms in patients with paroxysmal atrial fibrillation (AF. based on time of onset. Flecainide (150 mg/day. was administered as an antiarrhythmic drug to a total of 70 patients (54 men and 16 women: mean age 65 ± 10 years. after sinus rhythm was restored spontaneously or by electrical and/or pharmacological cardioversion. Paroxysmal AF was divided into three categories based on time of onset: diurnal type (N = 11), nocturnal type (N = 13), and mixed type (N = 46). The mean follow-up period was 37.7 ± 17.7 months. The duration of sinus rhythm maintenance in patients with diurnal and nocturnal paroxysmal AF was 32.4 ± 10.4 months and 20.8 ± 8.3 months, respectively; the duration of sinus rhythm maintenance in those with mixed paroxysmal AF was only 7.2 ± 2.1 months. Significant differences were observed in duration between diurnal and mixed cases (mean ± S.E., P < 0.05). Actuarial recurrence-free rates at 1, 3, 6, 9 and 12 months were 90.9%, 63.6%, 63.6%, 54.5%, and 54.5%, respectively, for diurnal cases; 84.6%, 76.9%, 53.8%, 38.5%, and 30.8%, respectively, for nocturnal cases; and 58.7%, 39.1%, 28.3%, 21.7%, and 15.2% respectively, for mixed cases. Significant differences in rates at 12 months were observed between diurnal and mixed cases (P < 0.05). These results suggest that flecainide is highly effective in preventing AF recurrence in patients with diurnal paroxysmal AF