Treatment with proinflammatory prostaglandin E2 (PGE2) produced a transient sensitization of whole-cell currents elicited by the vanilloid capsaicin. The intracellular signaling pathways that mediate the initiation of this PGE2-induced sensitization of the capsaicin-elicited current in rat sensory neurons are not well established. Treatment with either forskolin (100 nM to 10 microM) or membrane-permeant analogs of cAMP, 8-bromo-cAMP (8-Br-cAMP) and chlorphenylthio-cAMP (10 microM to 1 mM), transiently sensitized neuronal responses elicited by capsaicin in a manner analogous to that produced by PGE2. The duration of sensitization was lengthened with increasing concentrations of forskolin; however, higher concentrations of 8-Br-cAMP or chlorphenylthio-cAMP led to a shortening of sensitization. The inactive analog of forskolin, dideoxy-forskolin, had no effect on capsaicin responses. Inclusion of the inhibitor of protein kinase A in the recording pipette completely suppressed the sensitization produced by PGE2 or forskolin. In recordings from membrane patches in the cell-attached configuration, the bath application of capsaicin evoked single-channel currents in which the level of channel activity was concentration-dependent and had an EC50 of 1.4 microM. These single-channel currents evoked by capsaicin exhibited an apparent reversal potential of +4 mV and were blocked by the capsaicin antagonist capsazepine. Exposure of the sensory neuron to either PGE2 or forskolin produced a large and transient increase in the mean channel activity (NPo) elicited by capsaicin, although the unitary conductance remained unaltered. Taken together, these observations suggest that modulation of the capsaicin-gated channel by the cAMP-protein kinase A signaling pathway enhanced the gating of these channels and consequently resulted in the sensitization of the whole-cell currents.

Rationale Fibrillation-defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). Objective We hypothesized that activation of apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels are responsible for the postshock APD shortening in failing ventricles. Methods and Results A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca2+ and membrane potential (Vm) was performed in failing and non-failing ventricles. Three failing ventricles developed SVF (SVF group), 9 did not (no-SVF group). None of the 10 non-failing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF, increased postshock APD80 in SVF group from 126±5 ms to 153±4 ms (p<0.05), in no-SVF group from147±2 ms to 162±3 ms (p<0.05) but did not change of APD80 in non-failing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K+ current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density is significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca2+ response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca2+ sensitivity of IKAS in failing ventricles. The Kd was 232 ± 5 nM for failing myocytes and 553 ± 78 nM for normal myocytes (p = 0.002). Conclusions Heart failure heterogeneously increases the sensitivity of IKAS to intracellular Ca2+, leading to upregulation of IKAS, postshock APD shortening and recurrent SVF.

Background We hypothesize that left sided low-level vagus nerve stimulation (LL-VNS) can suppress sympathetic outflow and reduce atrial tachyarrhythmias in ambulatory dogs. Methods and Results We implanted in 12 dogs a neurostimulator to stimulate left cervical vagus nerve and a radiotransmitter for continuous recording of left stellate ganglion nerve activities (SGNA), vagal nerve activities (VNA) and electrocardiograms. Group 1 dogs (N=6) underwent 1 week continuous LL-VNS. Group 2 dogs (N=6) underwent intermittent rapid atrial pacing followed by active or sham LL-VNS on alternate weeks. Integrated SGNA was significantly reduced during LL-VNS (7.8 mV-s; 95% confidence interval [CI] 6.94 to 8.66] vs. 9.4 mV-s [CI, 8.5 to 10.3] at baseline, P=0.033) in Group 1.The reduction was most apparent at 8 AM, along with a significantly reduced heart rate (P=0.008). LL-VNS did not change VNA. The density of tyrosine hydroxylase-positive nerves in the left stellate ganglion one week after cessation of LL-VNS were 99684 µm2/mm2 (CI, 28850 to 170517) in LL-VNS dogs and 186561 µm2/ mm2 (CI, 154956 to 218166; P=0.008) in normal dogs. In Group 2, the frequencies of paroxysmal atrial fibrillation and tachycardia during active LL-VNS were 1.4/day (CI, 0.5/day to 5.1/day) and 8.0/day (CI, 5.3/day to 12.0/day), respectively, significantly lower than during sham stimulation (9.2/day [CI, 5.3/day to 13.1/day], P=0.001 and 22.0/day [CI, 19.1/day to 25.5/day], P<0.001, respectively). Conclusions LL-VNS suppresses SGNA and reduces the incidences of paroxysmal atrial tachyarrhythmias in ambulatory dogs. Significant neural remodeling of the left stellate ganglion is evident one week after cessation of chronic LL-VNS.

Background-Spinal cord stimulation (SCS) reduces the incidence of ventricular tachyarrhythmias in experimental models. This study investigated the effects of long-term SCS on ventricular function in a postinfarction canine heart failure model. Methods and Results-In stage 1, dogs underwent implantable cardioverter-defibrillator implantation and embolization of the left anterior descending artery followed by right ventricular pacing (240 ppm) for 3 weeks to produce heart failure. In stage 2, 28 surviving animals were assigned to the SCS (delivered at the T4/T5 spinal region for 2 hours 3 times a day), medicine (MED; carvedilol therapy at 12.5 mg PO BID), or control (CTRL; no therapy) group for the initial phase 1 study. In a subsequent phase 2 study, 32 stage 1 survivors were equally randomized to the SCS, MEDS (carvedilol plus ramipril 2.5 mg PO QD), SCS plus MEDS (concurrent therapy), or CTRL group. Animals were monitored for 5 weeks (phase 1) or 10 weeks (phase 2). In stage 3, all phase 1 animals underwent circumflex artery balloon occlusion for 1 hour. In the SCS group, left ventricular ejection fraction was 65Ϯ5% at baseline, 17Ϯ3% at the end of stage 1, and 47Ϯ7% at the end of stage 2. In the MED group, left ventricular ejection fraction was 61Ϯ4% at baseline, 18Ϯ3% at the end of stage 1, and 34Ϯ4% at the end of stage 2. In the CTRL group, left ventricular ejection fraction was 64Ϯ5% at baseline, 19Ϯ5% at the end of stage 1, and 28Ϯ3% at the end of stage 2. Left ventricular ejection fraction was significantly improved in the SCS compared with the MED and CTRL groups (PϽ0.001 for both). The mean number of spontaneous nonsustained ventricular tachyarrhythmias during stage 2 and the occurrence of ischemic ventricular tachyarrhythmias during stage 3 also were significantly decreased in the SCS (27Ϯ17 and 27%, respectively; PϽ0.03) and MED (58Ϯ42 and 33%; PϽ0.05) versus CTRL (88Ϯ52 and 76%) group. After 10 weeks in the phase 2 studies, the greatest recovery in ejection fraction was noted in the SCS (52Ϯ5%) and SCSϩMEDS (46Ϯ4%) groups compared with the MEDS (38Ϯ2%) and CTRL (31Ϯ4%) groups. Conclusion-SCS