Human muscle-derived cell injection in a rat model of stress urinary incontinence.

We investigated the use of human muscle-derived cells (hMDCs) for the treatment of stress urinary incontinence (SUI) in a nude rat model. hMDCs were isolated from adult skeletal muscle. Three groups of six animals consisting of controls, animals undergoing sciatic nerve transection (SNT) with periurethral sham-injection, and SNT with hMDCs (1 x 10(6) cells/20 microl saline) were utilized. Leak point pressure (LPP) was measured 4 weeks following injection. Bilateral SNT resulted in a significantly lower LPP that was significantly higher following hMDCs than sham injection. The results demonstrate the efficacy of human muscle cell therapy alone in improving physiologic outcomes in an animal model of SUI.

Cardiac autonomic modulation by estrogen in female mice undergoing ambulatory monitoring and in vivo electrophysiologic testing.

INTRODUCTION: Estrogen is an important modulator of cardiovascular risk, but its mechanism of action is not fully understood. We investigated the effect of ovariectomy and its timing on the cardiac electrophysiology in mice. METHODS: Thirty female mice (age 18.8 +/- 3.1 weeks) underwent in vivo electrophysiologic testing before and after autonomic blockade. Fifteen mice were ovariectomized prepuberty (PRE) and ten postpuberty (POST), 2 weeks prior to electrophysiologic testing. Five age-matched sham-operated female mice (Control) served as controls. A subset of 13 mice (5 PRE, 3 POST, and 5 Controls) underwent 24-hour ambulatory monitoring. RESULTS: With ambulatory monitoring, the average (668 +/- 28 vs 769 +/- 52 b/min, P = 0.008) and minimum (485 +/- 47 vs 587 +/- 53 b/min, P = 0.02) heart rates were significantly slower in the ovariectomized mice (PRE and POST groups) compared to the Control group. At baseline electrophysiologic testing, there were no significant differences among the ovariectomized and intact mice in any of the measured parameters. With autonomic blockade, the Control group had a significantly larger change (delta) in the atrioventricular (AV) nodal Wenckebach (AVW) periodicity (deltaAVW = 11.3 +/- 2.9 vs 2.1 +/- 7.3 ms, P = 0.05) and functional refractory period (deltaFRP = 11.3 +/- 2.1 vs 1.25 +/- 6.8 ms, P = 0.02) compared to the ovariectomized mice. These results were not altered by the time of ovariectomy (PRE vs POST groups). CONCLUSION: Our results suggest that estrogen modulates the autonomic inputs into the murine sinus and AV nodes. These findings, if replicated in humans, might underlie the observed clustering of certain arrhythmias around menstruation and explain the higher incidence of arrhythmias in men and postmenopausal women.

Strain-specific patterns of autonomic nervous system activity and heart failure susceptibility in mice.

Transgenic mice are widely used to study cardiac function, but strain-dependent differences in autonomic nervous system activity (ANSA) have not been explored. We compared 1) short-term pharmacological responses of cardiac rhythm in FVB vs. C57Black6/SV129 wild-type mice and 2) long-term physiological dynamics of cardiac rhythm and survival in tumor necrosis factor (TNF)-alpha transgenic mice with heart failure (TNF-alpha mice) on defined backgrounds. Ambulatory telemetry electrocardiographic recordings and response to saline, adrenergic, and cholinergic agents were examined in FVB and C57Black6/SV129 mice. In FVB mice, baseline heart rate (HR) was higher and did not change after injection of isoproterenol or atropine but decreased with propranolol. In C57Black6/SV129 mice, HR did not change with propranolol but increased with isoproterenol or atropine. Mean HR, but not indexes of HR variability, was an excellent predictor of response to autonomic agents. The proportion of surviving animals was higher in TNF-alpha mice on an FVB background than on a mixed FVB/C57Black6 background. The homeostatic states of ANSA are strain specific, which can explain the interstrain differences in mean HR, pharmacological responses, and survival of animals with congestive heart failure. Strain-specific differences should be considered in selecting the strains of mice used for transgenic and gene targeting experiments.

Direct mechanical stimulation of brainstem modulates cardiac rhythm and repolarization in humans.

Natural mechanical stimulation of the brainstem area by the blood pressure waves propagating in the adjacent arteries plays an important role in the homeostasis of the brainstem centers of cardiovascular control. However, effects of direct mechanical stimulation of this area on the cardiac elecrophysiology have never been studied in humans. In 12 patients (age: 54 +/- 13 years, 5 females) undergoing microvascular decompression, the left (9 patients) or the right (3 patients) side of the ventro-lateral surface of the medulla oblongata was exposed during the surgery, and a mechanical stimulation (duration: 1 min, frequency: 1-2 Hz) of the roots of the cranial nerves and the surface of the brainstem was performed at 3-7 sites using a 2-mm metallic ball. Spatial changes in cardiac repolarization were examined using the 32-lead/192 site electrocardiographic body surface potential maps. Blood pressure was monitored using intra-arterial line. The intervals between the onset of the Q-wave and the offset of the T-wave (QTe) and between the onset of the Q-wave and the peak of the T-wave (QTp), the activation-recovery intervals (ARi), the peak T-wave amplitude, and the QRS and STT integrals were measured using custom software. During the stimulation between the caudal rootlets of the 10th nerve, the peak T-wave amplitude decreased 22% (range: 6-50%) and RR-intervals decreased from 923 +/- 190 to 794 +/- 111 ms compared to the recordings obtained before the stimulation (P =.025 and.063, respectively), whereas QTe, QTp, Ari, and the QRS- and the STT-integrals did not change. Decreased T-wave amplitudes and unchanged QT-intervals suggest that brainstem stimulation might evoke spatially inhomogenious repolarization changes. Stimulation of a localized region surrounding the caudal rootlets of the 10th nerve elicits pronounced effects on cardiac rhythm and repolarization.