Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by α-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (α1-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (α2-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined α-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by α1,2-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal α-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that α-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

Our objective was to determine whether atrial fibrillation (AF) results from excessive activation of intrinsic cardiac neurons (ICNs) and, if so, whether select subpopulations of neurons therein represent therapeutic targets for suppression of this arrhythmogenic potential. Trains of five electrical stimuli (0.3-1.2 mA, 1 ms) were delivered during the atrial refractory period to mediastinal nerves (MSN) on the superior vena cava to evoke AF. Neuroanatomical studies were performed by injecting the neuronal tracer DiI into MSN sites that induced AF. Functional studies involved recording of neuronal activity in situ from the right atrial ganglionated plexus (RAGP) in response to MSN stimulation (MSNS) prior to and following neuromodulation involving either preemptive spinal cord stimulation (SCS; T 1-T 3, 50 Hz, 200-ms duration) or ganglionic blockade (hexamethonium, 5 mg/kg). The tetramethylindocarbocyanine perchlorate (DiI) neuronal tracer labeled a subset (13.2%) of RAGP neurons, which also colocalized with cholinergic or adrenergic markers. A subset of DiI-labeled RAGP neurons were noncholinergic/nonadrenergic. MSNS evoked an ~4-fold increase in RAGP neuronal activity from baseline, which SCS reduced by 43%. Hexamethonium blocked MSNS-evoked increases in neuronal activity. MSNS evoked AF in 78% of right-sided MSN sites, which SCS reduced to 33% and hexamethonium reduced to 7%. MSNS-induced bradycardia was maintained with SCS but was mitigated by hexamethonium. We conclude that MSNS activates subpopulations of intrinsic cardiac neurons, thereby resulting in the formation of atrial arrhythmias leading to atrial fibrillation. Stabilization of ICN local circuit neurons by SCS or the local circuit and autonomic efferent neurons with hexamethonium reduces the arrhythmogenic potential.

Komplette pharmakologische Unterbrechung des Baroreflexes mittels eines Ganglienblockers führt zu einer starken Zunahme der Wirkung vasoaktiver Substanzen auf den Blutdruck. Eine ähnliche Überempfindlichkeit gegenüber vasoaktiven Substanzen ist auch bei Erkrankungen zu beobachten, die mit Schädigungen des afferenten oder des efferenten Schenkels des Baroreflexes einhergehen. Variabilität der Baroreflexfunktion innerhalb der Population trägt somit in erheblichem Umfang zur Variabilität des Ansprechens auf vasoaktive Substanzen bei. Durch Vergleich der Wirkung kreislaufwirksamer Substanzen oder physiologischer Interventionen vor und während Ganglienblockade können zentrale und periphere Effekte voneinander unterschieden werden. Mit dieser Methode können Änderungen der vaskulären Sensitivität und der Pufferfunktion des Baroreflexes bei Krankheitszuständen charakterisiert werden. / Complete pharmacological interruption of the baroreflex using ganglionic blockade is associated with a profound increase in the blood pressure response to vasoactive substances. Similar hypersensitivity to vasoactive substances can be observed in disorders that involve the afferent arc or the efferent arc of the baroreflex. Therefore, interindividual variability in baroreflex function contributes substantially to the variability in the responsiveness to vasoactive substances. Comparison of the response to cardiovascular medications before and during ganglionic blockade can be used to dissect central and peripheral effects. This approach is also useful to characterize changes in vascular sensitivity and in baroreflex buffering function in diseases.