Gregory W Thompson

Bradycardia induced by intravascular versus direct stimulation of the vagus nerve

BACKGROUND Electrical stimulation of the parasympathetic nervous system results in slowing of the heart. We sought to determine whether cardiac vagal efferent axons can be stimulated adequately to induce bradycardia without disturbing the integrity of the thorax. METHODS Cardiodepressor effects elicited by direct stimulation of a vagus nerve in anesthetized dogs and pigs were compared with those generated when the same nerve was stimulated indirectly through bipolar electrodes placed in the adjacent superior vena cava. RESULTS The heart rate of dogs decreased by about 80% when electrical stimuli were delivered to the right thoracic vagus at the level of the thoracic outlet through bipolar electrodes placed either in the adjacent superior vena cava (intravascular method) or directly on the nerve (direct method). Maximal responses were achieved with 10-V, 5-ms, and 20-Hz stimuli. In anesthetized pigs, similar bradycardia occurred when the right cervical vagus or the right cranial thoracic vagus was stimulated either directly or indirectly through the intravascular method. Atrial dysrhythmias occurred when the stimulating electrodes were placed by either method within 1 cm of the right atrium in both animal models. CONCLUSIONS Controlled bradycardia can be induced during operation without the risk of generating cardiac dysrhythmias using electrical stimuli (10 V, 5 ms, and 10 to 20 Hz) delivered to the right cervical vagus nerve or the right cranial thoracic vagus nerve through adjacent intravascular electrodes.

The heart reinnervates after transplantation

BACKGROUND Whether cardiac reinnervation occurs after transplantation remains controversial. If reinnervation does occur, how sympathetic and parasympathetic efferent neurons do this remains unknown. METHODS Power spectral analysis of heart rate variability was assessed for 1 year after cardiac autotransplantation in 9 dogs. After induction of anesthesia 13 months after transplantation, cardiac and intrinsic cardiac neuronal responses elicited by both electrical stimulation of parasympathetic or sympathetic efferent neurons and systemic or local coronary artery administration of nicotine (5 microg/kg), angiotensin II (0.75 microg/kg), and tyramine (1.2 microg/kg) were studied. The transmembrane electrical properties of intrinsic cardiac neurons were studied in vitro. Ventricular tissue catecholamine content, alpha-tubulin expression, and beta-adrenergic receptor density and affinity were studied. The presence of axons crossing suture lines was sought histologically. RESULTS Nerves were identified crossing suture lines. Electrical or chemical (ie, nicotine or angiotensin II) activation of sympathetic efferent neurons enhanced cardiodynamics, as did tyramine. Stimulating vagal efferent preganglionic axons induced bradycardia in half of the dogs. Functional reinnervation did not correlate with specific power spectra derived from rate variability in the conscious state. Responding to nicotine and angiotensin II in situ, transplanted intrinsic cardiac neurons generated spontaneous activity. These neurons displayed nicotine-dependent synaptic inputs in vitro. Ventricular tissue had normal beta-adrenergic receptor affinity and density but reduced catecholamine and alpha-tubulin contents. CONCLUSIONS The intrinsic cardiac nervous system receives reduced input from extracardiac sympathetic efferent neurons after transplantation and inconsistent input from parasympathetic efferent preganglionic neurons. These heterogeneous neuronal inputs are not reflected in heart rate variability or ventricular beta-adrenergic receptor function. Transplanted angiotensin II-sensitive intrinsic cardiac neurons exert greater cardiac control than do nicotine-sensitive ones. The intrinsic cardiac nervous system remodels itself after cardiac transplantation, and this indicates that direct assessment of extracardiac and intrinsic cardiac neuronal behavior is required to fully understand cardiac control after transplantation.

Transmyocardial laser revascularization does not denervate the canine heart.

BACKGROUND Transmyocardial laser revascularization has been used as an indirect approach to improve myocardial perfusion in patients with refractory angina not amenable to conventional therapy. Three mechanisms have been proposed for its therapeutic effects: direct perfusion of the ischemic myocardium through patent channels; induction of angiogenesis; and regional denervation. We sought to determine whether transmyocardial laser revascularization modifies afferent and efferent axonal function within the affected myocardium. METHODS Studies were performed in 9 dogs that were artificially ventilated and underwent thoracotomy. Changes in ventricular dynamics and intrinsic cardiac neuronal activity were monitored before and after creating 20 transmural channels in the left ventricular ventral free wall with a holmium:yttrium-aluminum-garnet laser in response to three stimuli: application of veratridine or bradykinin to the epicardial sensory neurites of intrinsic cardiac afferent neurons; sympathetic or parasympathetic efferent neuronal activation either electrically (4 V, 10 Hz, 5 ms) or chemically (nicotine, 5 microg/kg intravenously), and direct cardiomyocyte beta-adrenergic receptor stimulation (isoproterenol hydrochloride, 5 microg intravenously). RESULTS Sensory neurites of right atrial afferent neurons in the studied epicardial region responded similarly to chemical stimulation before and after transmyocardial laser revascularization. Transmyocardial laser treatment did not reduce local ventricular contractile responses to direct activation of sympathetic or parasympathetic efferent neurons by electrical or chemical means, nor did it affect cardiomyocyte augmentor responses elicited by exogenous beta-adrenergic receptor challenge. CONCLUSIONS As transmyocardial laser revascularization does not affect afferent or efferent axonal function in the affected ventricle, the efficacy of this form of therapy cannot be ascribed to local denervation.

Functional interdependence of neurons in a single canine intrinsic cardiac ganglionated plexus

1 To determine the activity characteristics displayed by different subpopulations of neurons in a single intrinsic cardiac ganglionated plexus, the behaviour and co‐ordination of activity generated by neurons in two loci of the right atrial ganglionated plexus (RAGP) were evaluated in 16 anaesthetized dogs during basal states as well as in response to increasing inputs from ventricular sensory neurites. 2 These sub‐populations of right atrial neurons received afferent inputs from sensory neurites in both ventricles that were responsive to local mechanical stimuli and the nitric oxide donor nitroprusside. Neurons in at least one RAGP locus were activated by epicardial application of veratridine, bradykinin, the β1‐adrenoceptor agonist prenaterol or glutamate. Epicardial application of angiotensin II, the selective β2‐adrenoceptor agonist terbutaline and selective α‐adrenoceptor agonists elicited inconsistent neuronal responses. 3 The activity generated by both populations of atrial neurons studied over 5 min periods during basal states displayed periodic coupled behaviour (cross‐correlation coefficients of activities that reached, on average, 0·88 ± 0·03; range 0·71–1) for 15–30 s periods of time. These periods of coupled activity occurred every 30–50 s during basal states, as well as when neuronal activity was enhanced by chemical activation of their ventricular sensory inputs. 4 These results indicate that neurons throughout one intrinsic cardiac ganglionated plexus receive inputs from mechano‐ and chemosensory neurites located in both ventricles. That such neurons respond to multiple chemical stimuli, including those liberated from adjacent adrenergic efferent nerve terminals, indicates the complexity of the integrative processing of information that occurs within the intrinsic cardiac nervous system. 5 It is proposed that the interdependent activity displayed by populations of neurons in different regions of one intrinsic cardiac ganglionated plexus, responding as they do to multiple cardiac sensory inputs, forms the basis for integrated regional cardiac control.

Canine intrinsic cardiac neurons involved in cardiac regulation possess NK1, NK2, and NK3 receptors

To determine whether intrinsic cardiac neurons involved in cardiac regulation possess neurokinin (NK) receptor subtypes, we administered selective NK receptor agonists individually (100 μM; 0.1 ml) into the coronary arterial blood supply of right atrial intrinsic cardiac neurons of 18 anesthetized dogs. The selective NK1 receptor agonist [Sar9,Met(O2)11]-substance P depressed the spontaneous activity of right atrial neurons (26.7 ± 6.7 to 13.0 ± 4.0 impulses/min; P < 0.05) in 11 dogs and augmented such activity in the other 5 dogs (8.0 ± 3.1 to 27.8 ± 8.7 impulses/min; P < 0.05). Local administration of the selective NK2 receptor agonist [β-Ala8]-NKA-(4-10) depressed right atrial neuronal activity (27.3 ± 6.4 to 14.7 ± 3.8 impulses/min; P < 0.05), whereas the selective NK3 receptor agonist senktide augmented such activity (18.9 ± 6.4 to 53.1 ± 12.0 impulses/min; P < 0.05). Left ventricular chamber pressure fell when selective NK1 and NK2 receptor agonists were administered. Increases in heart rate and right ventricular intramyocardial systolic pressure occurred when the selective NK3 receptor agonist was studied. Administration of a selective NK1or NK2 receptor antagonist altered neuronal activity, with no subsequent change in activity occurring after administration of its respective receptor agonist. Receptor autoradiography demonstrated tachykinin receptors associated with ventral right atrial intrinsic cardiac neurons. It is concluded that intrinsic cardiac neurons involved in cardiac regulation possess NK1, NK2, and NK3 receptors and that some intrinsic cardiac neurons receive tonic input via endogenously released NKs.

Role of P1 purinergic receptors in myocardial ischemia sensory transduction

OBJECTIVES To characterize the role that cardiac sensory P(1) purinergic (adenosine A(1) or A(2)) receptors play in transducing myocardial ischemia. METHODS Porcine nodose ganglion cardiac sensory neuron adenosine A(1) or A(2) receptor function was studied in situ during control states as well as in the presence of the peptides bradykinin and substance P or focal ventricular ischemia. The responses of porcine nodose ganglion cardiac and non-cardiac afferent neuronal somata to adenosine were also studied in vitro. RESULTS Local application of A(1) or A(2) adenosine receptor agonists modified the activity generated by ventricular sensory neurites associated with 70 and 74% of identified nodose ganglion cardiac afferent somata in situ, respectively, exciting most neurons. In contrast, adenosine reduced the excitability of nodose ganglion cardiac afferent neuronal somata in vitro. Bradykinin and substance P affected 56 and 63%, respectively, of tested afferent neurons. The capacity of ventricular sensory neurites to transduce signals relating to these peptides was virtually eliminated by the presence of P(1) purinergic receptor antagonists. So was their capacity to transduce focal ventricular ischemia. Since most cardiac sensory neurites responded differently to adenosine in vivo than did cardiac afferent neuronal somata in vitro, it appears that the transduction properties of cardiac afferent neurons need to be characterized in situ. CONCLUSIONS Most ventricular sensory neurites associated with nodose ganglion afferent neurons possess adenosine A(1) and/or A(2) receptors that play a primary role in transducing myocardial ischemic events to central neurons. These data support clinical observations implicating cardiac sensory purinoceptors in transducing myocardial ischemic events.

Transduction capabilities of neonatal ventricular afferent neurons in vivo.

We sought to determine the capacity of ventricular sensory nerve endings (neurites) associated with neonatal nodose ganglion afferent neurons to transduce mechanical and chemical stimuli in situ. Spontaneous activity generated by 17 nodose ganglion cardiac afferent neurons was identified in 8 anesthetized neonatal pigs (10-21 days old) using extracellular recording recording techniques. The activity generated by afferent neurons was studied when their ventricular sensory neurites were exposed to local mechanical or chemical stimuli, following systemic administration of specific chemicals or during brief periods of apnea. Gentle mechanical distortion of their ventricular sensory fields enhanced the activity generated by 6 spontaneously active afferent neurons, while suppressing the activity generated by another 3 neurons. Afferent neuronal activity was either enhanced or suppressed when the following chemicals were applied to identified ventricular epicardial sensory fields: the sodium channel modifier veratridine (92% of tested neurons); the P1-purinoceptor agonist adenosine (92%); the neuropeptides angiotensin II (100%), bradykinin (90%) and substance P (90%); and the nitric oxide donor S-nitroso-N-acetylpenicillamine (100%). Epicardial application of isoproternol or nicotine induced modest neuronal responses. Cardiac afferent neurons were also affected when these chemicals were administered systemically. Apnea of 60-100 s duration modified (enhanced, n = 2; suppressed, n = 5) the activity generated by most identified afferent neurons. The estimated average conduction velocity of afferent axons associated with these neurons was 1.0 +/- 0.2 m/s. It is concluded that neonatal nodose ganglion cardiac afferent neurons respond to many of the chemicals known to modify adult cardiac afferent neurons. That cardiac afferent neurons are capable of sensing the mechanical and chemical milieu of the neonatal heart should be taken into account when considering altered neonatal cardiovascular status such as occurs during apnea.

Patent ductus arteriosus remodels cardiac sensory neuronal chemotransduction

We sought to determine the capacity of neonatal ventricular sensory nerve endings (neurites) to transduce the cardiac milieu in the presence of cardiovascular pathology. The spontaneous activity generated by nodose ganglion cardiac afferent neurons was identified in situ using extracellular recording techniques in two groups of piglets approximately 2 weeks old: (i). controls that underwent sham operations (n=19 piglets) 2 weeks earlier and (ii). a pathological model of patent ductus arteriosus stented open for about 2 weeks (n=16 piglets). The capacity of ventricular sensory neurites associated with nodose ganglion afferent neurons to transduce local mechanical (including alterations in right or left ventricular volumes) or chemical stimuli was studied in both groups. The average conduction velocity of afferent axons associated with identified neuronal somata was estimated to be 1.5+/-0.6 or 2.9+/-1.3 m s(-1). Ventricular afferent neurons transduced mechanical stimuli similarly in both groups. In control animals, ventricular afferent neurons transduced the following chemicals: the sodium channel modifier veratridine (delta 23+/-7 impulses min(-1)), the P(1)-purinoceptor agonist adenosine (Delta 24+/-8 impulses min(-1)), and the beta-adrenoceptor agonist isoproterenol (delta 18+/-7 impulses min(-1)). On the other hand, patent ductus arteriosus cardiac afferent neurons did not transduce these chemicals. It is concluded that neonatal cardiac afferent neuronal chemosensory-as opposed to mechanosensory-transduction remodels in the presence of a patent ductus arteriosus. The reduced capacity of neonatal cardiac afferent neurons to transduce chemicals in the presence of a patent ductus arteriosus should be taken into account when considering neonatal cardiovascular control in such a state.