The responses of A5 region neurons, the phrenic nerve, and systemic blood pressure to short-term hypoxia were examined in rats under conditions of spontaneous respiration. Tonic and respiration-modulated neurons increasing their discharge activity during hypoxia were identified. This hypoxia-induced response was more pronounced in the neurons with baseline discharge rate of 0.1-4.5 Hz (electrical activity of neurons increased by 4-5 times) compared to neurons with the baseline activity of 5.4-49.6 Hz (discharge rate increased by 1.4-2.0 times). The latency and duration of activation of all types A5 neurons correlated with the parameters of activation of the phrenic nerve. During hypoxia, activation of A5 neurons corresponded to the period of blood pressure drop (one-third of the reaction time), but not to the period of plateau or recovery phase. Low-, middle, and high-frequency A5 neurons participated in the modulation of hypoxia-provoked respiratory and hypotensive responses. Modulation of the respiratory response by A5 neurons was observed during the entire period of phrenic nerve activation, while modulation of the hypotensive response occurred only during blood pressure decrease.

Hypoxia was followed by more pronounced activation of the respiratory center and pronounced hypotensive response after unilateral injection of nitric oxide synthase blocker L-NAME into the A5 region. Microinjection of exogenous nitric oxide donor sodium nitroprusside into the A5 region abolished the effect of L-NAME on hypoxia-induced changes in activity of the respiratory center and blood pressure. Bilateral transection of the vagal and sinocarotid nerves suppressed the response of the respiratory center to hypoxia. However, the hypotensive response to hypoxia in these rats did not differ from that in intact animals. Under conditions of peripheral chemoreceptor deafferentation, the hypotensive response to hypoxia did not differ before and after blockade of nitric oxide synthase in the A5 region. The regulation of respiratory center activity and blood pressure during hypoxia was modulated by A5 neurons with the involvement of nitric oxide.

Surface perfusion of the rostral ventromedullar cerebral subdivisions with artificial cerebrospinal fluid containing exogenous NO donor sodium nitroprusside (0.1 mM) increased the discharge rate of the phrenic nerve and potentiated the response of the respiratory center to hypercapnia in narcotized mature rats. The latter reaction was prevented by blockage of NO-synthase in rostral ventromedullar neural structures with N(omega)-nitro-L-arginine methyl ester (L-NAME, 0.3 mM). It was hypothesized that rostral ventromedullar neural structures are involved in modulatory action of NO on central chemosensitive drive.

Electrical stimulation of neuronal structures in a rostral area of the ventral bulbar surface alters central inspiratory activity in anesthetized rats, augmenting the amplitude and velocity of this activity during the periods of its increase and plateau. The reactions are more pronounced in rats with transected vagal nerves. Blockade of pulmonary mechanoreceptors eliminates the influence of rostral neuronal structures only on the temporal" parameters of the plateau. Bilateral cooling of neuronal structures to 20~ results in complete block of central inspiratory activity. Key Words: rostral region of ventral bulbar structure; central inspiratory activity; respiratory centerCentral inspiratory activity (CIA) of the respiratory center forms under the influence of specific afferent pulses from chemo-and mechanoreceptors [6,71. The role of central chemoreceptors in this activity remains unclear because these receptors have not been identified. Recent studies have shown that neuronal structures located in the rostral region of the ventral surface of medulla oblongata (ventral bulbar surface, VBS) probably fulfil a chemosensory function and exert a complex effect on the respiratory center [2,4]. The mechanism of this effect is poorly understood. The purpose of the present study was to evaluate the role of the rostral region of the VBS in the mechanisms through which the CIA of the respiratory center is formed. MATERIALS AND METHODSThe study was carried out on 58 Nembutal-anesthetized (35 mg/kg) rats (body weight 200-250 g) with intact (n=36) or cut (n=22) vagal nerves. The VBS was exposed from the C1 level to the level of Department of Normal Physiolo9% State Medical University, Samara exit of roots of cranial nerves VI-VII and 4.0-4.5 mm lateral to the midline. Rostral neuronal structures of the VBS were stimulated via bipolar electrodes (interelectrode distance 100 g) with square pulses (100 Hz, 1 msec, 0.5-20 gA) delivered by an ESU-2 electrostimulator. Neuronal structures were cooled to 20~ unilaterally or bilaterally with a thermode. Electrical activity of the phrenic nerve was measured with bipolar silver electrodes, amplified, and integrated using standard equipment [1]. Arterial blood pressure was recorded with an ID-2I apparatus. The results were statistically analyzed by Student's t test with comparison of the means. RESULTSNeuronal structures of the VBS were electrically stimulated, with a step of 1 mm, at levels from the middle of cranial nerve XII roots to the exit of nerve VI roots (Fig. 1). A neurogram with its envelope showing variations of the phrenic nerve activity (PNA) before and after electrical stimulation is shown in Fig. 2. This activity changed, upon stimulation of a limited zone within the rostral region of the VBS.

We recorded spike activity of noradrenergic neurons of zone A5 (n = 89) in the brain of anesthetized rats under conditions of hypoxic stimulation (breathing with pure N 2 , 10 sec), thermonociceptive stimulation (tail-flick test), and reversible hypothermal blocking of the central respiratory activity. Hypoxic stimulation of peripheral О 2 -sensitive chemoreceptors considerably increased the discharge frequency in all the examined neurons and induced tachypnea and a hypotensive reaction. Sixty-nine (77.5%) neurons of the studied group were tested using nociceptive stimulation (thermal stimulation of the tail); such stimulation resulted in a multifold increase in their discharge frequency. This was accompanied by tachypnea and a hypertensive response. Thus, we first demonstrated the role of nociception in the control of activity of noradrenergic neurons in zone A5 and the role of nociceptive afferent signals in the modulation of functions of the respiratory and cardiovascular systems mediated by neurons of the above zone. Under conditions of blocking of the central respiratory activity, we examined 36 (40.4%) neurons of zone A5 and first observed the effect of strong activation of a significant proportion of these cells upon switching off of respiration. This fact shows that there is an activating "respiratory" drive on neurons of zone A5 (probably, from the side of an expiratory neuronal population of the respiratory center) and allows us to hypothesize on the genesis of "respiratory" modulation of these cells. The activity of 16 (18.0%) cells was recorded under conditions of consecutive applications of the above stimuli; all the neurons were activated by the respective afferent influences. The simultaneously induced effects of hypoxic and nociceptive stimulations on the activity of neurons of zone A5 were additive. Thus, we first obtained proofs in favor of the multimodality of noradrenergic neurons of the above zone. This feature is a significant factor providing integrative interaction between the respiratory and cardiovascular systems and the system of nociception.