Intra-atrial administration of phenylbiguanide has been shown to trigger, through the stimulation of vagal afferent C-fibers, reflex bradycardia, hypotension, and sympathoinhibition classically known as the Bezold-Jarisch (B-J) reflex (O. Krayer. Naunyn-Schmiedeberg's Arch. Exp. Pathol. Pharmacol. 240: 361-368, 1961). The effects of microinjections, into the nucleus tractus solitarius (NTS), of serotonin (5-HT) and 1-(m-chlorophenyl)-biguanide (CPBG), a potent 5-HT3 receptor agonist, on these reflex responses were studied in urethananesthetized rats. 5-HT (600 and 900 pmol) and CPBG (10-150 pmol) produced a dose-dependent inhibition of the atropine-sensitive bradycardiac component of the B-J reflex. The effect of both agonists was reversed by prior local microinjection of the 5-HT3 receptor antagonists zacopride (100 pmol) and ondansetron (100 pmol), but not by that of the 5-HT2 receptor antagonist ketanserin (10 pmol) or the mixed 5-HT1/5-HT2 receptor antagonist methysergide (100 pmol). In contrast, CPBG (150 pmol) did not affect the B-J reflex inhibition of lumbar sympathetic nerve discharge. These results show that stimulation of NTS 5-HT3 receptors produced an inhibition of the cardiovagal component of the B-J reflex without affecting its sympathetic component. Because the stimulation of these receptors also inhibits the cardiac component of the baroreflex, the present data suggest the participation of NTS 5-HT3 receptors in the mechanisms that modulate cardiac reflex responses elicited by messages from different vagal afferents.

The effects of serotonin3 (5-HT3)-receptor stimulation in the nucleus tractus solitarii (NTS) on the cardiovagal, sympathetic, and respiratory responses to activation of carotid body chemoreceptors were investigated in anesthetized rats. The chemoreflex responses were triggered by an intravenous administration of KCN (40 microg/kg) in spontaneously breathing urethan-chloralose-anesthetized rats or by an intracarotid administration of saline saturated with 100% CO2 in pancuronium bromide-paralyzed and artificially ventilated urethan-anesthetized rats. Microinjections of 5-HT (2.5-5 nmol) or the 5-HT3 agonist 1-(m-chlorophenyl)-biguanide (CPBG, 300-1,200 pmol) into the commissural NTS blocked in a dose-dependent manner the atropine-sensitive chemoreflex bradycardia elicited by KCN. However, neither 5-HT nor CPBG affected the KCN-induced increase in respiratory volume and the CO2-induced increases in blood pressure and lumbar sympathetic nerve discharge. The inhibitory effect of 5-HT or CPBG on KCN-induced bradycardia was blocked by prior intra-NTS microinjection of a 5-HT3 antagonist, such as zacopride (100 pmol) or ondansetron (100 pmol), or the A-type gamma-aminobutyric acid (GABA(A)) antagonist bicuculline (10 pmol). In contrast, local microinjections of antagonists acting at 5-HT1 and 5-HT2 receptors, such as methysergide (100 pmol) and ketanserin (10 pmol), respectively, did not prevent the actions of 5-HT or CPBG. These data show that the stimulation of 5-HT3 receptors in the NTS exerted an inhibitory influence, probably through the activation of a local GABAergic system, on the cardiovagal component of the chemoreflex. Because similar effects of 5-HT3-receptor stimulation in the NTS were previously found on the baroreflex and Bezold-Jarisch reflex responses, it can be inferred that NTS 5-HT3 receptors play a key modulatory role in the reflex control of the heart rate.

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In the present study, we analyzed in conscious rats the effects of microinjections of serotonin (5-HT; pmol range) into the nucleus of the solitary tract (NTS) on basal mean arterial pressure (MAP) and heart rate (HR) and also on the reflex bradycardia induced by the activation of the baro- and chemoreflex evaluated 1 min after 5-HT microinjection into the NTS. The data show that unilateral microinjection of 5-HT in the picomolar range into the NTS of unanesthetized rats produced a dose-dependent decrease in MAP and HR, which was blocked by previous microinjection of ketanserin (250 pmol/50 nl) into the NTS. The changes in MAP and HR induced by 5-HT were of very short duration, with a return to baseline values a few seconds later. The cardiovascular responses to baro- or chemoreflex activation 1 min after 5-HT microinjection into the NTS did not differ from the control, indicating that low doses of 5-HT produced no effect on the cardiovascular reflexes tested at that time. The present data show that, as also observed in anesthetized rats, the microinjection of picomolar doses of 5-HT into the NTS elicits the typical cardiovascular responses to baroreceptor activation. These effects, hypotension and bradycardia, seem to be mediated by 5-HT2 receptors because both were blocked by a selective 5-HT2 receptor antagonist. However, since microinjection of 5-HT (1 pmol) into the NTS produced no changes in the cardiovascular responses to the baro- and chemoreflex activated 1 min later, the role of 5-HT2 receptors in the processing of the cardiovascular afferent messages in the NTS remains to be elucidated.