Neuronal Blocker Research Articles

Central pathways relaying cardiovascular afferent information to amygdala.

It has been suggested that cardiovascular information to the amygdala is relayed through the paraventricular nucleus of the hypothalamus (PVH) and the parabrachial nucleus (PB;7). To test this possibility spontaneously firing units in the amygdala of 12 chloralose-anesthetized cats were monitored for changes in firing frequency during electrical stimulation of PVH and PB and for their responsiveness to baroreceptor (BA) and chemoreceptor (CA) activation. In the ipsilateral amygdala 27 of 140 units responded to PVH stimulation, 9 of which also responded to CA and none to BA, whereas 46 of 150 units responded to PB stimulation, 11 of which also responded to CA and 2 to BA. To demonstrate the relative contribution of the PVH and PB in relaying cardiovascular information to the amygdala, in an additional six cats, the effect of neuronal block and lesions of these two nuclei on potentials evoked in the amygdala by stimulation of the buffer nerves was tested. Reversible neuronal block with injections of procaine in the PB significantly attenuated these evoked potentials. Electrolytic and chemical (kainic acid) lesions in the same PB sites also were effective in attenuating the responses. The potentials were unaltered by injection of procaine in the PVH. These results indicate that the PB is a site of relay of chemoreceptor and of some baroreceptor information from the medulla to the amygdala.

Psychopharmacological investigation of the monoamine oxidase inhibitory activity of molindone, a dihydroindolone neuroleptic.

24 h pretreatment with molindone enhanced the behavioural effects of L-dopa and 5-HTP, precursors of biogenic amines (catecholamines and 5-HT respectively) preferentially deaminated by MAO-A, confirming that a metabolite of molindone inhibits MAO-A. 24 h pretreatment with molindone enhanced the behavioural effects of tryptamine and antagonized reserpine-induced ptosis, and in molindone-pretreated rats L-tryptophan induced behavioural effects, probably because of the MAO-A inhibitory activity exerted by a metabolite of molindone. Since 24 h pretreatment with molindone, unlike 30 min pretreatment with clomipramine, failed to antagonize fenfluramine and p-chloramphetamine-induced behavioural syndromes, it suggests that molindone and/or its metabolites most probably do not exert 5-HT neuronal uptake blocking activity and the potentiation of 5-HTP-induced behavioural syndrome is due to a metabolite's MAO-A inhibitory activity. As 2 h pretreatment with molindone induced catalepsy and antagonized apomorphine-induced climbing behaviour in mice and stereotypy in rats, while 24 h pretreatment failed to induce catalepsy and to antagonize apomorphine-induced behaviour, it appears that, at 24 h, the tissue levels of molindone are inadequate to block postsynaptic striatal and mesolimbic DA receptors and that, though a metabolite of molindone is biologically active so far as inhibition of MAO-A is concerned, the metabolites are devoid of neuroleptic activity. Further, since 2 h pretreatment with molindone failed to enhance the behavioural effects of L-dopa, it suggests that at 2 h the degree of MAO-A inhibition induced by molindone and/or the metabolite is not sufficient to counteract the neuroleptic activity of the parent compound.

Hypertension in pregnancy. Pathophysiology and management.

Hypertension in pregnancy has implications for both maternal and fetal welfare. Extrapolation from concepts of mechanisms operating in hypertension in general to pregnancy-related hypertension is not justified. In the latter, the major features are a hyper-adrenergic state, plasma volume reduction and an increased systemic resistance. A reduction in uteroplacental perfusion may result from or may activate the mechanisms that elevate blood pressure. Humoral factors (e.g. hormonal attenuation of vascular reactivity) and prostacyclin deficiency may be central to the disordered physiology. Treatment of hypertension in pregnancy should aim at avoiding the vascular damage due to blood pressure elevation but not cause a reduction in uteroplacental perfusion. Unlike earlier antihypertensive regimens using centrally acting sympatholytics, adrenergic neuron blockers or diuretics, regimens using beta-blockers or combinations of beta-blockers with alpha-blockers or vasodilating agents such as hydralazine permit effective blood pressure control, even in severe hypertension, and pregnancy can often proceed until term or until fetal maturity is secured. Adverse effects on the fetus (growth retardation, cardiorespiratory depression, hypoglycaemia, hyperbilirubinaemia) formerly attributed to beta-blockers are more likely related to poorly controlled hypertension. Specific benefits of maternal beta-adrenoceptor blockade are suggested by evidence for prevention of proteinuric deterioration and a decrease in the incidence and severity of respiratory distress in premature infants. Hypertension in pregnancy still presents a formidable therapeutic challenge and requires comprehensive management with close monitoring of fetal welfare. The presence or development of proteinuria in a hypertensive pregnant woman implies a major increase in risk to the fetus and warrants immediate admission to hospital for specialist management.

The antiarrhythmic activity of meobentine sulfate in man.

Meobentine (sulfate) has antifibrillatory and antiarrhythmic activity in canine models. The antiarrhythmic, pharmacokinetic, and adrenergic neuronal blocking effects of meobentine were assessed in 15 patients with chronic, high-frequency ventricular ectopic depolarizations (VEDs). Eleven of the 15 patients had recurrent nonsustained ventricular tachycardia. The patients were given a series of gradually increasing single doses of meobentine; six received oral meobentine and nine had infusions. The antiarrhythmic efficacy of meobentine was assessed by a comparison of arrhythmia frequency during placebo given on days just prior to meobentine. Oral therapy with meobentine at dosages above 20 mg/kg caused diarrhea, and well-tolerated dosages achieved peak concentrations of 0.69 micrograms/ml (range 0.5-1.0 micrograms/ml). Antiarrhythmic activity was seen in only one patient with oral meobentine. In contrast, intravenous infusions (6.75-34.2 mg/kg) achieved concentrations ranging from 1.3-9.8 micrograms/ml. There was a linear relationship between pseudo-steady-state plasma concentrations and dosage, r = 0.82, p less than 0.01. Antiarrhythmic activity was seen in four of nine patients who received intravenous meobentine over a range of concentrations from 2.5-4.5 micrograms/ml. Four patients developed evidence of adrenergic neuronal blockage (loss of the venous reflex response); two at dosages of 16.2 mg/kg, one at 24.3 mg/kg, and one at 34.2 mg/kg. In one individual (24.3 mg/kg), the adrenergic neuronal blockade was associated with an acute episode of shortness of breath, orthopnea, and cough. With intravenous meobentine, there was a linear relationship between dosage and AUC, and the elimination half-life ranged from 11-27 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Bretylium tosylate in patients with acute myocardial infarction

Experience with bretylium tosylate accumulated during a period of over 10 years, during which time > 1,500 patients with acute myocardial infarction were treated, is summarized. On the diagnosis of acute infarction, the agent was given by continuous intravenous drip at a rate of 10 mg/kg/24 hours for 5 to 7 days for prophylaxis of ventricular fibrillation. Bretylium administration prevented primary ventricular fibrillation in about 99% of these patients. No undesirable side effects were observed with this protocol, which lessens the initial sympathomimetic effect of the drug while allowing sufficient time for the adrenergic neuronal blocking effect to develop. The beneficial effects of the drug are believed to be due, in part, to a direct electrophysiologic effect on both normal and ischemic myocardium. This effect equalizes the duration of both the effective refractory periods and the ventricular action potentials, and it creates conditions capable of blocking reentrant pathways. Bretylium stabilizes the duration of electrical systole in patients with acute myocardial infarction. Hemodynamic studies during bretylium treatment further confirm the effectiveness of this drug and have prompted additional studies to evaluate its potential as an agent capable of decreasing impedance in acute myocardial infarction.

Is substance P necessary for corneal nociception?

Substance P (SP)-containing nerve fibers are few in the rabbit cornea, which is richly supplied with acetylcholinesterase-positive nerve fibers, presumably sensory in nature. Treatment with capsaicin given by retrobulbar injection 48 h prior to sacrifice caused SP to disappear from the SP nerves in the cornea without affecting the acetylcholinesterase-positive nerve fibers. The corneal sensitivity to a tactile stimulus (wetted cotton swabs) and to a chemical stimulus (local application of capsaicin) and the disruption of the blood-aqueous barrier after local injury (infrared irradiation of the iris) were tested after pretreatment with capsaicin (retrobulbar injection) the SP antagonist [D-Pro2,D-Trp7,9]SP (single topical application or long-term application twice daily for 2 months), the local anaesthetic oxibuprocaine (topical application), or the neuronal blocker tetrodotoxin (intravitreal injection). All these treatments abolished or reduced the disruption of the blood-aqueous barrier after local injury but only oxibuprocaine and tetrodotoxin abolished the corneal sensitivity to tactile and chemical stimuli. It is suggested that 1.(1) SP nerve fibers constitute a minor proportion of the sensory nerve supply to the cornea,2.(2) that the neurogenic mechanisms involved in the response to ocular injury differ from those involved in corneal nociception, and3.(3) that uveal SP is involved in the response to ocular trauma and that corneal SP is probably not necessary for corneal nociception.

The in vitro chronotropic and inotropic effects of vasoactive intestinal peptide (VIP) on the atria and ventricular papillary muscle from Cynomolgus monkey heart.

The in vitro chronotropic and inotropic effects of vasoactive intestinal peptide (VIP) and of isoproterenol, two agents known to stimulate cardiac adenylate cyclase were compared on the heart from Cynomolgus monkey using the spontaneously beating right atrium, the electrically stimulated left atrium, and the electrically-stimulated ventricular papillary muscle. VIP increased concentration-dependently the rate of beating of the right atrium as well as the contractility of both atria but its efficiency was lower than that of D,L-isoproterenol. VIP also stimulated concentration-dependently, and this time as efficiently as D,L-isoproterenol, the contractility of papillary muscle. These VIP effects were unaltered by the neuronal blocker tetrodotoxin. In addition, the moderate inhibition exerted by the beta-adrenergic blocker D,L-propranolol on VIP effects argued against the implication of beta-adrenergic receptors in VIP effects. These results indicate that VIP exerts a direct stimulatory influence on the rate and contractility of Cynomolgus monkey heart.

Role of Autoinhibitory Feedback in Cardiac Sympathetic Transmission

The relationship between two indices of transmitter release measured simultaneously and the frequency of 4 field pulses (0.125-2 Hz) were obtained from superfused guinea pig right atria after labelling with 3H-noradrenaline. The relationships between 3H-efflux or rate responses and frequency were hyperbolic. Autoinhibitory feedback did not play a role since phentolamine (1 microM) did not alter the 3H-efflux or rate responses to 4 field pulses that gave 50-60% of the maximum rate response. In the presence of neuronal uptake block (desipramine (0.1 microM) phentolamine enhanced 3H-efflux and rate responses to 4 field pulses at all frequencies. In the absence of desipramine prolonged trains of field pulses (8-12 pulses) at low frequency (0.25 Hz) were not sufficient to activate autoinhibitory feedback. At 2 Hz phentolamine enhanced both responses at 12 field pulses. We conclude that in the right atrium autoinhibitory feedback plays little role in the modulation of transmitter release at levels of stimulation that cause 50-60% of maximum tissue response. The presence of neuronal uptake inhibition or high stimulus strengths are necessary to evoke autoinhibitory feedback.

Effects of Intravenous Acetaldehyde, Acrolein, Formaldehyde and Propionaldehyde on Arterial Blood Pressure Following Acute Guanethidine Treatment

Guanethidine (G) is currently used in the treatment of essential hypertension. Acetaldehyde (A), acrolein (AR), formaldehyde (F) and propionaldehyde (P) are constituents of cigarette smoke and (A) is also an intermediate oxidative metabolite of ethanol. These aldehydes are known to produce sympathomimetic effects by the release of NE from adrenergic neurons and to exert cardioinhibitory effects. The type of predominant effect is dose-dependent. This study was undertaken to determine if these aldehydes result in sympathomimetic effects in the presence of G (15 mg/kg iv) in anesthetized rats. G enhanced the pressor responses to A and P in dose ranges of 5-20 and 5-10 mg/kg respectively. However, AR and F at dose ranges of 0.05-5 and 0.1-10 mg/kg, respectively, elicited only depressor responses after G. Thus, A and P exerted greater sympathomimetic effects through the release of intraneuronal NE in the presence of G. The adrenergic neuronal blocking action of G changes the blood pressure effects of AR and F. When these two compounds are administered in the absence of G, they cause predominant pressor effects, whereas in the presence of G a depressor response is noted. This depressor response is possibly by vagal stimulation and/or direct vasodilation.

Ocular responses evoked by capsaicin and prostaglandin E2 are inhibited by a substance P antagonist.

Injection of capsaicin or prostaglandin E2 into the vitreous chamber of the rabbit eye resulted in miosis and breakdown of the blood-aqueous barrier, manifested in aqueous flare. Pretreatment with the neuronal blocker tetrodotoxin or the substance P antagonist (D-Pro, D-Trp)-SP greatly reduced the ocular responses to capsaicin and prostaglandin E2. The results suggest a role for neuronal substance P in the ocular response to injury.

Partial isolation of an endogenous norepinephrine uptake inhibitor in canine plasma.

We have previously reported that homologous plasma inhibits the accumulation of [3H]norepinephrine ( [3H]NE) by the canine saphenous vein. The purpose of this study was to extract the inhibitory substance(s) from plasma and to examine some of its properties. The net accumulation of tritium by saphenous vein strips following incubations in [3H]NE was inhibited 34.4 +/- 6.1% by a 60% plasma in Krebs solution. An acetone extract of this plasma reconstituted to 83% of its original unextracted volume also significantly inhibited net tritium accumulation by 24.5 +/- 4.7%. After lyophilization of this extract, the inhibitor was not readily solubilized in dilute acetic acid but was soluble in dilute sodium bicarbonate solutions. This extract solution, reconstituted to 66% of the original plasma volume, significantly inhibited the accumulation of [3H]NE by 35.0 +/- 9.8%. Kinetic analysis using this preparation suggests that the inhibition may be competitive in nature. The activity was not sensitive to heat but was abolished by the neuronal uptake blocker cocaine. Further purification with gel chromatography produced a small molecular weight fraction that inhibited tritium accumulation. When this sample was reconstituted in a volume equivalent to that of the unextracted plasma, the contractile response of the isolated canine saphenous vein to electrical stimulation was significantly enhanced. Thus the inhibitory activity of plasma on the uptake of [3H]NE by the canine saphenous vein is due in part to a heat-stable small molecule that inhibits the initial rate of [3H]NE uptake.

Labetalol: a review of its pharmacology, pharmacokinetics, clinical uses and adverse effects.

Labetalol is a combined alpha- and beta-adrenoceptor blocking agent for oral and intravenous use in the treatment of hypertension. It is a nonselective antagonist at beta-adrenoceptors and a competitive antagonist of postsynaptic alpha 1-adrenoceptors. Labetalol is more potent at beta that at alpha 1 adrenoceptors in man; the ratio of beta-alpha antagonism is 3:1 after oral and 6.9:1 after intravenous administration. Labetalol is readily absorbed in man after oral administration, but the drug, which is lipid soluble, undergoes considerable hepatic first-pass metabolism and has an absolute bioavailability of approximately 25%. There are no active metabolites, and the elimination half-life of the drug is approximately 6 hours. Unlike conventional beta-adrenoceptor blocking drugs without intrinsic sympathomimetic activity, labetalol, when given acutely, produces a decrease in peripheral vascular resistance and blood pressure with little alteration in heart rate or cardiac output. However, like conventional beta-blockers, labetalol may influence the renin-angiotensin-aldosterone system and respiratory function. Clinical studies have shown that the antihypertensive efficacy of labetalol is superior to placebo and to diuretic therapy and is at least comparable to that of conventional beta-blockers, methyldopa, clonidine and various adrenergic neuronal blockers. Labetalol administered alone or with a diuretic is often effective when other antihypertensive regimens have failed. Studies have shown that labetalol is effective in the treatment of essential hypertension, renal hypertension, pheochromocytoma, pregnancy hypertension and hypertensive emergencies. In addition, preliminary studies indicate that labetalol may be of value in the management of ischemic heart disease. The most troublesome side effect of labetalol therapy is posture-related dizziness. Other reported side effects of the drug include gastrointestinal disturbances, tiredness, headache, scalp tingling, skin rashes, urinary retention and impotence. Side effects related to the beta-adrenoceptor blocking effect of labetalol, including asthma, heart failure and Raynaud's phenomenon, have been reported in rare instances.

Gastrins and cholecystokinins release acetylcholine but not substance P from neurons in the guinea-pig taenia coli

Gastrins and cholecystokinins contract the isolated taenia coli of the guinea-pig. Porcine CCK-39 produced the greatest contractile response and human gastrin-17 I and −34 the weakest. Pentagastrin had the highest affinity to the receptors and non-sulphated CCK-8 the lowest. The contractions produced by the CCK peptides were reduced by the neuronal blocker tetrodotoxin and by the muscarinic blocker atropine but not by the substance P antagonist [D-Pro2,D-Trp7,9]SP. It is concluded that gastrin/CCK peptides act directly on smooth muscle cells and that in addition these peptides, notably sulphated forms of CCK, are capable of exciting cholinergic neurons (but not SP neurons) to cause smooth muscle contraction.

Mechanism of lithium action on the adrener GIC function

The intravenous injection of Lithium chloride (LiCl) in two dose levels (25 & 50 mg/kg) has led to a significant potentiation of the pressor response of rabbits to the i.v administration of both epinephrine and norepinephrine. The i.v injection of LiCl (50 mg/kg) resulted in a marked depression of the carotid occlusion reflex in rabbits. In vitro experiments revealed that LiCl (1.6 mcg/ml) and guanethidine (0.8 mcg/ml) exert the same action on the rabbit mesenteric nerve-intestine preparation and abolish the intestinal relaxation induced by electrical stimulation of the mesenteric nerve. Results confirm the assumption that Li might display a pre-synaptic, guanethidine-like, adrenergic neuronal blocking activity.

Effect of Labetalol and YM-09538 on Neuronal Uptake of (3H)Norepinephrine in the Rat Vas Deferens

Labetalol and YM-09538 are combined alpha and beta receptor antagonists with demonstrated antihypertensive activity. Both compounds inhibited the uptake of (3H)norepinephrine into nerves in the rat vas deferens. However, labetalol was approximately 5 fold more potent than YM-09538 as an inhibitor of neuronal uptake. Inhibition of neuronal uptake occurred at concentrations 43 and 3800 times higher than necessary for inhibition of alpha receptors by labetalol and YM-09538, respectively. Thus YM-09538 shows a greater separation between neuronal uptake blocking properties and alpha receptor blocking properties than labetalol. This separation of activities may contribute to greater antihypertensive efficacy of YM-09538 relative to labetalol.

Anesthetics may restructure the hydrogen belts of membranes.

Anesthetic molecules can form hydrogen bonds or organize hydrogen-bond networks. It is argued that they affect the neuronal cell membrane not by an amorphous fluidization of the hyprophobic core of the lipid bilayer but by a restructuring of its hydrogen belts, i.e., the regions occupied by the CO and OH groups of the membrane lipids. The structured disturbance of the hydrogen-bond network is translated latitudinally to hydrogen-bonding sites of the proteins of the membrane, causing allosteric changes of ion channels that result in neuronal blocking.

Direct evidence against a role of ATP as the nonadrenergic, noncholinergic inhibitory neurotransmitter in guinea pig tenia coli.

Electrical field stimulation of the isolated guinea pig tenia coli in the presence of a muscarinic receptor antagonist (atropine) and an adrenergic neuron blocker (guanethidine) produces relaxation. A large amount of indirect evidence has suggested that the neurotransmitter that is released from these nonadrenergic, noncholinergic inhibitory neurons is ATP or a related nucleotide, and the nerves have been termed "purinergic." A photoaffinity analog of ATP, arylazido aminopropionyl ATP, which produces a specific pharmacological antagonism of P2 purinergic receptors in isolated guinea pig vas deferens and urinary bladder, was utilized in the present study to evaluate directly whether ATP is the nonadrenergic, noncholinergic inhibitory neurotransmitter in tenia coli. By blocking postjunctional P2 receptors, arylazido aminopropionyl ATP produced a pronounced antagonism of relaxations induced by exogenously added ATP. Responses produced by ADP, AMP, and adenosine also were antagonized by arylazido aminopropionyl ATP, but to a lesser extent. Inhibitory responses to isoproterenol were not antagonized. Under these conditions of established, specific P2-receptor blockade of responses to exogenously added ATP, relaxations induced by field stimulation of intrinsic inhibitory nerves in the presence of atropine (1 microM) and guanethidine (1 microM) were not antagonized. Though these results provide no indication of the actual substance involved, they suggest strongly that the nonadrenergic, noncholinergic inhibitory neurotransmitter in the guinea pig tenia coli is not ATP.

INHIBITORY EFFECT OF HISTAMINE ON THE RELEASE OF MELANIN-DISPERSING HORMONE IN THE FIDDLER CRAB,UCA PUGILATOR

Histamine (HA), a stimulator of H1 and H2 receptors, produced dose-dependent inhibition of the melanin dispersion which normally occurs when fiddler crabs, Uca pugilator, are transferred from a white to a black background. The HA precursor L-histidine, and 4-methyl histamine (4-MeHA), an H2 receptor agonist, also inhibited melanin dispersion. 2-Methyl histamine (2-MeHA), an H1 receptor agonist, enhanced melanin dispersion. The inhibitory effects of HA and 4-MeHA were abolished by the H2 receptor blocker metiamide but not by blockers of either H1 receptors or alpha1 adrenoceptors. Melanin-dispersing hormone (MDH) release is accomplished mainly by stimulation of alpha1 adrenoceptors with norepinephrine appearing to be the neurotransmitter involved. The H1 receptor blockers pyrilamine and SA-97 antagonized 2-MeHA. HA-induced inhibition of melanin dispersion was potentiated by the noradrenergic neuron blocker bretylium and the alpha2 adrenoceptor agonist B-HT 933. HA did not significantly affect melanin dispersion in crabs pretreated with 6-hydroxydopamine which destroys catecholaminergic neuroterminals. None of these drugs affected the melanophores directly. On the basis of these and previously obtained results it is suggested that H1 and H2 receptors are present on norepinephrine neurons involved in triggering MDH secretion, and administered HA inhibits MDH release by decreasing impulse-mediated noradrenergic neurotransmission through stimulation of H2 receptors.

Functions of adrenergic and cholinergic nerves in canine effectors of seminal emission.

Spontaneous activity responses to acetylcholine (ACh), adrenaline (A), noradrenaline (NA) and barium chloride as well as the effects of various autonomic drugs on effects of field stimulation of nerves and muscle cells of isolated pieces or strips of cauda epididymidis, vas deferens, ampulla ductus deferentis and prostate of dog were studied. The main results and conclusions are: the muscles show little spontaneous activity but rhythmicity can easily be produced by e.g. stimulating agonists. The muscles are contracted by alpha-adrenoceptor stimulants. ACh has usually no or a very weak contractile effect in high concentrations. Muscles of young dogs are more sensitive to ACh. The excitatory innervation of the muscles is adrenergic and completely blocked by adrenergic neuron blockers as well as alpha-adrenoceptor blocking drugs. Stimulation of adrenergic nerves leads to maximum response already at low frequencies (4-6 Hz). This response is very similar to that provoked by a supramaximal dose of NA. Scopolamine enhances neurogenic contractile effects while physostigmine suppresses them. Hence cholinergic nerves may act by muscarinic prejunctional inhibition of the excitatory adrenergic neurotransmission rather than act directly upon the smooth muscle cells. Since secretory cells receive cholinergic innervation prejunctional inhibition of the adrenergic myomotor nerves may be of functional significance in at least the long copulatory events of the dog.

Cardiovascular functions of brain serotonergic neurons in the rabbit as analysed from the acute and chronic effects of 5,6-dihydroxytryptamine.

The effects of intracisternal (i.c.) 5,6-dihydroxytryptamine (5,6-DHT) or creatinine sulphate vehicle on mean arterial pressure (MAP), heart rate, and baroreceptor-heart rate and nasopharyngeal reflex properties were studied in conscious rabbits. For the baroreflex we derived sigmoid MAP-heart period (HP) curves, and for the nasopharyngeal reflex we measured apnea time, rise in HP, and delta MAP. The acute effects occurring over the first few hours in intact and decerebrate rabbits included: (a) tachycardia and a decrease in baroreflex HP range and gain, which were mediated through bulbar or spinal pathways influencing vagal motoneurons; (b) a transient early rise in MAP through a bulbar or spinal pathway and a late suprapontine rise in MAP; and (c) shorter apnea time, less bradycardia, and less well-maintained MAP during nasopharyngeal stimulation. By day 14, when spinal cord serotonin was depleted by 70%, resting MAP and heart rate had recovered, HP range and gain had risen above initial control, but nasopharyngeal apnea time and bradycardia were still reduced. Some of the acute responses were due to synaptic release of serotonin (5HT); since the tachycardia and late component of the pressor response were blocked by pretreatment with i.c. methysergide, the acute changes in baroreflex parameters were opposite to the chronic changes, and a second injection of 5,6-DHT failed to produce these changes. On the other hand, the acute and chronic nasopharyngeal responses were similar, suggesting that the former were due to neuronal block and not 5HT release. These findings indicate that central serotonergic neurons inhibit cardiac vagal activity, increase blood pressure through both suprapontine and bulbar or spinal pathways, and are involved in the nasopharyngeal reflex.