Localization of the central sympatho-inhibitory effect of a narcotic analgesic agent, fentanyl, in cats.

Fentanyl (10 and 30 mug/kg), a narcotic analgesic, induced in cats a decrease in blood pressure and heart rate and reduced spontaneous splanchnic nerve activity. Fentanyl reduced the pressor response to medullary stimulation, but did not change the pressor response to hypothalamic or cervical spinal cord stimulation. Fentanyl reduced the potential evoked in the splanchnic nerve by stimulation at low frequency of a pressor area of the medulla oblongata. The potentials evoked in the splanchnic nerve by hypothalamic or cervical spinal cord stimulation were only slightly changed. Nalorphine (0.5 mg/kg) or naloxone (30 mug/kg) induced a recovery in blood pressure, heart rate and spontaneous splanchnic discharges which had been reduced by fentanyl, but nalorphine or naloxone did not restore pressor response to medullary stimulation or potentials evoked in the splanchnic nerve by medullary stimulation, which had been decreased by fentanyl.     

Activation of the central pathway of the baroreceptor reflex,a possible mechanism of the hypotensive action of clonidine

Summary Arterial blood pressure, heart rate and discharges in the preganglionic splanchnic and a postganglionic renal sympathetic nerve were recorded in cats anaesthetized with urethane. Electrical stimulation of the posterior hypothalamus or the fastigial nucleus of the cerebellum elicited an immediate increase in sympathetic nerve activity and a rise in blood pressure and heart rate. The stimulation-induced discharge pattern in the sympathetic nerves was characterized by a strong initial burst followed by a phase of inhibition and a final stabilization of the discharges at a level definitely lower than the initial burst. This pattern was reversibly converted into a constant high amplitude firing during a lowering of the blood pressure by bleeding the cats and irreversibly so after cutting the buffer nerves. These findings indicate that the inhibitory phase of the sympathetic discharge pattern during central stimulation is due to the rise in blood pressure and the ensuing baroreceptor-reflex activation.Clonidine (0.03 and 0.1 mg/kg i.v.) reduced the spontaneous sympathetic nerve activity and lowered blood pressure and heart rate. The sympathetic discharges evoked by central stimulation were partially inhibited by clonidine, an effect which could be overcome by raising the voltage used for central stimulation. Independent of the strength of this stimulation an inhibitory phase in the evoked discharge pattern was not observed after clonidine, even when the low blood pressure due to the drug action was raised by a noradrenaline infusion. After clonidine, the evoked discharge pattern closely resembled that after simultaneous stimulation of both sinus nerves and the hypothalamus or the fastigial nucleus, and it was not altered by additional stimulation of the sinus nerves. These observations have led to the hypothesis that clonidine causes a long-lasting activation within an as yet unidentified part of the central pathway of the depressor baroreceptor reflex. In view of the well-known -adrenoceptor stimulating property of clonidine, and since the central effect of clonidine was antagonized by the -adrenoceptor blocking agent piperoxan, it is likely that the central part of the baroreceptor-reflex pathway is modified by or contains adrenergic neurones.     

Centrally induced reduction in sympathetic tone-a postsynaptic alpha-adrenoceptor-stimulating action of imidazolines.

Naphazoline or oxymetazoline (both 30 mug/kg) were injected into the cisterna magna of anaesthetized cats and reduced blood pressure, heart rate and the electrical discharge rate of small fibre bundles of the preganglionic sympathetic splanchnic nerve. Cats were depleted of endogenous noradrenaline by pretreatment with reserpine (5 mg/kg, 18 h) and alpha-methyl-p-tyrosine (twice 300 mg/kg, 18 and 2 h). In these animals, intracisternal injection of 30 mug/kg oxymetazoline exerted a decrease of sympathetic discharges similar to that described for non-pretreated animals. In noradrenaline-depleted cats intracisternal injection of 1 mug/kg clonidine also decreased the sympathetic discharges. It is concluded that these imidazolines exert their sympathoinhibitory and cardiovascular effects by stimulation of postsynaptic alpha-adrenoceptors in the CNS.     

A study of the action of clonidine on secretion from the adrenal medulla in dogs.

The effects of clonidine on adrenal catecholamine (adrenaline and noradrenaline) secretion were investigated in chloralose-anaesthetized dogs. Intravenous administration of clonidine (10 and 20 micrograms kg-1) induced a decrease in both adrenal catecholamine secretion rates and cardiovascular parameters (blood pressure and heart rate). In contrast, a dose of 5 micrograms kg-1 was ineffective. Intracisternal clonidine (in a lower dose of 3 micrograms kg-1) also decreased adrenaline and noradrenaline release from the adrenal gland. Clonidine failed to modify adrenal catecholamine release evoked by electrical stimulation of the splanchnic nerve. These results demonstrate that clonidine decreases adrenaline release from the adrenal gland through a central and not a peripheral mechanism in dogs. This action might contribute to its antihypertensive effects.     

Centrally induced reduction in sympathetic tone — A postsynaptic α-adrenoceptor-stimulating action of imidazolines

Naphazoline or oxymetazoline (both 30 μg/kg) were injected into the cisterna magna of anaesthetized cats and reduced blood pressure, heart rate and the electrical discharge rate of small fibre bundles of the preganglionic sympathetic splanchnic nerve. Cats were depleted of endogenous noradrenaline by pretreatment with reserpine (5 mg/kg, 18 h) and α-methyl-p-tyrosine) twice 300 mg/kg, 18 and 2 h). In these animals, intracisternal injection of 30 μg/kg oxymetazoline exerted a decrease of sympathetic discharges similar to that described for non-pretreated animals. In noradrenaline-depleted cats intracisternal injection of 1 μg/kg clonidine also decreased the sympathetic discharges. It is concluded that these imidazolines exert their sympathoinhibitory and cardiovascular effects by stimulation of postsynaptic α-adrenoceptors in the CNS.In the isolated rat vas deferens, oxymetazoline was a much weaker agonist (intrinsic activity (i.a.) < 0.1) than naphazoline and clonidine (i.a. 0.6 or 0.8 respectively). All three imidazolines exerted considerable competitive antagonism against noradrenaline, with oxymetazoline being the most potent antagonist (pA₂: 6.0; clonidine 5.0; naphazoline 5.5). The order of agonistic activities of the three imidazolines on the vas deferens is different from that on other peripheral adrenergic systems and indicates different α-adrenoceptors. The possibility of receptor differences in the CNS is discussed.     

Effects of nicergoline on the cardiovascular system of dogs and rats

In pentobarbitalized closed-chest dogs, nicergoline (10--100 microgram/kg, i.v.) reduced blood pressure, heart rate, and splanchnic nerve activity. Intracisternal administration of nicergoline (3 microgram/kg) only reduced splanchnic nerve activity. In open-chest dogs, nicergoline reduced blood pressure, cardiac output, and total peripheral resistance but did not change heart rate. In pithed rats treated with a beta-adrenoceptor-blocking agent, nicergoline reduced the pressor responses to noradrenaline and adrenaline. Nicergoline slightly attenuated the pressor responses of dogs to noradrenaline and tyramine and, in addition, reversed the hypertension induced by adrenaline and dimethylphenylpiperazinium. Nicergoline (100 microgram/kg) increased the tachycardia induced in dogs by stimulation of the right cardiovascular nerve and prevented the inhibitory effect of clonidine on this response. However, nicergoline only partially antagonized the effect of clonidine once it was fully established. Nicergoline did not antagonize the hypotensive and bradycardic effects of clonidine when they were established. Nicergoline did not affect the vagally mediated bradycardia evoked by carotid nerve stimulation in beta-adrenoceptor-blocked dogs. The compound did not change blood pressure in Cl spinal cord transected dogs. In conclusion, nicergoline appears to decrease blood pressure by blocking alpha-adrenoceptors and, at least at some doses, by a central inhibition of the sympathetic tone. Nicergoline appears to be a preferential alpha 1-adrenoceptor-blocking agent.     

The mechanism of the depressor action of noradrenaline in the cat

In cats anaesthetized with pentobarbitone sodium or chloralose and injected with phenoxybenzamine or phentolamine, administration of (—)-noradrenaline (5 to 20 μg) produced a fall of blood pressure which resembled in onset and duration that produced by adrenaline under similar conditions. The depressor action of noradrenaline was due mainly to dilatation of the splanchnic blood vessels. This could be abolished by administration of pronethalol, a drug known to block sympathetic β-receptors.     

Clonidine-induced inhibition of sympathetic nerve activity: No indication for a central presynaptic or an indirect sympathomimetic mode of action

Summary The effects of clonidine on blood pressure, heart rate, contractile state of the nictitating membranes, spontaneous sympathetic nerve activity and response of sympathetic nerves to hypothalamic stimulation were compared in normal anaesthetized cats and in anaesthetized cats pretreated with reserpine and -methyl-p-tyrosine. The pretreatment lowered the noradrenaline content of various parts of the brain to less than 5 ng/g, i.e. to less than 1–3% of that of the controls. Under the conditions of this severe noradrenaline depletion, blood pressure and heart rate were low and spontaneous sympathetic nerve activity consisted of continous, high-amplitude discharges which contrasted with the low-amplitude bursts of activity—synchronous with the respiration—of the controls. In contrast to the controls, clonidine did not lower blood pressure and heart rate in the cats with noradrenaline depletion; however, the clonidine-induced contractions of the nictitating membranes were of similar magnitude and duration in both groups of animals. The efficacy of clonidine in reducing or abolishing spontaneous sympathetic nerve activity and in inhibiting the response of sympathetic nerves to hypothalamic stimulation was equal in controls and in cats with noradrenaline depletion, its potency being 3-fold higher in the former. The results indicate a direct stimulation of -adrenoceptors by clonidine both in the periphery and in the central nervous system and make it unlikely that the central effect of clonidine on blood pressure is due to a release of noradrenaline from central adrenergic neurones. It is further concluded that clonidine activates an adrenergic mechanism in the central nervous system by stimulation of postsynaptic -adrenoceptors. The inhibition of such a mechanism as a consequence of a diminished noradrenaline release due to stimulation of presynaptic -adrenoceptors—as proposed from in vitro experiments—seems to be of no importance for the central effect of clonidine on sympathetic nerve activity and blood pressure.Preliminary results have been presented at the 15th Spring Meeting of the German Pharmacological Society in Mainz (Haeusler, 1974a).     

Mechanism of the hypotensive effect of intravenous methaqualone in the cat

Methaqualone, a non-barbiturate hypnotic, has been reported to produce hypotension in animals. Experiments were undertaken to evaluate the mechanisms responsible for this effect. In chloralose-anesthetized cats, iv administration of 0.5 to 10.0 mg/kg of methaqualone produced dose-dependent decreases in blood pressure. The hypotension was associated with decreases in contractile force and heart rate at doses of 1 mg/kg or higher. Pretreatment with atropine or bilateral vagal nerve section did not influence these cardiovascular effects. In vagotomized cats: (1) spinal section markedly reduced the depressant effects of methaqualone on blood pressure, contractile force and heart rate and (2) removal of the stellate ganglia reduced the negative inotropic and chronotropic effects of the drug. Furthermore, administration of methaqualone (31.2–500 μg/kg) into a vertebral artery of vagotomized cats produced dose-dependent decreases in blood pressure, contractile force and heart rate. In the isolated cat hindquarters preparation perfused at constant blood flow, methaqualone (31.2–1000 μg) produced transient decreases in perfusion pressure which were not altered by pretreatment with phentolamine, propranolol, atropine or tripelennamine. In the rabbit perfused isolated heart, large doses of drug (0.25 to 2.0 mg) were required to depress contractile force. These results indicate that hypotension produced by iv methaqualone results primarily from a centrally mediated depression of sympathetic neural outflow to the heart and vasculature and, to a lesser extent, from direct relaxation of vascular smooth muscle and direct myocardial depression.     

Reductions in blood pressure,heart rate and renal sympathetic nerve discharge in cats after the central administration of muscimol,a GABA agonist

Muscimol, a central GABA receptor agonist, caused dose-related reductions in blood pressure and heart rate when administered intracerebroventricularly (i.c.v.) to anaesthetized cats (0.1–1.0 μg/kg). Renal sympathetic nerve discharge (RSND) was also inhibited at 0.3 and 1.0 μg/kg (i.c.v.). No effects were observed after the intravenous administration of muscimol. Bicuculline, a GABA receptor antagonist, completely reversed the effects of muscimol on blood pressure, heart rate and RSND, the most consistent, rapid and dramatic effects being observed after intravenous rather than intracerebroventricular administration. Pictrotoxin also reversed the effects of muscimol but the results were more variable than after bicuculline. Strychnine, a glycine receptor antagonist, and physostigmine, an acetylcholinesterase inhibitor, had no significant effects on the inhibition caused by muscimol. Muscimol was even more effective in baroreceptor denervated cats, than in non-denervated cats, probably as a result of the loss of compensatory reflex mechanisms. It is concluded that central stimulation of GABA receptors by muscimol results in marked reductions in blood pressure, heart rate and RSND which are specifically antagonized by GABA receptor antagonists.     

Interaction of prostaglandin E2 and bradykinin in the induction of afferent splanchnic nerve discharges in cats

In anesthetized cats, the administration of either bradykinin (BK) (0.3-3 micrograms/kg) or prostaglandin E2 (PGE2) (1-30 micrograms/kg) into the cranial mesenteric artery dose-dependently evoked the firing discharge in the proximal end of the afferent greater splanchnic nerves with a latency of about 10 sec, the pronounced contraction of the longitudinal muscle of the jejunum, and changes in blood pressure. PGE2 at the doses of 1-10 micrograms-kg i.a. potentiated the BK (1 microgram/kg i.a.)-induced firing discharge of the afferent splanchnic nerves of which latency was also shortened, but did not alter the BK-induced jejunal contraction and blood pressure change. However, trimoprostil (30 micrograms/kg i.a.), a trimethyl PGE2 derivative, did not change all of these responses to BK. Aspirin at 50 mg/kg i.v. markedly prevented the BK-induced nerve discharges, but not the BK-induced jejunal contraction. These results taken together indicate that PGE2 may be involved in the facilitatory response of afferent splanchnic nerve discharges to BK, but not involved in the BK-induced jejunal contraction and blood pressure change. The findings on trimoprostil present the possibility that derivatization of PGE2 could modify its inherent ability to produce adverse side-effects.     

Influence of the baroreceptor reflex on the modulation of noradrenaline overflow through prejunctional receptors in the portal vein of freely moving rats

1 The effects of alterations in mean arterial blood pressure (MAP), as induced by vasoactive drugs, on heart rate (HR), basal noradrenaline concentration and electrically evoked noradrenaline overflow and on blood flow in the portal vein of freely moving rats, were investigated. 2 By infusion of sodium nitroprusside or phenylephrine (0.5, 1.0 and 2.5 μg kg^?1 min^?1), MAP was altered over a range of 50 to 150 mmHg. The resulting changes in HR showed a sigmoidal relationship with MAP. Noradrenaline overflow increased linearly when MAP was decreased; when MAP was increased, however, noradrenaline levels only decreased to 70% and reached a plateau from 125 mmHg onwards. 3 Nitroprusside (2.5 μg kg^?1 min^?1) and fenoterol (0.25 mg kg^?1) decreased MAP to the same extent (– 46 mmHg). HR and basal noradrenaline concentration, however, were increased to a higher extent by fenoterol (+ 192 beats min^?1; + 373 pg ml^?1, respectively) than by nitroprusside (+ 78 beats min^?1; + 206 pg ml^?1, respectively). Electrically evoked overflow was not changed at all after nitroprusside, whereas fenoterol induced an increase to 206% of control. 4 Phenylephrine (2.5 μg kg^?1 min^?1) and angiotensin II (1 μg kg^?1 min^?1) increased MAP to the same extent (to 155 and 161 mmHg, respectively). Basal noradrenaline concentration decreased by 30% after phenylephrine, whereas angiotensin II increased noradrenaline levels to 226% of control. Evoked noradrenaline overflow was not changed after phenylephrine but was increased to 204% of control after angiotensin II. 5 Portal venous blood flow (15.3 ml min^?1) was not affected after brisk changes in MAP induced by nitroprusside (2.5 μg kg^?1 min^?1), fenoterol (0.25 mg kg^?1) or phenylephrine (2.5 μg kg^?1 min^?1). 6 The results showed that the electrically evoked overflow of endogenous noradrenaline in the portal vein of the freely moving rat is not influenced by baroreceptor reflex-induced changes in basal noradrenaline overflow. As a consequence, the prejunctional effects of drugs on the electrically evoked overflow are only of local origin. Portal venous blood flow is not changed by brisk changes in MAP or electrical stimulation, therefore no changes in noradrenaline spillover from nerve terminals are expected. However, the enhancement of basal noradrenaline overflow from numerous peripheral sympathetic junctions as seen with fenoterol and angiotensin II, is augmented or dampened, respectively, by baroreceptor reflexmediated changes of sympathetic activity.     

Effects of central GABA receptor agonism and antagonism on evoked diencephalic cardiovascular responses

The administration of the GABA agonists diazepam (0.3 mg/kg i.v.) and muscimol (0.3 μg/kg, i.c.v.) to chloralose-anaesthetized cats caused significant inhibition of the pressor responses elicited by electrical diencephalic stimulation. The inhibition was apparently a result of a reduction in centrally emanating sympathetic discharge to vasoconstrictor nerves. The GABA antagonist bicuculline (0.5 mg/kg i.v.) reversed the inhibition caused by muscimol but not by diazepam; however, pretreatment with bicuculline prevented the inhibition caused by diazepam. Muscimol caused significant and marked reductions in blood pressure and heart rate by decreasing central sympathetic nerve discharge; this action was also completely reversed by bicuculline. It is suggested that central activation of GABA receptors results in an inhibition of centrally evoked cardiovascular responses by preventing increases in sympathetic outflow. Furthermore, basal as well as evoked blood pressure, heart rate and sympathetic nervous discharge can be reduced by small doses of the directly acting GABA receptor stimulant muscimol.     

Block by capsaicin of voltage-gated K+ currents in melanotrophs of the rat pituitary.

1 The present study compares the effects on representative autonomic outflows of IVth ventricular application of tryptamine analogues which act at 5-HT1 receptors with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). 2 Cumulative doses of 8-OH-DPAT, N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT) and 5-carboxamidotryptamine (5-CT, 2.5-40 nmol kg-1), sumatriptan (10-160 nmol kg-1), indorenate (100-800 nmol kg-1), 5-hydroxytryptamine (5-HT, 20-640 nmol kg-1) both alone and in the presence of cinanserin (0.1 mg kg-1) were given into the IVth ventricle of cats which were anaesthetized with a mixture of alpha-chloralose and pentobarbitone sodium, neuromuscularly blocked and artificially ventilated. Recordings were made of arterial blood pressure, heart rate, renal, cardiac, splanchnic and phrenic nerve activities, femoral arterial flow, tracheal and intragastric pressures. 3 Central application of each of the agonists evoked significant falls in arterial blood pressure. In addition 8-OH-DPAT, DP-5-CT, 5-CT and 5-HT all evoked a differential inhibition of sympathetic nerve activities, with renal nerve activity being the most sensitive and cardiac nerve activity the least sensitive. In the dose-ranges used, administration of sumatriptan evoked reductions only in renal and splanchnic nerve activities whilst indorenate reduced activity in all three sympathetic nerves to a similar extent. 4 The effect of the agonists on heart rate was more inconsistent than the effects on sympathetic outflow.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of captopril and propranolol on the responses to posture and isometric exercise in patients with essential hypertension

The effects of captopril and propranolol on blood pressure, heart rate and plasma noradrenaline, renin and aldosterone, and on the responses to changes in posture and to isometric exercise were measured in patients with essential hypertension. During placebo administration blood pressure, heart rate and plasma noradrenaline rose on standing and during isometric exercise. The rise in diastolic blood pressure during isometric exercise correlated significantly with the rise in plasma noradrenaline. During captopril treatment blood pressure was significantly lower than during placebo administration when the patients were lying, standing or sitting, but the reduction during isometric exercise was not significant. Plasma renin increased, but heart rate, plasma noradrenaline and plasma aldosterone remained unchanged. The acute changes in blood pressure, heart rate and plasma noradrenaline produced by standing and isometric exercise during captopril treatment were similar to those during placebo administration. During propranolol treatment diastolic blood pressure was significantly lower than during placebo administration when the patients were lying, standing or sitting and during isometric exercise. Heart rate also fell. Plasma noradrenaline during standing, sitting and isometric exercise was significantly greater than during placebo administration. The changes in plasma noradrenaline measured during propranolol treatment with the patients supine were negatively correlated with noradrenaline values obtained during placebo administration: plasma noradrenaline fell in patients with higher, and increased in those with lower, initial concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Involvement of hypothalamic histamine-receptors in the central cardiovascular actions of histamine

Bilateral stereotaxic injections of histamine (0.01–10 μg) into the posterior hypothalamus of urethane-anaesthetised rats, elicited dose-related rises in blood pressure and heart rate. Pretreatments with mepyramine (25 and 50 μg) into the posterior hypothalamus, effected progressive parallel shifts of the histamine dose-response curve to the right, suggesting competitive histamine H₁-receptor antagonism. Pretreatments with either phentolamine (50 μg) or atropine (50 μg) did not significantly modify either of the histamine-induced responses. Histamine (1.0 μg) injected into the anterior hypothalamus also induced rises in blood pressure and heart rate, but when injected into the ventromedial hypothalamus, lateral hypothalamus or preoptic area failed to evoke any changes in blood pressure or heart rate. Local injections of 2-methyl histamine and 4-methyl histamine (1 and 10 μg) into the posterior hypothalamus elicited rises in blood pressure and heart rate, but these analogues were less potent than histamine. 5-Hydroxytryptamine, noradrenaline, adrenaline, isoprenaline and carbachol. all at a dose of 1.0 μg, elicited mixed cardiovascular responses when injected into the posterior hypothalamus.The results suggest that histamine H₁-receptor stimulation in selective areas of the hypothalamus of rats, elicits short-lasting rises in blood pressure and heart rate.     

Release of endogenous catecholamines in the nucleus tractus solitarii during experimentally induced blood pressure changes

Summary The nucleus tractus solitarii (subnucleus medialis) of anaesthetized cats was bilaterally superfused through push-pull cannulae and the release of endogenous catecholamines (dopamine, noradrenaline and adrenaline) determined in the superfusates. A moderate increase in blood pressure elicited by intravenously injected noradrenaline (0.3 g per kg body weight) reduced the rate of release of endogenous adrenaline, while a pronounced rise in blood pressure (at least 47 mm Hg) evoked by noradrenaline (3 g per kg) or blood injection inhibited the release of adrenaline and noradrenaline in the nucleus tractus solitarii. Bilateral carotid occlusion also diminished the release rates of adrenaline and noradrenaline. Decreases in blood pressure induced by controlled bleeding, intravenous injection of chlorisondamine or nitroprusside did not alter the rates of release of adrenaline or noradrenaline, but the rate of release of endogenous dopamine seemed to be reduced. The decreased adrenaline and noradrenaline release elicited by increases in blood pressure and the reduced release of dopamine induced by decreases in blood pressure may reflect a counteracting mechanism in the nucleus tractus solitarii so as to normalize alterations in blood pressure. The results suggest a hypertensive function of noradrenaline, and possibly a hypotensive role of dopamine at the level of the nucleus tractus solitarii.This work was supported by the Fonds zur Förderung der wissenschaftlichen Forschung (P 5750) Send offprint requests to C. Kobilansky     

Effect of phenobarbital pretreatment on cardiac neural discharge and pentylenetetrazol-induced epileptogenic activity in the cat

The effect of phenobarbital on autonomic function associated with ictal discharges and interictal spikes (IS) was examined. Phenobarbital (20 mg/kg, i.v.) was infused over 10 min; 1 h later, pentylenetetrazol (PTZ) 10, 20, 50, 100, 200, and 2,000 mg/kg was given intravenously at 10-min intervals. 10 mg/kg PTZ produced IS in only 3 of 9 phenobarbital-pretreated cats; when used alone, 10 mg/kg of PTZ produced IS in 8 of 9 cats. Ictal discharges first appeared at 20 mg/kg PTZ in 6 of 9 phenobarbital-pretreated cats; all 9 cats receiving only PTZ exhibited ictal discharges after 20 mg/kg. Phenobarbital pretreatment depressed heart rate, blood pressure and postganglionic cardiac sympathetic neural discharge. Maximal ictal discharges in the cats pretreated with phenobarbital occurred with 100 mg/kg PTZ. This discharge was associated with a 10 mm Hg increase in blood pressure and a slight decrease in heart rate, followed by a subsequent return to baseline. The concurrent sympathetic neural discharge increased. When maximal ictal discharges occurred in the cats receiving PTZ alone, blood pressure, heart rate, and sympathetic neural discharge increased significantly. Cardiac vagal neural discharge was not altered after PTZ even in phenobarbital-pretreated cats. Although phenobarbital suppressed PTZ-induced epileptogenic activity and the associated changes in blood pressure and heart rate, a X2 test indicated no significant difference in the incidence of arrhythmias between the two groups. Since phenobarbital did not prevent the changes in cardiac neural discharge and the arrhythmias associated with epileptogenic activity, its effectiveness in decreasing autonomic dysfunction is questionable.     

Inhibition of efferent sympathetic nerve activity by 5-hydroxytryptophan and centrally administered 5-hydroxytryptamine

In view of the similarity of the cardiovascular actions of the 5-hydroxytryptamine precursor 5-hydroxytryptophan (5-HTP) and those of l-DOPA and the finding that l-DOPA reduces efferent sympathetic nerve activity, the role of sympathetic outflow in the cardiovascular response to 5-HTP was examined in the present experiments. Intravenous injection of 5-HTP (3.2 32 mg/kg) after peripheral decarboxylase inhibition, resulted in a progressive reduction in blood pressure and heart rate in anaesthetized cats. Spontaneous electrical activity of the cardiac, renal and splanchnic nerves also decreased in a dose-related fashion. More direct administration of 5-HTP, as well as 5-hydroxytryptamine, to the brain via a lateral ventricle also produced a fall in pressure, heart rate and sympathetic nerve activity. These experiments indicate that the overall actions of 5-HTP on the central nervous system result in a diminution of sympathetic outflow leading to a reduction of blood pressure and heart rate and thus resemble the effects of l-DOPA. The actions of 5-hydroxytryptamine are consistent with the hypothesis that it mediates the response to 5-HTP.     

Evidence that the novel antihypertensive agent, flesinoxan, causes differential sympathoinhibition and also increases vagal tone by a central action

The effects of flesinoxan were studied on thoracic preganglionic, splanchnic and renal sympathetic nerve activity, carotid sinus nerve activity, blood pressure and heart rate in anaesthetised cats. In some experiments femoral or renal arterial conductance was also recorded. Flesinoxan (3-300 micrograms kg-1) caused a dose-related fall in blood pressure and heart rate and also caused sympathoinhibition. This fall in blood pressure was not associated with changes in femoral arterial conductance but was with a large increase in renal arterial conductance. In this respect flesinoxan had a greater sympathoinhibitory action on the renal nerve compared with the other sympathetic outflows. The bradycardia was unaffected by the 5-HT3 antagonist, MDL 72222, but was reversed by atropine and was abolished in bi-vagotomised cats. Flesinoxan also caused sympathoinhibition in bi-vagotomised cats and decreased carotid sinus nerve activity and blood pressure. It is concluded that flesinoxan acts centrally to cause sympathoinhibition and an increase in vagal tone.