Quipazine-induced hypertension in anaesthetized cats is mediated by central and peripheral 5-HT2 receptors: role of the ventrolateral pressor area.

Quipazine (0.5 mg/kg i.v.) produced a sustained pressor response and an increase in splanchnic nerve activity in intact as well as in baroreceptor-denervated cats without causing a significant change in heart rate. These effects were prevented by the 5-HT2 receptor antagonists, ritanserin (0.5 mg/kg i.v.) or BW 501 C (0.5 mg/kg i.v.). Quipazine induced an hypertensive response and an increase in splanchnic discharge in cats pretreated with prazosin (0.1 mg/kg) or hexamethonium (10 mg/kg i.v.). Bilateral application of quipazine (25 micrograms/side) to the ventrolateral pressor area produced a rapid increase in mean blood pressure and in splanchnic discharge. Pretreatment with prazosin (0.1 mg/kg i.v.) abolished the hypertension but not the sympatho-excitatory effects of quipazine. Local application of the 5-HT2 receptor antagonists, LY53857 (10 micrograms/side) or cyproheptadine (10 micrograms/side), had no effects on blood pressure and splanchnic nerve activity but prevented or reversed the actions of locally applied quipazine. LY 53857 (10 micrograms/side) antagonized the sympatho-excitatory effects of systemically administered quipazine. These results indicate that the cardiovascular changes induced by quipazine in anaesthetized cats are mediated by central 5-HT2 receptors located in the ventrolateral pressor area and by peripheral vascular 5-HT2 receptors.     

Substance P injection into the dorsal raphe increases blood pressure and serotonin release in hippocampus of conscious rats.

Microinjections of substance P (SP, 100 pmol) into the dorsal raphe nucleus (DRN) in conscious rats increased blood pressure and heart rate for 30-40 min. Concomitantly, the extracellular levels of 5-hydroxytryptamine (5-HT) in the ventral hippocampus, monitored by microdialysis, increased by 30% for 20 min compared with the vehicle control. Pretreatment with the 5-HT2 receptor antagonist, ritanserin (1 mg/kg i.v.), prevented the pressor response to SP but not the increase in heart rate. Pretreatment with the partial 5-HT1A receptor agonist, 8-methoxy-2-(N-2-chloroethyl-N-n-propyl)amino tetralin (8-MeO-CLEPAT, 10 micrograms/kg i.v.) prevented the increase in both blood pressure and heart rate. It is suggested that microinjections of SP into the DRN increase blood pressure through activation of serotonergic DRN neurons and that the postsynaptic receptor responsible for the pressor response is of the 5-HT2 type.     

Central administration of 5-HT activates 5-HT1A receptors to cause sympathoexcitation and 5-HT2/5-HT1C receptors to release vasopressin in anaesthetized rats.

1. The effects of intracerebroventricular injections to the right lateral ventricle (i.c.v.) of 5-hydroxytryptamine (5-HT, 40 and 120 nmol kg-1), N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT; 3 nmol kg-1), 5-carboxamidotryptamine (5-CT; 3 nmol kg-1), 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT; 3, 40 and 120 nmol kg-1) and 1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane (DOI; 40 and 120 nmol kg-1) on renal sympathetic nerve activity, blood pressure, heart rate and phrenic nerve activity were investigated in normotensive rats anaesthetized with alpha-chloralose. 2. 5-HT caused a long lasting pressor response which was associated with an initial bradycardia and renal sympathoinhibition followed by a tachycardia and renal sympathoexcitation. Pretreatment with the 5-HT2/5-HT1C receptor antagonists, cinanserin (300 nmol kg-1, i.c.v.) or LY 53857 (300 nmol kg-1, i.c.v.) reversed the initial bradycardia and sympathoinhibition to tachycardia and sympathoexcitation. Combined pretreatment with LY 53857 (300 nmol kg-1, i.c.v.) and the 5-HT1A antagonist, spiroxatrine (300 nmol kg-1, i.c.v.), blocked the effects of 5-HT on all the above variables. 3. Pretreatment with the vasopressin V1-receptor antagonist, beta-mercapto-beta,beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8-vasopressin [(d(CH2)5Tyr(Me)AVP, 10 micrograms kg-1, i.v.] did not affect the magnitude but reduced the duration of the pressor response produced by i.c.v. 5-HT and reversed the initial bradycardia and renal sympathoinhibition to tachycardia and sympathoexcitation. 4. 1-(2,5-Di-methoxy-4-iodophenyl)-2-aminopropane (DOI) caused a pressor effect which was associated with a bradycardia and sympathoinhibition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular responses to centrally administered serotonin in conscious normotensive and spontaneously hypertensive rats

Serotonin (5-HT, 1-10 micrograms), injected into the lateral ventricle of the urethanized, and conscious normotensive and spontaneously hypertensive rats produced a dose-dependent increase in blood pressure. In conscious rats, there was mainly a decrease in heart rate while variable changes in heart rate were elicited by intraventricular (i.c.v.) administration of 5-HT in anesthetized animals. These pressor responses and bradycardia caused by 5-HT in conscious rats were reduced by pretreatment with i.c.v. methysergide (25 micrograms). Microinjection of 5-HT (2.5-5 micrograms) directly into the medial hypothalamus and the anterior hypothalamus/preoptic area of conscious normotensive rats caused a pressor response accompanied by variable changes in heart rate. The present results indicate that urethane can affect the HR response to 5-HT injected i.c.v. without having a marked influence on the pressor response. These findings, which show that 5-HT produced a rise in BP independent of the anesthetized or conscious state and of normotension or hypertension, further confirm the idea that 5-HT plays a pressor role in the central regulation of the cardiovascular system.     

AN INVESTIGATION INTO THE MECHANISMS OF THE CARDIOVASCULAR EFFECTS OF 5-HYDROXYTRYPTAMINE IN CONSCIOUS NORMOTENSIVE AND DOCA-SALT HYPERTENSIVE RATS

• 1 The actions of intravenously administered 5-hydroxytryptamine (5-HT) have been analysed in conscious DOCA-salt hypertensive rats using selective 5-HT receptor agonists and antagonists to determine the receptor mechanisms involved and to compare them with those in conscious normotensive rats.
• 2 In both normotensive and hypertensive rats 5-HT, 3 and 10 μg i.v., produced a complex triphasic effect on blood pressure consisting of an initial short lasting depressor response, which was followed by a pressor response and then, finally, a hypotensive phase. Marked decreases in heart rate were observed immediately after dosing, which were followed by small increases in rate.
• 3 The selective 5-HT₃-receptor agonist, 2-methyl 5-HT, 3–30 μg i.v., produced immediate and marked dose-related decreases in blood pressure and heart rate in both normotensive and DOCA-salt hypertensive rats. The 5-HT₃-receptor antagonist, MDL 72222, 0.03 and 0.1 mg/kg i.v., antagonised these effects in both normotensive and DOCA-salt hypertensive rats. Treatment with MDL 72222, 0.3 mg/kg i.v., abolished the initial depressor response and bradycardia produced by 5-HT.
• 4 The 5-HT₂ receptor agonist, α-methyl 5-HT, 3–30 μg i.v., produced dose-related increases in blood pressure which were significantly greater in magnitude in DOCA-salt hypertensive than normotensive rats. Bradycardia was observed consistently at 30 μg only. The 5-HT₂ receptor antagonist, ketanserin, 0.03-0.3 mg/kg i.v., caused a dose-dependent antagonism of the pressor responses produced by α-methyl 5-HT, but had no effect on the increases in blood pressure produced by angiotensin. Ketanserin also antagonised the pressor responses produced by 5-HT in rats pretreated with MDL 72222.
• 5 5-Carboxamidotryptamine (5-CT), the selective ‘5-HT₁-like’ receptor agonist, at doses of 0.1–3 μg i.v. produced dose-related decreases in blood pressure which were more pronounced in the DOCA-salt hypertensive rats than in normotensive rats. These depressor responses were dose-dependently antagonised by methiothepin, 0.3 and 1 mg/kg, i.v. which did not antagonise the depressor responses produced by isoprenaline 0.1 μg/kg i.v. In rats pretreated with MDL 72222 and ketanserin, 5-HT produced dose-related depressor responses which were also antagonised by methiothepin 1 mg/kg i.v. and presumably mediated by 5-HT₁-like receptors.
• 6 In this study, selective 5-HT receptor agonists and antagonists have been used to mimic and block, respectively, the various phases of the 5-HT response. It is concluded that in the conscious rat, the complex cardiovascular effects of 5-HT involve stimulation of at least three different 5-HT receptors (for nomenclature see Bradley, Engel, Feniuk, Fozard, Humphrey, Middlemiss, Mylecharane, Richardson & Saxena, 1986). The initial depressor response and bradycardia involves activation of 5-HT₃-receptors, the secondary vasopressor effect, which is significandy greater in DOCA-salt than normotensive rats results from stimulation of 5-HT₂ receptors and the late vasodepressor response is due to vasodilatation via ‘5-HT₁-like’ receptors.

     

The central site of the sympatho-inhibitory action of 5-hydroxytryptamine in the cat

The aim of this study was to determine the site in the CNS at which 5-hydroxytryptamine (5-HT) inhibits efferent sympathetic nerve activity in the cat. 5-Hydroxytryptamine (3 and 10 micrograms/kg), given into the lateral cerebral ventricle, produced immediate non dose related increases in mean blood pressure (MBP), heart rate (HR) and renal nerve activity (RNA). Larger doses (30 and 100 micrograms/kg i.c.v.) produced gradual decreases in blood pressure, heart rate and renal nerve activity, which did not occur when access of the drug to the fourth ventricle was prevented. Administration of 5-HT (10 and 30 micrograms/kg) into the fourth ventricle produced only decreases in blood pressure, heart rate and renal nerve activity after 15-40 min, which were accompanied by decreases in cardiac output and renal vascular resistance, but little or no change in total peripheral resistance. Application of 5-HT onto the ventral surface of the medulla, into the subarachnoid space at various levels along the spinal cord or into various parts of the nucleus tractus solitarius produced no effect on blood pressure heart rate or renal nerve activity. However, application of a cotton wool pledget soaked in a 5-HT solution (3 mg/ml) over the entire obex/NTS region produced immediate decreases in blood pressure, heart rate and renal nerve activity. These studies suggest that the sympatho-inhibitory effect of 5-HT is due to an action at a site near the caudal end of the dorsal surface of the medulla.     

Vascular actions of MDMA involve alpha1 and alpha2-adrenoceptors in the anaesthetized rat

We have investigated the effects of methylenedioxymethamphetamine (MDMA, 'ecstasy'), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats. In pithed rats, the non-selective 5-HT receptor antagonist methiothepin (0.1 mg kg(-1)) and the alpha2-adrenoceptor antagonists methoxyidazoxan and yohimbine (1 mg kg(-1)) showed significant alpha1-adrenoceptor antagonist potency, but methiothepin did not show alpha2-adrenoceptor antagonist potency. MDMA (1 and 5 mg kg(-1)) produced pressor responses which were significantly reduced by the alpha(1)-adrenoceptor antagonist prazosin (0.1 mg kg(-1)), yohimbine (1 mg kg(-1)) or methiothepin (0.1 mg kg(-1)), but not by the 5-HT2 receptor antagonist ritanserin (1 mg kg(-1)). In anaesthetized rats, antagonists revealed two phases with three components to the effects of MDMA (5 mg kg(-1)) on DBP: an initial pressor response, a later pressor component at 1 min, the sustained depressor response. Methoxyidazoxan, methiothepin or the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the latter compounds alone had any effect. The pressor response to MDMA (5 mg kg(-1)) at 1 min was converted to a depressor response by prazosin and to a lesser extent methiothepin and methoxyidazoxan. The depressor response to MDMA (5 mg kg(-1)) was significantly reduced by methoxyidazoxan (0.1 mg kg(-1)), and by the noradrenaline re-uptake blocker cocaine 10 mg kg(-1) but not 1 mg kg(-1). However, the most marked reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine. It is concluded that the initial pressor response to MDMA (5 mg kg(-1)) in anaesthetized rats involves alpha2- and possibly alpha1-adrenoceptors and 5-HT2 receptors, the pressor component at 1 min is largely alpha1-adrenoceptor mediated, and the sustained depressor response involves alpha2-adrenoceptors.     

Pressor response induced by local anaesthetics perfused through the cerebral ventricles of dogs.

1 The antihistamines mepyramine and halopyramine which have local anesthetic properties, produced a rise in arterial blood pressure followed by a fall, similar to that seen with procaine, when perfused in a 10 mg/ml solution from the lateral ventricle to the cisterna magna in dogs. 2 The pressor response produced by procaine perfused through the cerebral ventricle is due to an action on structures situated in the caudal half of the floor of the fourth ventricle because a pressor response was obtained when a few microlitres of a 50 mg/ml solution of procaine were applied to a small area of the exposed floor of the fourth ventricle in a region 2 to 4 mm rostral to obex, and after cauterization of this area procaine perfused through the cerebral ventricles no longer raised arterial blood pressure. 3 Bilateral denervation of the carotid sinus did not affect the pressor response obtained with procaine perfused through the cerebral ventricles. 4 The pressor response to procaine is mediated through the sympathetic nervous system. It results partly from an increased adrenaline discharge from the adrenal glands and partly from increased sympathetic vasomotor tone, because the response is abolished or attenuated after removal of the adrenal glands and intravenous injections of hexamethonium and phentolamine.     

Central autonomic effects of prostaglandin F2α on the cardiovascular system of the dog

1. Prostaglandin F(2alpha) infused into the vertebral artery of the anaesthetized greyhound in doses which had no effect when given intravenously ((8-64 ng/kg)/min) caused an increase in blood pressure and heart rate.2. This response was not significantly altered by beta-adrenoceptor blockade with propranolol (10 mg i.v.) or by cervical cord section at C(4-6).3. The tachycardia was abolished and the pressor response greatly reduced by vagotomy or atropine (250 mug/kg i.v.).4. The pressor response which remained after vagotomy was abolished by subsequent sympathetic blockade with bethanidine (2-3 mg/kg i.v.) or bretylium (10 mg/kg i.v.).5. In contrast to the effects of propranolol or cervical cord section bethanidine (4-5 mg/kg i.v.) or bretylium (10 mg/kg i.v.) significantly reduced blood pressure and heart rate responses to intravertebral prostaglandin F(2alpha). This result suggests that bethanidine and bretylium have some central actions.6. It is concluded that the cardiovascular effects of intravertebral infusions of prostaglandin F(2alpha) are mediated by the autonomic nervous system and that the preferential pathway is withdrawal of vagal tone to the heart.     

Effects of mianserin, desipramine and maprotiline on blood pressure responses evoked by acetylcholine, histamine and 5-hydroxytryptamine in rats.

1 In rats anaesthetized with pentobarbitone, intravenous administration of desipramine (0.1 mg/kg), maprotiline (0.5 mg/kg) or mianserin (0.3-3.0 mg/kg) did not modify the blood pressure lowering effects of acetylcholine (0.25-1.0 micrograms/kg, i.v.) which were significantly reduced by atropine (3.0 micrograms/kg, i.v.). 2 Maprotiline and mianserin, like promethazine (0.1 mg/kg, i.v.), inhibited the vasodepressor responses evoked by histamine (2.5-10.0 micrograms/kg,i.v.). however, desipramine was inactive against histamine. 3 In pithed rats, the pressor effects of intravenous 5-hydroxytryptamine (5-HT: 5.0-20.0 micrograms/kg) were antagonized by mianserin (0.01-0.3 mg/kg, i.v.) and cyproheptadine (0.01 mg/kg) but were unaffected by maprotiline and desipramine. 4 In syrosingopine pretreated rats given mianserin 0.1 mg/kg, intravenously, 5-HT (20.0 micrograms/kg, i.v.) produced a significant fall in blood pressure which could be reduced by a large dose of mianserin (10.0 mg/kg, i.v.). 5 In conclusion, desipramine, maptrotiline and mianserin, in doses previously found to inhibit noradrenaline neuronal reuptake in the rat cardiovascular system, lack muscarinic receptor antagonist properties. Whilst maprotiline and mianserin blocked vascular histamine receptors, only mianserin (10.0 mg/kg, i.v.). 5 In conclusion, desipramine, maptrotiline and mianserin, in doses previously found to inhibit noradrenaline neuronal reuptake in the rat cardiovascular system, lack muscarinic receptor antagonist properties. Whilst maprotiline and mianserin blocked vascular histamine receptors, only mianserin, like cyproheptadine, was a potent antagonist of the 5-HT receptors that mediate increases in blood pressure in rats. Finally, the vasodepressor effects of 5-HT in syrosingopine pretreated rats given a small dose of mianserin were antagonized by a large dose of mianserin, suggesting that 5-HT may activate two distinct types of receptors in the rat.     

A hypertensive response to baclofen in the nucleus tractus solitarii in rats

The hypertension and tachycardia after intraperitoneal administration of baclofen, 5 mg kg⁻¹, to conscious rats was prevented by a midcollicular decerebration but not by a brain transection rostral to the hypothalamus. In conscious rats, local application of baclofen (50 ng) into the region of the nucleus tractus solitarii (NTS) caused a consistent pressor response while injections into the hypothalamus, n. fastiguus, nn. amygdala, nn. dorsalis raphe or n. locus coreuleus did not. The cardiovascular effects of NTS injections of baclofen in anaesthetized animals were variable. The reflex heart rate reduction to noradrenaline (0·5 μg i.v.) was prevented by administration of baclofen i.v. as well as locally into the NTS. It is concluded that baclofen causes elevation of blood pressure in the NTS, and that this structure is a possible locus of action for systemically administered baclofen in producing hypertension.     

Intravenously injected CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock: effect is mediated by central cholinergic activation

Intravenous (i.v.) administration of cytidine-5′-diphosphate choline (CDP-choline) (100, 250 and 500 mg/kg) increased blood pressure in normal rats and reversed hypotension in haemorrhagic shock. Choline (54 mg/kg; i.v.), at the dose equimolar to 250 mg/kg CDP-choline decreased blood pressure of rats in both conditions and caused the death of all hypotensive animals within 2-5 min. Equimolar dose of cytidine (124 mg/kg; i.v.) did not change cardiovascular parameters. Choline levels in plasma, lateral cerebral ventricle and hypothalamus increased after CDP-choline administration. Intracerebroventricular (i.c.v.) hemicholinium-3 pretreatment (20 μg), greatly attenuated the pressor effect of CDP-choline in both conditions. Atropine pretreatment (10 μg; i.c.v.) did not change the pressor effect of CDP-choline while mecamylamine (50 μg; i.c.v.) abolished the pressor response to drug. Besides, acetylcholine (1 μmol; i.c.v.) produced similar increases in blood pressure in normal and hypotensive conditions to that observed in CDP-choline given rats. CDP-choline (250 mg/kg; i.v.) increased plasma catecholamines and vasopressin levels but not plasma renin activity. Pretreatment of rats with either prazosin (0.5 mg/kg; i.v.) or vasopressin V₁ receptor antagonist, [β-mercapto,β,β-cyclopentamethylenepropionyl¹,O-Me-Tyr²-Arg⁸]vasopressin (10 μg/kg; i.v.), attenuated the pressor response to CDP-choline while simultaneous administration of these antagonists before CDP-choline injection completely blocked the pressor effect. Results show that i.v. CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock. Activation of central nicotinic cholinergic mechanisms by the increases in plasma and brain choline concentrations appears to be involved in the pressor effect of this drug. Moreover, the increases in plasma catecholamines and vasopressin levels mediate these effects.     

Diabetes-induced changes in the 5-hydroxytryptamine inhibitory receptors involved in the pressor effect elicited by sympathetic stimulation in the pithed rat

1. We investigated the effect of alloxan-induced diabetes on the inhibitory mechanisms of 5-hydroxytryptamine (5-HT) in the pressor responses induced by stimulation of sympathetic vasopressor outflow in pithed rats, and analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats by a single s.c. injection of alloxan, then 4 weeks later, they were anaesthetized, pretreated with atropine and pithed. Electrical stimulation of the sympathetic outflow from the spinal cord (0.1, 0.5, 1 and 5 Hz) resulted in frequency-dependent increases in blood pressure. 3. Intravenous infusions of 5-HT (1-80 microg kg(-1) min(-1)) reduced the pressor effects obtained by electrical stimulation. The 5-HT(1) receptor agonist 5-carboxamidotryptamine, 5-CT (5 microg kg(-1) min(-1)), caused an inhibition of the pressor response, whereas the selective 5-HT(2) receptor agonist, alpha-methyl-5-HT (5 microg kg(-1) min(-1)) and the selective 5-HT(3) receptor agonist, 1-phenylbiguanide (40 microg kg(-1) min(-1)), did not modify the sympathetic pressor responses. 5-HT had no effect on exogenous noradrenaline (NA)-induced pressor responses. 4. The inhibition of electrically induced pressor responses by 5-HT (10 microg kg(-1) min(-1)) was unable to be elicited after i.v. treatment with methiothepin (100 microg kg(-1)) because of the marked inhibition produced by methiothepin alone. The 5-HT-induced inhibition was blocked after i.v. administration of WAY-100,635 (100 microg kg(-1)) and not affected by ritanserin (1 mg kg(-1)), MDL 72222 (2 mg kg(-1)). 5. The selective 5-HT(1A) receptor agonist, 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT) (5-20 microg kg(-1) min(-1)) but neither the rodent 5-HT(1B) receptor agonist, CGS-12066B (5 microg kg(-1) min(-1)), nor the selective nonrodent 5-HT(1B) and 5-HT(1D) receptor agonist, L-694,247 (5 and 40 microg kg(-1) min(-1)), inhibited the electrically induced pressor response. The selective 5-HT(1A) receptor antagonist, WAY-100,635 (100 microg kg(-1)), blocked the inhibition induced by 8-OH-DPAT (10 microg kg(-1) min(-1)). 8-OH-DPAT had no effect on exogenous NA-induced pressor responses. 6. Experimental diabetes produces changes in the inhibitory effect induced by 5-HT on electrically induced sympathetic pressor responses, such that the inhibitory action induced by 5-HT in diabetic pithed rats is mediated by prejunctional 5-HT(1A) receptors.     

Ventrolateral medullary pressor area: site of hypotensive and sympatho-inhibitory effects of (±)8-OH-DPAT in anaesthetized dogs

Injections of 8-OH-DPAT (0.1–6 μg/kg) into the vertebral artery or into the cisterna magna (5 μg/kg) produced a dose-dependent decrease in blood pressure, heart rate and renal sympathetic nerve activity in intact anaesthetized dogs and baroreceptor-denervated dogs. 8-OH-DPAT reduced the renal sympathetic nerve activity without changing the blood pressure or heart rate in catecholamine-depleted animals. Methiothepin (0.2 mg/kg) injected into the vertebral artery reduced the blood pressure without changing the heart rate or renal sympathetic nerve activity in baroreceptor-denervated dogs. The pressor response to i.v. phenylephrine was largely attenuated. Subsequent administration of 8-OH-DPAT (3 μg/kg) into the vertebral artery failed to alter the sympathetic discharge. Methiothepin (0.2 mg/kg) injected into the vertebral artery reversed the sympatho-inhibitory effect of 8-OH-DPAT (3 μg/kg) injected by the same route without changing the blood pressure. (±)Pindolol (0.2 mg/kg) injected into the vertebral artery of baroreceptor-denervated dogs reduced the blood pressure and heart rate without changing renal sympathetic activity. Subsequent administration of 8-OH-DPAT (3 μg/kg) failed to alter the sympathetic discharge. Bilateral microinjection of 8-OH-DPAT (1 μg) into the nucleus tractus solitarii or into the medullary raphe nuclei failed to alter the blood pressure, heart rate or renal sympathetic activity. In contrast, bilateral microinjections of 8-OH-DPAT into the ventrolateral pressor area (VLPA) (0.2 μg) produced a marked decrease in blood pressure, heart rate and renal sympathetic nerve activity. These effects were prevented or reversed by microinjections of methiothepin (10 μg) at the same sites. These results indicate that the central sympatho-inhibitory effects of 8-OH-DPAT were due to the stimulation of 5-HT_1A receptors located in the ventrolateral pressor area. 5-HT autoreceptors did not seem to be involved.     

Pharmacological studies of lycorenine, an alkaloid of Lycoris radiata Herb.: Vasodepressor mechanism in rats

Vasodepressor mechanism of lycorenine (an alkaloid of Lycoris radiata Herb.) was investigated in anesthetized rats. Lycorenine (1--10 mg/kg i.v.) produced dose-related decreases in blood pressure and heart rate and tachyphylaxis developed with repeated injections. In the blood-perfused rat hindquarters, lycorenine (62.5--500 micrograms i.a.) produced dose-related decreases both in mean blood pressure and in perfusion pressure, and the lycorenine-induced decrease in perfusion pressure was abolished by phenoxybenzamine or hexamethonium. Lycorenine (more than 1 mg/kg i.v.) blocked the pressor response to sympathetic nerve stimulation, but failed to block the tachycardia induced by sympathetic nerve stimulation. Lycorenine (7.5 or 15 mg/kg i.v.) reduced the spontaneous splanchnic nerve activity. Lycorenine when given intracerebroventricularly produced decreases in blood pressure and heart rate only in large doses (over 500 micrograms). The maximal bradycardia induced by lycorenine was abolished by bilateral vagotomy. It is suggested that lycorenine may produce a decrease in blood pressure as the result of alpha-adrenergic blockade in conjunction with the reduction of the spontaneous sympathetic nerve activity, and produce bradycardia by modifying vagal activity.     

Pharmacological evidence that circumventricular organs may participate in the pressor effect of central serotonin.

The present study was to investigate the role of '5-HT2-like' receptors in the circumventricular organs in the pressor response elicited by the central injection of serotonin (5-HT) to conscious rats. The increase in blood pressure induced by intracerebroventricular (i.c.v.) 5-HT (2.5 micrograms) was attenuated by intravenous pretreatment will, the peripheral 5-HT2 antagonist xylamidine (100 or 300 micrograms/kg). A combination of xylamidine with prazosin or a V1-vasopressin antagonist did not produce a further attenuation in the pressor response. Our data suggest that when administered i.c.v., 5-HT increases blood pressure by acting on 5-HT2-like receptors located in circumventricular organs as well as areas of the brain protected by the blood-brain barrier.     

Effects of intracerebroventricular injected choline on cardiovascular functions and sympathoadrenal activity.

Intracerebroventricular (i.c.v.) injection of choline (50-150 micrograms) increased blood pressure (SP) and decreased heart rate (HR) in freely moving rats. Intracerebroventricular pretreatment of rats with mecamylamine (50 micrograms) blocked the reduction in HR and reduced the increase in SP induced by i.c.v. choline (150 micrograms). Central muscarinic blockade with atropine (10 micrograms, i.c.v.) reduced the pressor response to i.c.v. choline (150 micrograms) by about 70%, without influencing the decrease in HR. The decrease in HR induced by i.c.v. choline was prevented by intraarterial (i.a.) treatment of atropine methylnitrate (2 mg/kg). Intracerebroventricular choline (150 micrograms) produced a fivefold increase in catecholamine concentrations in adrenal venous plasma. Bilateral adrenalectomy reduced, but did not block, choline's effect on SP. Intracerebroventricular choline (150 micrograms) showed an ability to increase and restore SP in rats subjected to spinal cord transection or pretreatment with hexamethonium (15 mg/kg, i.a.) or with phentolamine (10 mg/kg, i.a.). Intracerebroventricular choline (150 micrograms) increased plasma vasopressin (VP) levels from 2.2 +/- 0.4 to 25.6 +/- 2.5 pg/ml. Pretreatment of rats with a VP antagonist reduced the pressor response to i.c.v. choline. It is concluded that (a) the reduction in HR results from a central nicotinic receptor-mediated increase in vagal tone, (b) the increase in SP appears to be due to activation of both nicotinic and muscarinic central cholinergic receptors, and that (c) the central activation of the adrenal medulla and the increase in plasma levels of VP are involved in the pressor response to i.c.v. choline.     

Cardiovascular effects of SL65.0472, a 5-HT receptor antagonist

In this study, we describe the cardiovascular effects of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno[3,2-c] pyridin-4-yl) piperazin-l-yl] ethyl]-1, 2-dihydroquinoline-1-acetamide), a novel 5-hydroxytryptamine (5-HT) receptor antagonist developed for the treatment of cardiovascular disease, in several in vivo models. The haemodynamic profile of SL65.0472 was evaluated in anaesthetised dogs. Following i.v. bolus doses of 0.03 mg/kg i.v. and 0.3 mg/kg, no significant changes in cardiac output, contractility or rate, systemic and pulmonary pressures, regional blood flows and vascular resistances or electrocardiogram were noted. After 1 mg/kg i.v. SL65.0472 significantly reduced arterial blood pressure. In conscious spontaneously hypertensive rats administration of SL65.0472 0.5 mg/kg p.o. had no effect on mean arterial blood pressure or heart rate. Vasoconstriction produced by 5-HT results primarily from the stimulation of two receptor subtypes, 5-HT(1B) and 5-HT(2A) receptors. In anaesthetised dogs SL65.0472 antagonised sumatriptan-induced decreases in saphenous vein diameter (5-HT(1B)-receptor mediated) with an ID(50) of 10.1 microg/kg i.v. (95% c.l. 8.3-12.4). In anaesthetised pithed rats SL65.0472 inhibited 5-HT pressor responses (5HT(2A)-receptor mediated) with ID(50) values of 1.38 microg/kg i.v. (95% c.l. 1.15-1.64) and 31.1 microg/kg p.o. (95% c.l. 22.6-42.6). The duration of the 5-HT(2A)-receptor antagonist effect of SL65.0472 following oral administration was evaluated in conscious rats. SL65.0472 (0.1 mg/kg p.o.) markedly inhibited 5-HT pressor responses 1 and 6 h after administration. Therefore, in vivo, SL65.0472 potently antagonises vasoconstriction mediated by 5-HT(1B) and 5-HT(2A) receptors but has minimal direct haemodynamic effects.     

Analysis of cardiovascular responses to central administration of 5-hydroxytryptamine in rats

5-hydroxytryptamine (5-HT, 1.5–6 μg), injected into the lateral or 4th cerebral ventricle of the rat produced a pressor response which was sometimes followed by a prolonged depressor response. The administration of 5-HT (5–15 μg) into the cisterna magna evoked a slow progressive and longlasting depressor effect with or without an initial presser effect. The pressor response to 5-HT was accompanied by variable changes in heart rate, but the depressor response, in the majority of experiments, by a bradyeardia. The pressor effect of 5-HT was abolished after transection of the spinal cord at C₁ or central administration of methysergide and peripheral administration of phenoxybenzamine, tolazoline, nicotine or methysergide; it was reduced after bilateral adrenalectomy or peripheral injection of bretylium, but it was not diminished after central or peripheral administration of hexamethoniuni, atropine and methylatropine, respectively. It is concluded that 5-HT injected centrally produces an increase as well as a decrease, in arterial blood pressure and heart rate, supporting the idea that 5-HT participates in the central physiological control of the rat cardiovascular system. The pressor response to intracerebroventricular administration of 5-HT results from the activation of central 5-HT receptor sites followed by the release of catecholamines from adrenergic nerve terminals and the adrenal medulla. It is tentatively suggested that in the sympathetic ganglia, in addition to cholinergic transmission, serotonergic transmission exists as well.     

Possible mechanisms underlying the hypertensive response to clonidine in freely moving, normotensive rats

Possible mechanisms underlying the hypertensive response to intracerebroventricular (i.c.v.) or intravenous (i.v.) injection of clonidine were investigated in freely moving, normotensive rats. In conscious rats, clonidine (2-20 micrograms) injected i.c.v. caused a dose-dependent and long-lasting pressor response associated with bradycardia. A similarly long-lasting pressor response was induced following an initial rapid rise in mean blood pressure after i.v. bolus injections of clonidine (5-50 micrograms/kg). In pentobarbital-anesthetized rats, the prolonged pressor responses to i.v. and i.c.v. injected clonidine at high doses were significantly smaller than those in conscious rats. Low doses of clonidine caused only depressor responses which developed gradually. No significant changes in concentrations of plasma norepinephrine and epinephrine were found during the pressor period after i.c.v. injection of clonidine (20 micrograms). Systemic (2 mg/kg, i.v.) or central (100 micrograms, i.c.v.) pretreatment with phentolamine abolished only the prolonged pressor response to both i.c.v. (20 micrograms) and i.v. (50 micrograms/kg) injected clonidine. The prolonged pressor response to clonidine (20 micrograms, i.c.v.) was enhanced by pretreatment with hexamethonium (25 mg/kg, i.v.), methylatropine (1 mg/kg, i.v.) or atropine (1 mg/kg, i.v.) and it was not affected by pretreatment with saralasin (300 micrograms/kg and 25 micrograms/kg/min, i.v.), d(CH2)5Tyr(Me)-arginine-vasopressin, a vasopressin antagonist (50 micrograms/kg, i.v.) or naloxone (1 mg/kg, i.v.). Neither adrenalectomy nor adrenal demedullation had an effect on the pressor response to clonidine (20 micrograms, i.c.v.). In adrenalectomized rats, systemic pretreatment with hexamethonium (25 mg/kg, i.v.) caused a potentiation of the pressor response to clonidine (20 micrograms, i.c.v.). These results suggest that clonidine induces the pressor response through activation of central alpha-adrenoceptors, probably the alpha 2 subtype, without an increase in sympatho-adrenomedullary activity. It is speculated that the response may be mediated by vasoactive humoral substance(s).