Sympathoinhibition by rilmenidine in conscious rabbits: involvement of α2-adrenoceptors

Summary Cardiovascular and sympathetic nervous system effects of the mixed ₂-adrenoceptor and imidazoline receptor agonist rilmenidine were studied in conscious rabbits chronically instrumented for the recording of the firing rate of renal sympathetic fibers. Separate experiments were carried out on pithed rabbits with electrically stimulated (2 Hz) sympathetic outflow. Drugs were administered intravenously in a cumulative manner.In conscious rabbits, rilmenidine 0.1, 0.3 and 1.0 mg kg^–1 dose-dependently lowered blood pressure, renal sympathetic nerve activity, heart rate and the plasma concentration of noradrenaline and adrenaline. The effect on blood pressure and plasma catecholamines was maximal after 0.3 mg kg^–1 whereas heart rate and renal sympathetic nerve activity decreased further after rilmenidine 1.0 mg kg^–1. Yohimbine 0.1 and 0.5 mg kg^–1, when injected subsequently, attenuated and at the higher dose abolished all effects of rilmenidine. The effects of rilmenidine were also antagonized by the ₂-adrenoceptor antagonist 2-(2,3-dihydro-2-methoxy-1,4-benzodioxin-2-yl)-4,5-dihydro-1H-imidazole HCl (RX821002; 0.1 and 0.5 mg kg^–1). Yohimbine 0.1 and 0.5 mg kg^–1 did not attenuate or attenuated only slightly the decrease of heart rate and renal sympathetic nerve activity produced by infusion of vasopressin. In pithed rabbits with electrically-stimulated sympathetic outflow, yohimbine 0.1 submaximally and yohimbine 0.5 mg kg^–1 maximally increased the plasma noradrenaline concentration.The experiments show by direct measurement of sympathetic nerve firing and plasma catecholamines that rilmenidine causes sympathoinhibition in conscious rabbits, presumably through central sites of action. The antagonism by yohimbine, at doses which are selective for ₂-adrenoceptors (vs. imidazoline receptors), demonstrates the involvement of ₂-adrenoceptors in the sympatho-inhibition.Correspondence to: B. Szabo at the above address     

Cardiac vagal effects of rilmenidine in the dog: comparison with clonidine

1 The cardiac vagal effects of rilmenidine (5 μg kg^?1 min^?1) and clonidine (0.5 μg kg^?1 min^?1) were studied in chloralose anaesthetized dogs. 2 Rilmenidine and clonidine progressively reduced the vagal stimulation-induced bradycardia. As indicated by the ED₇₀, rilmenidine was about 23 times less potent than clonidine in this respect. Concomitantly, both drugs dose-relatedly decreased heart rate and mean blood pressure with potency ratios of rilmenidine to clonidine of about 1:23 and 1:12, respectively. 3 Importantly, the heart rate values observed under vagal stimulation during drug infusion never exceeded the values under basal vagal stimulation, and with both drugs large interindividual variations occurred under vagal stimulation. 4 These results show that the vagal bradycardia inhibition produced by rilmenidine and clonidine results from their true bradycardic effects and not from actual cardiac vagolytic properties.     

An analysis of the mechanism of 5-hydroxytrypt-amine-induced vasopressor responses in ganglion-blocked anaesthetized dogs

5-Hydroxytryptamine (5-HT) administered intravenously (i.v., 1–30 μg kg^?1) to ganglion-blocked anaesthetized dogs produced dose-related increases in diastolic blood pressure and we have analysed the mechanism involved. Cyproheptadine and methysergide (10–100 μg kg^?1 i.v.) were potent and specific antagonists of the 5-HT induced rise in blood pressure, while the α-adrenoceptor blocking agent phentolamine (0·3–3 mg kg^?1 i.v.) also caused dose-related inhibition. Syrosingopine pretreatment converted the vasopressor action of 5-HT to a vasodepressor action and acute bilateral adrenalectomy caused a marked reduction in the 5-HT-induced rise in blood pressure. In two dogs, 5-HT (30 μg kg^?1 i.v.) markedly increased the venous plasma concentrations of noradrenaline and adrenaline. We concluded that the 5-HT-induced rise in diastolic pressure in the ganglion blocked anaesthetized dog is due largely to the release of catecholamines of which a substantial component is from the adrenal gland. The rise in diastolic blood pressure is specifically blocked by low doses of cyproheptadine and methysergide suggesting that the release of catecholamines is mediated by specific 5-HT receptors located mainly within the adrenal medulla.     

Pharmacological characterization of the inhibitory effect of (R)-α-methylhistamine on sympathetic cardiopressor responses in the pithed guinea-pig

1 The effect of (R)-α-methylhistamine (R-α-mHA), a selective histamine H₃-receptor agonist, on increases in blood pressure and heart rate mediated by activation of the sympathetic nervous system induced by electrical stimulation of the spinal cord, was characterized in the vagotomized, pithed guinea-pig. 2 The frequency-dependent nature of (R)-α-mHA's effect on sympathetic cardiopressor responses was studied at frequencies between 1 and 20 Hz. (R)-α-mHA (10–100 μg kg^?1, i.v.) produced a dose-dependent inhibition of the stimulated increase in both blood pressure (BP) and heart rate (HR). The inhibition was inversely related to frequency and maximum inhibition (BP, 61% at 1 Hz; HR, 50% at 1 Hz) was seen with 100 μg kg^?1 of (R)-α-mHA. Treatment with the H₃ receptor inactive stereoisomer, (S)-α-methylhistamine (300 αg kg^?1, i.v.) did not inhibit the neurogenic sympathetic cardiopressor responses. 3 Pretreatment with thioperamide (1 mg kg^?1, i.v.), a histamine H₃ receptor antagonist, blocked (R) -α-mHA's inhibitory effect on stimulation-induced sympathetic cardiopressor responses. 4 Combined pretreatment with the H₃-receptor antagonist cimetidine (3 mg kg^?1, i.v.) and the H₁-receptor antagonist chlorpheniramine (0.3 mg kg^?1, i.v.) did not attenuate (R) -α-mHA's inhibitory effects. 5 (R) -α-mHA (100 μg kg^?1) had no effect on the hypertensive or tachycardia effects induced by adrenaline (1 and 3 μg kg^?1, i.v.). 6 Treatment with a combination of prazosin (1 mgkg^?1, i.v.) and yohimbine (1.5 mg kg^?1, i.v.) to block α₁ and α₂-adrenoceptors, abolished the sympathetic hypertension without affecting the inhibition of sympathetic tachycardia induced by (R) -α-mHA. Conversely, pretreatment with the β-adrenoceptor antagonist propranolol (1 mg kg^?1, i.v.), which blocked the sympathetic tachycardia, did not block (R)-α-mHA's inhibition of sympathetic hypertensive responses. 7 In adrenalectomized guinea-pigs, (R) -α-mHA (100μg kg^?1, i.v.) also produced a frequency-dependent inhibition of sympathetic hypertensive cardiopressor responses that was not significantly different from intact animals. 8 These results demonstrate that (R) -α-mHA produces a frequency-dependent inhibition of the cardiopressor responses due to activation of the sympathetic innervation to the resistance vessels and the heart. These effects of (R)-α-mHA are mediated by a prejunctional inhibitory H₃-receptor mechanism, and an intact CNS is not needed to elicit these effects. The most likely site of action is on the postganglionic sympathetic neuroeffector junction whereas a site in the adrenal medulla, unlike the sympathetic ganglia can be excluded. Furthermore, the inhibitory modulation of the sympathetic tachycardia responses with (R)-α-mHA is not affected by α₁- and α₂-adrenoceptor blockade.     

Inhibition of serotonin-induced increase in canine external carotid blood flow by drugs that decrease the sympathetic outflow

1 The present study was designed to analyse the effect of the centrally-acting sympatho-inhibitory drugs, prazosin and ketanserin, on the increase in external carotid blood flow (external CBF) produced by 5-hydroxytryptamine (5-HT) in pentobarbital-anaesthetized dogs. 2 Intracarotid (i.c.) infusions of 5-HT (10 μ g min^?1 during 1 min) produced an increase in external CBF without changes in mean arterial blood pressure or heart rate. This response to 5-HT was dose-dependently blocked by intravenous (i.v.) administration of prazosin (1, 3, 10, 30 and 100 μg kg^?1) or ketanserin (10, 30, 100 and 300 μg kg^?1). 3 Furthermore, 5-HT-induced increase in external CBF was inhibited by either the ganglionic blocking agent, mecamylamine (0.03, 0.1, 0.3, 1, 3 and 10 mg kg^?1), the mixed 5-HT₁-like and 5-HT₂ receptor antagonist, methiothepin (3, 10 and 30 μ g kg^?1) or the 5-HT_1A ligand, spiroxatrine (10, 30, 100 and 300 μg kg^?1). In contrast, the selective 5-HT₂ and 5-HT_1C receptor antagonist, ritanserin (30 and 100 μg kg^?1, i.v.), was unable to block the above response to 5-HT. 4 It is concluded that the inhibition of 5-HT-induced increase in external CBF by prazosin, ketanserin, mecamylamine and spiroxatrine is due to a reduction in the sympathetic tone and not to a blockade of 5-HT receptors.     

Comparison between the cardiovascular effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and clonidine in the conscious sino-aortic denervated rat

1 The purpose of this study was to investigate the role of an intact baroreceptor reflex mechanism in the expression of the cardiovascular response to 8-OH-DPAT and to determine whether there are any differences between the activation of central α₂-adrenoreceptors and 5-HT_1A receptors in this respect. To this end, the effects of 8-OH-DPAT and clonidine have been assessed on blood pressure, heart rate, ECG and cardiac contractility indices in conscious sino-aortic baroreceptor denervated (SAD) rats and their sham-operated controls. 2 In both sham-operated and SAD rats, intravenous (i.v.) administration of 8-OH-DPAT (32 μg kg^?1) and clonidine (8 μg kg^?1) produced falls in systemic blood pressure, left ventricular systolic pressure and dP/dt_max. 3 8-OH-DPAT produced similar bradycardia in each group of rats; in contrast, clonidine had a greater effect in the SAD animals. Increases of the PQ interval mirrored the heart-rate changes with both compounds. 4 No significant changes in end diastolic blood pressure or in the myocardial contractility indices dP/dt_mas/P and V_max: were evident. 5 This study provides support for the view that i.v. 8-OH-DPAT lowers blood pressure and heart rate through a central mechanism. The effects occur independently of an intact baroreceptor reflex and are not associated with effects on myocardial contractility. 8-OH-DPAT shows close qualitative similarities to clonidine in this model.     

The effects of cadmium ions on blood pressure,dopamine-β-hydroxylase activity and on the responsiveness of in vivo preparations to sympathetic nerve stimulation,noradrenaline and tyramine

Changes in sympathetic nervous function of the rat caused by acute and chronic treatment with cadmium (Cd²⁺) have been studied in vivo by measurement of changes in blood pressure and plasma dopamine-β-hydroxylase (DBH) activity. In anaesthetized animals, acute injection of Cd²⁺ (0·1–1 μm) caused an initial fall followed by a rise in both diastolic and systolic blood pressure, plasma DBH activity increased in a dose-dependent manner. Animals subjected to repeated treatment with Cd²⁺ (0·5, 1 μm) daily for 12 days became markedly hypertensive, the increases in the systolic pressure being greater than those seen in the diastolic pressure. In pithed animals the blood pressure responses of the treated animals to electrical stimulation of the lower sympathetic outflow (T₁₀-L₁) and tyramine injection (35, 70, 140 nmol kg^?1) were markedly decreased, whilst responses to low doses of noradrenaline (NA) (7, 15, 30 nmol kg^?1) were potentiated compared with untreated animals. In addition, plasma DBH activities following sympathetic outflow stimulation and tyramine administration were markedly increased and decreased respectively compared with untreated controls. The data suggest that a correlation exists between changes in sympathetic nervous function and the induction of hypertension caused by Cd²⁺.     

Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys

Abstract— The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[N^α-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg^?1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vd_ss = 3·86±1·04 L kg^?1, plasma clearance = 2·22 ± 0·39 L kg^?1, and AUC= 1445 ± 266 ng h mL^?1. After 30 mg kg^?1 oral dose, maximum plasma concentration, t_max and AUC of YM-21095 were 28·8 ± 9·6 ng mL^?1, 0·25 h and 23·6 ± 7·7 ng h mL^?1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg^?1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg^?1 oral dose to monkeys was 71·8 ± 41·5 ng mL^?1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.     

Search for an endogenous cannabinoid-mediated effect in the sympathetic nervous system

Activation of CB₁ cannabinoid receptors by exogenous agonists causes presynaptic inhibition of neurotransmitter release from axon terminals. In the central nervous system, presynaptic CB₁ receptors can also be activated by endogenous cannabinoids (endocannabinoids) released from postsynaptic neurons. Except in the vas deferens, there is no indication of endocannabinoid-mediated presynaptic inhibition in the sympathetic nervous system. The aim of the present study was to search for such inhibition in pithed rats. Artificial sympathetic tone was established by continuous electrical stimulation of preganglionic sympathetic axons. The CB₁ cannabinoid receptor antagonist rimonabant (0.5 and 2 mg kg^–1 i.v.) did not change blood pressure, heart rate or plasma noradrenaline concentration. Since activation of G_q/11 protein-coupled receptors enhances endocannabinoid synthesis in the central nervous system, we attempted to stimulate endocannabinoid production by infusion of arginine vasopressin and phenylephrine (both activate G_q/11 protein-coupled receptors). Rimonabant (2 mg kg^–1 i.v.) did not change blood pressure, heart rate or plasma noradrenaline concentration during infusion of phenylephrine or vasopressin. In the final series of experiments we verified that an exogenous cannabinoid agonist produces sympathoinhibition. The synthetic CB₁/CB₂ receptor agonist WIN55212-2 (0.1 and 1 mg kg^–1 i.v.) markedly lowered blood pressure and plasma noradrenaline concentration in pithed rats with electrically stimulated sympathetic outflow. In contrast, in pithed rats with a pressor infusion of noradrenaline, WIN55212-2 did not change blood pressure or heart rate. The results verify that activation of peripheral presynaptic CB₁ receptors inhibits noradrenaline release from sympathetic nerve terminals. The lack of effect of the CB₁ receptor antagonist rimonabant indicates that, even under conditions favouring endocannabinoid synthesis, endocannabinoid-mediated presynaptic inhibition is not operating in the sympathetic nervous system of the pithed rat.     

Pharmacological and Pharmacokinetic Evaluation of EXP3312, an Orally-active Non-peptide Angiotensin II-Receptor Antagonist

EXP3312, 2-n-propyl-4-chloro-l-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylaldehyde, is a non-peptide angiotensin II (AII) AT₁-receptor antagonist. In the rabbit isolated aorta EXP3312 inhibited the contractile response to AII competitively with a pA₂ value of 8.24. In renal hypertensive rats EXP3312 reduced blood pressure with intravenous and oral ED30 values of 0.19 and 0.14 mg kg^?1, respectively. It also reduced blood pressure in frusemide-treated dogs when administered orally at 1 and 3 mg kg^?1. In rats and dogs, the absolute oral bioavailability of EXP3312 averaged 60 and 28%, respectively. When EXP3312 was administered intravenously to rats and dogs the plasma elimination half-lives were 1.20 and 2.52 h, respectively. In rats and dogs EXP3312 was metabolized to an active metabolite M1, 2-n-propyl-4-chloro-1-[(2′-(1H-tetrazol-5-yl)-biphenyl-4-yl)methyl]imidazole-5-carboxylic acid. M1 is about ten times more potent than EXP3312 in renal hypertensive rats; the intravenous ED30 value was 0.02 mg kg^?1. Because high plasma levels of M1 were found in rats after oral administration of EXP3312, it is likely that M1 contributes to the long duration of the antihypertensive effects of EXP3312 in renal hypertensive rats. The results show that EXP3312 is a potent, orally active, competitive and selective AT₁-receptor antagonist and a potent antihypertensive agent; it is likely to be therapeutically useful in the treatment of hypertension and congestive heart failure.     

Role of the central autonomic nervous system in the hypotension and bradycardia induced by (-)-delta 9-trans-tetrahydrocannabinol

(-)-Δ⁹-trans-Tetrahydrocannabinol (Δ⁹-THC), when given intravenously (2 mg kg^?1) to cats, produced marked decreases in blood pressure and heart rate which developed gradually and were of prolonged duration. Cervical spinal transection (C₁-C₂) abolished these effects whereas surgical removal of neurogenic tone to the myocardium selectively eliminated the bradycardia. Bilateral vagotomy alone did not modify the action of Δ⁹-THC upon heart rate or blood pressure. Recordings of spontaneous sympathetic outflow in the inferior cardiac nerve indicated a rapid reduction in neural discharge rate after Δ⁹-THC administration. These observations support the hypothesis that Δ⁹-THC produces a cardiodecellerator and hypotensive effect by acting at some level within the sympathetic nervous system. Experiments conducted to investigate transmission in the superior cervical and stellate ganglia demonstrated that Δ⁹-THC did not alter ganglionic function. Also, responses to intravenous isoprenaline and noradrenaline were unchanged which suggested that Δ⁹-THC did not interact with α- or β- adrenoceptors. The possible action of Δ⁹-THC on central sympathetic structures was investigated by perfusion of Δ⁹-THC into the lateral cerebral ventricle. Δ⁹-THC so administered produced a significant reduction in heart rate without a substantial lowering of blood pressure. Tritiated or ¹⁴C-Δ⁹-THC perfused into the lateral ventricle demonstrated that the amount of radioactive compound passing into the peripheral circulation was insignificant and could not account for the decrease in heart rate. The current data are in agreement with the proposal that Δ⁹-THC produces cardiovascular alterations by an action on the central nervous system which results in a decrease in sympathetic tone.     

Peripheral presynaptic and central effects of clonidine,yohimbine and rauwolscine on the sympathetic nervous system in rabbits

Summary The function of presynaptic ₂-autoreceptors at postganglionic sympathetic neurones under conditions of normal, ongoing sympathetic impulse traffic was studied in anaesthetized rabbits (alfadolone + alfaxalone). Clonidine was used as an ₂-adrenoceptor agonist, and yohimbine and rauwolscine were used as antagonists. Mean arterial pressure, postganglionic renal sympathetic firing rate, arterial plasma noradrenaline concentration and heart rate were measured before (basal values) and at the end of 3-min infusions of sodium nitroprusside and phenylephrine, which were given to modulate efferent activity in the sympathetic nervous system through the baroreflex.The nitroprusside- and phenylephrine-induced changes of mean arterial pressure produced the expected changes in sympathetic nerve activity, plasma noradrenaline and heart rate. Clonidine (5 µg kg^–1 + 0.5 µg kg^–1 min^–1) reduced the basal mean arterial pressure, sympathetic nerve activity and heart rate. It also reduced the nitroprusside-induced increase in the plasma noradrenaline level without changing the nitroprusside-induced increase in sympathetic firing. These results, as well as the mean arterial pressure-sympathetic nerve activity and the sympathetic nerve activity-plasma noradrenaline function curves indicate that clonidine inhibited both sympathetic tone centrally and the average release of noradrenaline per action potential peripherally. Yohimbine (1 mg kg^–1 + 0.1 mg kg^–1 h^–1) and rauwolscine (0.5 mg kg^–1 + 0.1 mg kg^–1 h^–1) increased the basal plasma noradrenaline level without any increase of renal sympathetic nerve activity. They also enhanced the nitroprusside-induced increase in plasma noradrenaline without any enhancement of the nitroprusside-induced increase in sympathetic firing. The hypotensive response to nitroprusside was attenuated, whereas the heart rate response was augmented. These results, as well as the mean arterial pressure-sympathetic nerve activity and the sympathetic nerve activity-plasma noradrenaline function curves indicate that the main effect of yohimbine and rauwolscine was to increase the average release of noradrenaline per action potential.The simultaneous measurement of postganglionic sympathetic nerve activity and the arterial plasma noradrenaline concentration proved suitable to differentiate central (or ganglionic; this distinction was not possible) effects of ₂-adrenoceptor ligands from peripheral presynaptic effects. The results show that endogenous presynaptic, ₂-adrenergic autoinhibition of noradrenaline release from postganglionic sympathetic neurones operates physiologically in anaesthetized rabbits with ongoing, uninterrupted sympathetic nerve activity. The results also indicate that blockade of ₂-autoreceptors enhances the sympathetic reflex compensatory response to a hypotensive stimulus. Send offprint requests to B. Szabo at the above address     

Effect of indomethacin on the blood pressure and plasma catecholamine responses to acute endotoxaemia

Injection of E. coli endotoxin (7 mg kg^?1 i.v.) to pentobarbitone anaesthetized cats resulted in prolonged decrease of systemic blood pressure and increases in plasma concentrations of adrenaline, noradrenaline and 6-ketoprostaglandin (PG) F_1α. Indomethacin pretreatment (10 mg kg^?1 i.v.) attenuated the decrease in blood pressure following endotoxin injection. Plasma adrenaline, noradrenaline and 6-keto-PG F_1α were significantly lower in the indo-methacin-treated cats. These data indicate that the superior haemodynamic status of the indomethacin pretreated animals exposed to endotoxic shock is not the result of potentiation of the peripheral sympathetic response.     

Attenuation of adenylate cyclase-induced increases in renal sodium excretion by the dopamine D-2 receptor agonist SK&F 89124

1 Although the existence of D-2 receptor binding sites in kidney has been identified, their functional significance in terms of influencing renal sodium excretion is not clear. In the present study we have examined the renal effects of a selective D-2 receptor agonist, SK&F 89124, in anaesthetized rats. 2 Intravenous infusion of SK&F 89124 (0.3, 1 and 3 μg kg^?1 min^?1 respectively) produced dose-dependent decreases in mean arterial blood pressure, heart rate and renal blood flow without causing any significant changes in urine output, urinary sodium excretion, renal vascular resistance or glomerular filtration rate. The changes in blood pressure, heart rate and renal blood flow caused by SK&F 89124 were abolished by a selective D-2 receptor antagonist, domperidone (50 μg kg^?1 i.v. bolus; 10 μg kg^?1 min^?1). 3 Treatment with 3-isobutyl-l-methylxanthine (IBMX, 1 mg kg^?1 bolus i.v.) or forskolin (200 μg kg^?1 bolus i.v.) produced increases in heart rate, urine output and urinary sodium excretion, but there was no change in mean blood pressure. The natriuretic and diuretic response, but not tachycardiac response to IBMX or forskolin, was attenuated by SK&F 89124 (0.3 μg kg^?1 min^?1). 4 These results suggest that the selective D-2 receptor agonist, SK&F 89124, produced a significant decrease in blood pressure and heart rate via prejunctional D-2 receptor-mediated inhibition of noradrenaline release from postganglionic sympathetic nerve terminals. Although activation of renal tubular D-2 receptors had no significant effect on renal excretory function under basal conditions, it is likely that these receptors may exert an opposing effect on cAMP-mediated increases in renal sodium and water excretion.     

Intracerebroventricular choline reverses hypotension induced by acute chemical sympathectomy

1 The effect of centrally administered choline on blood pressure was investigated in rats made hypotensive by chemical sympathectomy. Chemical sympathectomy was produced by intravenous (i.v.) injection of 50 mg kg^?1 of 6-hydroxydopamine (6--OHDA). Intracerebroventricular (i.c.v.) administration of choline (50–150 μg) 2 h after 6-OHDA treatment increased blood pressure and reversed the hypotension in a dose-dependent manner without affecting heart rate. The pressor response was associated with an increase in plasma vasopressin levels. 2 Pretreatment of rats with the nicotinic receptor antagonist, mecamylamine (50 μg, i.c.v.), but not the muscarinic receptor antagonist atropine (10 μg, i.c.v.), blocked both the pressor and vasopressin responses to choline (150 μg). Pretreatment of rats with hemicholinium-3 (HC-3), a high affinity choline uptake inhibitor, greatly attenuated the pressor response to i.c.v. choline (150 μg). 3 The vasopressin V1 receptor antagonist, (β-mercapto-β,β-cyclopentamethylenepropionyl-O-Me-Try,Arg)-vasopressin (10 μg kg^?1; i.v.), given 5 min after i.c.v. choline, decreased the blood pressure but failed to return it to the pre-choline levels. Prazosine (0.5 mg kg^?1; i.p.), an antagonist of α-adrenoceptors, also decreased blood pressure. Administration of both antagonists together eliminated the pressor response to choline, and the blood pressure was reduced further to below the pre-choline levels. 4 It is concluded that i.c.v. choline can increase blood pressure in rats made hypotensive by acute chemical sympathectomy through the activation of central nicotinic receptors by presynaptic mechanisms. An elevation in plasma levels of both vasopressin and catecholamines (possibly released from the adrenal medulla) is involved in the pressor response to choline.     

Interrelationship of Cardiovascular Effects,Plasma Levels of Nicorandil,and Vascular cGMP Formation in Conscious Rats

The relationship between the dual activity of nicorandil (K_ATP channel-opening activity and nitrate-like action), plasma levels, and changes in vascular cGMP levels and cardiovascular parameters was investigated in conscious rats. Nicorandil (3 mg kg^?1, p.o.) was rapidly absorbed and caused a significant reduction in blood pressure, lasting for at least 1 h, increases in heart rate and femoral blood flow, and decreases in femoral vascular resistance. These were entirely abolished by intravenous glibenclamide (20 mg kg^?1). The plasma concentration of nicorandil reached a maximum 30 min after dosing. After administration of nicorandil, a correlation was observed between blood pressure and plasma nicorandil level or femoral vascular resistance. A significant increase (P < 0.05) in the cGMP content of the thoracic aorta occurred 15 min after administration of nicorandil, and persisted for at least 2 h. These results imply that nicorandil induces vasodilatation by opening K_ATP channels in peripheral resistance vessels, leading to overt reduction of blood pressure, but acts on conductance vessels mainly through nitrate-like activity.     

Centrally mediated bradycardia and hypotension induced by narcotic analgesics: dextromoramide and fentanyl

Dextromoramide (0.01?0.2 mg/kg i.v.) and fentanyl (0.005?0.05 mg/kg) induced a dose dependent decrease in blood pressure and heart rate in dogs. These effects appear to be to a centrally mediated decrease in sympathetic tone, (i) Both drugs are 10?20 times more potent when injected into the vertebral artery or the cisterna magna than when they were injected intravanously, (ii) Both drugs reduced splanchnic nerve activity in intact animals.The effect appears to be localized to the medulla oblongata as suggested by central injections; transection of the brain stem at midpoint levels did not change the effects on blood pressure and heart rate induced by dextromoramide in intact bivagotomized dogs. After transection of the spinal cord at C₁, dextromoramide induced a strong decrease in heart rate and a hypertension. Cutting of both vagus nerves abolished the decrease in heart rate and blood pressure. The hypotensive effect was therefore due to the bradycardia reducing cardiac output. In contrast in intact and midpontine dogs, a reduction in sympathetic tone contributes to the hypothensive effect.Nalorphine prevented and reversed the hypotensive, bradycardic and sympatho-inhibitory effects of dextromoramide. Piperoxan and yohimbine, two potent peripheral and central α-adrenoceptor blocking agents did not change the effects of dextromoramide.However oxotremorine or acetylcholine administered into the cisterna magna and vertebral artery administration of physostigmine abolished or reversed the haemodynamic effects of dextromoramide. A tropine abolished the antagonistic effects of cholinomimetic agents on the central cardiovascular effects of dextromoramide. Muscarinic mechanism appear to be involved in the haemodynamic effects of analgesic agents.     

Desipramine inhibits sympathetic nerve activity in the rabbit

Summary The aim of the study was to determine the sites of action of intravenously administered desipramine on the sympathetic nervous system in anaesthetized rabbits (alfadolone + alfaxalone). Renal postganglionic sympathetic nerve activity was measured in order to determine central nervous and ganglionic effects. The clearance of noradrenaline from the plasma was determined with an isotope tracer method. From the noradrenaline clearance and the plasma concentration of noradrenaline the noradrenaline spillover rate was calculated. These parameters as well as blood pressure and heart rate were measured before (basal values) and at the end of 20-min infusions of sodium nitroprusside, which was given in order to modulate efferent sympathetic nerve activity through the baroreceptors.Desipramine 0.5 mg kg-1 + 0.05 mg kg^–1 h^–1 (bolus injection followed by infusion) and 2 mg kg^–1 + 0.2 mg kg^–1 h^–1 dose-dependently inhibited basal sympathetic nerve activity and the noradrenaline clearance. Desipramine had no effect on basal blood pressure, noradrenaline spillover rate or heart rate. Nitroprusside produced hypotension and simultaneously increased sympathetic nerve activity, noradrenaline spillover rate and heart rate; the clearance of noradrenaline was reduced with decreasing blood pressure. The relationship between sympathetic nerve activity and blood pressure was shifted by desipramine in a manner indicating central sympathoinhibition. Desipramine had no effect on the relationship of the noradrenaline spillover rate to blood pressure, whereas it shifted the heart rate-blood pressure relationship in a manner indicating an enhancement of reflex cardioacceleration. In a separate series of experiments, desipramine also inhibited sympathetic nerve activity in baroreceptor-denervated animals.The results show that desipramine centrally inhibits sympathetic outflow in the rabbit. Simultaneously, it enhances the noradrenaline spillover per action potential peripherally. In our study, the two effects compensated for each other, so that desipramine had no major effect on the relationship between noradrenaline spillover and blood pressure. In the heart, the peripheral effect of desipramine outweighed the central sympathoinhibition, hence the reflex cardioacceleration. Send of fprint requests to B. Szabo at the above address     

Effects of pinacidil on the sympatho-adrenal system in dogs.

1. The aim of the present work was to study the antihypertensive effect of pinacidil, a potassium channel opener, in sinoaortic denervated (SAD) conscious dogs and to investigate whether the involvement of the sympathetic nervous system induced by this vasodilator compound is only of baroceptor reflex origin. 2. Pinacidil (0.1, 0.2, 0.4 mg kg-1 i.v.) induced a dose-dependent decrease in blood pressure in normal as well as in SAD dogs. In contrast, the induced-tachycardia observed in normal dogs was not found in SAD animals. 3. Since pinacidil induced an increase in plasma catecholamines, free fatty acids, glucose, plasma renin activity and aldosterone in SAD dogs it is suggested that this sympathetic activation is independent of the baroreceptor reflex pathways. 4. The sympathetic activation is mainly of peripheral origin, since pinacidil (0.7 mg kg-1 i.v.) induced an increase in adrenaline release from the adrenal gland after section of the great splanchnic nerve in anaesthetized dogs. This increase is probably due to an effect that does not involve K+ channel opening. However, this effect of pinacidil was not observed during splanchnic nerve stimulation (in this case, the involvement of K+ channel opening is suggested).     

Analysis of the receptor involved in the central hypotensive effect of rilmenidine and moxonidine

The aim of this study was to determine whether α₂-adrenoceptors or imidazoline I₁-receptors are responsible for the central sympathoinhibition produced by rilmenidine and moxonidine, two clonidine-like antihypertensive drugs. Rilmenidine and moxonidine were compared with the indirectly acting α₂-adrenoceptor agonist α-methyldopa. Three antagonists were used. Yohimbine and SK & F86466 were used as selective α₂-adrenoceptor antagonists. They were compared with efaroxan which is also an α₂-adrenoceptor antagonist, but, in addition, possesses affinity for imidazoline I₁-receptors. According to some but not all studies, the affinity of efaroxan for I₁-receptors is much higher than its affinity for α₂-adrenoceptors. Drugs were administered into the cisterna cerebellomedullaris of conscious rabbits by a catheter implanted previously under halothane anaesthesia. Rilmenidine (10 μg kg^–1), moxonidine (0.3 μg kg^–1) and α-methyldopa (0.4 mg kg^–1) lowered blood pressure and the plasma noradrenaline concentration; the degree of sympathoinhibition produced by the three agonists was very similar. When injected after the agonists, efaroxan (0.1–14 μg kg^–1; cumulative doses), yohimbine (0.4–14 μg kg^–1) and SK & F86466 (0.4–44 μg kg^–1) counteracted the effects of the agonists on blood pressure and the plasma noradrenaline concentration. Efaroxan was about tenfold more potent than yohimbine and SK & F86466 at antagonizing the hypotensive effects of α-methyldopa. Similarly, efaroxan was two- to tenfold more potent than yohimbine and SK & F86466 against rilmenidine and moxonidine. Finally, efaroxan was about as potent against α-methyldopa as against rilmenidine and moxonidine. The results confirm previous observations that selective α₂-adrenoceptor antagonists are capable of completely antagonizing effects of rilmenidine and moxonidine. The effects of the α₂-adrenoceptor antagonist with an additional high affinity for imidazoline I₁-receptors, efaroxan, can also be explained by blockade of α₂-adrenoceptors. Efaroxan was more potent against rilmenidine and moxonidine than the selective α₂-adrenoceptor antagonists. This was probably due to the fact that the affinity of efaroxan for α₂-adrenoceptors is higher than the affinity of yohimbine and SK & F86466, since efaroxan was also the most potent of the three antagonists against the indirectly acting α₂-adrenoceptor agonist α-methyldopa. The observation that efaroxan was equally potent against rilmenidine and moxonidine and against α-methyldopa suggests that the same receptors were involved in the effects of the three agonists, α₂-adrenoceptors; this observation is not compatible with the high I₁/α₂ selectivity of efaroxan and the hypothesis that rilmenidine and moxonidine activate I₁-receptors, whereas α-methyldopa activates α₂-adrenoceptors. Thus, the data do not indicate involvement of I₁ imidazoline receptors in the central sympathoinhibition elicited by ril-menidine and moxonidine in rabbits. It is likely that ril-menidine and moxonidine produce sympathoinhibition by activating the same receptors which are activated by the indirectly acting catecholamine α-methyldopa, namely α₂-adrenoceptors. Received: 7 December 1998 / Accepted: 2 February 1999