THE EFFECTS OF ADRENALECTOMY ON THE CARDIOVASCULAR RESPONSES TO A'-TETRAHYDROCANNABINOL IN RATS

1. In urethane anaesthetized sham-operated rats, intravenous administration of Δ¹-THC (1 mg/kg) caused an immediate and prolonged fall in blood pressure, with a concomitant reduction in pulse rate. 2. In rats which had been adrenalectomized 24 h previously, Δ¹-THC (1 mg/kg, i.v.) also caused a depressor response, but it was significantly shorter in duration than that observed in sham-operated animals. The durations of the cardiac slowing effect were similar in both groups of rats. 3. Hydrocortisone pretreatment (25 μg/kg> i-v), given 45 min before Δ¹-THC, restored the duration of the depressor response to Δ¹-THC in adrenalectomized rats, but it did not have any effect on the bradycardia induced by Δ-THC. 4. Hydrocortisone did not produce any significant effect on the hypotensive action of Δ¹-THC in sham-operated rats, but the cardiac slowing effect was markedly potentiated. 5. These results suggest a lack of correlation between the hypotensive and cardiac slowing actions of the drug and that a certein level of adrenal steroids is necessary for the maintenance of the depressor response to Δ¹-THC.     

Tolerance to the cardiovascular effects of delta9-tetrahydrocannabinol in the rat.

1. Daily intraperitoneal injections of delta9-tetrahydrocannabinol (delta9-THC, 10 mg/kg) resulted in tolerance to the effects of the cannabinoid on body weight and body temperature within 1-2 weeks of treatment. 2. Tolerance failed to develop to the suppression of spontaneous motor activity produced by delta9-THC during 28 days of treatment with the cannabinoid (10 mg/kg, i.p. per day). 3. Following treatment with vehicle for 28 days, intravenous administration of delta9-THC in anaesthetized rats produced a transient pressor response followed by a sustained hypotension and bradycardia. 4. Tolerance to the hypotensive and negative chronotropic responses to intravenous delta9-THC was readily apparent in animals which had received daily intraperitoneal injections of delta9-THC (10 mg/kg) for 28 days. 5. Tolerance failed to develop to the pressor actions of intravenous delta9-THC after 28 days of preptreatment. 6. There was no difference in the pressor response to intravenous noradrenaline in vehicle-treated animals (1.0 ml/kg, i.p., per day for 28 days) and delta9-THC-treated animals (10 mg/kg, i.p., per day for 28 days).     

ATTENUATION OF PRESSOR RESPONSES TO SYMPATHETIC STIMULI IN THE RAT BY ENALAPRIL

Intravenous administration to pithed Wistar rats of the angiotensin converting enzyme inhibitor enalapril (0.1-1.0 mg/kg) lowered the diastolic blood pressure and reduced pressor responses occurring during electrical stimulation (1-30 Hz) of the spinal sympathetic outflow. These doses of enalapril given intravenously also attenuated pressor responses to intravenous injection of the muscarinic ganglion stimulant McNeil-A-343 (50, 100, 150 micrograms/kg) and noradrenaline (0.1-5.0 micrograms/kg). Enalapril (1.0 mg/kg, i.v.) reduced pressor responses to the nicotinic ganglion stimulant 1,1-dimethyl-4-phenyl-piperazinium (300 micrograms/kg, i.v.). These results confirmed that the actions of enalapril resemble those of captopril in the pithed rat, by causing reductions in both blood pressure and pressor responses to sympathetic stimuli.     

EFFECTS OF THE α2-ADRENOCEPTOR AGONIST UK14304 ON PRESSOR RESPONSES IN PITHED RATS

1. Intravenous infusions of UK14304 (0.3-10 micrograms/kg per min) in pithed rat produced dose-dependent pressor responses which were not affected by prazosin (10 micrograms/kg) but were reduced by yohimbine (0.3 mg/kg). 2. Pressor responses to noradrenaline (0.1 micrograms/kg), phenylephrine (1 micrograms/kg) and vasopressin (10 mU/kg) were enhanced during infusions of UK14304 (0.03-1 micrograms/kg per min). Likewise, pressor responses to spinal sympathetic stimulation were enhanced during infusions of low concentrations of UK14304 (0.03-0.3 microgram/kg per min) but were reduced during infusion of a higher concentration of UK14304 (10 micrograms/kg per min). 3. After administration of yohimbine (0.3 mg/kg) or the calcium channel blocking drug diltiazem (infused at 50 micrograms/kg per min), pressor responses to noradrenaline and UK14304 were reduced, and responses to noradrenaline during infusion of UK14304 were not enhanced. 4. Prazosin (10 micrograms/kg) revealed a secondary depressor component in the response to sympathetic stimulation which is due to beta-adrenoceptor activation, since it was abolished by ICI 118551 (0.3 mg/kg). In the presence of ICI 118551 plus prazosin, pressor responses to sympathetic stimulation were enhanced during infusions of UK14304. 5. The depressor response to nitroprusside and the depressor component of responses to sympathetic stimulation after prazosin were enhanced during infusions of UK14304 at concentrations that increased the blood pressure. 6. The findings show that alpha 2-adrenoceptor activation enhanced the pressor responses to sympathetic nerve stimulation, noradrenaline, phenylephrine and vasopressin in the pithed rat and beta-adrenoceptor activation produced depressor responses which increased with increasing blood pressure.     

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.     

ATTENUATION BY CAPTOPRIL OF PRESSOR RESPONSES TO PERIPHERAL SYMPATHETIC NERVE STIMULATION IN RATS IS ABOLISHED AFTER BILATERAL NEPHRECTOMY AND DURING MINERALOCORTICOID HYPERTENSION

Intravenous administration of captopril (0.1-0.3 mg/kg) to normotensive pithed rats, with or without unilateral nephrectomy, was followed by a sustained fall in arterial blood pressure. Concomitantly pressor responses to electrical stimulation of the spinal sympathetic outflow (T11-L3), ganglion stimulation with McNeil-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyl-trimethylammonium chloride) or intravenous injection of noradrenaline were reduced. Attenuation by captopril (1 mg/kg) of pressor responses to McNeil-A-343 persisted after intravenous propranolol (1 mg/kg). Tachycardia caused by electrical stimulation of the spinal sympathetic nerves (C7-T2) was unchanged after 3.0 mg/kg captopril. After procedures reducing the activity of the renin angiotensin system, bilateral nephrectomy or induction of mineralocorticoid hypertension by unilateral nephrectomy and administration of desoxycorticosterone acetate, pressor responses to McNeil-A-343 or noradrenaline were unchanged after 1 mg/kg captopril. It is concluded that in the pithed rat, basal arterial blood pressure and the height of pressor responses to either postganglionic sympathetic nerve activation or intravenous noradrenaline depend on converting enzyme activity maintaining circulating angiotensin II levels.     

L-TRYITOPHAN-INDUCED DEPRESSION OF THE PRESSOR RESPONSE TO CLONIDINE IN ANAESTHETIZED RATS

1. The interaction of the serotonin precursor L-tryptophan with the pressor responses of the anaesthetized rat to the intravenous injection of clonidine, adrenaline and angiotensin has been studied. 2. Pretreatment of rats with L-tryptophan (100 mg/kg) depressed the pressor response to clonidine but had no effect on the responses elicited by adrenaline or angiotensin. 3. The L-tryptophan-induced depression of the clonidine response was prevented by pretreating rats with either Rö 44602, carbidopa, BW 172C58, methys-ergide or by pithing. 4. Intravenous infusions of serotonin depressed the pressor responses to clonidine, adrenaline and angiotensin in both intact anaesthetized and pithed rats. 5. It is concluded that the depressant action of L-tryptophan is dependent on its conversion within the periphery to serotonin. This action is also dependent on or mediated by the sympathetic nervous system.     

ANGIOTENSIN II ACTIVATES PRESSOR AND DEPRESSOR SITES OF THE PONTOMEDULLA THAT REACT TO GLUTAMATE

1. In cats anaesthetized with a mixture of α-chloralose (40 mg/kg) and urethane (400 mg/kg) and in rats anaesthetized with a mixture of α-chloralose (60 mg/kg) and urethane (800 mg/kg), changes in systemic arterial pressure (SAP), heart rate (HR) and sympathetic activities of vertebral (VNA) and renal (RNA) nerves were determined following the micro-injection of angiotensin II (AngII; 0.16 mmol/L; 50 nL) into the pressor and depressor sites of the pontomedulla previously reacted to a microinjection of monosodium l -glutamate (Glu; O.1 mol/L; 50 nL). Pressor sites included gigantocellular tegmental field (FTG) and dorsal medulla (DM) and rostral ventrolateral medulla (VLM). The depressor site was the caudal VLM (CVLM). The effects of losartan (1 mmol/L; 50 nL), a specific AT₁ receptor non-peptide antagonist for AngII, on responses induced by AngII in the VLM, DM and CVLM were also determined. 2. In 30% of pressor sites in the FTG, 55% in the VLM and 67% in the DM and in 76% of depressor sites in the CVLM previously exposed to Glu, microinjection of AngII to the same site produced pressor or depressor responses similar to that of Glu, but smaller in magnitude, particularly in the pressor VLM. Changes in both VNA and RNA induced by AngII were also smaller than those induced by Glu, particularly RNA from DM activation. 3. In the dorsal motor nucleus of the vagus, AngII, as Glu, produced marked bradycardia, but again this was smaller in magnitude than the bradycardia produced by Glu. 4. In rats, in the DM near or around the nucleus of the solitary tract where Glu increased SAP, microinjection of AngII (0.8 mmol/L; 60 nL) produced a depressor response, while the microinjection of 1.6 mmol/L (60 nL) AngII produced a pressor response. 5. Losartan blocked the increases in SAP induced by AngII in the VLM and DM. Decreases in SAP induced by AngII in the CVLM, however, were only slightly decreased by losartan. 6. Our data suggest that a significant portion of pressor and depressor sites of the pontomedulla contain neurons responsive to both AngII and Glu. In neurons in the VLM and DM, AngII produced pressor responses that were primarily mediated through AT₁ receptors, while the depressor actions of AngII in the CVLM were not mediated by AT₁ receptors.     

EFFECTS OF NEUROPEPTIDE Y ON THE PRESSOR RESPONSES TO PHENYLEPHRINE AND TO ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN ANAESTHETIZED RATS

1. The effects of neuropeptide Y (NPY) on the pressor responses to intravenous injections of phenylephrine and to reflex activation of the sympathetic nervous system by stimulation of the sciatic nerve were examined in anaesthetized rats. 2. NPY (10-20 micrograms/kg) always potentiated the pressor response to exogenous phenylephrine (by a mean of 28.1 +/- 5.0%). The effect of the same dose of NPY on the pressor response to sciatic nerve stimulation was variable (sometimes inhibition, sometimes potentiation). 3. NPY appears to act by potentiating post-synaptic alpha-adrenoceptor-mediated vasoconstrictor effects. It may also inhibit noradrenaline release by a presynaptic action. Thus the net effect of NPY on sympathetic activation in vivo may depend on the balance between these two opposing actions.     

An investigation of the action of tyramine and its interrelationship with the effects of other sympathomimetic amines

Choline 2,6-xylyl ether potentiated the sympathomimetic effects of tyramine and adrenaline in anaesthetized and spinal cats; the effects of noradrenaline were not significantly affected. The pressor activity of tyramine was also potentiated by the drug in reserpine-treated spinal cats and in pithed rats. The acute intravenous injection of reserpine in pithed rats potentiated pressor responses to tyramine, but depressed those to adrenaline and noradrenaline. During the intravenous infusion of noradrenaline in spinal cats and pithed rats the pressor responses to tyramine were increased, whilst those to adrenaline and noradrenaline were decreased. Infusion of isoprenaline in a spinal cat depressed responses to tyramine and noradrenaline, but potentiated those to adrenaline. A lower rate of infusion of isoprenaline in the same animal subsequently potentiated adrenaline and noradrenaline, but continued to depress tyramine. These results are held to be inconsistent with the view that the sympathomimetic effects of tyramine are produced entirely by the release of catechol amines.     

POTENTIATION OF DEPRESSOR RESPONSES TO ARACHIDONIC ACID BY ANGIOTENSIN CONVERTING ENZYME INHIBITORS IN THE RAT

In chloralose anaesthetized rats, intravenous administration of captopril, SQ 20881, SA 446 or MK 421 (0.5 mg/kg) potentiated the depressor responses to arachidonic acid 3 mg/kg given intravenously. Same doses of the above angiotensin converting enzyme inhibitors caused an approximately 100-fold decrease in sensitivity to the pressor effects of angiotensin I, with a concomitant similar increase in sensitivity to the depressor effects of bradykinin. Depressor responses to arachidonic acid, both before and after administering the converting enzyme inhibitors, were abolished by intravenous indomethacin (5 mg/kg). These results suggest that increased synthesis of prostaglandins in the circulation may contribute to the hypotensive effect of the angiotensin converting enzyme inhibitors, a group of newly developed antihypertensive agents.     

Effect of postprandial hyperglycemia and hyperinsulinemia on vascular responsiveness

Recent clinical studies demonstrated that transient postprandial hyperglycemia and hyperinsulinemia may contribute to the development of hypertension. Therefore, we investigated influence of acute hyperglycemia and/or hyperinsulinemia induced by glucose or insulin infusion on neuronal and humoral control of vascular tone in rats. Euglycemic male Wistar rats were pithed under anesthesia and arterial blood pressure was measured. Changes in vascular responses to spinal cord stimulation (SCS) and intravenous bolus injections of noradrenaline, angiotensin II, calcitonin gene-related peptide (CGRP), acetylcholine and sodium nitroprusside (SNP) were studied by infusing various concentration of glucose or insulin. Continuous glucose infusion, which increased both blood glucose and serum insulin levels, significantly augmented adrenergic nerve-mediated pressor responses to SCS without affecting injection of pressor responses to noradrenaline or angiotensin II. In pithed rats with artificially increased blood pressure and blockade of autonomic outflow, glucose infusion attenuated CGRPergic nerve-depressor responses to SCS without affecting depressor responses to injection of CGRP, acetylcholine or SNP. In pithed rats treated with octreotide, which increased blood glucose without increasing serum insulin levels, glucose infusion caused only significant augmentation of adrenergic nerve-mediated pressor responses. Combined infusion of insulin and glucose, which resulted in increased serum insulin levels with euglycemic, significantly augmented adrenergic nerve-mediated pressor responses and attenuated CGRPergic nerve-mediated depressor responses. The present results suggest that acute hyperglycemia and hyperinsulinemia increases adrenergic nerve-mediated vasoconstriction, which is partly associated with the blunted CGRPergic nerve function, and that plasma insulin concentration associated with hyperglycemia may be responsible for alteration of neuronal vascular regulation.     

CAPTOPRIL POTENTIATES DEPRESSOR RESPONSES TO ARACHIDONIC ACID IN THE RAT

1. In chloralose anaesthetized rats intravenous administration of captopril (0.5 mg/kg) was followed by an approximately 100-fold decrease in sensitivity to the pressor actions of angiotensin I. Concomitantly there was a 100-fold increase in sensitivity to the depressor effects of bradykinin. 2. Depressor responses to intravenous prostacyclin (PGI₂), prostaglandin E₂ (PGE₂) or a low dose of arachidonic acid (1 mg/kg) were not changed by captopril administration, but responses to a high dose of arachidonic acid (3 mg/kg), given either intravenously or into the aortic arch, were enhanced for up to two hours afterwards. 3. Depressor responses to arachidonic acid, both before and after captopril, were inhibited after intravenous indomethacin (1 mg/kg). 4. These results support the hypothesis that increased synthesis of prostaglandins in the circulation contributes to the hypotensive action of captopril.     

Effects of insulin on vascular responses to spinal cord stimulation and vasoactive agents in pithed rats

1. Effects of insulin (2-600 pmol kg(-1) min(-1), i.v.) on vascular responses to spinal cord (lower thoracic vertebra, Th 9-12) stimulation (SCS) and to i.v. injection of noradrenaline (NA, 125-500 ng kg-1), angiotensin II (Ang II, 40-200 pmol kg(-1), acetylcholine (ACh, 1 nmol kg(-1), calcitonin gene-related peptide (CGRP, 0.1 nmol kg(-1) and sodium nitroprusside (SNP, 5 microg kg-1) were examined in pithed rats. 2.In euglycemic pithed rats, low and medium doses of insulin dose-dependently potentiated vasopressor responses to SCS (2-8 Hz), NA, while higher doses of insulin had little effect on SCS- and NA-induced pressor responses. All doses of insulin significantly augmented pressor responses to Ang II. 3. In pithed rats with artificially increased blood pressure, SCS (2 and 4 Hz) induced a frequency-dependent depressor response, which was blocked by infusion of CGRP(8-37) (CGRP receptor antagonist, 60 nmol kg(-1) min(-1). 4. In euglycemic pithed rats, low-doses of insulin significantly attenuated depressor responses to SCS and CGRP, but medium and high doses of insulin remained unaffected. 5. All doses of insulin significantly inhibited depressor response to ACh, while SNP-induced depressor response was not significantly affected by any doses of insulin. 6. These results suggest that insulin at low and medium concentrations increases adrenergic vasoconstriction, which is partly associated with inhibition of CGRPergic nerve function and endothelium function. It is also suggested that lack of insulin effect at higher concentrations may result from acute desensitization of insulin action, possibly via insulin receptors.     

The central actions of lidocaine and a pesticide, chlordimeform

The injection of 300–1000 μg of lidocaine or chlordimeform (CDM) into the lateral ventricles of rats lightly anaesthetized with urethane produced similar dose-dependent pressor (or depressor) responses. Stimulation of the dorsal raphe nucleus caused suppression of the spontaneous EEG recorded from bipolar electrodes implanted in the amygdala. Intraventricular lidocaine and CDM blocked the raphe-mediated suppression of the amygdala EEG activity.

Higher doses (3–4 mg) of intraventricular lidocaine or CDM resulted in clonic limb movements, spikes in the amygdala EEG and blood pressure oscillation. All seizure manifestations could be blocked by intense raphe stimulation or by intravenous diazepam (1 mg/kg).

These studies indicate a central origin for the secondary pressor response that is observed with higher intravenous doses (10–50 mg/kg) of lidocaine or CDM.     

The lack of beta-adrenoceptor involvement in the cardiac action of delta 1-tetrahydrocannabinol in rats

1. Rat isolated hearts perfused with delta 1-THC (0.5 micrograms/ml) showed a reduction in the rate of beating which was not altered by pretreatment with propranolol (2 micrograms/ml), atropine (4 micrograms/ml) or hexamethonium (4 micrograms/ml). 2. Propranolol (2 micrograms/ml) also caused a decrease in the rate of beating, which was not affected by pretreatment with delta 1-THC (0.5 micrograms/ml). 3. In pithed rats, propranolol (2 mg/kg, i.v.) caused a decrease in the pulse rate, which was not altered by prior administration of delta 1-THC (1mg/kg, i.v.). 4. In both preparations, the responses to isoprenaline were markedly reduced or abolished by propranolol, but they were unaffected by delta 1-THC. 5. It is concluded that the hypotensive and cardiac slowing actions of delta 1-THC are not mediated by activation of parasympathetic nerves or by beta-adrenoceptor blockade.     

Effects of delta-9-tetrahydrocannabinol on the cardiovascular system, and pressor and behavioral responses to brain stimulation in rats

Effects of delta-9-tetrahydrocannabinol (delta 9-THC) on the cardiovascular system, and pressor and behavioral responses to brain stimulation were investigated in rats. In urethane-anesthetized rats, intravenous administration of delta 9-THC (1, 2 and 5 mg/kg) produced a significant and transient dose-related rise but no fall in blood pressure. delta 9-THC at these doses also produced marked reduction in heart rate which was antagonized by atropine (0.5 mg/kg i.v.) or bilateral vagotomy. In freely moving rats with chronically implanted electrodes and arterial cannula implants, intraperitoneal administration of delta 9-THC (4, 6 and 8 mg/kg) induced a rise in blood pressure and marked bradycardia. Abnormal behavior such as catalepsy, walking backwards and pivoting was also observed. delta 9-THC failed to inhibit the pressor responses to electrical stimulation of the posterior hypothalamus and midbrain reticular formation, whereas the drug suppressed the behavioral responses to stimulation of both regions. It is concluded that the cardiovascular effects seen with delta 9-THC injection are mainly the result of alteration of the efferent vagal activity by acting on the central nervous system and a more potent influence is exerted on the behavioral changes than on autonomic responses to brain stimulation.     

In-vivo pharmacological studies of 2-N-carboxamidinonormianserin, a histamine and 5-hydroxytryptamine antagonist lacking central effects.

The in-vivo pharmacological properties have been examined of FCC5 (2-N-carboxamidino-1,2,-3, 4, 10, 14b-hexahydrodibenzo (c.f.) pyrazino (1, 2-alpha)azepine hydrochloride), a guanidino analogue of mianserin. FCC5 (30-100 micrograms kg-1, i.v.) caused long-lasting (> 1 h) attenuation of histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in the anaesthetized guinea-pig. FCC5 (< or = 1 mg kg-1, i.v.) had no effect on submaximal bronchoconstrictor responses caused by i.v. acetylcholine or the thromboxane A2-mimetic U46619 ((15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid). The pressor effects of 5-HT in anaesthetized and pithed rats were inhibited by FCC5 (0.3-1.0 mg kg-1, i.v.). Higher doses of FCC5 (3 mg kg-1, i.v.) reduced bradycardia and depressor responses to 5-HT in anaesthetized rats. In anaesthetized cats and rats and also pithed rats, FCC5 (0.1-1.0 mg kg-1, i.v.) caused sympathomimetic effects as demonstrated by pressor responses and tachycardia. FCC5 (0.1-0.3 mg kg-1, i.v.) inhibited pressor responses to tyramine whereas those to noradrenaline and sympathetic nerve stimulation were potentiated. Oedema in the rat paw caused by intraplantar 5-HT was inhibited by FCC5 (ID50 0.76 mg kg-1, i.p.; and 2.7 mg kg-1, p.o.). In decerebrate rats which had been spinalized at T6-8, fenfluramine-induced facilitation of the flexor reflex of the anterior tibialis muscle was inhibited by mianserin (ID50 0.36 mg kg-1, i.p.) but not by FCC5 (< or = 3 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)     

The cardiovascular effects of apomorphine in the anaesthetized rat

In urethane-anaesthetized rats, apomorphine, 0.01–1.0 mg/kg, i.v., produced a short-lasting fall in blood pressure and, at the higher doses (0.5–1.0 mg/kg), a marked bradycardia. Pretreatment with either reserpine or 6-hydroxydopamine did not affect the magnitude of the depressor responses. Haloperidol, spiroperidol and sulpiride failed to influence the responses to apomorphine whilst transection at the midcollicular level abolished the hypotensive responses. In pithed rat preparations, small pressor responses to apomorphine were obtained; similar effects were also observed in the anaesthetized rat treated with atropine or after bilateral vagotomy. The efferent vagal discharges were markedly increased by apomorphine, 0.1–1.0 mg/kg, whilst the discharges from the splanchnic nerve were almost completely abolished at the highest dose of apomorphine (1 mg/kg). It is concluded that the depressor effect of apomorphine is central in origin and mainly due to an increased efferent activity of the vagal nerves. This effect of apomorphine is probably not mediated by central dopaminergic receptors.     

The nitric oxide synthesis/pathway mediates the inhibitory serotoninergic responses of the pressor effect elicited by sympathetic stimulation in diabetic pithed rats

We investigated the involvement of the nitric oxide pathway in the inhibitory mechanisms of 5-hydroxytryptamine (5-HT) in the pressor responses induced by stimulation of sympathetic vasopressor outflow in diabetic pithed rats. Diabetes was induced in male Wistar rats by a single s.c. injection of alloxan. Four weeks later, the animals 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. The inhibition of electrically induced pressor responses by 5-HT (10 microg/kg/min) in diabetic pithed rats could not be elicited after i.v. treatment with 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) (10 microg/kg), a guanylyl cyclase inhibitor, or N-omega-L-Arginine methyl ester hydrochloride (L-NAME) (10 mg/kg), a nitric oxide synthase (NOS) inhibitor. The inhibitory effect produced by infusion of the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT) (20 microg/kg/min) was abolished in the presence of ODQ (10 microg/kg), or L-NAME (10 mg/kg) in diabetic pithed rats. The administration of L-Arginine (100 mg/kg) 30 min after L-NAME reproduced the inhibitory effect caused by 5-HT (10 microg/kg/min) and 8-OH-DPAT (20 microg/kg/min) on the electrically induced pressor responses, whereas in the presence of D-Arginine (100 mg/kg)+L-NAME the 5-HT or 8-OH-DPAT inhibitory effect on the pressor responses was abolished. In conclusion, in diabetic pithed rats, the inhibition produced by prejunctional 5-HT(1A) activation on electrically induced sympathetic pressor responses is mediated by the NO synthesis/pathway.