A comparative study of the reversal by different alpha 2-adrenoceptor antagonists of the central sympatho-inhibitory effect of clonidine.

1. The recovery of the clonidine-induced hypotension, bradycardia and sympatho-inhibition produced by several putative alpha 2-adrenoceptor antagonists was investigated in pentobarbitone anaesthetized rats. The activity of four substances containing an imidazoline structure: idazoxan, methoxy-idazoxan, BRL44408 and atipamezole was compared with the effect of fluparoxan, yohimbine and L-657,743; in addition the effect of the alpha 1-adrenoceptor antagonist, prazosin, was also studied. 2. Prazosin (0.03-1 mg kg-1, i.v.) failed to alter the sympatho-inhibitory and hypotensive effects of clonidine (10 micrograms kg-1, i.v.). L-657,743 (0.01-1 mg kg-1, i.v.) induced a recovery of blood pressure, heart rate and renal sympathetic nerve activity. Yohimbine (0.03-3 mg kg-1, i.v.) completely reversed the sympatho-inhibitory effect of clonidine but did not alter its hypotensive effect. 3. The four imidazoline drugs: idazoxan (10-300 micrograms kg-1, i.v.), methoxy-idazoxan (1-100 micrograms kg-1, i.v.), BRL44408 (0.1-3 mg kg-1, i.v.) and atipamezole (0.03-1 mg kg-1, i.v.) and fluparoxan (10-300 micrograms kg-1, i.v.) reversed the clonidine-induced hypotension but produced only a partial recovery of the renal sympathetic nerve activity and of the heart rate. After pretreatment with prazosin (0.1 mg kg-1, i.v.), the recovery of the sympathetic nerve activity elicited by these compounds was significantly higher. In hexamethonium (10 mg kg-1, i.v.) pretreated rats, these five drugs induced dose-related hypertension which was reduced by pretreatment with prazosin (0.1 mg kg-1, i.v.). 4. Our results indicate that the putative alpha 2-adrenoceptor antagonists idazoxan, methoxy-idazoxan, BRL44408, atipamezole and fluparoxan also have a peripheral hypertensive effect which is mediated through activation of vascular alpha 1-adrenoceptors; this property of the compounds may be partly responsible for the reversal of the hypotensive action of clonidine. Considering the structure and the affinities of the drugs tested, our data indirectly suggest that alpha 2A-adrenoceptors may be implicated in the central sympatho-inhibitory effects of clonidine.     

A comparison of the cardiovascular effects of centrally administered clonidine and adrenaline in the anaesthetized rat.

Intracerebroventricular (i.c.v.) injections of clonidine and adrenaline-induced hypotension and bradycardia in urethane anaesthetized spontaneous hypertensive rats. The hypotension induced by clonidine (3 microgram i.c.v.) was antagonized by pretreatment with the alpha-antagonists piperoxan, which also antagonized clonidine-induced bradycardia, and yohimbine. The hypotension and bradycardia induced by adrenaline (10 microgram i.c.v.) were unaffected by alpha-antagonist pretreatment, while beta-antagonist pretreatment with (--)-propranolol or metoprolol was effective against adrenaline but not clonidine-induced hypotension and bradycardia. Pretreatments with the histamine H2-receptor antagonists metiamide and cimetidine antagonized clonidine but not adrenaline-induced hypotension. These data indicate that different central mechanisms are involved in mediating the hypotension and bradycardia induced by centrally administered clonidine and adrenaline and do not, therefore, support the hypothesis that the hypotensive effects of clonidine (i.c.v.) are mediated by central adrenaline receptor activation in urethane-anaesthetized spontaneous hypertensive rats.     

Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine

Modification of clonidine-induced cardiovascular effects by endothelin-1 (ET-1) was studied in male Sprague-Dawley rats. A dose-dependent decrease in blood pressure and heart rate was produced by clonidine (100, 250 and 500 μg/kg i.v.). Lower doses produced only a fall in blood pressure (through central -adrenoceptors) while higher doses of clonidine produced an initial hypertensive response (through peripheral -adrenoceptors) and subsequent longer lasting hypotension and bradycardia. The hypotension and bradycardia induced by 100 and 250 μg/kg i.v. dose of clonidine were completely blocked by ET-1 (100 ng/kg i.v.) pretreatment. Conversely, the hypertensive response induced by high dose of clonidine (500 μg/kg i.v.) was significantly potentiated by ET-1 pretreatment. In cervical sectioned rats, i.v. administered clonidine failed to produce any hypotensive effect, indicating lack of central effect of clonidine. ET-1 significantly (P< 0.0005) potentiated the hypertensive response of a low dose (50μg/kg i.v.) of clonidine in cervical-sectioned rats. I.c.v administration of clodinine (1, 2, 4 and 6 μg) produced a dose-dependent decrease in blood pressure and heart rate. ET-1 pretreatment (25 ng i.c.v. transietly blocked the clonidine-induced decrease in blood pressure and heart rate for about 10 min but the hypotension and bradycardia was observed subsequently. Since the major site of action of clonidine is the ventral surface of medulla, clonidine was applied directly to the ventral surface of medulla and produced a decrease in blood pressure and heart rate. ET-1 pretreatment at the ventral surface of medulla blocked the clonidine-induced decrease in blood pressure and heart rate initially but the fall in blood pressure and heart rate was observed subsequently. To explore the possibility that transient antagonism of clonidine-induced effects is due to vasoconstriction, studies were performed with angiotensin II, a powerful vasoconstrictor. Angiotensin II (5 μg i.c.v.) pretreatment like ET-1 blocked the hypotensive and bradycardic effect of i.c.v. or i.v. administered clonidine. It is concluded that ET-1 blocks the hypotensive and potentiates the hypertensive effect of clonidine, possible mechanisms have been discussed.     

Evidence for a peripheral component in the sympatholytic effect of clonidine in rats.

In an attempt to assess separately the peripheral and central effects of clonidine on cardiovascular parameters and plasma catecholamine levels, the selective alpha 2-adrenoceptor antagonist idazoxan (RX 781094) was given either intravenously (i.v.) or intracerebroventricularly (i.c.v.) to anaesthetized rats before administration of intravenous clonidine. Plasma noradrenaline and plasma growth hormone concentrations were used as indices of peripheral sympathetic nervous activity and central alpha-adrenoceptor stimulation, respectively. Peripheral and central administration of idazoxan antagonized the cardiovascular responses to i.v. clonidine, 5 micrograms kg-1. However, idazoxan was more effective against the hypotension than the bradycardia induced by clonidine. Idazoxan 300 micrograms kg-1 i.v. and 50 micrograms i.c.v. prevented clonidine-induced falls in plasma noradrenaline and adrenaline. The results suggest that 50 micrograms idazoxan i.c.v. caused some blockade of peripheral as well as central alpha 2-adrenoceptors. Idazoxan, 10 micrograms i.c.v., caused similar inhibition of the hypotensive response to clonidine as 300 micrograms kg-1 i.v. and 50 micrograms i.c.v. but did not significantly inhibit the clonidine-induced fall in plasma noradrenaline concentration. Animals pretreated with i.v. or i.c.v. idazoxan had significantly lower levels of plasma growth hormone than vehicle-treated rats. Idazoxan 10 micrograms and 50 micrograms i.c.v. suppressed growth hormone secretion to the same extent. These results suggest that stimulation of peripheral, prejunctional alpha 2-adrenoceptors in anaesthetized rats may contribute to the fall in plasma catecholamines produced by i.v. clonidine, and confirm that the hypotensive effect is centrally mediated.     

Differential effects of K+ channel blockers on antinociception induced by alpha 2-adrenoceptor, GABAB and kappa-opioid receptor agonists.

1. The effects of several K+ channel blockers (sulphonylureas, 4-aminopyridine and tetraethylammonium) on the antinociception induced by clonidine, baclofen and U50,488H were evaluated by use of a tail flick test in mice. 2. Clonidine (0.125-2 mg kg-1, s.c.) induced a dose-dependent antinociceptive effect. The ATP-dependent K+ (KATP) channel blocker gliquidone (4-8 micrograms/mouse, i.c.v.) produced a dose-dependent displacement to the right of the clonidine dose-response line, but neither 4-aminopyridine (4-AP) (25-250 ng/mouse, i.c.v.) nor tetraethylammonium (TEA) (10-20 micrograms/mouse, i.c.v.) significantly modified clonidine-induced antinociception. 3. The order of potency of sulphonylureas in antagonizing clonidine-induced antinociception was gliquidone > glipizide > glibenclamide > tolbutamide, which is the same order of potency as these drugs block KATP channels in neurones of the CNS. 4. Baclofen (2-16 mg kg-1, s.c.) also induced a dose-dependent antinociceptive effect. Both 4-AP (2.5-25 ng/mouse, i.c.v.) and TEA (10-20 micrograms/mouse, i.c.v.) dose-dependently antagonized baclofen antinociception, producing a displacement to the right of the baclofen dose-response line. However, gliquidone (8-16 micrograms/mouse, i.c.v.) did not significantly modify the baclofen effect. 5. None of the K+ channel blockers tested (gliquidone, 8-16 micrograms/mouse; 4-AP, 25-250 ng/mouse and TEA, 10-20 micrograms/mouse, i.c.v.), significantly modified the antinociception induced by U50,488H (8 mg kg-1, s.c.). 6. These results suggest that the opening of K+ channels is involved in the antinociceptive effect of alpha 2 and GABAB, but not kappa-opioid, receptor agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reversal of clonidine-induced hypotension by beta-adrenoceptor blocking drugs

The interaction between clonidine, propranolol and sotalol was investigated using conscious normotensive and spontaneously hypertensive rabbits as well as conscious normotensive and spontaneously hypertensive rats. Clonidine (20 micrograms/kg) administration into the marginal ear vein of rabbits produced persistent hypotension and bradycardia. In propranolol (0.5 mg/kg, i.v.)-pretreated animals, clonidine-induced hypotension was prevented. In rats, daily oral or subcutaneous clonidine as well as propranolol produced hypotension and bradycardia. Significant antagonism of the observed hypotensive effects resulted when clonidine was given to propranolol-pretreated animals or when propranolol was added to the treatment regimen of animals being maintained on clonidine. No antagonism between sotalol and clonidine was demonstrable. In view of the known central site of action of clonidine, and the failure of sotalol to antagonize clonidine-induced hypotension it would appear that the central nervous system is a possible site of the observed drug interaction.     

No evidence for central histamine-receptor involvement with the hypotensive effect of clonidine in cats

In conscious hypertensive cats, intraventricular (i.c.v.) administration of clonidine (25 μg), induced hypotension and bradycardia. Pretreatment with metiamide (2 mg i.c.v.) did not significantly antagonise either the hypotension or bradycardia induced by clonidine (25 μg), but induced marked behavioural changes. Central pretreatment with mepyramine (200 μg, i.c.v.) or procaine (600 μg i.c.v.), reduced the hypotension evoked by clonidine (25 μg), but no antagonism of the clonidine-induced bradycardia was apparent. Central phentolamine (200 μg, i.c.v.) or tolazoline (200 μg, i.c.v.) antagonised the hypotension and bradycardia evoked by i.c.v. clonidine.     

Evidence for a central alpha-sympathomimetic action of clonidine in the rat.

The antihypertensive effects of clonidine (0.15 mg kg-1, i.p.) were studied in conscious DOCA/saline hypertensive rats having chronically implanted arterial cannulae. The response to clonidine was markedly reduced by simultaneously administered desipramine (3 mg kg-1, i.p.), antagonized dose-dependently by piperoxan (2-10 mg kg-1, i.v.) and prevented by pretreatment with phentolamine (0.2 mg, i.c.v.). Pretreatment with 6-hydroxydopamine (3 x 250 mu-g, i.c.v.), haloperidol (1 mg kg-1, i.p.), p-chloro-N-methylamphetamine (3.5 mg kg-1, i.p.) or 5,6-dihydroxytryptamine (50 mu-g and 25 mu-g, i.c.v.) did not significantly modify the antihypertensive response. It is concluded that the antihypertensive response to clonidine is mediated via stimulation of central alpha-adrenoceptors and is independent of central dopaminergic receptors and intact central serotoninergic neurons. The necessity for intact central noradrenergic neurons remains uncertain.     

Inhibition of sympathetic hypertensive responses in the guinea-pig by prejunctional histamine H3-receptors.

1. The effect of (R)-alpha-methylhistamine, a selective H3-histamine receptor agonist, was examined on the neurogenic hypertension and tachycardia that is induced by stimulation of areas in the medulla oblongata of guinea-pigs. Electrical medullary stimulation (32 Hz, 3-5 s trains, 0.5-1.0 ms square pulse, 25-400 microA) produced intensity-dependent increases in blood pressure and a more variable tachycardia. 2. (R)-alpha-methylhistamine inhibited the hypertension and tachycardia due to submaximal CNS stimulation. The inhibition of hypertension by (R)-alpha-methylhistamine was dose-dependent (10-300 micrograms kg-1, i.v.) and was not seen at high intensities of stimulation. 3. (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) did not attenuate the pressor response to adrenaline (1 and 3 micrograms kg-1, i.v.), indicating that the effect of (R)-alpha-methylhistamine was not mediated by a postjunctional action on smooth muscle. 4. The inhibition of CNS-induced hypertension by (R)-alpha-methylhistamine (300 micrograms kg-1, i.v.) was blocked by the H3 antagonists, thioperamide (ID50 = 0.39 mg kg-1, i.v.), impromidine (ID50 = 0.22 mg kg-1, i.v.) and burimamide (ID50 = 6 mg kg-1, i.v.). The rank order potency of these antagonists is consistent with activity at the H3B receptor subtype. Chlorpheniramine (30 micrograms kg-1, i.v.) and cimetidine (3 mg kg-1, i.v.) did not antagonize the inhibition of CNS-hypertension by (R)-alpha-methylhistamine. 5. These results suggest that (R)-alpha-methylhistamine inhibits sympathetic hypertensive responses in guinea-pigs by activation of prejunctional H3-receptors, possibly located on postganglionic nerve terminals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduction by phentolamine of the hypotensive effect of methionine enkephalin in anaesthetized rabbits.

In intact rabbits anaesthetized with pentobarbitone, methionine enkephalin (Met enkephalin, 1-1,000 micrograms kg-1 i.v.) produced a dose-dependent bradycardia and hypotension. The bradycardia and hypotension were antagonized by naloxone hydrochloride (1 mg kg-1), but not by naloxone methobromide (1.3 mg kg-1). Phentolamine (1 and 4 mg kg-1 i.v.) blocked both the hypotension and bradycardia produced by Met enkephalin. The inhibitory effect of phentolamine was not due to a simple hypotensive action of this drug per se because a similar degree of hypotension induced by nitroprusside (15 micrograms kg-1, i.v.) caused a further reduction of pressure when Met enkephalin was added. Atropine (2 mg kg-1) reduced the bradycardia but not the hypotensive response to Met enkephalin. Met enkephalin did not antagonize the vasopressor effect of exogenous noradrenaline (2-8 micrograms kg-1, i.v.). Met enkephalin had no significant effects in superfused thoracic aortic strips and in isolated perfused hearts of rabbits. It is concluded that the cardiovascular effects of Met enkephalin are more probably due to an action on the central nervous system, although a peripheral site of action cannot be completely excluded.     

Central cardiovascular action of penicillin in anaesthetized dogs and rats

Penicillin (2-3 mg X kg-1) administered into the cisterna magna (i.c.) of dogs anaesthetized with alpha-chloralose induced a significant increase in mean blood pressure (MBP) and bradycardia, whereas intravenous injections of the same doses had negligible effects. Moreover, dogs receiving central injections of penicillin showed seizures abolished by administration of decamethonium bromide (100 micrograms X kg-1, i.v.). In urethane anaesthetized rats, intracerebroventricular (i.c.v.) injections of penicillin (0.3-3 mg X kg-1) caused dose-dependent increases in mean blood pressure while the intravenous route led to opposite effects. gamma-aminobutyric acid (GABA) (1 mg X kg-1), its agonist muscimol (2 micrograms X kg-1) and the alpha 2-adrenoceptor agonist clonidine (1 micrograms X kg-1) injected intracisternally induced hypotension and bradycardia in dogs. These effects were abolished in animals pretreated with penicillin. In rats, the same agents injected intraventricularly respectively at 0.5 mg X kg-1, 0.5 micrograms X kg-1 induced also hypotension. The effect of clonidine only, was antagonized by pretreatment with penicillin, while penicillin administered at the peak of the hypotensive effect caused by GABA or muscimol reversed it. It is suggested that penicillin acts centrally as a GABA-antagonist, and that the cardiovascular effects of clonidine seem to be mediated, at least in part, by the stimulation of a GABAergic pathway controlling the autonomic nervous system.     

Production by R-alpha-methylhistamine of a histamine H3 receptor-mediated decrease in basal vascular resistance in guinea-pigs.

1. The effect of the selective histamine H3 receptor agonist, R-alpha-methylhistamine given intravenously (10-100 micrograms kg-1) was examined on baseline total peripheral resistance (TPR), and cardiovascular haemodynamics in bilaterally vagotomized, anaesthetized guinea-pigs. 2. R-alpha-methylhistamine produced a dose-dependent hypotension and fall in TPR at 30 and 100 micrograms kg-1. A decrease in heart rate (HR) was observed at a dose of 100 micrograms kg-1. R-alpha-methylhistamine (10-100 micrograms kg-1) also produced a dose-dependent fall in rate pressure product (RPP). There was no effect on cardiac output (CO) or stroke volume (SV) at these doses. 3. Histamine H1 and H2 blockade in animals pretreated with a combination of chlorpheniramine (0.3 mg kg-1) and cimetidine (3.0 mg kg-1) did not alter the haemodynamic actions of R-alpha-methyl-histamine (100 micrograms kg-1, i.v.). Pretreatment with the selective H3 antagonist, thioperamide (1 mg kg-1), completely blocked the action of R-alpha-methylhistamine on haemodynamic parameters. 4. To study the mechanism of action of R-alpha-methylhistamine, the vasodilator hydralazine (1 mg kg-1, i.v.) was used. Hydralazine lowered BP, TRP and RPP in guinea-pigs pretreated with ipratropium (50 micrograms kg-1, i.v.). Hydralazine had no effect on HR, SV or CO. 5. R-alpha-methylhistamine (100 micrograms kg-1) did not affect the vasopressor action and increases in TPR produced by adrenaline (1 and 3 micrograms kg-1). On the other hand, the vasodilator hydralazine (1 mg kg-1, i.v.) inhibited the effects of adrenaline (3 micrograms kg-1) on TPR and RPP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Furosemide inhibits the centrally-mediated pressor response to clonidine in conscious, normotensive rats.

1. The effect of furosemide on the pressor response induced by intracerebroventricular (i.c.v.) injection of clonidine was investigated in freely moving, normotensive rats with chronically implanted arterial catheters. 2. When injected i.c.v., clonidine at doses of 5 and 10 micrograms produced a dose-dependent pressor response and a decrease in heart rate. No depressor response was induced by clonidine. 3. Systemic (i.v.) pretreatment with furosemide (2-10 mg kg-1) increased urine volume and dose-dependently inhibited the pressor response to i.c.v. clonidine (10 micrograms), and a long-lasting depressor response to clonidine was observed. However, furosemide treatment did not alter the bradycardia produced in response to clonidine. 4. The systemic treatment with furosemide (10 mg kg-1, i.v.) had no effect on the pressor response to i.v. noradrenaline. 5. These results suggest that reduction of body fluid volume inhibits the centrally-mediated pressor response to clonidine and leads to the hypotensive effect. We also suggest that combined treatment with a diuretic increases the hypotensive efficacy of clonidine.     

Involvement of central dopamine receptors in the hypotensive action of pergolide

The involvement of central dopamine receptors in the hypotensive action of the dopaminergic ergoline, pergolide was determined in anesthetized rats. Intravenous (i.v.) or intracerebroventricular (i.v.t.) administration of pergolide (12.5, 25 and 50 micrograms/kg) produced dose-dependent decreases in blood pressure. The magnitude of hypotension seen following either i.v. or i.v.t. administration of pergolide was similar. However, while both sulpiride (1 mg/kg, i.v.) as well as phentolamine (1 mg/kg, i.v.) antagonized the hypotensive action of i.v. pergolide, only sulpiride (1 mg/kg, i.v.t.) was able to antagonize the hypotension seen following i.v.t. administration of pergolide. Phentolamine (1 mg/kg, i.v.t.) did not alter the central hypotensive action of pergolide. In a separate group of rats, clonidine (25 micrograms/kg, i.v.t.) also produced a decrease in blood pressure. While phentolamine (i.v.t.) antagonized the central hypotensive action of clonidine, sulpiride (i.v.t.) did not have any effect on the action of clonidine. These results show that selective activation of central dopamine receptors was responsible for the hypotensive action of centrally-administered pergolide. In a separate group of rats greater splanchnic sympathetic nerve activity was measured. Intravenous pergolide produced similar hypotensive response as seen in previous groups, and this was accompanied by a concomitant decrease in the sympathetic nerve activity. The maximum fall in blood pressure (26 +/- 6 mm Hg) was correlated with a 40% reduction in sympathetic nerve activity. The return of blood pressure to control levels occurred after 60-70 min and was also associated with the return of sympathetic nerve activity to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation by central postsynaptic alpha 2-adrenoceptors of the jaw-opening reflex induced by orofacial stimulation in rats.

1. The modulation by alpha 2-adrenoceptors of the jaw-opening reflex (digastric electromyographic responses) elicited by orofacial electrical stimulation (OF-JOR) in pentobarbitone anaesthetized rats was investigated. 2. Increasing doses of clonidine (0.1-1000 micrograms kg-1, i.v.) reduced, in a dose-dependent manner until abolition, the amplitude and duration of the OF-JOR and increased the latency to onset. The sum of amplitudes of the reflex was the most sensitive parameter to the inhibitory effects of clonidine (ED50 = 13.9 micrograms kg-1). 3. Pretreatment with the alpha 2-adrenoceptor antagonist, idazoxan (0.03-1 mg kg-1, i.v.), caused a dose-dependent shift (1.5 to 37 fold) to the right of the dose-response curve for clonidine without significant change of maximum inhibitory effect, in a manner compatible with competitive antagonism (ED50B = 29.0 micrograms kg-1). Pretreatment with yohimbine (0.3 mg kg-1, i.v.) also antagonized the inhibitory effect of clonidine on the OF-JOR. In contrast, the alpha 2-adrenoceptor antagonist ARC-239 (0.3 mg kg-1, i.v.) did not antagonize the effect of clonidine on the reflex. 4. In rats pretreated with reserpine (5 mg kg-1, s.c., 18 h) the OF-JOR was not modified, but the potency of clonidine in inhibiting the reflex was potentiated (ED50 value decreased to 6.8 micrograms kg-1) without a significant change of maximum inhibitory effect. 5. Increasing doses of amphetamine (0.1-3000 micrograms kg-1, i.v.) caused a dose-related, but partial, inhibition of the OF-JOR (ED50 = 135 micrograms kg-1; Emax = 67%).(ABSTRACT TRUNCATED AT 250 WORDS)     

Captopril potentiates the vasodepressor action of Met-enkephalin in the anaesthetized rat

The transient vasodepressor action of Met-enkephalin (10-80 micrograms kg-1, i.v.) in anaesthetized rats was significantly potentiated by the angiotensin-converting enzyme inhibitor, captopril (2 mg kg-1, i.v.); at this dose, it failed to modify the transient vasodepressor action of the non-specific vasodilator, nitroprusside (2.5, 5.0, 10 micrograms kg-1, i.v.). Captopril (2 mg kg-1, i.v.) caused a slow, progressive fall in the blood pressure of anaesthetized spontaneously hypertensive (SH) rats when compared to vehicle-treated controls. Pretreatment with naloxone (1.5 mg kg-1, i.v.) 30 min earlier failed to alter significantly the hypotensive action of captopril in anaesthetized SH rats. It was concluded that although captopril potentiated the vasodepressor action of Met-enkephalin in anaesthetized normotensive rats, potentiation of endogenous opioids does not appear to be involved in the hypotensive action of captopril in anaesthetized SH rats.     

The effect of cyclic AMP elevating agents on bradykinin- and carbachol-induced signal transduction in canine cultured tracheal smooth muscle cells.

1. The effects of the beta 2-adrenoceptor agonist, procaterol, on sympathetic neuroeffector transmission were studied in the pithed adrenal demedullated rat to determine if generation of angiotensin II was involved in its effect. Pressor responses were elicited by either electrical stimulation (20 V, 2 Hz) of the entire spinal sympathetic outflow or methoxamine (0.1 mg kg-1, i.v.). 2. Sodium nitroprusside (3 and 5 micrograms kg-1 min-1, i.v.) produced hypotension and the pressor responses to both sympathetic nerve stimulation and methoxamine were reduced. This indicates that decreasing blood pressure in pithed rats reduces pressor responses. Procaterol (10 and 30 ng kg-1 min-1, i.v.) also produced hypotension but did not alter pressor responses to sympathetic nerve stimulation. Nevertheless, procaterol (10 and 30 ng kg-1 min-1, i.v.) did reduce pressor responses to to methoxamine. Together these results suggest that procaterol may have enhanced sympathetic neurotransmitter release. This was confirmed in another series of experiments where procaterol (30 ng kg-1 min-1, i.v.) increased plasma noradrenaline levels during sympathetic nerve stimulation. 3. Captopril (5 mg kg-1, i.v.) produced hypotension and as expected reduced pressor responses to sympathetic nerve stimulation. When the hypotensive effect of captopril was abolished by concomitant vasopressin infusion (1.5-4.5 i mu kg-1 min-1, i.v.), pressor responses to sympathetic nerve stimulation were restored to pre-captopril levels. (ABSTRACT TRUNCATED AT 250 WORDS)     

Thromboxane-mimetic U46619 causes depressor responses in anaesthetized rats.

Intravenous (i.v.) or intra-arterial injections of U46619, a thromboxane A2 (TxA2)-mimetic agent, into chloralose-anaesthetized rats dose-dependently decreased the arterial blood pressure. Indomethacin (8 mg kg-1) or atropine (1 mg kg-1), given i.v. 30 min beforehand, attenuated the hypotensive effect of U46619 i.v. whereas methysergide pretreatment (5 mg kg-1 i.v.) was without action. Pretreatment with AH23848 (5 mg kg-1 i.v.), a specific TxA2-receptor antagonist, completely abolished the depressor responses to U46619. The findings suggest that the vasodepressor effect of U46619 appears to be mediated via TxA2-receptor activation, with the release of prostacyclin and/or acetylcholine both of which produce vasodilatation.     

Mediation of the hypotensive action of systemic clonidine in the rat by alpha 2-adrenoceptors.

1. During the past few years it has been shown that the sympatholytic effect resulting from localized microinjection of clonidine and other imidazolines into the rostral ventrolateral medulla (RVL) results from activation of 'imidazoline' receptors (I1 receptors) rather than from an alpha 2-adrenoceptor-mediated effect. 2. The relative contributions of these two receptor systems to the hypotensive action of systemically administered clonidine have not been studied. Clonidine has affinity for both I1 and alpha 2-adrenoceptors; guanabenz represents a useful pharmacological tool, since it activates only the alpha 2-adrenoceptor. 3. Antagonists acting at both I1 and alpha 2-adrenoceptors (idazoxan) and at only alpha 2-adrenoceptors (SK&F 86466; 6-chloro-3-methyl-2,3,4,5-tetrahydro-3-benzazepine) are available. Idazoxan (1 mg kg-1, i.v.) and SK&F 86466 (3 mg kg-1, i.v.) produced an equivalent degree of blockade of the pressor response to guanabenz or clonidine in the pithed rat, a response mediated by the alpha 2-adrenoceptor. 4. Guanabenz (30 micrograms kg-1, i.v.) and clonidine (10 micrograms kg-1, i.v.) lowered blood pressure in the chloralose-anaesthetized spontaneously hypertensive rat by 48 +/- 4.6 mmHg and 44 +/- 5.4 mmHg, respectively; this response, for either agonist, was blocked by both idazoxan and SK&F 86466. 5. These data show that the hypotensive effect of intravenously administered clonidine results from activation of central alpha 2-adrenoceptors, with no significant contribution from an I1-mediated effect. Thus clonidine can lower blood pressure by different receptor mechanisms, dependent on the route of administration.     

2-Chloroadenosine induction of vagally-mediated and atropine-resistant bronchomotor responses in anaesthetized guinea-pigs.

1. The bronchoconstrictor effects of intravenous administration of adenosine derivatives in anaesthetized non-curarized guinea-pigs have been studied. 2. 2-Chloroadenosine (2-Cl-Ade), 5'-N-ethylcarboxamideadenosine (NECA) and L-N6-phenylisopropyl-adenosine (L-PIA) all produced dose-dependent, transient increases in tracheal insufflation pressure, with an order of potency (NECA greater than or equal to 2-Cl-Ade much greater than L-PIA) typical of A2-receptor mediated biological responses. 3. 2-Chloradenosine-induced bronchoconstrictor responses disappeared after vagotomy or topical application of tetrodotoxin (TTX) on cervical vagal trunks. 4. 2-Chloradenosine-induced bronchospasm was unaffected by atropine (1 mg kg-1 i.v.), physostigmine (50 micrograms kg-1 i.v.) and hexamethonium (30 mg kg-1 i.v.) but was significantly reduced by theophylline (25 mg kg-1 i.v.). 5. The magnitude of 2-Cl-Ade-induced bronchospasm was significantly reduced by acute (10 micrograms kg-1 i.v.) or chronic (55 mgkg-1 s.c. four days before the experiment) pretreatment with capsaicin. 6. Guanethidine (20 mg kg-1 s.c on two consecutive days), prazosin (10 micrograms kg-1 i.v.), diphenhydramine (1 mg kg-1 i.v.) and indomethacin (1 mg kg-1 i.v.) failed to block the bronchomotor response to 2-Cl-Ade. In contrast, cyproheptadine (1-5 mgkg-1 i.v.) markedly reduced, but did not abolish the bronchospasm elicited by the purine derivative. 7. We conclude that in anaesthetized non-curarized guinea-pigs, a transient vagally-mediated bronchospasm can be induced by stimulation of A2-purinoceptors. This effect is complex and involves, at least in part, stimulation of capsaicin-sensitive sensory nerves and 5-hydroxytryptamine release.(ABSTRACT TRUNCATED AT 250 WORDS)