Sympathoinhibitory effects of rilmenidine may be mediated by sites located below the brainstem.

1. To determine the site of action of rilmenidine, we examined its effets on arterial blood pressure (BP), heart rate (HR) and postganglionic renal sympathetic nerve activity (RSNA) after intracerebroventricular (i.c.v.) administration (300 micrograms kg-1), in groups (all n = 6) of conscious and freely moving, pentobarbitone-anaesthetized and pentobarbitone-anaesthetized and spinally transected, fifteen week-old male spontaneously hypertensive rats (SHRs). 2. In conscious SHRs, which exhibited a low sympathetic nerve activity (RSNA: 3.4 +/- 0.9 muV), rilmenidine was inactive on systolic BP (SBP), diastolic BP (DBP), HR and RSNA. 3. In intact pentobarbitone-anaesthetized SHRs, which exhibited an elevated sympathetic nerve activity (RSNA: 10.6 +/- 0.9 muV), rilmenidine exerted potent antihypertensive (delta SBP: -37 +/- 4%; delta DBP: -43 +/- 6%), bradycardic (delta HR: -32 +/- 3%) and sympathoinhibitory (delta RSNA: -68 +/- 9%) activities. 4. In pentobarbitone-anaesthetized SHRs with cervical spinal cord transection, BP was markedly decreased and sympathetic nerve activity (RSNA: 10.3 +/- 3.1 muV) returned to the level observed in conscious SHRs (RSNA: 3.6 +/- 0.5 muV). In these conditions, rilmenidine remained sympathoinhibitory (delta RSNA: -74 +/- 5%). 5. In conclusion, we have shown that pentobarbitone-anaesthesia enhances the peripheral sympathetic tone by a central action, as the spinal cord transection allows RSNA to return to normal levels and that, spinal or ganglionic structures could be a major site of the sympathoinhibitory action of rilmenidine.     

CARDIOVASCULAR EFFECTS OF RILMENIDINE, A NEW α2-ADRENOCEPTOR AGONIST, AND CLONIDINE IN CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS

1. The acute and chronic effects of rilmenidine, a partial agonist of alpha 1- and alpha 2-adrenoceptors with antihypertensive properties, were compared to those of clonidine on blood pressure (BP), heart rate (HR) and the urinary excretion of catecholamines, which was used as an index of sympathetic activity. 2. As these drugs are known to interfere centrally and peripherally with the sympathetic nervous system, long-term arterial blood pressure recordings in freely moving unstressed adult spontaneously hypertensive rats (SHR) were used. 3. Acute i.v. administrations of rilmenidine (0.3 mg/kg at 1200 h, 1.2 mg/kg at 1700 and 2200 h) and clonidine (12 micrograms/kg at 1200 h, 50 micrograms/kg at 1700 and 2200 h) induced short-lasting increases in BP associated with a decrease in HR, which were followed by prolonged, dose-dependent decreases in BP without bradycardia. The pressor effect was less marked and the associated bradycardia was more marked in active SHR with physiologically high sympathetic activity than in resting SHR. 4. A 12-day oral treatment with rilmenidine (6.0 mg/kg daily) or clonidine (150 micrograms/kg daily) induced moderate decreases in BP without change in HR. Rilmenidine but not clonidine decreased normetanephrine (NMN) excretion in active but not in resting SHR. 5. Finally, during the 24 h following the cessation of the treatments, BP returned to normal, without significantly exceeding that of untreated controls. However, upswings in BP or HR were observed, more markedly and frequently after clonidine than after rilmenidine. 6. In conclusion the effects of alpha 2-adrenoceptor agonists appear to be influenced by the pre-existing sympathetic tone. The general agreement between these data and those observed in patients demonstrates that the use of conscious unstressed animals is of value to determine the cardiovascular effects of drugs which act on the sympathetic nervous system.     

The pressor response to central administration of beta-endorphin results from a centrally mediated increase in noradrenaline release and adrenaline secretion.

1. The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of beta-endorphin (0.01, 0.1 and 1.0 nmol kg-1) were examined in conscious rabbits. 2. After i.c.v. beta-endorphin, mean arterial pressure (MAP) increased, heart rate (HR) fell, plasma noradrenaline, adrenaline and glucose increased and there was a rise in PaCO2 and fall in PaO2; these effects were reversed by intravenous (i.v.) naloxone (300 nmol kg-1). 3. A combination of prazosin (2 mg kg-1) and yohimbine (1 mg kg-1), given i.v., prevented the rise in MAP induced by i.c.v. beta-endorphin. 4. After i.c. beta-endorphin, MAP, HR and plasma catecholamines were not significantly altered but there was a similar degree of respiratory depression. 5. Clonidine (1.0 micrograms kg-1, i.c.) reduced MAP and HR; these effects were not blocked by i.v. naloxone (6 mumol kg-1). 6. These results demonstrate that beta-endorphin acts centrally, probably mainly on periventricular mu-opioid receptors, to increase adrenaline secretion and sympathetic nerve activity leading to alpha-adrenoceptor-mediated vasoconstriction. The respiratory depression is probably mediated by brainstem mu-receptors. 7. A role for beta-endorphin in the central hypotensive action of alpha 2-adrenoceptor agonists was opposed by finding that opioid receptor antagonism with naloxone did not block the effects of clonidine.     

Antiarrhythmic action of rilmenidine on adrenaline-induced arrhythmia via central imidazoline receptors in halothane-anaesthetized dogs.

1. To elucidate the role of central imidazoline receptors in the genesis of adrenaline-induced arrhythmias under halothane anaesthesia, we investigated the effects of rilmenidine, a selective agonist at imidazoline receptors, on this type of arrhythmia in dogs. Rilmenidine (1, 3, 10 micrograms kg-1, i.v.) did not affect basal haemodynamic parameters (heart rate and blood pressure), but dose-dependently inhibited adrenaline-induced arrhythmias under halothane anaesthesia. 2. Although, rilmenidine has a weak affinity for alpha(2)-adrenoceptors, pretreatment with idazoxan (10 micrograms kg-1, intracisternally i.c.), an imidazoline receptor antagonist which has also alpha(2)-adrenoceptor blocking potency, blocked the antiarrhythmic effect of rilmenidine (10 micrograms kg-1, i.v.). In contrast, pretreatment with rauwolscine (20 micrograms kg-1, i.c.), a classical alpha(2)-adrenoceptor antagonist with little affinity for imidazoline receptors, did not affect the effect of rilmenidine (10 micrograms kg-1, i.v.). Furthermore, bilateral vagotomy completely blocked the antiarrhythmic action of rilmenidine (10 micrograms kg-1, i.v.). 3. It is suggested that the antiarrhythmic action of rilmenidine is due to the activation of central imidazoline receptors and that vagal tone is critical for this action of rilmenidine.     

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.     

Importance of central noradrenergic and serotonergic pathways in the cardiovascular actions of rilmenidine and clonidine.

We examined the role of central monoamine neurotransmitters noradrenaline and serotonin in the cardiovascular actions of the alpha 2-adrenoceptor agonist rilmenidine in the conscious rabbit and compared it to clonidine. Rilmenidine and clonidine were equieffective in producing a maximum 24% reduction in blood pressure and heart rate when given intracisternally (i.c.), but rilmenidine was approximately 20-30 times less potent than clonidine. The effective i.c. doses of both drugs were 25-30 times lower than those required peripherally (i.v.). Comparison of the time course of an equieffective dose of rilmenidine and clonidine showed that the time to reach maximum effect was 10 min for both drugs but time to recovery was greater for rilmenidine (2.5-3 h vs. 1.5 h for clonidine). Destruction of central noradrenergic neuron pathways with i.c. 6-hydroxydopamine attenuated the hypotensive and bradycardic actions of both rilmenidine and clonidine at 2, 4, and 8 weeks after treatment. The maximum observed attenuation of the hypotension was at 8 weeks (40% of control for rilmenidine and 29% for clonidine), while for the bradycardia this was at 2 weeks (9 and 2% of control, respectively) with some recovery by 8 weeks (29 and 50% of control). Destruction of the central serotonergic neurons with i.c. 5,6-dihydroxytryptamine also attenuated the hypotension and bradycardia to rilmenidine and clonidine but was slower in onset, needing the full 8 weeks to reach its maximum effect. At this time the hypotension and bradycardia to rilmenidine and clonidine were reduced to between 35 and 48% of control.(ABSTRACT TRUNCATED AT 250 WORDS)     

Investigation of the mechanism(s) of 8-OH-DPAT-mediated inhibition of plasma insulin in spontaneously hypertensive rats.

1. Effects of the prototype selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-dipropylamino)tetralin (8-OH-DPAT), were studied on the glycaemia and insulinaemia in conscious spontaneously hypertensive (SH) rats concurrently with blood pressure (BP) and heart rate (HR); underlying mechanism(s) were investigated in anaesthetized and pithed SH rats and in the perfused rat pancreas. 2. Intravenous (i.v.) injections of 8-OH-DPAT (150 micrograms kg-1, i.v.) into fasted conscious but not anesthetized SH rats increased glycaemia; glucose-stimulated (i.v. glucose tolerance test) plasma insulin levels were significantly inhibited in both cases without significant changes in glucose tolerance. Metabolic changes were associated with prominent decreases in BP and HR. 3. No inhibitory effect of 8-OH-DPAT, 150 micrograms kg-1 i.v., on glucose-stimulated plasma insulin was observed in pithed SH rats; in contrast, clonidine (8 micrograms kg-1 i.v.), produced marked inhibition of insulin levels in association with glucose intolerance. Neither compound decreased BP; rather, pronounced vasopressor effects were observed. 4. In the isolated perfused pancreas of the rat, 8-OH-DPAT, at 10(-8) and 10(-7) M, concentrations known to activate 5-HT1A receptors in vitro, failed to modify glucose-stimulated insulin release. Inhibition (39 +/- 7%) was seen only at a high concentration of 10(-6) M. 5. The present data suggest that like the cardiovascular effects of 8-OH-DPAT, the inhibition of glucose-stimulated insulin release is mediated via the central nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Haemodynamic and abdominal motor reflexes elicited by neurotensin in anaesthetized guinea-pigs.

1. Single intraperitoneal (i.p.) injections of neurotensin (NT) (0.14- 140 nmol kg-1) in anaesthetized guinea-pigs were found to trigger transient abdominal wall contractions (TAWC) accompanied by relatively sustained increases of systemic blood pressure (BP) and heart rate (HR). The modification of the latter NT effects by various drugs and surgical manipulations was examined to obtain some insight into the nature of, and possible relationship between, these responses. 2. The abdominal motor response (i.e. TAWC) to i.p. NT (14 nmol kg-1) was inhibited by prior i.v. injection of the guinea-pigs with pancuronium (0.27 mumol kg-1), morphine (1.5 and 15 mumol kg-1), clonidine (0.34 mumol kg-1), by concomitant i.p. injection of procaine 2% w/v, or by acute spinalization. It was potentiated by naloxone (2.8 and 28 mumol kg-1), but not affected by i.v. injection of autonomic drugs (i.e. pentolinium, prazosin, yohimbine and atropine), by capsaicin desensitization, or by acute bilateral cervical vagotomy. In spinalized animals a sustained abdominal wall contraction (SAWC) was unmasked, which was resistant to i.v. morphine, clonidine or baclofen but suppressed by i.v. pancuronium or i.p. lignocaine 2% w/v. 3. Haemodynamic responses to i.p. NT were not affected by i.v. pancuronium, morphine, naloxone, atropine, or by vagotomy. They were inhibited by i.v. pentolinium or clonidine (BP, HR), i.v. prazosin (BP), i.p. procaine 2% w/v (BP, HR), capsaicin desensitization or acute spinalization (BP, HR). Yohimbine (i.v.) potentiated BP and HR increases caused by i.p. NT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor transgenic mice

1. We investigated the cardiovascular effects of rilmenidine, moxonidine and clonidine in conscious wild-type and D79N alpha2A-adrenoceptor mice. The in vitro pharmacology of these agonists was determined at recombinant (human) alpha2-adrenoceptors and at endogenous (dog) alpha2A-adrenoceptors. 2. In wild-type mice, rilmenidine, moxonidine (100, 300 and 1000 microg kg(-1), i.v.) and clonidine (30, 100 and 300 microg kg(-1), i.v.) dose-dependently decreased blood pressure and heart rate. 3. In D79N alpha2A-adrenoceptor mice, responses to rilmenidine and moxonidine did not differ from vehicle control. Clonidine-induced hypotension was absent, but dose-dependent hypertension and bradycardia were observed. 4. In wild-type mice, responses to moxonidine (1 mg kg(-1), i.v.) were antagonized by the non-selective, non-imidazoline alpha2-adrenoceptor antagonist, RS-79948-197 (1 mg kg(-1), i.v.). 5. Affinity estimates (pKi) at human alpha2A-, alpha2B- and alpha2C-adrenoceptors, respectively, were: rilmenidine (5.80, 5.76 and 5.33), moxonidine (5.37, <5 and <5) and clonidine (7.21, 7.16 and 6.87). In a [35S]-GTPgammaS incorporation assay, moxonidine and clonidine were alpha2A-adrenoceptor agonists (pEC50/intrinsic activity relative to noradrenaline): moxonidine (5.74/0.85) and clonidine (7.57/0.32). 6. In dog saphenous vein, concentration-dependent contractions were observed (pEC50/intrinsic activity relative to noradrenaline): rilmenidine (5.83/0.70), moxonidine (6.48/0.98) and clonidine (7.22/0.83). Agonist-independent affinities were obtained with RS-79948-197. 7. Thus, expression of alpha2A-adrenoceptors is a prerequisite for the cardiovascular effects of moxonidine and rilmenidine in conscious mice. There was no evidence of I1-imidazoline receptor-mediated effects. The ability of these compounds to act as alpha2A-adrenoceptor agonists in vitro supports this conclusion.     

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.     

Renal effects of infusion of rilmenidine and guanabenz in conscious dogs: contribution of peripheral and central nervous system alpha 2-adrenoceptors.

1. We tested the renal effects of the alpha 2-adrenoceptor agonists, rilmenidine and guanabenz and the antagonists, 2-methoxyidazoxan and idazoxan, in conscious dogs. Our aim was to test the hypothesis that putative imidazoline (I) receptors influence renal function. We reasoned that since rilmenidine and guanabenz are selective for I1- and I2-binding sites respectively, an influence of one of these receptive sites on renal function would be reflected in qualitative differences between the effects of these agents. Moreover, effects mediated by putative I-receptors should be relatively resistant to antagonism by the selective alpha 2-adrenoceptor antagonist, 2-methoxyidazoxan. Since the effects of these drugs on renal function could be mediated in the central nervous system or periphery, the dogs were studied under both normal and ganglion-blocked conditions. 2. In dogs with intact autonomic reflexes, 2-methoxyidazoxan (15 micrograms kg-1 plus 0.6 micrograms kg-1 min-1) produced effects consistent with a generalized increase in sympathetic drive, including increases in mean arterial pressure and plasma renin activity, and a reduction in sodium excretion. In ganglion-blocked dogs, 2-methoxyidazoxan reduced sodium excretion but had no discernible effect on systemic or renal haemodynamics. We conclude that an alpha 2-adrenoceptor-mediated mechanism in the central nervous system tonically inhibits sympathetic drive in the conscious dog. 3. In ganglion-blocked dogs idazoxan (3-300 micrograms kg-1) dose-dependently increased arterial pressure. This was not abolished by concomitant administration of 2-methoxyidazoxan (0.3-30 micrograms kg-1). The pressor effect of idazoxan is therefore probably mediated by an agonist action at alpha 1-adrenoceptors. 4. The effects of infusions of rilmenidine (0.1-1.0 mg kg-1) and guanabenz (10-100 micrograms kg-1) were indistinguishable. They comprised dose-dependent increases in mean arterial pressure, urine excretion, and glomerular filtration rate (the latter in ganglion blocked dogs only), and dose-dependent reductions in heart rate, renal blood flow and sodium excretion (only in dogs with intact autonomic reflexes). All of these effects were antagonized by 2-methoxyidazoxan. 5. We conclude that the renal effects of rilmenidine and guanabenz infusions in conscious dogs are predominantly, if not completely, attributable to activation of alpha 2-adrenoceptors. Our results do not support the hypothesis that putative I-receptors contribute towards the renal effects of these agents.     

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)     

The interaction of cimetidine with various antihypertensive agents in the spontaneously hypertensive rat

The H2-receptor antagonist cimetidine (250 micrograms) administered intracerebroventricularly (i.c.v.) 15 and 30 min before clonidine (25 micrograms kg-1 i.v.), significantly antagonized clonidine-induced hypotension in anaesthetized spontaneously hypertensive rats. The hypertensive response of cimetidine was correlated with the inhibition of clonidine-induced hypotension. In addition, cimetidine (250 micrograms i.c.v.) counteracted the hypotensive effects of pentolinium (5.0 mg kg-1 i.v.), guanethidine (5.0 mg kg-1 i.v.) and minoxidil (1.0 mg kg-1 i.v.) These data do not support previous suggestions that the hypotensive action of clonidine is caused by stimulation of the H2-receptor, but suggest that central administration of cimetidine causes peripheral vasoconstriction and this may offer resistance to the hypotensive action of different antihypertensive agents.     

Role of the sympathetic control of vascular resistance in ethanol-clonidine hemodynamic interaction in SHRs.

Our previous studies showed that ethanol selectively counteracts centrally mediated hypotensive responses. In this study, we investigated the role of sympathetic nerve activity, cardiac output (CO), and total peripheral resistance (TPR) in this antagonistic hemodynamic interaction between ethanol and clonidine. Changes in blood pressure (BP), heart rate (HR), CO, stroke volume (SV), and TPR elicited by intracisternal (i.c.) clonidine and subsequent ethanol or saline were evaluated in conscious freely moving spontaneously hypertensive rats (SHRs). Clonidine (0.5 microg, i.c.) evoked hypotension was due to a significant reduction in TPR (from 3.6+/-0.21 to 2.8+/-0.17 mm Hg/ml/min/100 g), which was associated with a significant (p < 0.05) reduction in plasma norepinephrine (NE, from 660+/-115 to 310+/-50 pg/ml), measured as index of sympathetic activity. Ethanol (1 g/kg, i.v.) counteracted the hypotensive effect of clonidine and produced significant (p < 0.05) increases in plasma NE and TPR. Further support for the hypothesis that ethanol selectively counteracts centrally mediated hypotension was sought by investigating the effect of ethanol on peripherally mediated hemodynamic responses to hydralazine. Hydralazine (0.4 mg/kg, i.v.) produced a hypotension similar in magnitude to that produced by clonidine, which was also due to a significant reduction in TPR. However, unlike the case with clonidine, reflex increases in HR, SV, and hence CO were evident. Ethanol given after hydralazine produced a short-lived pressor effect (<10 min vs. 60 min in case of clonidine) in spite of a sustained increase in TPR. The latter was offset by the simultaneous decreases in CO, SV, and HR. A 30% increase in plasma NE caused by hydralazine returned to baseline level after ethanol or saline. Blood ethanol concentrations were similar in all treatment groups. These findings suggest that ethanol selectively counteracts centrally evoked hypotensive responses by counteracting the sympathoinhibition-mediated decreases in TPR elicited by centrally administered clonidine in conscious SHRs.     

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.     

Haemodynamic effects of dicentrine, a novel alpha 1-adrenoceptor antagonist: comparison with prazosin in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

1. The haemodynamic effects of dicentrine, an aporphine derivative isolated from the plant Lindera megaphylla, were investigated and compared with prazosin in rats. 2. In anaesthetized normotensive Wistar-Kyoto (WKY) rats, i.v. administration of dicentrine (0.1, 0.5, 1.0 mg kg-1) and prazosin (0.01, 0.05, 0.1 mg kg-1) induced a dose-related reduction of mean arterial pressure (MAP) which reached a maximal effect 5-10 min after injection and persisted for 2 h. 3. In anaesthetized WKY rats, a higher dose of dicentrine (1.0 mg kg-1, i.v.) did not cause any significant changes in heart rate (HR), cardiac output (CO) and stroke volume (SV) but markedly increased tail blood flow. In contrast, a higher dose of prazosin (0.1 mg kg-1, i.v.) produced a decrease in HR which paralleled the time course of the hypotensive response. 4. The hypotensive activity of dicentrine was completely abolished by alpha-adrenoceptor blockade. Both dicentrine and prazosin significantly attenuated pressor responses to noradrenaline but failed, even at maximal hypotensive doses, to impair the pressor effects of angiotensin II or vasopressin. These observations suggest that dicentrine appears to exert its hypotensive action through alpha 1-adrenoceptor blockade. 5. In conscious normotensive and spontaneously hypertensive (SH) rats, dicentrine (0.5-2.0 mg kg-1, i.v.) and prazosin (0.05-0.2 mg kg-1, i.v.) also evoked dose-related decreases in MAP which were of greater magnitude in SH rats. Oral administration of dicentrine (5 and 8 mg kg-1) to conscious SH rats caused a hypotensive effect which persisted for over 15 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

An investigation into the selectivity of a novel series of benzoquinolizines for alpha 2-adrenoceptors in vivo.

The potencies and selectivities of a novel series of benzoquinolizines for the alpha 2-adrenoceptor have been investigated in the rat in comparison with yohimbine and indoramin. Peripheral postjunctional alpha 2- and alpha 1-adrenoceptor blockade was measured as the reversal of B-HT 933 and methoxamine-induced pressor responses, respectively, in the pithed rat. Peripheral prejunctional alpha 2-adrenoceptor blockade was measured as the reversal of B-HT 933-induced inhibition of an electrically evoked tachycardia in the pithed rat. Central alpha 2-adrenoceptor blockade was measured as a reversal of the hypotension induced in anaesthetized rats by central (i.c.v.) administration of clonidine. Wy 25309, Wy 26392, Wy 26703 and yohimbine (0.3-3 mg kg-1 i.v.) evoked dose-dependent shifts to the right of the dose-response curves to B-HT 933 whilst having minimal effects on the methoxamine dose-response curve. The selectivity for alpha 2-adrenoceptors increased with the dose of antagonist administered. In general, the order of selectivity was Wy 25309 greater than Wy 26392 greater than Wy 26703 greater than yohimbine. Indoramin (1 mg kg-1 i.v.) shifted the methoxamine pressor dose-response curve to the right without affecting the B-HT 933 dose-response curves, confirming its selective alpha 1-antagonist activity. Peripheral administration of all three benzoquinolizines (1-100 micrograms kg-1 i.v.) led to a dose-dependent reversal of the hypotension evoked by central administration of clonidine (500 ng i.c.v.). The reversal was incomplete, higher doses causing a further decrease in blood pressure. (ABSTRACT TRUNCATED AT 250 WORDS)     

UK-52,046 (a novel alpha 1-adrenoceptor antagonist) and the role of alpha-adrenoceptor stimulation and blockade on atrioventricular conduction.

The effects of increasing intravenous (i.v.) doses of prazosin, phenylephrine, flecainide, and UK-52,046 on blood pressure (BP), heart rate (HR) and the specialized conduction system (AH and HV intervals) were investigated in anaesthetized dogs. Results indicated that UK-52,046 (1-8 micrograms/kg) had no effect on BP or HR, but reduced (p less than 0.05) BP at doses of 16 and 32 micrograms/kg; no change occurred in HR. During sinus rhythm (SR) the AH or HV intervals did not change as compared with placebo; on pacing (PA) UK-52,046 (4-16 micrograms/kg) decreased the AH interval. After prazosin BP decreased (p less than 0.05) after 20-40 micrograms/kg; HR increased after all doses (5-40 micrograms/kg). The HV interval was unaltered, but the AH interval decreased after 40 micrograms/kg during SR and PA. After phenylephrine (continuous infusion, 50 micrograms/ml/min) BP increased at 33 min and HR was decreased at 23 and 33 min. The AH interval lengthened during PA (p less than 0.05), but there was no effect on the HV interval. Administration of flecainide (0.5-2.0 mg/kg) had no effect on BP or HR but increased the HV interval during SR and PA (1 and 2 mg/kg, p less than 0.05). The results indicate that the alpha 1-adrenoceptor agonist phenylephrine and the alpha 1-adrenoceptor antagonist prazosin, on PA altered the AH (but not the HV) intervals in opposite directions in association with changes in HR and BP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of CH-38083, a selective antagonist of alpha 2-adrenoceptors, on renal sympathetic function

The effects of 7,8-(methylenedioxi)-14-alpha-hydroxyalloberbane HCl (CH-38083), a structurally new, selective and potent alpha 2-adrenoceptor antagonist, and of idazoxan, were studied on both the spontaneous activity of the postganglionic sympathetic renal nerve and on the clonidine- or xylazine-induced inhibitory action in anaesthetized cats. The drug CH-38083 (30-200 micrograms/kg, i.v.) caused a sustained increase of the sympathetic activity and blood pressure. Larger doses of idazoxan (200-500 micrograms/kg, i.v.) were needed to induce similar effects. Both antagonists were effective in antagonizing the sympatho-inhibitory effect of clonidine or xylazine. The excitatory response to selective alpha 2-adrenoceptor antagonists suggests that the sympathetic output undergoes tonic inhibition due to a permanent alpha 2-adrenoceptor stimulation.