The role of the sympathetic nervous system in the cardiovascular responses to angiotensin in the pithed rat

1. Angiotensin (200-500 ng, intravenously) produced a biphasic pressor response accompanied by reflex bradycardia in rats anaesthetized with sodium pentobarbitone. In pithed rats and in anaesthetized animals treated with a ganglion blocking agent there was a similar pressor response but an increase in the heart rate which was coincident with the second phase of the pressor response. In pithed preparations an increase in cardiac contractile force accompanied the heart rate changes.2. Acute or chronic adrenalectomy did not alter the pressor responses and chronotropic effect of angiotensin in the pithed rat. Propranolol abolished the chronotropic and inotropic action of angiotensin, but left the biphasic pressor response unaltered. Bethanidine, or pretreatment with reserpine, altered the pressor response to a simple rise, and also abolished the chronotropic action of angiotensin. Phentolamine also abolished the second pressor component. Desmethylimipramine produced a marked potentiation of the cardiovascular effects of angiotensin at all dose levels tested (10-500 ng).3. It is concluded that in the rat only large doses of angiotensin are capable of indirectly stimulating the sympathetic nerves either at the site of their ganglionic cells or their post-ganglionic nerve ending.     

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.     

alpha 1-adrenoceptor activation can increase heart rate directly or decrease it indirectly through parasympathetic activation.

1 The chronotropic effects of alpha- and beta-adrenoceptor agonists were investigated in the pithed rat. 2 The beta-adrenoceptor agonist, isoprenaline, produced only a positive chronotropic response. alpha 1-Adrenoceptor agonists, phenylephrine and amidephrine, produced positive and negative chronotropic effects. Part of the response to phenylephrine was beta-mediated. 3 A positive chronotropic response to amidephrine and phenylephrine was mediated directly through cardiac alpha 1-adrenoceptors and had a different time course from beta-adrenoceptor-mediated responses. 4 A negative chronotropic response to alpha-agonists was potentiated by neostigmine and blocked by atropine, tetrodotoxin or hexamethonium as well as by alpha 1-adrenoceptor antagonists. This may indicate alpha 1-adrenoceptors on preganglionic parasympathetic nerves, stimulation of these receptors causing release of acetylcholine. 5 The alpha 2-adrenoceptor agonist, xylazine, produced a direct negative chronotropic effect on the heart, independent of alpha-adrenoceptors. No evidence was found for functional post-junctional alpha 2-adrenoceptors. At high doses xylazine stimulated cardiac alpha 1-adrenoceptors.     

Cardioregulatory properties of indoramin in the rat

The antihypertensive action of the competitive α-adrenoceptor antagonist indoramin is not accompanied by reflex tachycardia in animals or man. The possibility that the established local anaesthetic property of indoramin is involved in its cardioinhibitory action has been investigated. Indoramin evoked a dose-dependent bradycardia in anaesthetized/pithed rats. The decrease in heart rate was slightly greater than that evoked in anaesthetized intact animals suggesting that indoramin had a direct action on the heart. Reflex tachycardia was simulated in pithed rats by increasing the frequency of cardiac nerve stimulation from 0·3 to 1 Hz. Indoramin and the local anaesthetic agents, lignocaine and procaine, reduced the positive chronotropic response without markedly altering the basal rate. The response curves were parallel. In contrast, phentolamine decreased the positive chronotropic response, but only at high doses which were associated with a marked decrease in the basal rate. Thymoxamine and prazosin had no significant effects on the chronotropic response. These experiments suggest that the cardioregulatory action of indoramin is attributable to its local anaesthetic property and this action further distinguishes it from the other α-adrenoceptor antagonists tested.     

An evaluation of the alpha-adrenoceptor antagonism produced by SK&F 86466 in healthy normotensive males.

SK&F 86466 is a novel, potent alpha-adrenoceptor antagonist which, in animal experiments, is reported to show a high selectivity for alpha 2-adrenoceptors at both pre- and post-junctional sites. The effects of two intravenous doses of 80 and 200 micrograms kg-1 of SK&F 86466 were assessed in a placebo-controlled, double-blind, randomised study in eight young, healthy, normotensive males. Two indices of alpha-adrenoceptor activity were investigated: i) Pressor responsiveness to the relatively selective alpha 1-adrenoceptor agonist phenylephrine and to the preferential alpha 2-adrenoceptor agonist alpha-methylnoradrenaline. ii) Circulating levels of noradrenaline. SK&F 86466 at a dose of 200 micrograms kg-1 produced rightward shifts of the pressor dose-response curves to both agonists: a 1.4 fold shift for phenylephrine (P = 0.023) and a 1.6 fold shift for alpha-methylnoradrenaline (P = 0.051). Erect plasma noradrenaline sampled at 105 min into the infusion was significantly increased from 2.9 to 5.0 nmol l-1 by SK&F 86466 200 micrograms kg-1 (P = 0.002). The change in the phenylephrine responses indicates post-junctional alpha 1-adrenoceptor blockade and the rise in noradrenaline is consistent with pre-junctional alpha 2-adrenoceptor antagonist activity. Overall the results of this study suggest that SK&F 86466, at a dose of 200 micrograms kg-1, causes both alpha 1- and alpha 2-adrenoceptor antagonism in human subjects.     

Characterization of the receptors and mechanisms involved in the cardiovascular actions of sCCK-8 in the pithed rat.

1. The cardiovascular actions of cholecystokinin and related peptides were investigated in the pithed rat. The receptors and the mechanisms involved in these experiments were characterized. 2. Sulphated cholecystokinin octapeptide (sCCK-8, 0.1-100 nmol kg-1, i.v.) elicited a dose-dependent bradycardia and increase in mean arterial blood pressure. Neither gastrin-17 nor pentagastrin had any effect at concentrations up to 100 nmol kg-1. 3. Both the pressor response and bradycardia elicited by sCCK-8 were reduced by the selective CCKA receptor antagonists, devazepide (0.5-50 nmol kg-1) and lorglumide (1-7 mumol kg-1). The selective CCKB receptor antagonists, CI-988 (1 mumol kg-1) and L-365,260 (15 mumol kg-1) did not inhibit the effects of sCCK-8. 4. The pressor response induced with sCCK-8 was reduced by treatment with either phentolamine (3 mumol kg-1) or guanethidine (2 mumol kg-1) and was unaffected by treatment with propranolol, atropine or hexamethonium. The pressor response also persisted following bilateral adrenalectomy. 5. The bradycardia induced with sCCK-8 was unaffected by treatment with phentolamine, propranolol, guanethidine, atropine, hexamethonium or bilateral adrenalectomy. 6. The tetrapeptide of cholecystokinin (CCK-4) elicited a dose-dependent pressor response but did not induce bradycardia. The pressor response was unaffected by devazepide (50 nmol kg-1), L-365260 (15 mumol kg-1) or phentolamine (3 mumol kg-1). 7. In the pithed rat, sCCK-8 acted via CCKA receptors to increase arterial blood pressure indirectly, at least in part, through activation of alpha-adrenoceptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analysis of the cardiovascular responses to McN-A-343 and DMPP in pithed guinea-pigs

General characteristics and pharmacological properties of the presser response and tachycardia produced by intravenous administration of 4-(m-chlorophenylcarbamoyloxy-2-butynyltrimethylammonium (McN-A-343) in pithed guinea-pigs were compared with those of 1,1-dimethyl-4-phenylpiperazinium (DMPP). The pressor effect and positive chronotropic effect of McN-A-343 were abolished and reduced, respectively, by atropine; both effects were blocked by bretylium and small doses of nicotine, but not by large doses of nicotine. The cardiovascular response to DMPP was reduced by bretylium and hexamethonium; in addition it was sensitive to both small and large doses of nicotine. The cardiovascular effect of McN-A-343 was not appreciably affected by hexamethonium, while that of DMPP by atropine. It is concluded that the pressor response to McN-A-343 results mainly from the activation of muscarinic receptors in sympathetic ganglia, providing evidence that these receptors exist in guinea-pig ganglia as well. The tachycardia produced by McN-A-343 is mediated via the cardiac sympathetic ganglia and consists of one component sensitive to atropine and the other component resistant to atropine and hexamethonium. The cardiovascular effect of DMPP is due to the activation of nicotinic receptors both in the sympathetic ganglia and the adrenal medulla, and probably to a tyraminelike action of the drug.     

Differential Effects of rANF and Chronic Guanabenz to Presynaptic and Postsynaptic α2-Adrenoceptor-Mediated Cardiovascular Response in Pithed Rats

• 1.In normal rats, intracerebroventricular (ICV) guanabenz induced a decrease in blood pressure (BP) and heart rate (HR), and this hypotension or bradycardia was not changed by rANF pretreatment (3 μg ICV).
• 2.In pithed rats, intravenous (IV) guanabenz, an α2-adrenoceptor agonist, produced an increase in mean blood pressure (MBP) in a dose-dependent manner. The pressor response by guanabenz was attenuated by infusion of rANF. This attenuation was additive when incubated in combination with yohimbine.
• 3.In pithed rats, the pressor response due to the increase of sympathetic outflow with electrical stimulation was partially blocked by rANF infusion or chronic guanabenz treatment. This reduction was not augmented by chronic guanabenz plus rANF treatment.
• 4.The inhibitory action of guanabenz in tachycardia evoked by electrical stimulation at the C7–T1 site was attenuated by rANF, but not by chronic treatment with guanabenz.

     

Cardiac slowing induced by peripheral kappa-opiate receptor stimulation in rats

The cardiovascular effects of ethylketocyclazocine were studied in rats anaesthetized with pentobarbital and artificially ventilated. Ethylketocyclazocine (1 mg X kg-1 i.v.) induced a fall in heart rate and blood pressure. The bradycardia and the hypotension were not altered by bilateral vagotomy and atropine, but were inhibited by naloxone and Mr 2266 BS. Ethylketocyclazocine always induced bradycardia in beta-adrenoreceptor-blocked and pithed animals. This bradycardia was prevented by Mr 2266 BS. These results would suggest that a direct peripheral action may occur at kappa-sites, located on the heart after intravenous injection of ethylketocyclazocine in the rat.     

Investigation into the cardioregulatory properties of the alpha 1-adrenoceptor blocker indoramin.

The cardioregulatory properties of the alpha 1-adrenoceptor blocker indoramin have been compared with those of prazosin in the anaesthetized rat. The effects of autonomic blockade on heart rate responses evoked by these two agents and their effects on blood pressure and heart rate after peripheral or central administration have been compared. Cumulative administration of indoramin (0.8-25.6 mg kg-1 i.v.) evoked significant decreases in arterial blood pressure and a concomitant bradycardia. Pithing or autonomic blockade, by pretreatment with a combination of practolol and bilateral vagotomy, prevented the bradycardia evoked by indoramin (0.8-3.2 mg kg-1 i.v.). Atropine sulphate pretreatment abolished the bradycardia until a cumulative dose of 25.6 mg kg-1(i.v.) of indoramin had been reached. Bilateral vagotomy, intravenous administration of atropine methylnitrate or practolol pretreatment attenuated the bradycardia. Prazosin (0.02-0.64 mg kg-1 i.v.) evoked a fall in arterial blood pressure of similar magnitude to that observed following indoramin. A bradycardia was evoked only at a relatively high dose (0.64 mg kg-1 i.v.). Intracisternal injection of indoramin or prazosin evoked bradycardia and hypotension at a dose which had no effect after intravenous injection (25 micrograms). Intracerebroventricular injection of indoramin (25 micrograms) had no significant effect on heart rate or blood pressure compared to control values, whereas prazosin (25 micrograms) evoked a significant tachycardia and hypotension. It is concluded that the bradycardia evoked by indoramin in the rat is not due to a direct action on the heart except possibly at high doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular effects of SK&F 104078, a novel alpha-adrenoceptor antagonist, in normotensive and hypertensive rats.

SK&F 104078 is a novel alpha-adrenoceptor antagonist derived from the 3-benzazepine alpha 2-adrenoceptor antagonist SK&F 86466. SK&F 104078 will block both alpha 1- and vascular postjunctional alpha 2-adrenoceptors but does not block most prejunctional alpha 2-adrenoceptors. Intravenous (i.v.) administration of SK&F 104078 decreased blood pressure (BP) in both spontaneously hypertensive and DOCA-salt hypertensive rats. SK&F 104078 potentiated the hypotensive response to tilt in anesthetized spontaneously hypertensive rats (SHR). Although SK&F 104078 had no effect on BP in normotensive rats, the tilt-induced decrease in BP in these animals was also potentiated. In this regard, SK&F 104078 resembled the selective alpha 1-adrenoceptor antagonist prazosin, rather than the alpha 2-adrenoceptor antagonists rauwolscine or SK&F 86466. Oral administration of SK&F 104078 had no significant effect on BP in SHR unless extremely high doses were administered. This was consistent with low plasma concentrations of SK&F 104078 observed after oral administration. After i.v. administration, the clearance of SK&F 104078 from plasma was 123 ml/min/kg, the steady-state volume of distribution was 17 L/kg, and the fraction excreted unchanged in urine was less than 1%. The low oral bioavailability of SK&F 104078 did not appear to be due to high first-pass oxidative metabolism, since pretreatment of SHR with the suicide substrate inhibitor of cytochrome P-450, 1-aminobenzotriazole (ABT), did not result in increased oral efficacy. SK&F 101253, a close structural analogue of SK&F 104078, was an effective antihypertensive when administered orally. Comparison of the stability of SK&F 101253 and SK&F 104078 in acid media showed SK&F 104078, but not SK&F 101253, to be rapidly degraded.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactions between the autonomic nervous system and the cardiovascular effects of ouabain in guinea-pigs

Anaesthetized guinea-pigs were intoxicated with an intravenous infusion of ouabain. This infusion induced a marked pressor response which was reduced in bilaterally adrenalectomized or pithed animals. Ouabain produced initial bradyarrhythmias in 60% of guinea-pigs. Bilateral vagotomy or pretreatment with atropine abolished the bradyarrhythmias and sensitized the animals to the arrhythmic effects of ouabain. Pithing or beta-adrenoceptor blockade reduced the potency of ouabain for producing arrhythmias, but bilateral adrenalectomy did not give protection. Preferential alpha 2-adrenoceptor stimulation with clonidine (10-300 micrograms . kg-1 i.v.) also reduced the arrhythmogenic effects of ouabain, whereas no protection was found with St 91, a clonidine related compound which does not cross the blood-brain barrier. The effect of clonidine was antagonized by piperoxan. Preferential alpha 2-adrenoceptor blockade with piperoxan (6 mg . kg-1 i.v.) did not change the pressor response to ouabain, but sensitized the animals to the arrhythmogenic effects of ouabain. In contrast, the preferential alpha 1-antagonistic agent AR-C 239 (0.3 mg . kg-1 i.v.) abolished the pressor response to ouabain and in addition increased the dose of ouabain required to produced ventricular premature beats and ventricular fibrillation. These experiments indicate: (i) that ouabain produces in guinea-pigs a pressor response which seems to be due to catecholamine release from the adrenal medulla probably by an action on the central nervous system; (ii) that the ventricular arrhythmias induced by ouabain are due in part to stimulation of the central nervous system leading to an increase in beta-adrenoceptor activity; (iii) that central alpha-adrenoceptors appear to be involved in the arrhythmogenic effects of ouabain, as clonidine reduced these effects. On the other hand piperoxan, a preferential alpha 2-adrenoceptor antagonist did not change the pressor response to ouabain and increased the arrhythmogenic effects whereas AR-C 239 had opposite effects.     

Characterization of alpha-adrenoceptors mediating sympathetic vasoconstriction in rat autoperfused hindlimb: effects of SK&F 104078

In the autoperfused hindlimb of pithed rats, vasoconstrictor responses to intra-arterial infusions of the selective alpha 2-adrenoceptor agonist, B-HT 933, were antagonized by the alpha 2-adrenoceptor antagonist, rauwolscine (1 mg/kg i.v.), and by the selective postjunctional alpha 2-adrenoceptor antagonist, SK&F 104078 (1 mg/kg), but not by the selective alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg). In contrast, responses to the selective alpha 1-adrenoceptor agonist, methoxamine, were antagonized by prazosin, but not by rauwolscine or SK&F 104078. Vasopressor responses to stimulation of sympathetic nerves were inhibited by prazosin, increased by rauwolscine, and not affected by SK&F 104078. The results indicate that vascular neuroeffector transmission in rat hindlimb is mediated by postjunctional alpha 1-adrenoceptors, and that SK&F 104078 is a selective antagonist of postjunctional alpha 2-adrenoceptor, and lacks the prejunctional alpha 2-adrenoceptor antagonist action of rauwolscine.     

Involvement of hypothalamic periventricular GABAergic nerves in the central pressor response to clonidine in freely-moving conscious rats

Microinjection of the α(2)-adrenoceptor agonist clonidine into the hypothalamic periventricular nuclei (PVN) induces the pressor response associated with bradycardia in freely-moving conscious rats. This study investigated the involvement of γ-aminobutyric acid nerves (GABAergic nerves) and glutamatergic nerves in the cardiovascular response to microinjection of clonidine in the PVN. Male Wistar rats were chronically implanted with a microinjection cannula into the PVN and an arterial catheter into the abdominal aorta through the femoral artery. Blood pressure and heart rate were measured under a conscious unrestrained state. PVN injection of clonidine induced a dose-dependent pressor response concomitant with bradycardia. PVN pretreatment with GABA, muscimol (GABA(A)-receptor agonist), or bicuculline (GABA(A)-receptor antagonist) significantly inhibited the pressor response to PVN-injected clonidine without affecting bradycardia. PVN pretreatment with baclofen (GABA(B)-receptor agonist), 2-hydroxysaclofen (GABA(B)-receptor antagonist), or kynurenic acid (non-selective NMDA-type glutamate-receptor and ionotropic glutamate-receptor antagonist) did not affect the pressor response to PVN-injected clonidine. These results suggest that clonidine induces a pressor response by stimulating the presynaptic α(2)-adrenoceptor of GABAergic nerves in the PVN, thereby inhibiting GABAergic nerve activity.     

SK&F 86466, a novel alpha-adrenolytic drug: effects on heart rate, blood pressure, and neuroendocrine function in supine resting position and in response to postural and cold stimulation in normal humans

SK&F 86466 is a novel alpha-adrenoceptor blocking drug shown in preclinical profiling to have relative selectivity for the pre- and postjunctional alpha 2-adrenoreceptor. In the present clinical study, the effects of single oral doses of 10, 25, and 50 mg SK&F 86466 on supine and stimulated circulatory and neuroendocrine function were assessed in eight normal subjects studied in a placebo-controlled balanced cross-over design with the drugs administered in double-blind fashion. SK&F 86466 caused a dose-related increase in stimulated (postural and cold challenge) and supine plasma norepinephrine (NE) concentrations. This increase was associated with an increase in supine heart rate (HR) and plasma renin activity and orthostatically stimulated HR, with little increase in systolic blood pressure (SBP) and no increase in diastolic blood pressure (DBP). Assuming that no changes occurred in catecholamine clearance, SK&F 86466 thus appeared to have a prejunctional alpha 2-adrenoreceptor blocking effect, which was countered by a post-junctional alpha-adrenoreceptor blocking effect at the level of the resistance vessels, whereas this latter effect did not alter the pressor responses to cold and postural challenge.     

Histamine-Independent Modulation of the Neuropeptide Y-Induced Pressor Response by α-Trinositol in the Pithed Rat

Abstract: The modulatory effects of α-trinositol (D-myo-inositol-1.2.6-trisphosphate; PP 56) on the systemic arterial blood pressor responses induced by neuropeptide Y, preganglionic nerve stimulation, phenylephrine and vasopressin were studied in pithed rats. Intravenous administration (within 2 min.) of α-trinositol reduced the neuropeptide Y-induced increase in mean arterial pressure within a defined dose range without altering the heart rate. The influence of α-trinositol on the neuropeptide Y-induced pressor response in the presence of non-selective as well as H₁- and H₂-selective histamine antagonists (diphenhydramine, mepyramine and cimetidine respectively) were investigated. The maximal increase in mean arterial pressure induced by neuropeptide Y as well as the duration of the pressor response was enhanced after non-selective (diphenhydramine) or H₁-selective (mepyramine) histamine blockade. The enhancement of the neuropeptide Y-induced pressor response by the H₁ specific antagonist mepyramine was significantly more pronounced compared to the H₂-selective agent. The exaggerated increase in mean arterial pressure in response to neuropeptide Y after histamine blockade was inhibited by α-trinositol to a similar extent as without such pretreatment. We conclude that neuropeptide Y interacts with histamine in the pithed rat and that this action may partially offset the pressor actions of the peptide. The neuropeptide Y-induced pressor responses may be inhibited by α-trinositol within a defined dose range indicating that this non-peptide agent may act as a functional inhibitor to neuropeptide Y in vascular tissue.     

Yohimbine antagonises α1A- and α1D-adrenoceptor mediated components in addition to the α2A-adrenoceptor component to pressor responses in the pithed rat

We have recently shown that responses to pressor nerve stimulation in the pithed rat are mediated by α(1A)- and α(1D)-adrenoceptors, with no evidence for α(2)-adrenoceptor involvement, and that responses previously identified as α(2)-adrenoceptor mediated are actually α(1D)-adrenoceptor mediated. We have now re-examined the subtypes of α-adrenoceptor involved in pressor responses produced by exogenous agonists in the pithed rat preparation to confirm whether α(2)-adrenoceptors are involved in these responses. The α(2)-adrenoceptor and α(1D)-adrenoceptor antagonist yohimbine (1mg/kg) and the α(2A)-adrenoceptor antagonist methoxy-idazoxan (5 mg/kg) significantly shifted, but the α(1D)-adrenoceptor antagonist BMY 7378 (8-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspir o[4.5]decane-7,9-dione dihydrochloride) (1 mg/kg) did not affect, the pressor potency of the α(2)-adrenoceptor agonist xylazine. α(1)-adrenoceptor antagonists showed low potency against pressor responses to xylazine. The pressor potency of the α(1)-adrenoceptor agonist amidephrine was not affected by BMY 3778 (1 mg/kg) but significantly shifted by prazosin (0.01 mg/kg) and by yohimbine (1 mg/kg). In contrast, the pressor potency of phenylephrine was significantly shifted by both yohimbine and BMY 7378 (1 mg/kg), but to a greater extent by the α(1A)-adrenoceptor antagonist RS 100329 (5-Methyl-3-[3-[3-[4-[2-(2,2,2,trifluroethoxy) phenyl]-1-piperazinyl]propyl]-2,4-(1H,3H)-pyrimidinedione] hydrochloride) (0.1 mg/kg). In conclusion, we have identified and separated α(1A)-, α(1D)- and α(2A)-adrenoceptor antagonist actions of yohimbine against pressor responses. Pressor responses to exogenous agonists in the pithed rat involve both α(1A)- and α(1D)-adrenoceptors and in addition, α(2A)-adrenoceptors.     

The triple effect induced by delta 9-tetrahydrocannabinol on the rat blood pressure

The intravenous injection of delta 9-tetrahydrocannabinol (2-10 mg/kg) produced dose-related changes in the rat blood pressure. Three effects were detected: (1) an immediate and short-lasting hypotension related to bradycardia, blocked after atropine, vagotomy hexamethonium and pithing; (2) A rise in blood pressure 30 seconds after injection, insensitive to yohimbine, hexamethonium, pithing and reserpine treatment; (3) a slow and persistent hypotension, 5 min later, insensitive to atropine and vagotomy but inhibited by hexamethonium, pithing and reserpine treatment. It was concluded that intravenous injection of THC in rats may induce vagal stimulation and hypotension. This effect was reversed and followed by hypertension due to direct vasoconstriction not dependent on sympathetic activity. After this action a central decrease in sympathetic tonus led to a persistent hypotension an effect which is commonly reported for mammals.     

An in vivo investigation of the negative chronotropic effect of cholic acid in the rat

1. Experimental obstructive jaundice in the Wistar rat causes a significant decrease in heart rate. 2. Intravenous administration of cholic acid in vivo elicits a dose-dependent negative chronotropic effect. 3. Atropine or vagotomy significantly reduces, but does not abolish, the negative chronotropic effect of cholic acid. 4. Ganglion blockade and decerebration diminishes the negative chronotropic effect of cholic acid, but to a lesser extent than atropine or vagotomy. 5. Sympathetic depletion by reserpine slightly potentiates the response to cholic acid. 6. The effect of cholic acid injected cranially into the common carotid artery is less than when administered into the jugular vein. 7. The haemolysis caused by cholic acid does not appear to be involved in the negative chronotropic effect. 8. It is concluded that cholic acid causes both a direct as well as a vagally mediated negative chronotropic effect in the Wistar rat.     

Some pharmacological effects of δ-aminolaevulinic acid on blood pressure in the rat and on rabbit isolated ear arteries

1. The effects of δ-aminolaevulinic acid (ALA) have been examined on the blood pressure of anaesthetized rats and pithed rats and on the perfusion pressure in isolated preparations of the rabbit ear artery. 2. ALA has a hypotensive effect in both anaesthetized and pithed rats. 3. In anaesthetized rats, the hypotensive response was produced with either continuous infusion or single injections of ALA, and was not blocked by hexamethonium, propanolol, phentolamine, atropine or mepyramine. 4. In the pithed rat, ALA had no effect on the pressor response to nicotine. 5. The hypotensive response to ALA could be counteracted by the pressor effect of adrenaline or noradrenaline. In pithed rats, the pressor response of vasopressin was reduced by ALA. 6. Vasoconstrictor response of the isolated perfused rabbit ear artery to noradrenaline and sympathetic nerve stimulation were usually not affected by ALA, but in a few experiments they were increased. ALA produced an increase in perfusion pressure in a few experiments. 7. Since ALA appears to cause an increase in capillary permeability, it is probable that the hypotensive effect is associated with capillary dilatation.