Roles of peripheral and central angiotensin-converting enzyme (ACE) in hypovolemic thirst induced by compound 48/80 in rats

Subcutaneous (s.c.) injection of Hoe 498, an angiotensin converting enzyme (ACE) inhibitor, at the doses of 0.1, 0.5, 1.0 and 4.0 mg/kg produced a dose-related inhibition of compound 48/80-induced hypovolemic thirst in rats. A significant time-response relationship was observed between the pretreatment time of Hoe 498 at a dose of 4.0 mg/kg and the inhibition of compound 48/80-induced water intake. Nearly 90% of plasma ACE activity was inhibited by Hoe 498 at all doses used, and this inhibition at the dose of 4.0 mg/kg of Hoe 498 continued for more than 4 hr. Intracerebroventricular (i.c.v.) or s.c. injection of Hoe 498 in doses ranging from 0.5 to 20 micrograms comparably inhibited plasma ACE activity in a dose-dependent manner. The compound 48/80-induced water intake was significantly reduced by i.c.v. injection of Hoe 498 (20 micrograms) 30 min after compound 48/80 administration, but not reduced when the drug was given 15 min prior to injection of dipsogen. The inhibition of water intake by Hoe 498 seems to be dependent on the dose and time between administration of Hoe 498 and compound 48/80. The present data suggest that brain ACE is more involved in compound 48/80-induced water intake than peripheral systemic ACE.     

Modulation of morphine antinociception by peripheral [Leu5]enkephalin: a synergistic interaction

This study determined whether the modulation of morphine antinociception by [Leu5]enkephalin, a compound which does not produce detectable antinociception when given i.p., was additive or synergistic. Co-administration of graded i.p. doses of morphine and [Leu5]enkephalin 20 min before testing resulted in a progressive leftward and parallel displacement of the i.p. morphine dose-response line. The increase in potency produced by i.p. [Leu5]enkephalin, but not the antinociception of i.p. morphine alone, was blocked by i.c.v. ICI 174,864. The data demonstrate strong and dose-related synergism between the two compounds, supporting the view that (a) peripheral administration of [Leu5]enkephalin can modulate morphine antinociception, apparently at the level of the brain and (b) that the interaction between mu and delta opioid agonists is not the result of simple additive action at the same (i.e., mu) receptor. Further evidence is thus provided for the existence of functional mu-delta interactions.     

Hypotensive and antiarrhythmic effects of a new alkaloid, the 13-hydroxylupanine-2-pyrrolcarbonic acid ester, from the Madagascan plant Cadia ellisiana.

The alkaloid 13-hydroxylupanine-2-pyrrolcarbonic acid ester (Hoe 933) from the Madagascan plant Cadia ellisiana has an hypotensive and antiarrhythmic effect. The hypotensive effect in dogs, monkeys, and rats anaesthetized with barbiturates reaches its maximum with 0.2 mg/kg i.v. However, the hypotensive effect is much weaker in conscious animals. The enteral absorption in the dog is good; an intraduodenal dose of only 0.5 mg/kg lowered the blood pressure. In the isolated rabbit heart whose accelerator nerves were intact, the perfusion with concentrations of 0.6 mug/min Hoe 933 (total dose 6 mug) decreased the release of norepinephrine from the nerve endings, reduced the positive inotropic effect, and diminished the increase in heart rate produced by electrical stimulation of the accelerator nerve. The effect of the stimulation of the accelerator nerve on dp/dt in dogs in situ was considerably diminished by such low doses as 10 and 25 mug/kg i.v. Consequently, the alkaloid inhibits sympathetic impulse transmission. Sympathetic circulatory reflexes are weakened by the compound. The alkaloid has also a ganglionic blocking effect, which is demonstrated on the upper cervical ganglion of the cat. The effect of preganglionic stimulation of the nictitating membrane was reduced with 200 mug Hoe 933/kg i.v. In the isolated guinea pig heart the effect of nicotine on heart rate and contraction was diminished. In this respect the ganglion blocker pentolinium is 8 times more active. The antifibrillatory effect of Hoe 933 was demonstrated with 0.3 mg/kg i.v. in supercooled cats, the antiarrhythmic activity was evident with 0.5 mg/kg i.v. in dogs intoxicated with K-strophanthin. In isolated hearts of guinea pigs, a dose of only 6 mug/heart inhibited ventricular fibrillation induced by aconitine and digitoxin. Even the toxicity of digoxin was diminished by previous administration of 300 mug/kg i.v. The relative refractory period and the duration of the action potential were prolonged in the isolated papillary muscle of the guinea pig heart.     

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.     

Evidence for the involvement of bradykinin in chemically-evoked cystitis in anaesthetized rats

Summary The effect of Hoe 140, a potent bradykinin B2 receptor antagonist, on the micturition reflex and detrusor hyperreflexia induced by chemical cystitis has been investigated in anaesthetized rats. Hoe 140 (1–100 nmol/kg i. v.) produced a dose-dependent blockade of the contraction of the rat urinary bladder induced by i. v. administration of bradykinin (100 nmol/kg) without affecting the response produced by the selective tachykinin NK-1 receptor agonist, [Sar⁹] substance P (SP) sulfone (1 nmol/kg i. v.). At doses which produce selective and long-lasting blockade of bradykinin receptors in the urinary bladder, Hoe 140 did not modify urodynamic parameters in normal rats.Intravesical instillation of xylene in female rats decreased bladder capacity and increased micturition frequency. These effects also occurred in rats pretreated with capsaicin as adults. Hoe 140 did not modify xylene-induced cystitis. Intraperitoneal administration of cyclophosphamide (150 mg/kg, 48 h before) decreased bladder capacity and increased micturition frequency. These effects of cyclophosphamide were abolished in rats pretreated with capsaicin as adults. Hoe 140 increased bladder capacity and decreased micturition frequency in rats pretreated with cyclophosphamide.Addition of bradykinin (10 µmol/l) to the medium in the superfused rat urinary bladder preparation evoked a prompt increase in the outflow of calcitonin gene-related peptide like immunoreactivity (CGRP-LI). Hoe 140 (3 µmol/l) inhibited (by about 50%) the CGRP-LI outflow stimulated by bradykinin.These findings demonstrate the participation of bradykinin, through 132 receptors, in the genesis of detrusor hyperreflexia during cyclophosphamide-induced cystitis. Capsaicin-sensitive primary afferent neurons are a likely target for Hoe 140 action in this model of experimental cystitis, as exemplified by its ability to prevent CGRP-LI outflow by bradykinin.Correspondence to C. A. Maggi at the above address     

Antagonism of enkephalin action on acetylcholine release by methylxanthines: lack of a purine link.

Theophylline (Theo) and caffeine antagonized the inhibitory effect of methionine (Met)-enkephalin, leucine (Leu)-enkephalin and morphine on the twitch height of the field stimulated myenteric plexus longitudinal muscle (MPLM) preparation of the guinea-pig ileum. Antagonism by Theo was observed only in tissues stimulated submaximally, but that by caffeine was observed in tissues stimulated submaximally and supramaximally. Injection of Theo (20, 40 mg kg-1) or caffeine (40 mg kg-1) reversed or blocked the inhibitory effects of Leu-enkephalin (50 micrograms i.c.v.) and a systemically active enkephalin FK 33,824 (0.5 mg kg-1) on the release of acetylcholine (ACh) from the rat cortex in vivo. Injections of morphine (2.5, 5.0 mg kg-1 i.v.) did not modify the in vivo release of radiolabelled purines from the cerebral cortex prelabelled with [3H]-adenosine (2.8 X 10(-7) M). Application of K+ (60 mM) to the cortex readily stimulated this release. Injection of morphine (5.0 mg kg-1 i.v.) increased the spontaneous release of radiolabelled purines from the cortex prelabelled with a higher concentration of [3H]-adenosine (10(-4) M) in six out of eleven experiments. Under similar conditions neither Leu-enkephalin (50 micrograms i.c.v.) nor FK 33,824 (0.5 mg kg-1 i.v.) stimulated purine release. It is concluded that methylxanthines can antagonize the inhibitory action of opioids on the peripheral and central release of ACh. However, this antagonism does not reflect an intermediary purine step in the action of opioids on the release of ACh.     

Characterisation of alpha2-adrenoceptor subtypes involved in gastric emptying, gastric motility and gastric mucosal defence

The effect of clonidine on ethanol-induced gastric mucosal damage, gastric emptying and gastric motility was compared. The clonidine-induced gastroprotective effect (0.03-0.09 micromol/kg, s.c.) was antagonised by yohimbine (5 micromol/kg, s.c.), prazosin (0.23 micromol/kg; alpha2B-adrenoceptor antagonist) and naloxone (1.3 micromol/kg, s.c.). Clonidine also inhibited the gastric emptying of liquid meal (0.75-3.75 micromol/kg, s.c.) and gastric motor activity (0.75 micromol/kg, i.v.) stimulated by 2-deoxy-D-glucose (300 mg/kg, i.v.). Inhibition of gastric emptying and motility was reversed by yohimbine (5 and 10 micromol/kg, s.c., respectively), but not by prazosin (0.23 micromol/kg, s.c.) or naloxone (1.3 micromol/kg, s.c.). Oxymetazoline-an alpha2A-adrenoceptor agonist-inhibited both gastric emptying (0.67-6.8 micromol/kg, s.c.) and motility (0.185-3.4 micromol/kg, i.v.), whereas it failed to affect gastric mucosal lesions. The results indicate that in contrast to the gastroprotective effect, which is mediated by alpha2B-adrenoceptor subtype, alpha2A-adrenoceptor subtype may be responsible for inhibition of gastric emptying and motility. However, the site of action (central, peripheral, both) remains to be established.     

Special pharmacology of the new sulfonylurea glimepiride

Glimepiride (Hoe 490) is a new sulfonylurea. After oral administration of Hoe 490 to rabbits, blood glucose was lowered 3.5 times more than after glibenclamide (HB 419) and after intravenous administration, 2.5 times more. This superiority in efficacy was demonstrated by onset, maximum and duration of action. In rats, intravenous and oral Hoe 490 has a much shorter effect on blood glucose than HB 419, but the initial effect of Hoe 490 orally was up to 6 times and i.v. up to 2 times stronger than that of HB 419. In dogs, oral and intravenous Hoe 490 had a considerably longer blood glucose-lowering effect than HB 419. However, the effect of intravenous Hoe 490 was only half as intense as that of HB 419 in the first hours after treatment and the effect of oral Hoe 490 was initially stronger and thereafter temporarily distinctly weaker than that of HB 419. The more rapid decrease in blood glucose in the dog after oral administration of Hoe 490 was accompanied by a correspondingly earlier and higher plasma insulin increase. In accordance with the less intense initial blood glucose decrease in the dog after intravenous Hoe 490 there was a weaker and slower rise and faster drop of plasma insulin. The long action of oral and intravenous Hoe 490 in the dog can, however, not be sufficiently explained by the plasma insulin values. In the isolated rat pancreas perfused with glucose-free medium, HB 419 released glucagon beside insulin and somatostatin. The threshold concentration for the glucagon secretion was lower as those for the insulin and somatostatin release.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intrathecal [Met5]enkephalin antibody blocks analgesia induced by intracerebroventricular beta-endorphin but not morphine in mice

Intrathecal (i.t.) injection of antibody directed to [Met5]enkephalin antagonized intracerebroventricularly (i.c.v.) administered beta-endorphin-induced inhibition of the tail-flick response but not the hot-plate response. [Met5]enkephalin antibody injected i.t., however, did not affect inhibition of either the tail-flick and hot-plate response induced by morphine given i.c.v. The antibodies to [Leu5]enkephalin, dynorphin A-(1-13) and beta-endorphin even at a high dose injected i.t. did not affect the inhibition induced by i.c.v. administered beta-endorphin or morphine either in the tail-flick and hot-plate test. Our results with antibodies support the results of previous studies that beta-endorphin but not morphine produces its analgesic action by selectively releasing [Met5]enkephalin.     

Different targets for i.v. vs. i.c.v. administered morphine for its effect on colonic motility in dogs

The effects of intracerebroventricular (i.c.v.) or intravenous (i.v.) administration of morphine on colonic motility were investigated in conscious dogs chronically fitted with a strain gauge transducer sutured to the serosa of the proximal colon. Morphine administered i.v. (100 micrograms/kg) or i.c.v. (10 micrograms/kg) induced similar increases in the motility index for about 3 h. The pattern of colonic contractions after i.v. morphine mainly consisted of an increase in the number of phases of contractile activity each lasting about 5 min. Morphine i.c.v. administered induced a peculiar pattern consisting of short (0.5-1.5 min) phases of contractile waves occurring at a high rate (10-15 per h). The effects of i.v. morphine were abolished after previous i.v. (1 microgram/kg) or i.c.v. (0.1 micrograms/kg) administration of naloxone or methyl-levallorphan, a narcotic antagonist with a high peripheral selectivity (100 micrograms/kg i.v., 10 micrograms/kg i.c.v.). The effects of i.c.v. morphine were not modified by previous i.v. or i.c.v. administration of naloxone (100 micrograms/kg). These results suggest that the stimulatory effect of i.v. morphine on colonic motility involves both central and peripheral components. The i.c.v. administration of morphine does not reproduce its central effect when given i.v. but acts on different central receptors.     

The involvement of opiate receptors in the effects of trimebutine on intestinal motility in the conscious dog

The effects of intravenous (i.v.) vs intracerebroventricular (i.c.v.) administration of trimebutine on the motility of the small intestine and colon of fasted dogs were assessed using chronic electromyography. Trimebutine, injected intravenously, stimulated small intestinal motility, by inducing a propagated phase of regular spike activity, and inhibited colonic motility for some 4 h. These effects were not reproduced by i.c.v. administration which disrupted the cyclic motor profile of the small intestine for about 2.5 h and did not modify colonic motility. The stimulation of the small intestine motility induced by i.v. administration of the drug was blocked by previous i.v. but not by i.c.v. administration of naloxone. It was concluded that in the dog, the effects of trimebutine on the small intestine but not on the colon, involve peripheral opiate receptors.     

Presynaptic inhibition of vascular sympathetic neurotransmission by adenosine

Infusion of adenosine (1 mg/kg/min i.v.) to pentobarbital-anesthetized dogs resulted in a decrease in blood pressure and significant attenuation of the femoral vasoconstrictor responses to lumbar sympathetic nerve stimulation. The vasoconstrictor action of exogenous norepinephrine was unaltered during adenosine infusion. The inhibitory action of adenosine on responses to sympathetic nerve stimulation could be antagonized by theophylline (5 mg/kg i.v.), but not indomethacin (10 mg/kg i.v.). Additional experiments were performed to study the role of this sympathoinhibitory action of adenosine in the vasodilator effect of the compound. Intraarterial administration of adenosine produced dose related femoral vasodilatation. Sympathetic denervation of the femoral vascular bed did not alter the vasodilatory action of adenosine. Continuous lumbar sympathetic nerve stimulation or intraarterial norepinephrine infusion also did not change the vasodilatation produced by adenosine. The vasodilatory action of adenosine was antagonized by theophylline. These results suggest that adenosine causes inhibition of sympathetic neurotransmission to the femoral vasculature via an action on presynaptic purinergic receptors. However, this presynaptic inhibitory action of adenosine is not involved in the femoral vasodilatation produced by the compound.     

Effect of Hoe 140, a new bradykinin receptor antagonist, on bradykinin- and platelet-activating factor-induced bronchoconstriction and airway microvascular leakage in guinea pig.

We have investigated the effect of a new bradykinin receptor antagonist, Hoe 140 (D-Arg- Hyp3,Thi5,D-Tic7,Oic8]-bradykinin), on bradykinin- and platelet-activating factor (PAF)-induced bronchoconstriction and airway microvascular leakage in anesthetized guinea pigs. Extravasation of Evans blue dye and lung resistance were measured simultaneously. Both i.v. (15 nmol/kg) and inhaled bradykinin (1 mM, 45 breaths) caused a significant increase in lung resistance and leakage of dye at all airway levels. Hoe 140 (100 nmol/kg i.v.) almost completely inhibited these airway responses induced by bradykinin except for dye extravasation in trachea induced by inhaled bradykinin. Inhaled PAF (3 mM, 30 breaths) significantly increased lung resistance and leakage of due at all airway levels, but Hoe 140 had no effect on these responses. Bradykinin-induced bronchoconstriction and airway microvascular leakage are predominantly mediated by activation of B2 receptor, since Hoe 140 is a B2 receptor antagonist. Bradykinin receptor-mediated mechanisms do not play an important role on inhaled PAF-induced bronchoconstriction and microvascular leakage.     

Comparative effects of opiate agonists on proximal and distal colonic motility in dogs

The colonic motility index was measured in dogs, by using strain-gauge transducers, before and after administration of opiate agonists. Fentanyl, a μ-compound, ethylketazocine (EKC), a κ-compound, [D-Ala²,Leu⁵]enkephalin (DADLE), a δ-agonist, were administered by intravenous (i.v.) or intrathecal (i.t.) routes. Fentanyl (2–10 nmol · kg⁻¹ i.v.) induced a dose-related period of hyperactivity characterized by an increase in both tone and frequency of contractions in the distal portion of the colon, whereas a period of hypomotility following a short-lived period of increased activity was elicited on the proximal colon. Fentanyl (0.1, 0.2 nmol · kg⁻¹ i.t.) had inhibitory effects on both proximal and distal colon. Small doses of EKC (2–4 nmol · kg⁻¹) administered i.t. or larger doses (20–40 nmol · kg⁻¹ i.v.) inhibited colonic motility for a dose-related duration, the effects of EKC being more marked on the distal colon than on the proximal colon. The administration of DADLE, 1–2 nmol · kg⁻¹ i.t., and 40-20 nmol · kg⁻¹ i.v., inhibited and stimulated the colonic contractions, respectively, in both proximal and distal colon. The results demonstrated that the colonic opiate-mediated responses may vary according to the route of administration, the portion of the colon studied and the opioid agonist used. Opiate agonists when administered centrally show a tendency to modulate colonic activity in a similar way whatever the type of agonist.     

Contribution of spinal dopamine receptors to the hypotensive action of bromocriptine in rats.

Bromocriptine, a dopamine (DA) receptor agonist, has been reported to have hypotensive effects in anesthetized and conscious normotensive rats but its mechanism of action is still not fully understood. Therefore, we studied the changes in mean arterial blood pressure (MAP) and heart rate (HR) elicited by an intravenous (i.v.) administration of bromocriptine (150 micrograms/kg), in either pentobarbital-anesthetized or conscious normotensive rats, pretreated with either i.v. (0.3 mg/kg) or intrathecal (i.t.) (93 nmol) domperidone, a DA receptor antagonist that does not cross the blood-brain barrier. In these preparations, i.v. administration of bromocriptine elicited dose-dependent decreases in MAP and rises in HR. The hypotensive effect was antagonized partially by i.t. and fully by i.v. domperidone. However, the latter compound did not modify the tachycardia, which could be blocked by propranolol (0.5 mg/kg i.v.). In rats pretreated with the latter beta-adrenoceptor antagonist, bromocriptine produced only a decrease in blood pressure that was inhibited by i.v. and i.t. domperidone. These results suggest that, in anesthetized and conscious normotensive rats, the hypotension induced by systemic administration of bromocriptine is fully mediated by DA2 dopamine receptors, which are located partly within the spinal cord and partly in the peripheral circulation.     

Centrally mediated inhibitory effect of 5-[2-(diethylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4- b]pyridine trihydrochloride (KW-5805) on gastric acid secretion in rats

KW-5805, 5-[2-(diethylamino)ethyl]amino-5,11-dihydro[1]benzoxepino[3,4- b]pyridine trihydrochloride, is a new tricyclic compound with antiulcer activities. Its effect on stimulated gastric acid secretion was investigated in the perfused stomach of anesthetized rats. KW-5805 at 0.3-10 mg/kg, i.v., dose-dependently inhibited gastric acid secretion stimulated by 2-deoxy-D-glucose (2-DG). On the other hand, the compound at 10-20 mg/kg, i.v., exerted a moderate decrease in gastric acid secretion stimulated by bethanechol; and at 10 mg/kg, i.v., it produced no change in gastric acid secretion evoked peripherally by vagal electrical stimulation. When applied intracerebroventricularly at 1-5 micrograms/rat, this compound dose-relatedly reduced gastric acid secretion stimulated by 2-DG. Three main metabolites (KF-10504, KF-9530 and KF-10847) of KW-5805 at 1 mg/kg, i.v., caused no significant decrease in gastric acid secretion stimulated by 2-DG. Doxepin, a tricyclic compound, definitely depressed the 2-DG stimulated gastric acid secretion at 1 mg/kg, i.v. It is suggested that intravenous administration of KW-5805 inhibits gastric acid secretion stimulated by 2-DG, mainly via centrally mediated mechanisms, and that biotransformation of KW-5805 to the metabolites contributes little to the development of the antisecretory effect.     

Electrophysiological actions of nicotine on substantia nigra single units.

Extracellular recordings of single unit activity were made in the substantia nigra (SN) of chloral hydrate-anaesthetized rats. Dopaminergic neurones of the pars compacta (SNC) were stimulated by (-)-nicotine bitartrate (1.0 mg kg-1) given subcutaneously (s.c.). This action was prevented by the secondary amine mecamylamine HCl (2.0 mg kg-1 i.v.) but not by a ganglion-blocking dose of the bisquaternary compound chlorisondamine Cl (0.1 mg kg-1 i.v.). Mecamylamine reduced the spontaneous activity of dopaminergic neurones. Nicotine, when administered intravenously (2-128 micrograms kg-1 cumulative dose), also stimulated dopamine cells and this action was dose-related. Nicotine, administered intravenously, (2-128 micrograms kg-1 cumulative dose) markedly excited non-dopamine cells in the pars reticulata (SNR) in a dose-related manner. In rats pretreated with chlorisondamine (0.1 mg kg-1 i.v.), nicotine induced a small excitatory or depressant action, but the marked excitation was not seen. Mecamylamine (2 mg kg-1 i.v.) completely prevented the actions of nicotine. The results are consistent with a direct excitatory action of nicotine on dopaminergic neurones of the substantia nigra pars compacta. The pronounced excitatory action of systemically administered nicotine on non-dopamine cells of the pars reticulata appears to be of peripheral origin.     

Development of hyperthermia following intracerebroventricular administration of endotoxin in the rat: effect of kinin B1 and B2 receptor antagonists.

1. E. coli lipopolysaccharide (LPS) produced a dose-dependent (dose range: 0.02-150 micrograms) increase in rat core temperature that was maximal 6 h after intracerebroventricular (i.c.v.) administration. LPS (200 ng) increased core temperature by 1.0 +/- 0.2 degrees C, 6 h following administration, as compared to vehicle-treated controls (-0.2 +/- 0.2 degrees C). 2. LPS-induced (200 ng) hyperthermia was prevented by co-administration of the bradykinin (BK) B2 receptor antagonist, Hoe 140 (10 and 30 pmol, i.c.v.) or by indomethacin (10 nmol, i.c.v.). 3. Systemic administration of Hoe 140 at doses up to 1 mumol kg-1, s.c., did not attenuate LPS-induced (200 ng, i.c.v.) hyperthermia. However, LPS hyperthermia was significantly reduced by systemic administration of indomethacin (1 mumol kg-1, i.v.). 4. Co-administration of the selective B1 receptor antagonists, [des-Arg9, Leu8]BK (0.1 - 1 nmol, i.c.v.) or [des-Arg10] Hoe 140 (0.1 - 1 nmol, i.c.v.), did not prevent LPS-induced hyperthermia. 5. It is concluded that the development of hyperthermia following central administration of endotoxin requires activation of central, but not peripheral bradykinin B2 receptors. The formation of kinins within the CNS may be an important initial component of CNS inflammation following infection.     

Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits.

1. We tested the effects on systemic haemodynamics and renal function, of inhibition of endopeptidase (EP) 24.15 (E.C. 3.4.24.15), in conscious uninephrectomized rabbits in which the activities of angiotensin converting enzyme (ACE, E.C. 3.4.15.1) and neutral endopeptidase (EP 24.11, E.C. 3.4.24.11) were already inhibited. To test the role of bradykinin B2-receptors in mediating the effects following inhibition of these enzymes, the antagonist Hoe 140 was used. 2. Hoe 140 (0.1 mg kg-1, i.v.) did not affect resting mean arterial pressure or heart rate, but antagonized the depressor effect of right atrial administration of bradykinin. The dose-response curve for bradykinin was shifted more than 1000 fold to the right for more than 4 h. Hoe 140 approximately doubled resting urine flow and increased fractional Na+ excretion from 4.2 to 6.0%; consistent with the hypothesis that it exerts a partial agonist effect on the kidney. 3. Combined inhibition of ACE (captopril; 0.25 mg kg-1 plus 0.2 mg kg-1h-1) and EP 24.11 (SCH 39370; 3 mg kg-1 plus 3 mg kg-1h-1) was followed by a sustained reduction in arterial pressure (-6 +/- 2 mmHg) and increase in heart rate (35 +/- 7 beats min-1). There was a small increase in renal blood flow (by 6.5 +/- 3.2% relative to vehicle-treatment) without a change in glomerular filtration rate, and about a 150% increase in Na+ excretion. Hoe 140 (0.1 mg kg-1, i.v.) pretreatment did not influence the renal effects of captopril and SCH 39370, although it did appear to blunt their hypotensive and tachycardic effects. 4. When EP 24.15 was inhibited with N-[1-(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate (cFP-AAY-pAB; 5 mg kg-1 plus 3 mg kg-1h-1, i.v.) in rabbits pretreated with captopril and SCH 39370, no changes in systemic haemodynamics or renal function were observed. 5. We concluded that in conscious uninephrectomized rabbits, EP 24.15 does not play a major role in modulating renal function, at least under conditions where ACE and EP 24.11 are already inhibited. In contrast, ACE and/or EP 24.11 do modulate renal function in this model, but their influences are mediated chiefly through metabolism of peptides other than bradykinin.     

Effects of Hoe 065, a compound structurally related to inhibitors of angiotensin converting enzyme, on acetylcholine metabolism in rat brain

Hoe 065, a compound structurally related to inhibitors of angiotensin converting enzyme, caused a fall in the content of acetylcholine (ACh) in different brain areas of the rat following i.p. administration in the range 0.03-30 mg/kg. This effect occurred 0.5 h after a single injection and lasted for at least 6 h. Simultaneous administration of the choline uptake inhibitor hemicholinium-3 (HC-3) with Hoe 065 potentiated the decrease in ACh content induced by HC-3. In the same dose range Hoe 065 acutely enhanced the activity of the enzyme choline acetyltransferase as well as the capacity of the high-affinity choline uptake system which is considered as the rate-limiting step in the synthesis of ACh. Cholinesterase activity in vivo was not altered by the compound. Hoe 065 produced a concurrent elevation of brain cyclic GMP content. Taken together, these results suggest that Hoe 065 acutely increases cholinergic activity within its physiological range, probably by means of an enhanced release of ACh.