L-365,260, a potent CCK-B/gastrin receptor antagonist, suppresses gastric acid secretion induced by histamine and bethanechol as well as pentagastrin in rats.

We evaluated the effects of a potent cholecystokinin (CCK)-B/gastrin receptor antagonist, L-365,260 (3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin - 3-yl)-N'-( 3-methylphenyl) urea); a selective CCK-A receptor antagonist, devazepide (L-364,718); and cimetidine on gastric acid secretion induced by pentagastrin, histamine and bethanechol in anesthetized rats. We also evaluated the effects of L-365,260 and cimetidine on acid secretion in pylorus-ligated rats. Intravenous administration of L-365,260, L-364,718 and cimetidine dose-dependently reduced acid secretion induced by pentagastrin (20 nmol/kg/hr), with ED50 values of 0.63, 19.1 and 2.5 mumol/kg, respectively. Of interest was the finding that L-365,260, like cimetidine, dose-dependently inhibited acid secretion induced by histamine (100 mumol/kg/hr) and bethanechol (5 mumol/kg/hr) with ED50 values of 5.9 and 4.3 mumol/kg, respectively. L-364,718, even at 30 mumol/kg, i.v., had only a slight effect on histamine- or bethanechol-induced acid secretion. Gastric acid secretion was suppressed by treatment with L-365,260 (3-100 mumol/kg, i.v.) and cimetidine (11.9-396.4 mumol/kg, i.v.) in pylorus-ligated rats, with ED50 values of 13.3 and 96.9 mumol/kg, respectively. These results indicate that L-365,260 suppresses acid secretion induced by histamine and bethanechol in rats and that the gastrin receptor plays an important role in acid secretion in pylorus-ligated rats.     

Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine

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

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

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

Comparison of the gastric antisecretory effects of ramixotidine dihydrochloride (CM 57755), a new H2 receptor antagonist, and cimetidine in dogs

This paper compares the effects of ramixotidine dihydrochloride (CM 57755) with those of cimetidine on gastric acid secretion and gastrin release in conscious dogs chronically fitted with Heidenhain pouches and/or gastric fistulae. At equimolar doses, intravenous (i.v.) or intragastric (i.g.) CM 57755 caused similar inhibition of dimaprit- or pentagastrin-induced secretion than cimetidine. Acid secretion stimulated by a meat meal was significantly reduced by both CM 57755 and cimetidine. Neither CM 57755 (4.5 and 9 mumol/kg) nor cimetidine (4 mumol/kg) modified gastrin release, while cimetidine (8 mumol/kg) significantly increased it. Judging from these results, while CM 57755 appears to be an inhibitor of gastric acid secretion induced by different stimulants in dogs with potency comparable to cimetidine. The increase in plasma gastrin levels seen after cimetidine but not after CM 57755 suggests that cimetidine releases gastrin by a mechanism independent of H2 receptor antagonism.     

Effects of selective tachykinin receptor antagonists on capsaicin- and tachykinin-induced bronchospasm in anaesthetized guinea-pigs.

Bronchospasm induced by i.v. injection of equieffective doses of acetylcholine, capsaicin or selective tachykinin receptor agonists ([Sar9]SP sulfone or [beta-Ala8]neurokinin A (NKA-4-10)) (for NK1 and NK2 receptors, respectively) was studied in anaesthetized guinea-pigs. The NK1 and NK2 receptor antagonists, (+/-)-CP96,345 (3 mumol/kg i.v.) and MEN 10,376 (3 mumol/kg i.v.), selectively abolished the bronchoconstriction induced by the respective agonist, showing that both NK1 and NK2 receptors mediate bronchoconstriction in guinea-pig airways and that they are activated independently. Capsaicin-induced bronchospasm was inhibited by atropine (1.5 mumol/kg i.v.) and MEN 10,376 (3 mumol/kg i.v.), but unaffected by (+/-)-CP96,345 (3 mumol/kg i.v.). Hexamethonium (79 mumol/kg i.v.), propranolol (17 mumol/kg i.v.) and physostigmine (0.9 mumol/kg i.v.) enhanced the airway constriction induced by acetylcholine, capsaicin, [Sar9]SP sulfone or [beta-Ala8]NKA-(4-10) while guanethidine (67 mumol/kg s.c. for two days) increased only bronchoconstriction induced by capsaicin or the selective NK2 receptor agonist. In hexamethonium-treated animals, MEN 10,376 still abolished the increase in insufflation pressure induced by [beta-Ala8]NKA-(4-10) and reduced the increase elicited by capsaicin. In summary, in anaesthetized guinea pig i.v. capsaicin-induced bronchospasm through activation of postjunctional NK2 (but not NK1) receptors along with activation of cholinergic pathways. This motor response is moderated by the simultaneous stimulation of a sympathetic bronchodilating mechanism(s), possibly through activation of NK2 receptors localized in sympathetic ganglia.     

Mechanisms underlying the cardiovascular effects of a labdenic diterpene isolated from Moldenhawera nutans in normotensive rats

Cardiovascular effects of Labd-8 (17)-en-15-oic acid (Labd-8), a labdenic diterpene isolated from methanolic extract of Moldenhawera nutans were investigated in normotensive rats. Additionally, this study examined the role of autonomic nervous system in the mediation of these cardiovascular effects. In pentobarbital-anesthetized rats, bolus intravenous (i.v.) injection of Labd-8 (1-10 mg/kg) induced dose-dependent hypotensive and tachycardiac responses. After cervical bivagotomy, hypotensive responses to Labd-8 were significantly enhanced whereas the tachycardia was completely abolished. In conscious rats, Labd-8 (1-10 mg/kg, i.v.) also decreased blood pressure and increased heart rate in a dose-dependent manner. Pretreatment with methylatropine (1 mg/kg, i.v.) or propranolol (2 mg/kg, i.v.) significantly reduced the tachycardia evoked by Labd-8 without affecting the hypotension. Blockade of ganglionic neurotransmission with hexamethonium (30 mg/kg, i.v.) reduced and abolished the hypotensive and tachycardic effects of Labd-8, respectively. However, hypotensive effects of Labd-8 were not reduced by pretreatment with N(w)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg, i.v.), a nitric oxide synthase inhibitor. In rat endothelium-containing aorta preparations, Labd-8 (1-1000 micro g/ml) induced a concentration-dependent reduction of potassium (60 mM)-induced contraction [IC(50) (geometric mean +/-95% confidence interval)=313.6 (191.4-513.8) micro g/ml], an effect that remained unaffected [IC(50)=440.8 (225.1-863.3) micro g/ml] by removal of vascular endothelium. These results show that i.v. treatment with Labd-8-induced dose-dependent hypotensive and tachycardiac effects in both conscious and anesthetized rats. The tachycardia is mediated reflexly through inhibition of vagal and activation of sympathetic drive to the heart. The hypotension is mainly due to withdrawal of sympathetic tone to the vasculature and also partly to an active vascular relaxation. Released nitric oxide from vascular endothelial cells is not involved in the mediation of Labd-8-induced hypotension.     

New pharmacological data on the bronchospasmolytic activity of bamifylline

Resistance to lung inflation and blood pressure were monitored together with biological and radioimmunological determination of circulating thromboxane A2 (TxA2) in anaesthetized guinea-pig. Bamifylline, a 2-benzyl-[4,5-d]-imidazopyrimidine derivative, and theophylline were compared for their antagonistic activity against the pulmonary effect of histamine (0.05 mumol/kg i.v.), leukotriene C4 (LTC4, 0.016 mumol/kg i.v.), platelet-activating factor (PAF, 0.0002 mumol/kg i.v.) and acetylcholine (0.1 mumol/kg i.v.). Bamifylline, as well as theophylline, showed a dose-dependent antagonistic activity against both bronchoconstriction and TxA2 generation induced by the above agonists. However, except for histamine where the two compounds were equiactive, bamifylline was 2 times more potent than theophylline. The maximal inhibitory activity was found against bronchoconstriction induced by PAF (ED50 = 6.5 mumol/kg i.v.) followed by histamine (ED50 = 9.5 mumol/kg i.v.), acetylcholine (ED50 = 24.3 mumol/kg i.v.) and LTC4 (ED50 = 31.6 mumol/kg i.v.). Bamifylline (3, 10, 30, 100 mumol/kg i.v.) and theophylline (3, 10, 30, 100 mumol/kg i.v.) protected guinea-pig from antigen-induced bronchoconstriction and TxA2 generation in ovalbumin actively sensitized animals. Also in this series of experiments bamifylline was more potent than theophylline, the ED50 being 9.3 mumol/kg i.v. and 22.9 mumol/kg i.v., respectively. These pharmacological data represent new support for the protecting effect of bamifylline against respiratory damage induced by well known anaphylaxis mediators.     

Hypotensive effects of intravenously administered uridine and cytidine in conscious rats: involvement of adenosine receptors

In the present study, we investigated the cardiovascular effects of intravenously injected uridine or cytidine, and the role of adenosine receptors in mediating these effects, in conscious normotensive rats. Intravenous (i.v.) administration of uridine (124, 250, 500 mg/kg) dose-dependently decreased arterial pressure and heart rate. Cytidine (124, 250, 500 mg/kg; i.v.) produced slight dose-related hypotension without changing heart rate. Plasma uridine and cytidine concentrations increased time- and dose-dependently while plasma adenosine levels did not change after injection of the respective nucleosides. Pretreatment with intravenous caffeine (20 mg/kg), 8-phenyltheophylline (8-PT) (1 mg/kg), nonselective adenosine receptor antagonists, or 8-p-sulfophenyltheophylline (8-SPT) (20 mg/kg), a nonselective adenosine receptor antagonist which does not cross the blood-brain barrier, abolished the cardiovascular effects of uridine (250 mg/kg; i.v.) or cytidine (250 mg/kg; i.v.). Intracerebroventricular (i.c.v.) caffeine (200 microg) or 8-SPT (50 microg) pretreatment did not change the magnitude of the cardiovascular responses induced by nucleosides. Intravenous 8-cyclopenthyl-1,3-dipropylxanthine (DPCPX) (5 mg/kg), a selective adenosine A(1) receptor antagonist, greatly attenuated the cardiovascular responses to uridine and cytidine. Pretreatment with 3,7,-dimethyl-1-propargylxanthine (DMPX) (2 mg/kg), an adenosine A(1)/A(2) receptor antagonist, attenuated hypotension induced by uridine and blocked the arterial pressure decrease in response to cytidine. Uridine-induced bradycardia was blocked by DMPX. 4-(2-[7-amino-2-(2-furyl[1,2,4]-triazolo[2,3-a[1,3,5]triazin-5-yl-aminoethyl)phenol (ZM241385) (1 mg/kg; i.v.), a selective adenosine A(2A) receptor antagonist, pretreatment produced an only very small blockade in the first minute of the hypotensive effects of uridine without affecting the bradycardia. ZM241385 pretreatment completely blocked cytidine's hypotensive effect. In Langendorff-perfused rat heart preparation, uridine (10(-3) M), but not cytidine, decreased the heart rate. Our results show that intravenously injected uridine or cytidine is able to decrease arterial pressure by activating peripheral adenosine receptors. The data also implicates that the mainly adenosine A(1) receptor activation is involved in the uridine-induced cardiovascular effects, while both adenosine A(1) and A(2A) receptor activations mediate the cytidine's effects.     

Endogenous opiate system and dihydropyridine-induced central regulation of sympathetic tone in rats

Intracerebroventricular injections of nicardipine (10 micrograms/kg) to SHR induced hypotension which was suppressed by pretreatment with 6-OHDA. This hypotension was also inhibited by a previous injection of naloxone (100 micrograms/kg i.c.v.) whereas the hypotension induced by intravenously injected nicardipine (10 micrograms/kg) was not changed. It is suggested that the release of endogenous opioids is involved in the sympatho-inhibitory effect of centrally administered dihydropyridine calcium channel antagonists.     

Characterization of vascular dopamine receptors in the gastric circulation of the rabbit

An in vivo model is presented for studying the vasodilator effect of dopamine on the gastric vascular bed of the anesthetized rabbit. Dopamine was injected into the common hepatic artery simultaneously measuring the blood flow through the left gastric artery at constant perfusion pressure. The vasoconstrictor response to dopamine was blocked by pretreatment with phenoxybenzamine (0.5 mg/kg i.a.). Dopamine dilated the gastric vascular bed dose-dependently with an average ED50 of 15 nmol. Apomorphine caused vasodilation with an ED50 of 38.8 nmol; the maximum response was significantly lower than dopamine. (-)Isoproterenol was ineffective. cis-Flupentixol (3.5 and 7.0 mumol/kg i.v.) and (+)butaclamol (3.0 mumol/kg i.v.), but not trans-flupentixol (7.0 mumol/kg i.v.) and (-)butaclamol (6.0 mumol/kg i.v.) shifted the dopamine dose-response curve to the right in a parallel fashion, indicating competitive antagonism. Haloperidol, bulbocapnine, and sulpiride also acted as competitive inhibitors of dopamine-induced vasodilation. The antagonists inhibited the dopamine-induced vasodilation in the following order of potency: (+)butaclamol greater than cis-flupentixol greater than haloperidol greater than bulbocapnine greater than sulpiride. The results suggest that the vascular dopamine receptors in the stomach of the rabbit resemble the DA1-receptors in the mesenteric vascular bed of dogs.     

The potentiation of cardiodepressant and hypotensive effects of bradykinin by enalapril and captopril both in vitro and in vivo.

1. Bradykinin (cumulative concentrations of 0.007-0.09 micrograms ml-1) produced a dose-related, but statistically insignificant depression of the isometric contraction of the isolated, spontaneously beating atria of the guinea-pig. The same concentrations of bradykinin did not change the atrial rate, but a tendency to a slight decrease was observed. 2. Enalapril (4.06 or 13.54 mumol l-1), produced a dose-related potentiation of the effect of the highest concentration of bradykinin on the isometric contraction. 3. Captopril (equimolar concentrations) also potentiated the effect of the highest concentration of bradykinin on the isometric contraction. This effect of captopril was not dose-related. 4. Both enalapril and captopril did not change the effect of bradykinin on the heart rate. 5. Bradykinin induced dose-related hypotensive responses in anaesthetized cats (0.03-1.0 microgram/kg b.w., i.v.) with a tendency towards bradycardia. 6. Enalapril (0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. However, the potentiating effect of enalapril was not dose-dependent. 7. Captopril (0.1, 0.3 and 1.0 mg/kg b.w., i.v.) significantly potentiated bradykinin-induced hypotension and bradycardia. Also, the potentiating effect of captopril was not dose-dependent. 8. The failure of ACE inhibitors to potentiate the cardiodepressant and hypotensive effects of bradykinin in a dose-dependent manner is explained with some other mechanism(s) independent of ACE inhibition.     

Effects of intracerebroventricular administration of magnesium sulphate on blood pressure and heart rate in anesthetized normotensive and hypertensive rats

Intracerebroventricular (i.c.v.) injection of magnesium sulphate (MgSO4:2.5, 5 and 10 mumol in 5 microliters) decreased blood pressure and heart rate in both anesthetized normotensive (WKY) and hypertensive rats (SHR). The effects were greater in WKY than in SHR. Moreover, a pretreatment with hexamethonium (2 mg/kg, i.v.) significantly blunted the hypotensive and bradycardic effects induced by i.c.v. injection of 10 mumol of MgSO4 in both WKY and SHR. Our data suggest that MgSO4 produces hypotensive and bradycardic effects when injected i.c.v. in both WKY and SHR.     

Beneficial attenuating effect of L-threo-3,4-dihydroxyphenylserine on postural hypotension in anesthetized rats

The effects of L-threo-DOPS (L-threo-3,4-dihydroxyphenylserine), a non-physiologic precursor amino acid of the natural form of norepinephrine, on postural hypotension were assessed in anesthetized rats. Rats were pretreated with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), a norepinephrine-decreasing agent acting on central and peripheral tissues, or hexamethonium, a ganglion-blocking agent. Postural hypotension was induced by 60 degrees head-up tilt for 4 min. L-Threo-DOPS (1-10 mg/kg, i.v.) produced an increase in basal blood pressure and attenuation of the postural hypotension, which persisted in a dose-related manner in rats pretreated with DSP-4 (50 mg/kg, i.p. 24 h prior to the tilt-experiment). Hexamethonium (5 mg/kg, i.v.)-induced postural hypotension was also attenuated dose-dependently by i.p. (3-30 mg/kg)- or p.o. (30 and 100 mg/kg)-administered L-threo-DOPS, associated with an increase in basal blood pressure. Neither attenuation of postural hypotension nor increase in basal blood pressure was observed after L-threo-DOPS (30 mg/kg i.p.) in rats pre-injected with carbidopa (20 mg/kg i.v.), a peripheral aromatic L-amino acid decarboxylase inhibitor, under the hexamethonium pretreatment. The effects of L-threo-DOPS administered by cumulative i.v. infusion (12.5-50 micrograms/kg/min) on the pressor responses to either spinal sympathetic nerve stimulation (1-10 Hz) or i.v. bolus-injected tyramine were also examined. L-Threo-DOPS dose-relatedly potentiated the pressor response to nerve stimulation in rats either untreated or pretreated with DSP-4 and the pressor response to tyramine in rats pretreated with DSP-4.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intravenously injected CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock: effect is mediated by central cholinergic activation

Intravenous (i.v.) administration of cytidine-5′-diphosphate choline (CDP-choline) (100, 250 and 500 mg/kg) increased blood pressure in normal rats and reversed hypotension in haemorrhagic shock. Choline (54 mg/kg; i.v.), at the dose equimolar to 250 mg/kg CDP-choline decreased blood pressure of rats in both conditions and caused the death of all hypotensive animals within 2-5 min. Equimolar dose of cytidine (124 mg/kg; i.v.) did not change cardiovascular parameters. Choline levels in plasma, lateral cerebral ventricle and hypothalamus increased after CDP-choline administration. Intracerebroventricular (i.c.v.) hemicholinium-3 pretreatment (20 μg), greatly attenuated the pressor effect of CDP-choline in both conditions. Atropine pretreatment (10 μg; i.c.v.) did not change the pressor effect of CDP-choline while mecamylamine (50 μg; i.c.v.) abolished the pressor response to drug. Besides, acetylcholine (1 μmol; i.c.v.) produced similar increases in blood pressure in normal and hypotensive conditions to that observed in CDP-choline given rats. CDP-choline (250 mg/kg; i.v.) increased plasma catecholamines and vasopressin levels but not plasma renin activity. Pretreatment of rats with either prazosin (0.5 mg/kg; i.v.) or vasopressin V₁ receptor antagonist, [β-mercapto,β,β-cyclopentamethylenepropionyl¹,O-Me-Tyr²-Arg⁸]vasopressin (10 μg/kg; i.v.), attenuated the pressor response to CDP-choline while simultaneous administration of these antagonists before CDP-choline injection completely blocked the pressor effect. Results show that i.v. CDP-choline increases blood pressure and reverses hypotension in haemorrhagic shock. Activation of central nicotinic cholinergic mechanisms by the increases in plasma and brain choline concentrations appears to be involved in the pressor effect of this drug. Moreover, the increases in plasma catecholamines and vasopressin levels mediate these effects.     

Differences between the effects of calcium antagonists in the pithed rat preparation

The drugs classed as calcium antagonists display marked differences in vitro and it has been proposed that different subclasses of antagonists exist (Spedding M. Naunyn Schmiedebergs Arch Pharmacol 1982; 318:234-40). The effects of these drugs have now been compared in vivo using the pithed rat preparation. Whereas the hypotensive effects of verapamil (0.1-3 mumol/kg i.v.) and diltiazem (0.1-10 mumol/kg i.v.) were accompanied by prolongation of PR intervals and second-degree atrioventricular block with little bradycardia, fendiline (0.1-30 mumol/kg i.v.), cinnarizine (0.1-10 mumol/kg i.v.), and pimozide (0.1-10 mumol/kg i.v.) reduced heart rate at hypotensive doses but had less marked effects on AV conduction, thus implying different selectivities among calcium antagonists for the sinus or AV nodes. These differences were not secondary to effects on the autonomic nervous system. In contrast, nifedipine (0.01-1 mumol/kg i.v.) had no effect on the ECG in doses which markedly reduced blood pressure elevated by an infusion of angiotensin II and thus showed specificity for vascular smooth muscle. The marked differences between the effects of the calcium antagonists in vivo confirm the disparate nature of this group of drugs. The reasons for these differences are discussed.     

Antianaphylactic and antihistaminic activity of the non-steroidal anti-inflammatory compound nimesulide in guinea-pig

Nimesulide (4-nitro-2-phenoxymethane sulfonanilide, Aulin, Mesulid) is a non-steroidal anti-inflammatory compound which shows antihistaminic activity and inhibits the immune release of histamine. The antihistaminic activity of this compound is specific for H1-receptor and has been demonstrated on isolated strips of guinea-pig trachea and on histamine-induced multiphasic inotropic response in left atria of guinea pig electrically driven. The effect of nimesulide is of non competitive type and, at the concentration of 1 x 10(-5) mol/l, is nearly 2 time less potent than pyrilamine (mepyramine) at 1 x 10(-6) mol/l. Nimesulide (1.6 mumol/kg i.v.) inhibits both bronchoconstriction (69%) and TXB2 formation (93%) induced by histamine (0.05 mumol/kg i.v.) in anaesthetized guinea-pigs. In contrast indomethacin (1.6 mumol/kg i.v.) decreases the generation of TXB2 (89%) without affecting the enhancement in tracheal insufflation pressure induced by histamine. In actively sensitized guinea-pigs both nimesulide and indomethacin protect the animals from deadly anaphylactic crisis. The rise in tracheal pressure induced by the antigenic challenge is inhibited of 80% and 63% respectively by nimesulide and indomethacin (6.4 mumol/kg i.v.). At this dose the two compounds reduced of 90% approximately the immunological release of TXB2 in the circulation. The release of histamine, induced by the anaphylactic reaction caused in perfused lungs obtained from actively sensitized guinea-pigs, is lessened by nimesulide (EC50 = 3.06; fid. lim. 2.59-3.63 mumol/l) and potentiated by indomethacin (EC50 = 0.89; fid. lim. 0.67-1.17 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of cardiovascular events mediated by platelet activating factor during systemic anaphylaxis.

Previous studies have shown that an anaphylactic reaction in the isolated perfused heart is characterized by drastic coronary constriction, arrhythmias, and severe impairment of contractility. In vivo anaphylaxis is associated with myocardial ischemia and rapid cardiovascular failure. Recently, not only histamine but also platelet activating factor (PAF) has been implicated in cardiac manifestation of anaphylaxis. The present study was designed to separate the effects of PAF from those of histamine on cardiovascular function during systemic anaphylaxis. In guinea pigs, sensitization was produced by subcutaneous (s.c.) application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous (i.v.) infusion of ovalbumin were tested in anesthetized artificially ventilated guinea pigs. The renewed application of the antigen induced severe cardiac dysfunction. Within 3 min, cardiac output (CO) had already decreased by 90% and left ventricular end-diastolic pressure (LVEDP) increased significantly, indicating left ventricular pump failure. Concurrently, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of atrioventricular block. After 4 min, blood pressure (BP) rapidly decreased. All animals died within 10 min. Pretreatment with the H1-receptor antagonist mepyramine (1 mg/kg i.v.) in combination with the H2-receptor antagonist cimetidine (10 mg/kg i.v.) delayed onset of myocardial ischemia, arrhythmias and cardiac pump failure. After 10 min, however, LV contractility and BP steadily decreased, leading to severe hypotension within 30 min. If the selective PAF antagonist WEB 2086 (1 mg/kg i.v.) was administered in addition to cimetidine and mepyramine, myocardial ischemia and LV contractile failure were markedly inhibited further. In contrast, pretreatment with WEB 2086 alone had no beneficial effects on the anaphylactic cardiovascular changes. Therefore, we conclude that histamine is the predominant mediator during the early phase of systemic anaphylaxis whereas PAF-mediated effects are involved in cardiac dysfunction during the protracted late phase of anaphylaxis.     

Enhanced hypotensive effects of the essential oil of Ocimum gratissimum leaves and its main constituent, eugenol, in DOCA-salt hypertensive conscious rats

The cardiovascular effects of intravenous (i.v.) treatment with the essential oil of Ocimum gratissimum (EOOG) and its main constituent, eugenol (Eug) were investigated in the experimental model of deoxycorticosterone acetate (DOCA-salt)-hypertensive rats. In both conscious DOCA-salt hypertensive rats and their uninephrectomized controls, i.v. bolus injections of EOOG (1 - 20 mg/kg) or Eug (1 - 10 mg/kg) induced dose-dependent hypotension and bradycardia. Treatment with DOCA-salt significantly enhanced the maximal decreases in mean aortic pressure (MAP) elicited by hexamethonium (30 mg/kg, i.v.) as well as the hypotensive responses to both EOOG and Eug without affecting the bradycardia. However, the enhancement of EOOG-induced hypotension in hypertensive rats remained unaffected by i.v. pretreatment with either hexamethonium (30 mg/kg) or methylatropine (1 mg/kg). These results show that i.v. treatment with EOOG or Eug dose-dependently decreased blood pressure in conscious DOCA-salt hypertensive rats, and this action is enhanced when compared with uninephrectomized controls. This enhancement appears related mainly to an increase in EOOG-induced vascular smooth relaxation rather than to enhanced sympathetic nervous system activity in this hypertensive model.     

Cardiovascular effects of eugenol, a phenolic compound present in many plant essential oils, in normotensive rats

Cardiovascular effects of intravenous (i.v.) treatment with eugenol (Eug), a natural pungent present in many plant essential oils, were investigated in normotensive rats. In either anesthetized or conscious rats, i.v. bolus injections of Eug (1 to 10 mg/kg) elicited immediate and dose-dependent hypotension and bradycardia. Magnitude of Eug-induced hypotension was similar in both groups. Pretreatment of anesthetized rats with bilateral vagotomy almost abolished the bradycardic responses to Eug without affecting the hypotension. Likewise, i.v. pretreatment of conscious rats with methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) significantly reduced the Eug-induced bradycardia without affecting the hypotension. However, i.v. pretreatment with the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl (L-NAME, 20 mg/kg), affected neither the hypotension nor the bradycardia elicited by Eug. In rat mesenteric bed preparations precontracted with potassium (60 mM), Eug (0.1-2 mM) induced a reversible and concentration-dependent vasodilator effect, which remained unaffected by atropine (1 microM). These results show that i.v. treatment of rats with Eug induces dose-dependent hypotension and bradycardia, which occurred independently. The bradycardia appears dependent upon the presence of an intact and functional parasympathetic nerve drive to the heart while the hypotension is due to an active vascular relaxation rather than withdrawal of sympathetic tone. Released nitric oxide from vascular endothelial cells seems to be not involved in the mediation of Eug-induced hypotension.     

Cardiovascular responses to intraventricular adrenaline in spontaneous hypertensive rats.

The effects of intracerebroventricular (i.c.v.) injections of adrenaline on the blood pressure and heart rate of spontaneous hypertensive (SH) rats have been investigated. Adrenaline induced dose-related falls in blood pressure and heart rate in both conscious and urethane anaesthetised rats. In conscious rats, the hypotension and metoprolol, but were unaffected by pretreatment with phentolamine, piperoxan, fluphenazine or methysergide. However, in urethane-anaesthetised rats, the hypotension and bradycardia induced by i.c.v. adrenaline was not significantly affected by i.c.v. pretreatment with propranolol or oxprenolol, while metoprolol significantly antagonised only the bradycardia. Piperoxan, fluphenazine and methysergide were also without effect. Pretreatment with mecamylamine (i.p.) abolished the cardiovascular depressor effects of i.c.v. adrenaline in both conscious and urethane anaesthetised SH rats. It is concluded that the cardiovascular depressor effects of i.c.v. adrenaline are mediated by central adrenoceptors in SH rats and that, in conscious rats, these depressor effects may be mediated by central beta-adrenoceptors rather than alpha-adrenoceptors.