Vascular pharmacology of BIIE0246, the first selective non-peptide neuropeptide Y Y(2) receptor antagonist, in vivo

BIIE0246, a recently introduced non-peptide neuropeptide Y (NPY) Y(2) receptor antagonist, was pharmacologically characterized in vivo, on vascular responses evoked in the anaesthetized pig. The NPY Y(2) receptor agonist N-acetyl[Leu(28)Leu(31)]NPY(24-36) evoked dose-dependent vasoconstriction in spleen. These vascular responses were potently and dose-dependently antagonized by BIIE0246. Significant inhibition was seen already at 1 nmol kg(-1), whereas at 100 nmol kg(-1) of BIIE0246 these responses were completely abolished. The ID(50) value for this antagonism was 2.1 nmol kg(-1). Peptide YY (PYY) evoked dose-dependent vasoconstriction in both kidney and spleen, vascular responses mediated by the NPY Y(1) receptor and both NPY Y(1) and Y(2) receptors, respectively. Only the splenic response was inhibited by BIIE0246, the effect of which reached significance at 1 nmol kg(-1). Already 30 min after the last dose of BIIE0246 there was a significant recovery of the PYY-evoked splenic vasoconstriction, and a further 60 min later, this response was no longer significantly inhibited compared to control. BIIE0246 (100 nmol kg(-1)) did not affect renal and splenic vasoconstrictor responses either to the NPY Y(1) receptor agonist [Leu(31)Pro(34)]NPY, the alpha(1)-adrenoceptor agonist phenylephrine, the P2X(1)-purinoceptor agonist alpha,beta-methylene ATP or angiotensin II, demonstrating both selectivity and specificity for the NPY Y(2) receptor in vivo. It is concluded that BIIE0246 is a highly potent and selective NPY Y(2) receptor antagonist, albeit with rather short duration of action, in vivo. BIIE0246 thus represents the first interesting tool for studies on NPY Y(2) receptor-mediated transmission in vivo.     

Pharmacologic characterization of an endothelinA (ETA) receptor antagonist in conscious rats.

The present experiments describe the endothelin-1 (ET-1) antagonist activity of BQ123 (cyclic D-Asp-L-Pro-D-Val-L-Leu-D-Trp) in conscious Sprague-Dawley (SD) rats, and we also examined the effect blockade of ETA receptors had on blood pressure in four experimental models of hypertension. Rats were anesthetized with methoxyflurane and instrumented with femoral arterial and venous catheters. In SD rats, BQ123 (0.1-10.0 mg/kg i.v.) administered 5 or 60 min prior to ET-1 inhibited both the magnitude and duration of the ET-1 (0.25 nmol/kg i.v.) pressor response. In addition, BQ123 (10.0 mg/kg) inhibited the pressor response evoked by administration of the ET-1 precursor, proendothelin-1 (1.0 nmol/kg). However, BQ123 (10.0 mg/kg) had no effect on the pressor response evoked by ET-3 (0.75 nmol/kg). In Wistar-Kyoto rats, BQ123 (10.0 mg/kg) reversed the hypertension produced by an infusion of ET-1 (0.01 nmol/kg/min). Administration of BQ123 produced a mild antihypertensive effect in normal- to low-renin models of hypertension, but no blood pressure lowering was observed in high-renin models of hypertension. These studies demonstrated the selectivity of the ETA receptor antagonist, BQ123 for ET-1, but not ET-3-induced pressor responses. Furthermore, ET-1 does not appear to be a major contributing factor to the maintenance of elevated levels of blood pressure in four experimental models of hypertension.     

Effects of the ETA/ETB receptor antagonist, bosentan on endothelin-1-induced myocardial ischaemia and oedema in the rat.

1. The purpose of this study were to assess the role of ETB receptors in mediating endothelin-1 (ET-1)-induced myocardial ischaemia and oedema in rats and to study the inhibitory action of the novel nonpeptide ETA/ETB receptor antagonist, bosentan on these actions of ET-1. 2. Intravenous bolus injection of ET-1 (1 nmol kg-1) into anaesthetized rats produced marked ST segment elevation of the electrocardiogram without causing arrhythmias. ST segment elevation developed within 30-50 s and persisted for at least 30 min following injection of the peptide. 3. Pretreatment of the animals with bosentan (10 mg kg-1, i.v.) inhibited on average by 96% the ST segment elevation elicited by ET-1 (1 nmol kg-1) compared to the 82% inhibition observed with the ETA receptor-selective antagonist, FR 139317 (2.5 mg kg-1, i.v.). 4. Bolus injection of ET-1 (1 nmol kg-1, i.v.) to conscious chronically catheterized rats evoked a transient depressor response followed by a prolonged pressor effect. Corresponding to changes in blood pressure, a transient tachycardia and a sustained bradycardia were observed. ET-1 (1 nmol kg-1) enhanced albumin extravasation by 119 and 93% in the left ventricle and right atrium, respectively, as measured by the local extravascualr accumulation of Evans blue dye. 5. Pretreatment of the animals with bosentan (10 mg kg-1) inhibited by 71 and 90% the depressor and pressor actions of ET-1 (1 nmol kg-1) and the accompanying tachycardia and bradycardia, respectively. FR 139317 (2.5 mg kg-1) attenuated the pressor response to ET-1 and accompanying bradycardia by 75%, without affecting the depressor action and accompanying tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increase in sensitivity of the baroreceptor reflex following microinjection of carbachol into the posterior hypothalamic nucleus of awake rats

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Spontaneously hypertensive rats cholinergic hyper-responsiveness: central and peripheral pharmacological mechanisms.

1. The mechanisms and the subtypes of muscarinic receptors implicated in the cardiovascular effects of physostigmine were investigated in conscious normotensive and spontaneously hypertensive rats. 2. Intravenous (i.v.) physostigmine (50 microg kg-1) induced in both strains a long pressor response, accompanied by a bradycardia. This pressor response was larger in spontaneously hypertensive (+41+/-6 mmHg) than in Wistar-Kyoto (+25+/-2 mmHg) rats (P<0.05). 3. Pretreatment with atropine sulphate (0.4 mg kg-1 i.v.), completely abolished the physostigmine-induced pressor response in both normotensive and hypertensive rats. In both strains, the physostigmine pressor response was significantly reduced by the systemic administration of either an alpha1-adrenoceptor antagonist (prazosin, 1 mg kg-1) or a V1A-vasopressin receptor antagonist (AVPX, 20 microg kg-1). This physostigmine pressor effect was completely abolished in both strains when both antagonists were administered concomitantly. 4. In WKY rats, the pressor response to physostigmine (50 microg kg-1 i.v.) was inhibited in a dose-dependent manner by i. c.v. administration of atropine (ID50=3.70 nmoles), the M1 receptor antagonist pirenzepine (ID50=10.71 nmoles), the M2 receptor antagonist methoctramine (ID50=4.31 nmoles), the M3 receptor antagonist p-F-HHSiD (ID50=60.52 nmoles) and the M4 receptor antagonist tropicamide (ID50=214.20 nmoles). In the hypertensive strain, the ID50 were found to be significantly higher for atropine (7.34 nmoles), pirenzepine (21.60 nmoles) and p-F-HHSiD (139.50 nmoles) (P<0.05). 5. The present results indicate that physostigmine acts in normotensive and spontaneously hypertensive rats, through stimulation of both central M2 and M1 cholinoceptors to induce a rise in blood pressure mediated by an increase in plasma vasopressin and sympathetic outflow. Moreover, our results suggest that some modifications of the M1 receptor subtypes in terms of expression or affinity could be responsible for the hyper-responsiveness of the hypertensive strain to cholinomimetic agents.     

Endothelin-1 enhances vascular permeability in the rat heart through the ETA receptor.

Intravenous injection of endothelin-1 (ET-1, 0.1 and 1 nmol/kg) resulted in a dose-dependent increase in vascular permeability in the coronary circulation of conscious rats. The increase was almost completely abolished by the selective ETA receptor antagonist, BQ-123 (1 mg/kg). The ET-1 analogue, [Trp(For)21]ET-1, which is devoid of the depressor but not the pressor activity, evoked changes in protein extravasation similar to those with ET-1. These data indicate that the permeability effect of ET-1 is mediated through the ETA receptor.     

Comparative Cardiovascular Effects of the Angiotensin II Type 1 Receptor Antagonists ZD 7155 and Losartan in the Rat

Binding experiments show that ZD 7155 is a potent angiotensin II type 1 receptor antagonist. In this study this novel substance was studied in normotensive and hypertensive rats. The relative potency and duration of the antihypertensive effects of ZD 7155 were compared with those of the reference substance, losartan. The inhibitory effects of both compounds on angiotensin II-induced pressor actions were studied in the conscious normotensive Sprague-Dawley (SD) rat and in the conscious, spontaneously hypertensive rat (SHR). Arterial blood pressure and heart rate (HR) were obtained by direct intraarterial recording. Angiotensin II infusion was administered intravenously in the dose range 53.3 ng—12.8 μg kg^?1 min^?1 to the conscious rats. ZD 7155 was administered in a bolus dose of 1.082 μmol kg^?1 (0.51 mg kg^?1) and losartan in bolus doses of 2.165 and 6.495 μmol kg^?1 (1.0 and 3.0 mg kg^?1). In conscious SD rats, ZD 7155 and losartan behaved as competitive antagonists and the pressor response curve to angiotensin II was shifted to the right. Experiments in conscious SD rats also showed that ZD 7155 was approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response (240 ng kg^?1; 10 min infusion). In addition, experiments with conscious rats demonstrated that ZD 7155 could suppress the angiotensin II-induced pressor response for approximately 24 h when ZD 7155 was administered intravenously in a 1.082 μmol kg^?1 bolus dose and angiotensin II was given at 240 ng kg^?1 (in a 10?min infusion). Experiments in conscious SHRs using ZD 7155 (1.082 μmol kg^?1) and losartan (6.495 μmol kg^?1) as intravenous boluses indicated that both ZD 7155 and the reference compound losartan exhibited a significant antihypertensive effect. These results demonstrate that ZD 7155 is a potent angiotensin II-type 1 antagonist which is approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response. Furthermore, ZD 7155 may suppress the angiotensin II-induced pressor response for 24 h and in the SHR ZD 7155 induces a pronounced and persistent antihypertensive effect.     

Cardiovascular responses evoked by carbachol microinjection into the posterior hypothalamus involves ganglionic nicotinic and muscarinic mechanisms

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Diabetes-induced changes in 5-hydroxytryptamine modulation of vagally-induced bradycardia in rat heart

1. In the present study, we investigated how alloxan-induced diabetes affects the ability of 5-hydroxytryptamine (5-HT) to modulate bradycardia induced in vivo by electrical stimulation of the vagus nerve in pithed rats. We also analysed the type and/or subtype of 5-HT receptors involved. 2. Diabetes was induced in male Wistar rats with a single injection of alloxan (150 mg/kg, s.c.). Four weeks later, rats were anaesthetized, pretreated with atenolol and pithed. Electrical stimulation (3, 6 and 9 Hz) of the vagus nerve resulted in frequency dependent decreases in heart rate (HR). 3. In diabetic rats, intravenous bolus administration of high doses of 5-HT (100 and 200 microg/kg) increased the bradycardia induced by vagal electrical stimulation. Similarly, low doses (10 microg/kg) of the 5-HT(1/7) receptor agonist 5-carboxamidotryptamine (5-CT), increased vagally induced bradycardia. However, at high doses (50, 100 and 150 microg/kg), 5-CT reduced the bradycardia. Attenuation of the vagally induced bradycardia evoked by the higher doses of 5-CT was reproduced by L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors. Enhancement of the vagally induced bradycardia elicited by low doses of 5-CT was reproduced by the selective 5-HT(1A) receptor agonist 8-hydroxydipropylaminotretalin hydrobromide (8-OH-DPAT; 50 microg/kg). These stimulatory and inhibitory actions on vagal stimulation-induced bradycardia in diabetic rats were also observed after administration of exogenous acetylcholine. 4. Vagally induced bradycardia in diabetic rats was not affected by administration of the selective 5-HT(2) receptor agonist alpha-methyl-5-HT (150 microg/kg), the selective 5-HT(3) receptor agonist 1-phenylbiguanide (150 microg/kg) or the selective 5-HT(1B) receptor agonist CGS-12066B (50 microg/kg). 5. Enhancement of the electrical stimulation-induced bradycardia in diabetic rats caused by 5-CT (10 microg/kg) or 8-OH-DPAT (50 microg/kg) was abolished by the selective 5-HT(2/7) receptor antagonist mesulergine (1 mg/kg) and the selective 5-HT(1A) receptor antagonist WAY-100,635 (100 microg/kg), respectively. Similarly, pretreatment with the non-selective 5-HT(1) receptor antagonist methiothepin (0.1 mg/kg) blocked the inhibitory effect of 5-CT (50 microg/kg) on the bradycardia induced by vagal electrical stimulation in diabetic rats. BRL-15572 (2 microg/kg), a selective 5-HT(1D) receptor antagonist, inhibited the action of L-694,247 (50 microg/kg), a selective agonist for the non-rodent 5-HT(1B) and 5-HT(1D) receptors, on the vagally induced bradycardia. 6. In conclusion, in the present study, experimental diabetes evoked changes in both the nature and 5-HT receptor types/subtypes involved in vagally induced bradycardia.     

Vascular actions of MDMA involve alpha1 and alpha2-adrenoceptors in the anaesthetized rat

We have investigated the effects of methylenedioxymethamphetamine (MDMA, 'ecstasy'), i.v., on diastolic blood pressure (DBP) in pithed and pentobarbitone anaesthetized rats. In pithed rats, the non-selective 5-HT receptor antagonist methiothepin (0.1 mg kg(-1)) and the alpha2-adrenoceptor antagonists methoxyidazoxan and yohimbine (1 mg kg(-1)) showed significant alpha1-adrenoceptor antagonist potency, but methiothepin did not show alpha2-adrenoceptor antagonist potency. MDMA (1 and 5 mg kg(-1)) produced pressor responses which were significantly reduced by the alpha(1)-adrenoceptor antagonist prazosin (0.1 mg kg(-1)), yohimbine (1 mg kg(-1)) or methiothepin (0.1 mg kg(-1)), but not by the 5-HT2 receptor antagonist ritanserin (1 mg kg(-1)). In anaesthetized rats, antagonists revealed two phases with three components to the effects of MDMA (5 mg kg(-1)) on DBP: an initial pressor response, a later pressor component at 1 min, the sustained depressor response. Methoxyidazoxan, methiothepin or the combination ritanserin/prazosin significantly reduced the initial pressor response, although neither of the latter compounds alone had any effect. The pressor response to MDMA (5 mg kg(-1)) at 1 min was converted to a depressor response by prazosin and to a lesser extent methiothepin and methoxyidazoxan. The depressor response to MDMA (5 mg kg(-1)) was significantly reduced by methoxyidazoxan (0.1 mg kg(-1)), and by the noradrenaline re-uptake blocker cocaine 10 mg kg(-1) but not 1 mg kg(-1). However, the most marked reduction in the depressor response was produced by the combination of methoxyidazoxan and cocaine. It is concluded that the initial pressor response to MDMA (5 mg kg(-1)) in anaesthetized rats involves alpha2- and possibly alpha1-adrenoceptors and 5-HT2 receptors, the pressor component at 1 min is largely alpha1-adrenoceptor mediated, and the sustained depressor response involves alpha2-adrenoceptors.     

Activation of spinal metabotropic glutamate receptors elicits cardiovascular responses in pentobarbital anesthetized rats

The aim of this study was to examine whether intrathecal (i.t.) injection of metabotropic glutamate (mGlu) receptor agonists at the thoracolumbar level of the spinal cord causes changes either in the blood pressure or in the heart rate of pentobarbital anesthetized rats. The broad spectrum mGlu receptor agonist (+/-)-1-aminocyclopentane- trans-1,3-dicarboxylic acid ( trans-ACPD) and the Group III mGluR agonist L-(+)-2-amino-4-phosphonobutyric acid ( L-AP4) induced pressor effects at doses of 300 nmol and 600 nmol (i.t.) but did not induce changes at a lower dose (150 nmol, i.t.). The specific Group I mGlu receptor agonist ( RS)-3,5-dihydroxyphenylglycine (3,5-DHPG), as well as the highly selective Group II mGlu receptor agonist 2 R,4 R-4-aminopyrrolidine-2,4-dicarboxilate (2 R,4 R-APDC), induced pressor effects at a dose of 300 nmol only. The compounds (150-600 nmol) did not modify the heart rate in these experiments. On the other hand, low doses of Group II mGlu receptor agonists (75 nmol 2 R,4 R-APDC; 1.5 nmol 2 S,2' R,3' R)-2-(2',3'-dicarboxychloropropyl)glycine; DCG IV) induced hypotension and bradycardia when spinal N-methyl- D-aspartate (NMDA) receptors were previously blocked by 2-amino-5-phosphonovaleric acid (APV; 30 nmol; i.t.). The pressor response to trans-ACPD was probably mediated by activation of both Group I and Group II mGluRs because i.t. injection of either the selective Group I mGlu receptor antagonist ( S)-4-carboxyphenylglycine (4CPG) or the selective Group II mGlu receptor antagonist (2 S,3 S,4 S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG) antagonized the increases in the blood pressure produced by the agonist. Moreover, 4CPG and MCCG antagonized the pressor effects of 3,5-DHPG and 2 R,4 R-APDC, respectively. Blockade of spinal Group II mGlu receptors by MCCG also prevented the hypotensive and bradycardic effects of 2 R,4 R-APDC and DCG IV in rats pretreated with APV. On the other hand, the pressor response to L-AP4 (300 nmol) was prevented by the selective antagonist ( S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4).These results suggest that activation of spinal Group I, II and III mGlu receptors increases the mean blood pressure in pentobarbital anesthetized rats and that, after blockade of NMDA receptors, low doses of Group II mGlu receptor agonists induce hypotension and bradycardia.     

Central administration of 5-HT activates 5-HT1A receptors to cause sympathoexcitation and 5-HT2/5-HT1C receptors to release vasopressin in anaesthetized rats.

1. The effects of intracerebroventricular injections to the right lateral ventricle (i.c.v.) of 5-hydroxytryptamine (5-HT, 40 and 120 nmol kg-1), N,N-di-n-propyl-5-carboxamidotryptamine (DP-5-CT; 3 nmol kg-1), 5-carboxamidotryptamine (5-CT; 3 nmol kg-1), 8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT; 3, 40 and 120 nmol kg-1) and 1-(2,5-di-methoxy-4-iodophenyl)-2-aminopropane (DOI; 40 and 120 nmol kg-1) on renal sympathetic nerve activity, blood pressure, heart rate and phrenic nerve activity were investigated in normotensive rats anaesthetized with alpha-chloralose. 2. 5-HT caused a long lasting pressor response which was associated with an initial bradycardia and renal sympathoinhibition followed by a tachycardia and renal sympathoexcitation. Pretreatment with the 5-HT2/5-HT1C receptor antagonists, cinanserin (300 nmol kg-1, i.c.v.) or LY 53857 (300 nmol kg-1, i.c.v.) reversed the initial bradycardia and sympathoinhibition to tachycardia and sympathoexcitation. Combined pretreatment with LY 53857 (300 nmol kg-1, i.c.v.) and the 5-HT1A antagonist, spiroxatrine (300 nmol kg-1, i.c.v.), blocked the effects of 5-HT on all the above variables. 3. Pretreatment with the vasopressin V1-receptor antagonist, beta-mercapto-beta,beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8-vasopressin [(d(CH2)5Tyr(Me)AVP, 10 micrograms kg-1, i.v.] did not affect the magnitude but reduced the duration of the pressor response produced by i.c.v. 5-HT and reversed the initial bradycardia and renal sympathoinhibition to tachycardia and sympathoexcitation. 4. 1-(2,5-Di-methoxy-4-iodophenyl)-2-aminopropane (DOI) caused a pressor effect which was associated with a bradycardia and sympathoinhibition.(ABSTRACT TRUNCATED AT 250 WORDS)     

Characterization of receptors mediating vascular responses to endothelin-1 in the conscious rat.

1. The present study has determined the receptors mediating the vascular responses (pressor and depressor actions and vascular permeability effect) to endothelin-1 (ET-1) in the conscious rat by using the novel non-peptide ETA/ETB receptor antagonist, bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2 hydroxyethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine- 4-yl]benzene-sulphonamide), the ETA receptor-selective antagonist, FR 139317 and the ETB receptor-selective peptide agonist, IRL 1620. 2. Bolus injection of ET-1 (1 nmol kg-1, i.v.) resulted in a prolonged pressor effect (maximum increase in mean arterial blood pressure (MABP) was 47 +/- 3 mmHg, n = 6) preceded by a transient depressor response (maximum decrease in MABP was 17 +/- 1 mmHg). Both these responses were inhibited by bosentan (1-20 mg kg-1, i.v. bolus) in a dose-dependent manner. The maximum inhibition of ET-induced depressor and pressor responses did not exceed 53 and 87%, respectively. FR 139317 (2.5 mg kg-1, i.v.) attenuated the pressor response to ET-1 by 75% without affecting the depressor response. Furthermore, FR 139317, but not bosentan, prolonged the depressor action of ET-1. Corresponding to changes in blood pressure, a small transient tachycardia (delta heart rate 15 +/- 5 beats min-1) followed by a sustained bradycardia (delta heart rate -48 +/- 10 beats min-1, n = 6) was observed following injection of 1 nmol kg-1 ET-1. FR 139317 and bosentan (10 mg kg-1) inhibited ET-1-induced bradycardia by 79% and 71%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of the cardiac autonomic transmission of pithed rats by presynaptic opioid OP4 and cannabinoid CB1 receptors

We studied the effects of nociceptin, the endogenous ligand of the opioid OP4 receptor, and of two cannabinoid receptor agonists WIN 55,212-2 and CP-55,940 (0.001-1 micromol/kg each) on the neurogenic tachycardia and bradycardia in pithed rats. Electrical stimulation (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibres and injection of nicotine 2 micromol/kg or isoprenaline 0.5 nmol/kg increased heart rate by about 70 beats/min (bpm) in pithed rats pretreated with atropine 1.5-2 micromol/kg. The electrically induced tachycardia was reduced dose dependently by nociceptin, WIN 55,212-2 and CP-55,940 (by 60, 30 and 20% at the highest dose, respectively). The OP4 and cannabinoid receptor agonists diminished the nicotine- but not the isoprenaline-stimulated increase in heart rate. In pithed rats pretreated with propranolol 3 micromol/kg, vagal stimulation (5 Hz, 1 ms, 15 V for 10 s) or injection of methacholine (5-10 nmol/kg) decreased heart rate by about 30 bpm. Nociceptin, but not WIN 55,212-2 or CP-55,940 decreased the vagal bradycardia dose dependently (the inhibitory effect of 1 micromol/kg was about 40%). Nociceptin failed to modify the methacholine-induced decrease in heart rate. The OP4 receptor antagonists naloxone benzoylhydrazone 5 micromol/kg and/or [Phe1Psi(CH2-NH)Gly2]-nociceptin(1-13)NH2 0.7 micromol/kg, but not the OP(1-3) receptor antagonist naloxone 10 micromol/kg, diminished the inhibitory action of nociceptin on the neurogenic tachycardia and bradycardia. The inhibitory effect of both cannabinoid receptor agonists on the neurogenic tachycardia was abolished by the CB1 receptor antagonist SR 141716 0.1 micromol/kg. The present data suggest that the postganglionic sympathetic nerve fibres innervating the rat heart are endowed with presynaptic opioid OP4 and cannabinoid CB1 receptors, activation of which inhibits the neurogenic tachycardia. The parasympathetic nerve fibres innervating the heart and causing bradycardia are endowed with presynaptic opioid OP4 but not cannabinoid receptors.     

Involvement of endothelin in the pressor response following injection of NMDA to the periaqueductal gray area of rats.

Microinjection of N-methyl-D-aspartate (NMDA) (0.068 to 6.8 nmol) into the periaqueductal gray area (PAG) of anaesthetized rats caused dose-dependent increases in blood pressure. Preinjection (10 min before) of FR 139317 (an ETA receptor selective antagonist; 5 nmol) or SB 209670 (an ETA/ETB receptor non-selective antagonist; 5 nmol) to the PAG reduced the pressor response to NMDA whereas BQ-788 (an ETB receptor selective antagonist; 5 nmol) did not affect the NMDA-induced hypertension. Pretreatment with DL-2-amino-5-phosphono valeric acid (2-APV) (an NMDA receptor selective antagonist, 5 nmol) also abolished the pressor response induced by NMDA. Dose-dependent increases in blood pressure induced by injection of angiotensin II (0.1-10 nmol) to the PAG were unaffected by FR 139317 or SB 209670. Thus, our data indicate that endogenous ET-1, via an action on ETA receptors, contributes to the pressor effects of NMDA within the brain.     

Interaction of the beta adrenergic receptor antagonist bucindolol with serotonergic receptors

Bucindolol is a nonselective beta-adrenergic receptor antagonist that has additional vasodilating properties. Because some beta-adrenergic receptor antagonists such as cyanopindolol are used as 5-HT1A/5-HT1B receptor antagonists, we tested the hypothesis that bucindolol can interact with 5-HT receptors. Both in vitro and in vivo methods were used to examine the interaction of bucindolol with 5-HT receptors relevant to the cardiovascular system-the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptors-and with alpha1-adrenergic receptors. In binding studies, bucindolol displayed high affinity for the 5-HT1A receptor (Ki, 11 nM), modest affinity for the 5-HT2A receptor (Ki, 382 nM), and no measurable affinity for the 5-HT1D receptor; binding affinity for the 5-HT2B receptor was not studied. Bucindolol also displayed significant binding affinity (Ki, 69 nM) for the alpha1-adrenergic receptors. Alpha1-Adrenergic receptor antagonist activity was confirmed by the ability of bucindolol (1 mg/kg) to act as a competitive antagonist against 0.01-30 microg/kg phenylephrine-induced pressor responses in conscious rats. In conscious permanently instrumented rats, bucindolol (0.1-3.0 mg/kg, i.v.) did not cause bradycardia similar to that elicited by the 5-HT1A-receptor agonist 8-OH-DPAT (3-300 microg/kg, i.v.), nor did bucindolol (1 mg/kg) block the 8-OH-DPAT-induced bradycardia. Bucindolol (10(-9)-10(-5) M) did not cause relaxation in the PGF2alpha-contracted, endothelium-intact porcine coronary artery, nor did bucindolol (10(-5) M) block 5-HT-induced coronary artery relaxation, indicating that bucindolol does not have significant interactions at the 5-HT1D receptor. Bucindolol also displayed no agonist activity at the 5-HT2A and 5-HT2B receptor (endothelium-denuded rat thoracic aorta and rat stomach fundus, respectively), but did act as a weak 5-HT2A-receptor antagonist (-log K(B) [M] = 5.4+/-0.1) and 5-HT2B-receptor antagonist (-log K(B) [M] = 7.8+/-0.1). Thus, these data suggest that bucindolol lacks the ability to activate the 5-HT1A, 5-HT1D, 5-HT2A, and 5-HT2B receptor, but can block alpha1-adrenergic receptors and act as a weak 5-HT2A- and 5-HT2B-receptor antagonist. The relevance of these serotoninergic effects as it pertains to the mechanism of bucindolol-induced vasodilation is unknown.     

Incomplete inhibition of endothelin-1 pressor effects by an endothelin ETA receptor antagonist

Incomplete inhibition of endothelin-1-induced pressor effects by FR-139317, a novel, potent ET_A receptor antagonist, was observed in conscious, normotensive rats. Maximum inhibition by FR-139317 of the endothelin-1 pressor response (0.1, 0.3, 1.0 nmol/kg) was 49 ± 7, 41± 3, 62 ± 5%, respectively. Two ET_B-selective receptor ligands induced pressor responses in conscious rats. A portion of the endothelin-1 pressor response may be mediated by ET_B receptors, and ET_B-mediated vasoconstriction may contribute to incomplete inhibition of the pressor response to endothelin-1 by an ET_A-selective receptor antagonist.     

Endothelin-1-induced myocardial ischaemia and oedema in the rat: involvement of the ETA receptor, platelet-activating factor and thromboxane A2.

1. The objectives of the present experiments were to assess the role of ETA receptors in mediating endothelin-1 (ET-1)-induced myocardial ischaemia and oedema and to study the involvement of platelet-activating factor (PAF) and thromboxane A2 (TxA2) in these actions of ET-1 in rats. 2. Intravenous bolus injection of ET-1 (0.1-2 nmol kg-1) into anaesthetized rats induced ST segment elevation of the electrocardiogram in a dose-dependent manner without causing arrhythmias. ST segment elevation developed within 20-90 s and persisted for at least 10-20 min following administration of ET-1. 3. Pretreatment of the animals with the selective endothelin ETA receptor antagonist, FR 139317 (2.5 mg kg-1, i.v.) inhibited by 86% the ST segment elevation elicited by ET-1 (1 nmol kg-1). Pretreatment with intravenous administration of BM 13505 (1 mg kg-1), a TxA2 receptor antagonist, OKY-046 (10 mg kg-1), a thromboxane synthase inhibitor or the specific PAF receptor antagonist, WEB 2086 (1 mg kg-1) or BN 52021 (10 mg kg-1) markedly suppressed ST segment elevation in response to ET-1. Infusion of indomethacin (3 mg kg-1 bolus plus 2 mg kg-1 h-1) did not significantly affect ET-1-induced ST segment elevation. 4. Bolus injection of ET-1 (1 nmol kg-1, i.v.) to conscious rats resulted in a prolonged pressor effect preceded by a transient depressor response. Corresponding to changes in blood pressure, a small transient tachycardia was followed by a sustained bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Regulation of cardiovascular sympathetic neurons by substance P and gamma-aminobutyric acid in the rat spinal cord.

The spinal regulation of cardiovascular sympathetic preganglionic neurons by substance P (SP) and gamma-aminobutyric acid (GABA) was investigated in conscious rats. Intrathecal injection at the T-9 spinal level of bicuculline, a GABAA receptor antagonist, evoked increases in mean arterial pressure (MAP) and heart rate (HR) which were maximal at 5.0 and 0.5 nmol, respectively. Phaclofen, a GABAB receptor antagonist, produced no cardiovascular changes up to 2 mumol while 10 mumol evoked a rise in MAP and HR. Muscimol, a GABAA receptor agonist, produced a decrease in MAP which was maximal at 5.0 nmol and had no effect on HR. Baclofen, a GABAB receptor agonist, was without cardiovascular effects up to 5.0 nmol, while 50 and 100 nmol evoked a fall in MAP and HR. The pressor response to SP (16.25 nmol, T-9) was antagonised by 0.5-50 nmol muscimol or baclofen in a dose-related manner and the pressor response to SP was still inhibited by 40 nmol GABA in capsaicin-treated animals. However, when SP was injected at T-2, the rise in both MAP and HR was blocked by 50 nmol baclofen. Similarly, 50 nmol muscimol blocked the rise in both MAP and HR induced by 15 nmol thyrotropin-releasing hormone. In contrast, 50 nmol glycine failed to alter the cardiovascular response to SP co-injected either at T-9 or T-2. Baclofen was found to reduce significantly the basal release of epinephrine when injected at the T-9 level. These results provide pharmacological evidence for a possible tonic GABAergic inhibitory input onto cardiovascular sympathetic preganglionic neurons mediated by GABAA and GABAB receptors.     

Modulation of cardiac activity by tachykinins in the rat substantia nigra.

1. The effects of tachykinin NK(1), NK(2) and NK(3) receptor agonists and antagonists were measured on blood pressure (MAP) and heart rate (HR) after bilateral microinjection into the substantia nigra (SN) of awake, unrestrained rats. 2. Increasing doses (25 pmol - 1 nmol) of selective agonists at NK(1) ([Sar(9),Met(O(2))(11)]SP), NK(2) ([beta-Ala(8)]NKA(4 - 10)) and NK(3) (senktide) receptors into the SN produced tachycardia which was selectively and reversibly blocked by the prior injection of tachykinin antagonists at NK(1) (RP67580, 250 pmol), NK(2) (SR48968, 250 pmol) and NK(3) (R-820, 500 pmol) receptor. A rapid fall in MAP followed by a pressor response was seen with 1 nmol of [Sar(9),Met(O(2))(11)]SP. Behavioural activity was elicited by 1 nmol of [Sar(9),Met(O(2)(11)]SP (sniffing > face washing = grooming) and senktide (sniffing > wet dog shake > rearing = locomotion). Tachykinin antagonists had no direct cardiovascular or behavioural effects. 3. The tachycardia produced by 100 pmol of [beta-Ala(8)]NKA(4 - 10) or senktide was abolished by an i.v. treatment with atenolol (beta(1)-adrenoceptor antagonist, 5 mg kg(-1)) while that evoked by [Sar(9),Met(O(2))(11)]SP was reduced. A combination of atenolol (5 mg kg(-1)) and atropine (muscarinic antagonist, 1 mg kg(-1)) blocked the response evoked by [Sar(9),Met(O(2))(11)]SP. 4. These data suggest that the SN is a potential site of modulation of cardiac activity by tachykinins. In addition to the withdrawal of the cardiovagal activity by NK(1) receptor, the three tachykinin receptors appear to increase the sympatho/adrenal drive to the heart. This occurs independently of changes in MAP and behaviour. Hence, this study highlights a new central regulatory mechanism of cardiac autonomic activity.