Naloxone pretreatment blocks the hypotensive effects of atenolol in SHR and WKY rats

The present study examined the interaction of opioidergic systems in the hypotensive action of atenolol. Anesthetized, adult spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats were instrumented to monitor blood pressure and heart rate. Atenolol (100 micrograms/kg, i.v.) produced a decrease in blood pressure of similar magnitude in both SHR and WKY rats. However, the bradycardia was greater in SHR. Pretreatment with naloxone (0.1 mg/kg, i.v.) 15 min prior to the administration of atenolol completely prevented the hypotensive response in SHR and decreased the maximum hypotensive response by approximately 50% in WKY rats. The atenolol-induced bradycardia was unaffected in both groups of animals. Additionally, pretreatment with yohimbine, an alpha 2-receptor antagonist, inhibited the hypotensive response of atenolol in SHR. Collectively, these results suggest an interaction between opioidergic and catecholaminergic systems as a possible site of action of antihypertensive drugs.     

Antihypertensive effect of naftopidil (KT-611), a novel alpha 1-adrenoceptor antagonist, in freely moving experimental hypertensive rats and dogs

The antihypertensive effect of naftopidil (KT-611) following single oral administration was investigated in normotensive Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), DOCA-Salt hypertensive rats (DHR), 2-kidney 1-clip renal hypertensive rats (RHR) and Grollman type renal hypertensive dogs with 1-kidney (RHD); and it was compared with that of the selective alpha 1-adrenoceptor antagonist prazosin. The blood pressure and heart rate were measured under the unanesthetized, unrestrained state through an arterial catheter that was chronically implanted into the abdominal aorta. In SHR and WKY, both KT-611 (10 and 30 mg/kg, p.o.) and prazosin (1 and 3 mg/kg, p.o.) markedly inhibited the pressor response to the alpha 1-adrenoceptor agonist phenylephrine (3 micrograms/kg, i.v.). KT-611 (10 to 100 mg/kg, p.o.) showed a dose-dependent hypotensive effect in SHR, DHR and RHR but not in WKY. The hypotensive effect of KT-611 reached maximum at 0.5-1 hr, lasted for 4-6 hr and was more potent in DHR and RHR than in SHR. The potency of KT-611 was 1/10-1/30 weaker than that of prazosin. In RHD, single oral administration of KT-611 (1 to 10 mg/kg) caused a dose-dependent and long-lasting hypotensive effect. These results suggest that KT-611 has a long-lasting hypotensive effect in experimental hypertensive animal models.     

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.     

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on tissue ACE activity in normotensive, spontaneously hypertensive, and renal hypertensive rats

Effects of an angiotensin-converting enzyme (ACE) inhibitor, SA446, on the renin-angiotensin system, particularly on tissue ACE activity, were studied in Wistar-Kyoto normotensive rats (WKY), spontaneously hypertensive rats (SHR), and two-kidney, one-clip renal hypertensive rats (RHR) by repeated oral administration for 7 days. SA446 (45 mg/kg/day p.o.) inhibited ACE activity in the lung, brain, kidney, heart, and whole blood throughout the administration period in WKY, but showed a slight hypotensive action and no inhibition of aorta ACE activity. On the other hand, SA446 had an apparent hypotensive action at the same dose in SHR and inhibited ACE activity significantly in the aorta as well as the kidney and whole blood during the administration period. Furthermore, enzyme activity in the aorta, kidney, heart, and whole blood was also inhibited at a hypotensive dose of SA446 (10 mg/kg/day p.o.) in RHR. The inhibition in whole blood and kidney was almost complete, and the inhibition in the aorta was greater on day 7 than on day 1. The maximum decrease of blood pressure was correlated with the maximum inhibition in aorta ACE activity, but not in brain, lung, or heart ACE activity. In addition, a good positive correlation was observed between the basal blood pressure and the basal aorta ACE activity in WKY, SHR, and RHR, although there was no correlation in the brain, lung, kidney, heart, or whole blood. These results suggest that the antihypertensive action of SA446 by repeated administration may be due to inhibition of arterial ACE activity in addition to inhibition of plasma and kidney ACE activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of opioidergic component in the antihypertensive effect of clonidine

The role of opioidergic system in the antihypertensive effect of clonidine was investigated in albino normotensive and renal-DOCA-salt hypertensive models of rats. Clonidine (2.5, 5 and 10.0 micrograms/kg, iv) produced a dose-related depressor response. Yohimbine (2 mg/kg, ip) blocked the clonidine-induced responses in both normotensive and hypertensive rats. Naloxone (2 mg/kg, iv) blocked the clonidine-induced depressor responses in hypertensive rats, but not in normotensive animals. Morphine (0.11 mg/kg, iv) produced a depressor response in both normotensive and hypertensive rats. Yohimbine (1 mg/kg, iv) did not affect the hypotensive effect of morphine in normotensive or hypertensive rats, whereas pretreatment with naloxone significantly blocked the hypotensive effect of morphine in both groups of animals. It is concluded that the hypotensive effect of clonidine in hypotensive rats could be due to an opioidergic mechanism since it is blocked by both naloxone and yohimbine.     

Effect of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the blood pressure in rats (author's transl)]

The effects of acebutolol, a cardioselective beta-adrenoceptor blocking agent, on the systolic blood pressure and heart rate were investigated in conscious Kyoto Wistar normotensive rats (WKY), spontaneously hypertensive rats (SHR) and DOCA-NaCl hypertensive rats (DOCA rats) and the results compared with those of propranolol and practolol. In WKY and DOCA rats, the intraperitoneal administration of acebutolol, propranolol and practolol (0.5 approximately 20 mg/kg) produced a hypotensive action, however, these effects were observed only with restricted doses and there was no evidence of a dose-dependency. The heart rate was decreased by acebutolol and propranolol, but was increased by practolol which possesses an intrinsic sympathomimetic activity. In SHR, propranolol produced a dual action, a slight rise followed by a slight fall, the change not being significant, while practolol induced a slight hypertension. On the other hand, acebutolol in high doses induced a dose-dependent hypotensive action. The heart rate was markedly and dose-dependently decreased by these three agents. Thus, while propranolol and practolol produced hypotensive effects in WKY and DOCA rats, acebutolol produced hypotensive effects in WKY, SHR and DOCA rats. These results suggest that acebutolol is a beta-adrenoceptor blocking agent which possesses hypotensive activity in hypertensive rats.     

Effect of nebivolol on beat-to-beat and short-term blood pressure variability in spontaneously hypertensive rats

Cardiovascular effects and pharmacokinetics of nebivolol were assessed in spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) animals. Male SH and WKY rats were treated with vehicle or nebivolol 0.3, 3, or 10 mg kg(-1) (i.v.) and effects on blood pressure (BP), heart rate, and blood pressure variability (BPV) were recorded. Plasma pharmacokinetics of d- and l-nebivolol was studied by traditional blood sampling. Short-term and beat-to-beat BPV was assessed by standard deviation and spectral analysis of BP recording, respectively. Nebivolol showed enantioselective pharmacokinetics in both experimental groups; clearance of l-nebivolol was significantly greater than d-enantiomer. Clearance of nebivolol was significantly reduced in SHR with regards to WKY animals. Hypotensive response to nebivolol 3 and 10 mg kg(-1) was significantly enhanced in SHR compared with normotensive animals. Spectral analysis of beat-to-beat BPV showed a greater reduction in low frequency BPV in SHR than in WKY rats. Nebivolol 3 and 10 mg kg(-1) significantly reduced ratio low frequency/high frequency BPV only in SHR. Short-term BPV was markedly reduced by nebivolol 0.3, 3, and 10 mg kg(-1) in WKY and SHR. In conclusion, the hypertensive stage in SHR modifies nebivolol pharmacokinetic properties and enhances its hypotensive response due to a greater attenuation in vascular sympathetic activity and enhancement of endothelial-derived NO activity. Nebivolol markedly attenuates short-term BPV in both experimental groups providing beneficial cardiovascular effects by both controlling high blood pressure and its short-term variability.     

Age-related hypotensive effect of atropine in unanesthetized spontaneously hypertensive rats

Intravenous injection of atropine (0.5–20 mg/kg) produced a dose- and age-dependent decrease in the mean arterial pressure (MAP) of conscious spontaneously hypertensive (SH) rats 11–20 weeks of age. No effect on blood pressure occurred in age-matched Wistar-Kyoto (WKY) controls; however, heart rate was increased in both groups. In contrast to atropine, the same doses of methylatropine increased MAP and heart rate in both SH and WKY rats. Methylatropine also failed to modify the hypotensive effect of atropine in SH rats. The difference between the effects on blood pressure of atropine and methylatropine in SH rats was not seen when the animals were anesthetized with pentobarbital. In this case both agents reduced MAP. Intracerebroventricular (i.c.v.) injection of atropine in doses up to 200 μg in SH rats failed to modify MAP and was without effect on the hypotensive response to intravenous injection of atropine. Likewise, i.c.v. injection of hemicholinium-3 (which reduced MAP in SH rats) failed to modify the hypotensive effect of atropine. However, intravenous injection of atropine (10 mg/kg) prevented the hypotensive effect of hemicholinium-3. Theser results are discussed in terms of central and peripheral muscarinic mechanisms.     

Involvement of central dopamine receptors in the hypotensive action of pergolide

The involvement of central dopamine receptors in the hypotensive action of the dopaminergic ergoline, pergolide was determined in anesthetized rats. Intravenous (i.v.) or intracerebroventricular (i.v.t.) administration of pergolide (12.5, 25 and 50 micrograms/kg) produced dose-dependent decreases in blood pressure. The magnitude of hypotension seen following either i.v. or i.v.t. administration of pergolide was similar. However, while both sulpiride (1 mg/kg, i.v.) as well as phentolamine (1 mg/kg, i.v.) antagonized the hypotensive action of i.v. pergolide, only sulpiride (1 mg/kg, i.v.t.) was able to antagonize the hypotension seen following i.v.t. administration of pergolide. Phentolamine (1 mg/kg, i.v.t.) did not alter the central hypotensive action of pergolide. In a separate group of rats, clonidine (25 micrograms/kg, i.v.t.) also produced a decrease in blood pressure. While phentolamine (i.v.t.) antagonized the central hypotensive action of clonidine, sulpiride (i.v.t.) did not have any effect on the action of clonidine. These results show that selective activation of central dopamine receptors was responsible for the hypotensive action of centrally-administered pergolide. In a separate group of rats greater splanchnic sympathetic nerve activity was measured. Intravenous pergolide produced similar hypotensive response as seen in previous groups, and this was accompanied by a concomitant decrease in the sympathetic nerve activity. The maximum fall in blood pressure (26 +/- 6 mm Hg) was correlated with a 40% reduction in sympathetic nerve activity. The return of blood pressure to control levels occurred after 60-70 min and was also associated with the return of sympathetic nerve activity to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effect of arotinolol (S-596), a new adrenergic beta blocking agent, on experimental hypertension

Effects of a new adrenergic beta-blocking agent, arotinolol (S-596), on the blood pressure and heart rate were assessed in comparison with those of other beta-blocking agents in deoxycorticosterone acetate (DOCA)-saline induced and spontaneously hypertensive rats (SHR). The relationship between the antihypertensive effect and the beta- or alpha-adrenoceptor blocking action of S-596 was also investigated in normotensive conscious rats. In the rat, a cannula was implanted chronically in a femoral artery, from which blood pressure was recorded. The test drugs were administered orally once a day for 14 days at several dose levels. The development of hypertension in DOCA-saline treated rats was clearly retarded with the consecutive oral administration of propranolol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day), but not with S-596 (20, 50 and 100 mg/kg/day) or pindolol (10 mg/kg/day). On the other hand, in SHR, S-596 (more than 10 mg/kg/day) propranolol (50 mg/kg/day), pindolol (10 mg/kg/day), labetalol (100 mg/kg/day) and hydrochlorothiazide (10 mg/kg/day) produced definite antihypertensive effects after the chronic administration. In normotensive conscious rats, the vasodepressor responses induced by isoproterenol were reduced by the beta-blocking agents at lower dose levels than those required for development of antihypertensive effects. The acute effects on blood pressure were determined in hypertensive rats during the chronic treatment with the test drugs. In either type of hypertension, S-596, (10-50 mg/kg/day) showed a depressor effect at 4 and/or 8 hr after administration. In normotensive conscious rats, S-596 antagonized the pressor responses to phenylephrine at doses more than 30 mg/kg. It is therefore suggested that an adrenergic alpha-blocking property is at least partly involved in the hypotensive effect of S-596 as labetalol. In the experiment of acute effect in SHR, pindolol and labetalol showed prominent hypotensive effect after the 1st administration, but lesser effect after the 10th administration. Propranolol showed a marked rise in blood pressure in this experiment.     

HYPOTENSIVE EFFECTS OF CAPTOPRIL ADMINISTERED CENTRALLY IN INTACT CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS AND PERIPHERALLY IN ANEPHRIC ANAESTHETIZED SPONTANEOUSLY HYPERTENSIVE RATS

1. The hypotensive response to captopril in anaesthetized spontaneously hypertensive rats (SHR) is not modified by bilateral nephrectomy performed 1 or 24 h previously. 2. Intracerebroventricular injection (i.c.v.) of captopril (2 mg kg^?1) significantly lowered blood pressure of conscious SHR over a 7-h period of observation but there was no significant blood pressure response to i.c.v. vehicle, or to intravenous captopril (2 mg kg^?1) in SHR. 3. There was no significant blood pressure response to captopril (2 mg kg”') i.c.v. in the normotensive Wistar Kyoto controls (NT-WK). 4. These results indicate that captopril can lower the blood pressure of SHR by mechanisms independent of the kidneys or the circulating renin-angiotensin system. 5. The hypotensive effect of central captopril in SHR but not in the NT-WK suggests biochemical differences between the brains of the two rat strains.     

Beta-endorphin: a common factor in the antihypertensive action of clonidine-type imidazolines in spontaneously hypertensive rats

The hypotensive action of two novel imidazolinic alpha-adrenergic agonists (ICI-106270 and UK-14304) with similar pharmacological properties to clonidine was shown in spontaneously hypertensive (SH) rats. The antihypertensive effect of the clonidine-type agents was prevented by either peripheral administration of the opiate antagonist naloxone or by intracerebroventricular (i.c.v.) injection with a specific antibody against human beta-endorphin (BEN). A dose-response relationship was found for the hypotensive effect of i.c.v. given BEN in SH rats, the low blood pressure being significantly reversed by further treatment with either naloxone or anti-beta h-endorphin. These data confirm and extend the notion of a BEN mediation in the antihypertensive action of clonidine-type alpha-adrenergic agonists in SH rats.     

Effect of ketanserin on blood pressure in rats

Ketanserin, a selective serotonergic (5-HT2) antagonist, also has affinity for alpha 1-adrenoceptors. It is not clear whether the hypotensive mechanism of ketanserin is due to its antagonistic action to 5-HT2 receptor or to its affinity for alpha 1 adrenoceptors. The hypotensive mechanism of ketanserin was studied in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY). Anesthetized rats were used (alpha-chloralose + urethane, i.p.). Up to 3 ml of blood was drawn from each rat for analysis. Plasma norepinephrine (NE) was determined by radioenzymatic assay. Plasma serotonin (5-HT) was determined by HPLC-ECD. Adrenal nerve discharges were counted by a digital pulse counter. Ketanserin (0.5 mg/kg, 5.0 mg/kg, i.v.) produced a dose-dependent reduction of mean arterial pressure (MAP) in both SHRSP and WKY. MAP of SHRSP decreased significantly as compared with WKY. Both plasma NE and 5-HT showed a tendency to increase during ketanserin administration (5.0 mg/kg, i.v.). Ketanserin significantly antagonized the BP response induced by exogenously injected 5-HT (30 micrograms/kg) and NE (10 micrograms/kg). Adrenal nerve activity was reduced in parallel with the decrease in BP and HR. These findings suggest that ketanserin produced a decrease in BP via both peripheral and central action in rats.     

Effects of brain natriuretic peptide-45, a circulating form of rat brain natriuretic peptide, in spontaneously hypertensive rats.

Rat brain natriuretic peptide-45 (rat BNP-45) has recently been isolated from rat heart and shown to be a circulating form of rat BNP. We investigated the effects of rat BNP-45 in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) and compared them with those of rat alpha-atrial natriuretic peptide (alpha-ANP). BNP-45 was a potent natriuretic and hypotensive agent in both strains. The effects were comparable with those of alpha-ANP and were far greater than those of porcine BNP-26 reported previously. In SHR blood pressure decreased more than in WKY following injection of the highest dose (2.0 nmol/kg) of BNP-45 or alpha-ANP. However, WKY were more susceptible than SHR to BNP-45 for diuresis, natriuresis and urinary cGMP excretion. Moreover, a high dose of BNP-45 led to a prolonged lowering of blood pressure and urinary cGMP excretion compared to alpha-ANP, and these features were prominent in WKY. BNP-45 disappeared more slowly than alpha-ANP when the two peptide (2.0 micrograms) were injected i.v. in WKY. Thus, rat BNP-45 and alpha-ANP had comparable hypotensive and natriuretic potency; however, the action and plasma half-life of rat BNP-45 were more prolonged.     

Cardiovascular effects of leukotriene D4 in SHR and WKY rats

Leukotriene D4 (LTD4, 0.8-4 micrograms/kg i.a.) increased blood pressure and heart rate of conscious SHR and WKY rats. LTD4, 20 micrograms/kg (i.a.), caused a short lasting increase in blood pressure and heart rate in WKY. In SHR, LTD4, 20 micrograms/kg (i.a.) caused a triphasic effect: hypotension and bradycardia (0.5-1 min), hypertension and tachycardia (2-5 min) and prolonged hypotension and bradycardia (5-180 min). Leukopenia was observed after LTD4, 20 micrograms/kg in both groups of rats but platelets count was unaffected. These results show that SHR are mor sensitive than WKY to the hypotension-bradycardia effect of LTD4.     

Effect of captopril on converting enzyme activity in chemically sympathectomized, spontaneously hypertensive rats

Effect of subacute angiotensin converting enzyme (ACE) blockade on the converting enzyme activity (ACE activity) in plasma, aorta, lung, kidney and whole brain was evaluated in chemically-sympathectomized (with 6-hydroxydopamine) normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) using captopril given peripherally via the intraperitoneal (i.p) route and centrally through intracerebroventricular (i.c.v.) administration. Daily i.p. injection of 25 mg/kg for 8 days reduced the blood pressure of both WKY rats and SHR, and the ACE activity in the aorta, lung and plasma of both WKY rats and SHR were correspondingly depressed. The brain ACE activity remained unaltered in both strain of rats. The ACE activity in the kidney of WKY was depressed, while that of SHR remained unchanged. These observations are independent of peripheral sympathectomy with 6-hydroxydopamine (6-OHDA). Daily central captopril administration at a dose of 2 mg/kg, i.c.v., for 8 days significantly reduced the blood pressure of SHR but not WKY rats, whereas the ACE activity of the whole brain of both WKY and SHR were depressed. Central sympathectomy with 6-OHDA did not alter these responses. It is concluded that captopril exerts its antihypertensive effect not only via reduction of the ACE activity in the plasma and lungs as reported earlier, but also that of other organs, principally the aorta, and that these effects are independent of the sympathetic nervous system.     

Prominent depressor response to endothelin in spontaneously hypertensive rats

Administration of endothelin (0.03-3.0 micrograms/kg i.v.) caused transient depressor responses followed by sustained pressor responses in anesthetized spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). The initial depressor response occurred at lower doses (0.1 versus 0.3 micrograms/kg i.v.) in SHR versus WKY. The secondary pressor response was attenuated in SHR compared to WKY in both the threshold dose (3.0 versus 0.1 microgram/kg i.v.) and maximum effect at high doses (52 versus 91% at 3.0 micrograms/kg i.v.). In conscious SHR and WKY, endothelin elicited comparable initial depressor responses with increases in heart rate; the secondary pressor responses were attenuated compared to those in anesthetized rats. Therefore endothelin elicits a prominent depressor response, which may be associated with afterload reduction, in SHR.     

Acute tolerance to the hypotensive effect of pindolol in spontaneously hypertensive rats (SHR)

The development and mechanism of acute tolerance to hypotension produced by pindolol in conscious SHR were examined. At a daily dose of 3 mg/kg, i.p., the hypotensive effect of pindolol (50 +/- 4 mmHg) on the first day was attenuated to 12 +/- 2 mmHg on the fourth day. The development of this acute tolerance was not reduced by combined administration with captopril or trichlormethiazide. The hypotensive effect of pindolol was not reduced by repeated administration of isoproterenol. Thus, activation of the renin-angiotensin system, fluid retention and beta-adrenoceptor subsensitivity seemed to be ruled out from the mechanism of this acute tolerance to pindolol. SHR tolerant to pindolol displayed marked hypotensive effects to prazosin, clonidine, hydralazine, nifedipine and captopril, which were similar to those in saline-treated SHR. However, the depressor response to isoproterenol was markedly reduced in SHR tolerant to pindolol. The correlation between the hypotensive responses to isoproterenol (X) and pindolol (Y) in these SHR could be expressed by: Y = 1.00 X + 0.56, gamma = 0.837 (P less than 0.001). Therefore, acute tolerance to pindolol seemed to be mainly due to "autoblockade" by the remaining pindolol in the body.     

Antihypertensive activity of the aqueous extract of Retama raetam Forssk. leaves in spontaneously hypertensive rats

The antihypertensive and diuretic effects of the aqueous extract of Retama raetam Forssk. (RR) leaves were studied in both normotensive (WKY) and spontaneously hypertensive rats (SHR). In SHR rats, daily oral administration of RR (20 mg/kg) for three weeks exhibited a significant reduction in blood pressure. The systolic blood pressure decreased significantly from the seventh day (P < 0.01) and persisted through the end of treatment (P < 0.001) in SHR rats. The RR significantly enhanced the diuresis in WKY rats (P < 0.001). Furthermore, oral administration of RR at a dose of 20 mg/kg produced a significant increase on urinary excretion of sodium (P < 0.05), potassium (P < 0.01) and chlorides (P < 0.01) in SHR rats. In WKY rats, RR treatment induced a significant increase on urinary potassium elimination (P < 0.05) without affecting sodium and chloride excretion. Irbesartan (Avapro) 20 mg/kg (body weight), an angiotensin II receptor antagonist, was used as reference drug. No significant changes were noted in heart rate after RR treatment in SHR as well as in WKY rats. Glomerular filtration rate showed a significant increase after RR administration in WKY rats (P < 0.01) and a no significant increase in SHR rats. These results suggest that oral administration of aqueous RR extract exhibited antihypertensive and diuretic effects in SHR rats and diuretic action in WKY rats.     

The central sympatho-inhibitory effect of 5,6-dihydroxy-2-dimethylaminotetralin (M7) is mediated by α2-adrenoceptors

M7 (5,6-dihydroxy-2-dimethylaminotetralin) produces in anesthetized rats a hypotensive response previously attributed to peripheral dopaminergic mechanisms. We re-examined the effects of this drug on arterial blood pressure, heart rate and sympathetic nerve activity in anesthetized rats and dogs. M7 (1–100 μg/kg i.v.) produced in the rats transient dose-dependent pressor effects, with bradycardia and sympatho-inhibition, followed by long-lasting dose-dependent hypotension, bradycardia and sympatho-inhibition. The sympatho-inhibitory and hypotensive effects were comparable in baroreceptor-denervated rats and were reversed by idazoxan (0.1 mg/kg i.v.). The sympatho-inhibitory response induced by M7 (1–100 μg/kg) was prevented by treatment with the specific α₂-adrenoceptor antagonist, 2-methoxy-idazoxan (0.03 mg/kg i.v.). This central effect of M7 was not altered by treatment with the α₁-adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.) and was reduced by treatment with the α₂-adrenoceptor antagonists, yohimbine (1 mg/kg i.v.) or idazoxan (0.3 mg/kg i.v.), and the dopaminergic antagonists, haloperidol (0.5 mg/kg i.v.) or sulpiride (3 mg/kg i.v.). Bilateral microinjections of M7 (0.3–3 nmol) into the rostroventral medulla in the rat produced dose-dependent hypotension, bradycardia and sympathetic nerve inhibition which were reversed and prevented by bilateral microinjection of 2-methoxy-idazoxan (1 nmol) into the same sites. Microinjections of 2-methoxy-idazoxan into the rostroventral medulla also inhibited the central effects of M7 at 0.03 mg/kg i.v. In anesthetized dogs, M7 administered into the cisterna magna (1–10 μg/kg) reduced arterial blood pressure, heart rate and sympathetic nerve activity; these effects were reversed by administration of 2-methoxy-idazoxan (0.03 mg/kg i.v.). In conclusion, M7, a rigid catecholamine, produces a potent central sympatho-inhibitory and hypotensive effect by activation of α₂-adrenoceptors.