DEMONSTRATION OF α-ADRENOCEPTOR ANTAGONISM BY THE 5HT2 ANTAGONIST, KETANSERIN (R49945), IN SHEEP

Serotonin causes a dose related (0.1-20 micrograms/kg i.v.) increase in mean arterial blood pressure (MAP) and heart rate in conscious sheep. Ketanserin (0.1 mg/kg per h i.v.) causes a decrease in blood pressure, and an increase in heart rate. In the presence of ketanserin, serotonin induced increases in MAP are attenuated, or abolished, but the increases in heart rate are enhanced. Ketanserin (10 mg/kg per h i.v.) attenuates or abolishes the increase in blood pressure induced by the alpha-adrenoceptor agonist phenylephrine in conscious sheep. When administered in the presence of the alpha-adrenoceptor antagonist prazosin, ketanserin (0.1 mg/kg per h i.v.) fails to induce a further hypotensive response. These data suggest that in the conscious sheep ketanserin exhibits predominantly alpha-adrenoceptor antagonism.     

AN INVESTIGATION INTO THE MECHANISMS OF THE CARDIOVASCULAR EFFECTS OF 5-HYDROXYTRYPTAMINE IN CONSCIOUS NORMOTENSIVE AND DOCA-SALT HYPERTENSIVE RATS

• 1 The actions of intravenously administered 5-hydroxytryptamine (5-HT) have been analysed in conscious DOCA-salt hypertensive rats using selective 5-HT receptor agonists and antagonists to determine the receptor mechanisms involved and to compare them with those in conscious normotensive rats.
• 2 In both normotensive and hypertensive rats 5-HT, 3 and 10 μg i.v., produced a complex triphasic effect on blood pressure consisting of an initial short lasting depressor response, which was followed by a pressor response and then, finally, a hypotensive phase. Marked decreases in heart rate were observed immediately after dosing, which were followed by small increases in rate.
• 3 The selective 5-HT₃-receptor agonist, 2-methyl 5-HT, 3–30 μg i.v., produced immediate and marked dose-related decreases in blood pressure and heart rate in both normotensive and DOCA-salt hypertensive rats. The 5-HT₃-receptor antagonist, MDL 72222, 0.03 and 0.1 mg/kg i.v., antagonised these effects in both normotensive and DOCA-salt hypertensive rats. Treatment with MDL 72222, 0.3 mg/kg i.v., abolished the initial depressor response and bradycardia produced by 5-HT.
• 4 The 5-HT₂ receptor agonist, α-methyl 5-HT, 3–30 μg i.v., produced dose-related increases in blood pressure which were significantly greater in magnitude in DOCA-salt hypertensive than normotensive rats. Bradycardia was observed consistently at 30 μg only. The 5-HT₂ receptor antagonist, ketanserin, 0.03-0.3 mg/kg i.v., caused a dose-dependent antagonism of the pressor responses produced by α-methyl 5-HT, but had no effect on the increases in blood pressure produced by angiotensin. Ketanserin also antagonised the pressor responses produced by 5-HT in rats pretreated with MDL 72222.
• 5 5-Carboxamidotryptamine (5-CT), the selective ‘5-HT₁-like’ receptor agonist, at doses of 0.1–3 μg i.v. produced dose-related decreases in blood pressure which were more pronounced in the DOCA-salt hypertensive rats than in normotensive rats. These depressor responses were dose-dependently antagonised by methiothepin, 0.3 and 1 mg/kg, i.v. which did not antagonise the depressor responses produced by isoprenaline 0.1 μg/kg i.v. In rats pretreated with MDL 72222 and ketanserin, 5-HT produced dose-related depressor responses which were also antagonised by methiothepin 1 mg/kg i.v. and presumably mediated by 5-HT₁-like receptors.
• 6 In this study, selective 5-HT receptor agonists and antagonists have been used to mimic and block, respectively, the various phases of the 5-HT response. It is concluded that in the conscious rat, the complex cardiovascular effects of 5-HT involve stimulation of at least three different 5-HT receptors (for nomenclature see Bradley, Engel, Feniuk, Fozard, Humphrey, Middlemiss, Mylecharane, Richardson & Saxena, 1986). The initial depressor response and bradycardia involves activation of 5-HT₃-receptors, the secondary vasopressor effect, which is significandy greater in DOCA-salt than normotensive rats results from stimulation of 5-HT₂ receptors and the late vasodepressor response is due to vasodilatation via ‘5-HT₁-like’ receptors.

     

Intrinsic pressor activity of midaglizole, an alpha-2 adrenoceptor antagonist, in pithed rats

Midaglizole (3 and 30 mg/kg, i.v.) increased blood pressure in pithed rats. The pressor response was not inhibited by intravenous prazosin (0.3 mg/kg), yohimbine (1 mg/kg), ketanserin (1 mg/kg) or diphenhydramine (5 mg/kg). Diltiazem (1 mg/kg) antagonized the hypertension. Idazoxan (10 mg/kg) also increased blood pressure, and the pressor response was inhibited by prazosin, but not by yohimbine. These results suggest that the vascular effect of midaglizole is due to a mechanism different from that of idazoxan.     

Influence of acute and chronic ethanol administration on the vasopressor effect of serotonin in pithed rats

In pithed rats, the intravenous administration of serotonin (3, 10, 30, 100, 300 and 1,000 micrograms/kg) produced a dose-dependent increase in blood pressure. This action of 5-HT was not changed by chronic ethanol intoxication (6.0 g/kg/day for 2 weeks). The pressor responses to serotonin were, in a dose-dependent manner, significantly reduced by acute ethanol administration (0.5, 1.0, 2.0 and 4.0 g/kg p.o.) and by ketanserin injection (0.03 mg/kg i.v.). However, ethanol (2.0 g/kg) did not amplify the dilator effect of serotonin in pithed rats pretreated with ketanserin (3.0 mg/kg i.v.). We also demonstrated that, in contrast to ketanserin (10(-7) mol/l), ethanol (0.05 mol/l) potentiated the serotonin-induced vasoconstriction of isolated rat tail arteries. These data suggest that the action of ethanol on the vasopressor effect of serotonin in pithed rats does not depend on its influence on serotonergic receptors in blood vessels.     

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.     

Acute cardiovascular effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in anaesthetised normotensive rats

This is the first study of the in vivo potential activity of (+)-nantenine (a natural aporphinoid alkaloid) on the rat cardiovascular system. In anaesthetized normotensive rats, acute intravenous ( i. v.) administration of (+)-nantenine (3 - 6 mg/kg) produced a dose-dependent fall in mean arterial pressure (MAP), accompanied by a significant decrease in heart rate (HR). In addition, (+)-nantenine (5 mg/kg i. v.) did not modify the cardiovascular effects induced by angiotensin II (0.2 microg/kg i. v.) and the selective alpha (2)-adrenoceptor agonist B-HT 920 (0.2 mg/kg i. v.) [unlike nifedipine (0.8 mg/kg i. v.) and yohimbine (1 mg/kg i. v.), respectively] but markedly attenuated [like prazosin (0.2 mg/kg i. v.)] the hypertension evoked by phenylephrine (PE, 25 microg/kg, i. v.), a selective alpha (1)-adrenergic receptor agonist and, like ketanserin (1 mg/kg i. v.), the second phase (rise in MAP) of the cardiovascular response caused by 5-hydroxytryptamine (5-HT, 0.3 mg/kg i. v.). On the other hand, pre-treatment of anaesthetised rats with NG-nitro- L-arginine ( L-NOARG, 5 mg/kg i. v.) did not significantly affect the cardiovascular effects of (+)-nantenine. These results indicate that the hypotension and bradycardia elicited by this aporphine alkaloid in anaesthetised normotensive rats seem to be due, at least in part, to a combined alpha (1)-adrenergic and 5-HT (2A) receptor blockade but not to the release of nitric oxide (NO) from vascular endothelium, to an alpha (2)-adrenoceptor antagonism or to a calcium antagonist activity. Abbreviations. BP:blood pressure HR:heart rate 5-HT:5-hydroxytryptamine i. v.:intravenous L-NOARG: NG-nitro- L-arginine MAP:mean arterial pressure NO:nitric oxide PE:phenylephrine     

Study of the in vivo and in vitro cardiovascular effects of four new analogues of ketanserin: implication of 5-HT2A and alpha1 adrenergic antagonism in their hypotensive effect

The in vivo and in vitro cardiovascular effects of the novel 5-HT2A/alpha1/H1 antagonist ketanserin analogues QF 0303B, QF 0307B, QF 0311B, QF 0313B were studied in anaesthetized normotensive rats (ANR) and in isolated rubbed rat aorta (IRRA). In ANR, 0.2 mg x kg(-1) i.v. of each compound produced a rapid, remarkable but short-lasting fall in mean arterial blood pressure (MAP) accompanied by bradycardia. All compounds significantly modified the pressor effects induced by 5-hydroxytryptamine (5-HT) and noradrenaline (NA). In IRRA, the compounds inhibited NA- and 5-HT-induced contractions in a competitive fashion. Furthermore, the analogues displayed lower H1-antagonist activity than ketanserin. Compounds tested showed low 5-HT2B affinity and no activity at muscarinic, nicotinic, or 5-HT3 receptors, nor any marked ability to produce smooth muscle relaxation via calcium entry blockade. There is a significant correlation between hypotension reached and inhibition of the 5-HT-induced pressor responses (but not for NA). A certain degree of correlation was observed between hypotensive effect endurance vs. alpha1-adrenoceptor blockade (but not for serotonin). These results indicate that in this series the brief hypotensive activity in ANR is attributed to a 5-HT1A receptor blockade and the duration of the effect is better attributed to an alpha1 adrenoceptor blockade.     

Hypotensive effect in dogs and rats of intravenous injections of the alpha 1-adrenoreceptor antagonist benoxathian

The hypotensive effect of the alpha 1-adrenoreceptor antagonist benoxathian has been evaluated in rats and dogs, in comparison to that evoked by WB 4101 and prazosin. In anaesthetized dogs, i.v. injection of benoxathian (25-100 micrograms/kg), WB 4101 (5-25 micrograms/kg) and prazosin (50 micrograms/kg) produced an immediate fall in diastolic blood pressure, which reached a maximum at about 30 sec after drug administration. Whereas the hypotensive effect of prazosin persisted up to 3 hr following injection, the effect of both benoxathian and WB 4101 completely disappeared after 30-60 min. The hypotensive effect of benoxathian was dose-dependent. Pressor responses to i.v. noradrenaline (5 micrograms/kg), adrenaline (5 micrograms/kg) and phenylephrine (20 micrograms/kg) were markedly inhibited (60-75%) by benoxathian (100 micrograms/kg) whilst the pressor response to angiotensin II (0.05 micrograms/kg) was not reduced, but indeed slightly increased. The hypotensive effect of benoxathian (100 micrograms/kg) was abolished following pre-treatment with prazosin (50 micrograms/kg) or hexamethonium (1000 micrograms/kg). In anaesthetized rats similar results were obtained although recovery in blood pressure from the initial drop after i.v. injection of the drugs was slower than in dogs. Benoxathian was slightly more toxic than WB 4101 in rats. In conclusion, present findings show that benoxathian causes a profound hypotensive effect in dogs and in rats through postsynaptic alpha-adrenoreceptor blockade; however its effect, as well as that of WB 4101, is shorter lasting than that of prazosin.     

Effects of ketanserin on hemodynamics and baroreflex effects in conscious spontaneously hypertensive rats

Ketanserin is an antihypertensive compound that binds to 5-HT2 receptors as well as to alpha 1-adrenoceptors. The relative importance of the two pharmacological interactions is still unclear. In the present study we compared the central hemodynamic effects of ketanserin with those of the alpha 1-adrenoceptor antagonist prazosin in conscious, unrestrained spontaneously hypertensive rats (SHR). Both drugs rapidly reduced mean arterial pressure (0.1 mg/kg prazosin, -22 +/- 3%; 3 mg/kg ketanserin, -27 +/- 4%) and total peripheral resistance (30 +/- 4 and 26 +/- 4%, respectively). The compounds differed with respect to their effects on heart rate and cardiac output, which increased following prazosin treatment and did not change following ketanserin administration. To investigate involvement of the baroreflex in the latter phenomenon, SHR were challenged with angiotensin II and sodium nitroprusside to increase and decrease blood pressure. Ketanserin did not influence bradycardia following elevation of blood pressure. However, reduction of blood pressure with nitroprusside following ketanserin treatment resulted in extreme vagal bradycardia. This phenomenon was not observed following administration of other antihypertensive agents or serotonin antagonists in SHR. We conclude that this latter interaction with the baroreflex is specific for ketanserin and that it may substantially contribute to its antihypertensive effect. The exact pharmacological mechanism underlying this effect is still under investigation.     

Haemodynamic effects of dicentrine, a novel alpha 1-adrenoceptor antagonist: comparison with prazosin in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

1. The haemodynamic effects of dicentrine, an aporphine derivative isolated from the plant Lindera megaphylla, were investigated and compared with prazosin in rats. 2. In anaesthetized normotensive Wistar-Kyoto (WKY) rats, i.v. administration of dicentrine (0.1, 0.5, 1.0 mg kg-1) and prazosin (0.01, 0.05, 0.1 mg kg-1) induced a dose-related reduction of mean arterial pressure (MAP) which reached a maximal effect 5-10 min after injection and persisted for 2 h. 3. In anaesthetized WKY rats, a higher dose of dicentrine (1.0 mg kg-1, i.v.) did not cause any significant changes in heart rate (HR), cardiac output (CO) and stroke volume (SV) but markedly increased tail blood flow. In contrast, a higher dose of prazosin (0.1 mg kg-1, i.v.) produced a decrease in HR which paralleled the time course of the hypotensive response. 4. The hypotensive activity of dicentrine was completely abolished by alpha-adrenoceptor blockade. Both dicentrine and prazosin significantly attenuated pressor responses to noradrenaline but failed, even at maximal hypotensive doses, to impair the pressor effects of angiotensin II or vasopressin. These observations suggest that dicentrine appears to exert its hypotensive action through alpha 1-adrenoceptor blockade. 5. In conscious normotensive and spontaneously hypertensive (SH) rats, dicentrine (0.5-2.0 mg kg-1, i.v.) and prazosin (0.05-0.2 mg kg-1, i.v.) also evoked dose-related decreases in MAP which were of greater magnitude in SH rats. Oral administration of dicentrine (5 and 8 mg kg-1) to conscious SH rats caused a hypotensive effect which persisted for over 15 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

In vivo and in vitro activity of selective 5-hydroxytryptamine2 receptor antagonists

The abilities of ketanserin, ritanserin, R56413 and LY53857 to inhibit 5-hydroxytryptamine (5-HT) and noradrenaline-induced vasoconstrictor responses both in vitro and in vivo and to lower blood pressure in the rat, were compared. In the isolated perfused mesenteric artery preparation of the rat all of the compounds tested were found to be potent inhibitors of 5-HT-induced vasoconstrictor responses. Ritanserin was the most potent compound, producing more than 50% inhibition of a near maximal response to 5-HT at a concentration of 10(-11) M. All four compounds were found to be competitive antagonists of noradrenaline; ketanserin being the most potent with a pA2 value of 7.64 +/- 0.06. 5-HT-induced pressor responses in the pithed rat were inhibited by low doses (0.3-10 micrograms kg-1) of the four compounds. Ketanserin, at doses of 0.1-3.0 mg kg-1, resulted in rightward shifts of the control dose-response curve to noradrenaline in the pithed rat. None of the other compounds had any significant effect on the noradrenaline-induced pressor responses. Ketanserin (0.1-1 mg kg-1) produced a dose-dependent decrease in the mean arterial blood pressure of anaesthetized rats. The maximum decrease in blood pressure observed following a dose of 1 mg kg-1 ketanserin was 73.7 +/- 4.7 mmHg. The other compounds at doses of 1.0-3.0 mg kg-1 produced a decrease in blood pressure of a lesser magnitude than that following ketanserin. In addition, this effect did not appear to be dose-dependent. It is suggested that the acute hypotensive effect of ketanserin results predominantly from alpha 1-adrenoceptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

Potentiation by naloxone of pressor reflexes.

1 The effect of intravenous naloxone, and opiate antagonist, was studied on the pressor responses elicited by stimulation of afferent nerves (vagus and laryngeal superior nerves) in anaesthetized dogs. 2 Although naloxone (0.1 mg/kg i.v.) alone failed to modify basic blood pressure, the pressor responses induced by stimulation of either the vagus or laryngeal nerve were potentiated by naloxone. 3 Morphine (0.2 mg/kg i.v.) suppressed these two cardiovascular responses. These depressor effects of morphine were reversed by subsequent injection of naloxone (0.1 mg/kg i.v.). 4 The results suggest the involvement of endogenous opiate peptides in pressor reflexes elicited by stimulation of the afferent nerves.     

Effects of terazosin on the blood pressure responses to tilting in conscious animals: comparison with prazosin

Inhibitory effects of terazosin on the compensatory blood pressure responses to tilting were studied in conscious rabbits and spontaneously hypertensive rats (SHR). In rabbits, doses which reduced the mean blood pressure by 15 mmHg were 330 micrograms/kg, i.v., for terazosin and 42 micrograms/kg, i.v., for prazosin, while those which depressed the blood pressure responses to tilting by 30 mmHg were 180 micrograms/kg, i.v., for terazosin and 54 micrograms/kg, i.v., for prazosin. In SHR, almost equal decreases in the mean blood pressure (about 30%) were observed by 1 mg/kg prazosin, p.o., 20 mg/kg hexamethonium, i.p., 3 mg/kg hydralazine, p.o., or 3 mg/kg nicardipine, p.o. In these conditions, prazosin and hexamethonium markedly depressed the blood pressure responses to tilting, whereas hydralazine and nicardipine showed little effect. The results with these antihypertensive drugs closely paralleled the established orthostatic profiles seen clinically. In this SHR tilting model, when the mean blood pressure was reduced by 15%, prazosin significantly depressed the tilting reflexes; however, terazosin produced no depression. Considering the dose ratio of terazosin to prazosin for antihypertensive effects and inhibitory effects on the tilting reflexes, the orthostatic liability of terazosin was about 3 times as low as that of prazosin. On the basis of these results, it is expected that terazosin causes less orthostatic hypotension than prazosin in clinical use.     

Effects of intravenous and intracerebroventricular terazosin, prazosin and clonidine on spontaneous sympathetic outflow in rats

The hypotensive activity of terazosin has been attributed to inhibition of postsynaptic alpha-1 adrenoceptors. The present study examined the influence of terazosin on spontaneous sympathetic outflow in anesthetize and immobilized rats. The effects on blood pressure and heart rate were also evaluated. Intravenously (i.v.) injected terazosin 0.3 mg/kg and prazosin 0.1 mg/kg increased a sympathetic outflow by 15.4 and 21.6%, respectively. These drugs produced a significant and long-lasting fall in blood pressure with slight heart rate change. On the contrary, clonidine 0.1 mg/kg, i.v. significantly inhibited the sympathetic outflow by 69.2%. The intracerebroventricularly administered 10 micrograms/kg clonidine also showed the sympathoinhibitory effect. However 3 micrograms/kg, i.c.v. of terazosin and prazosin increased the sympathetic tone by 16 and 7.2%. During these periods, in both drugs slightly decreased the blood pressure. These changes in hemodynamic parameters and nerve activities were obtained at 2 approximately 3 min after the i.c.v. administration. The 10 micrograms/kg, i.c.v. of terazosin and prazosin significantly inhibited the pressor response by phenylephrine 1 micrograms/kg, i.v. These results indicate the peripheral effect of terazosin and prazosin through the penetration of the drugs from the brain. The results provide evidence that terazosin, like prazosin, dose not affect cardiovascular regulation by a central action.     

ATTENUATION OF PRESSOR RESPONSES TO SYMPATHETIC STIMULI IN THE RAT BY ENALAPRIL

Intravenous administration to pithed Wistar rats of the angiotensin converting enzyme inhibitor enalapril (0.1-1.0 mg/kg) lowered the diastolic blood pressure and reduced pressor responses occurring during electrical stimulation (1-30 Hz) of the spinal sympathetic outflow. These doses of enalapril given intravenously also attenuated pressor responses to intravenous injection of the muscarinic ganglion stimulant McNeil-A-343 (50, 100, 150 micrograms/kg) and noradrenaline (0.1-5.0 micrograms/kg). Enalapril (1.0 mg/kg, i.v.) reduced pressor responses to the nicotinic ganglion stimulant 1,1-dimethyl-4-phenyl-piperazinium (300 micrograms/kg, i.v.). These results confirmed that the actions of enalapril resemble those of captopril in the pithed rat, by causing reductions in both blood pressure and pressor responses to sympathetic stimuli.     

Hypotension and bradycardia after intrathecal ketanserin and phentolamine in the rat

Intrathecal administration of ketanserin and phentolamine elicited dose-dependent falls in arterial blood pressure and heart rate in anaesthetized rats without attenuation of the pressor responses to i.v. injections of phenylephrine. It is concluded that both ketanserin and phentolamine can decrease arterial blood pressure by acting within the spinal cord.     

SELECTIVE STIMULATION OF VASCULAR POSTJUNCTIONAL α1-ADRENORECEPTORS BY (-)-AMIDEPHRINE IN RATS AND CATS

• 1 The vasopressor and chronotropic responses of (-)-amidephrine and the receptor types involved were studied in pithed rats of different strains and in pithed cats.
• 2 The increase in diastolic pressure of pithed rats after i.v. administration of (-)-amidephrine was not influenced by pretreatment with propranolol (1 mg/kg, i.v.), reserpine (2 times 5mg/kg in 48 h i.p.) or yohimbine (1 mg/kg, i.v.), but was strongly antagonized by prazosin (0.1 mg/kg, i.v.). In pithed cats, the pressor responses were antagonized by prazosin (1 mg/kg, i.v.) but much less so by yohimbine (1 mg/kg, i.v.).
• 3 (-)-Amidephrine elicited minor positive chronotropic responses in pithed rats and pithed cats. This tachycardia was not influenced by propranolol (1 mg/kg, i.v.) but was abolished by prazosin (0.1 – 1.0 mg/kg).
• 4 The results show that (-)-amidephrine acts as a selective agonist at vascular postjunctional α-adrenoreceptors in pithed rats and pithed cats. The positive chronotropic effects are attributable to stimulation of α-adrenoreceptors in the heart.

     

Blood pressure effects of intravenous apomorphine in conscious deoxycorticosterone-acetate salt-hypertensive rats

SUMMARY: The present study reports the effects of apomorphine (APO) on blood pressure and the principal site of action of this agonist in 4-week deoxycorticosterone-acetate (DOCA)-hypertensive conscious rats. In these preprations, intravenous (i.v.) administration of APO (0.50-1 mg/kg) induced short-lasting and dose-dependent decreases in mean arterial pressure. The hypotensive response to APO (0.3 mg/kg) was reversed into a significant pressor effect by i.v. hexamethonium (30 mg/kg), whereas it was enhanced by i.v. pretreatment with the vasopressor antagonist of arginine vasopressin (AVP) d(CH2)5Tyr(Me)AVP (10 microg/kg) and/or prazosin (1 mg/kg). This depressor effect was suppressed by the central and peripheral dopamine D2 receptor antagonist metoclopramide (5 mg/kg i.v.), unaffected by the selective dopamine D1 receptor antagonist SCH 23390 (0.2 mg/kg i.v.), partly reduced by intrathecal domperidone (40 microg per rat at T9-T10 level), a dopamine D2 receptor antagonist which does not cross the blood-brain barrier, and reversed into a significant pressor effect by i.v. domperidone (0.5 mg/kg). The latter pressor effect was fully abolished by combined i.v. pretreatment with the vasopressor antagonist of AVP and prazosin. These results show that, in conscious DOCA salt-hypertensive rats, APO induced a brief, initial depressor effect, which is opposed to a central pressor component. The depressor component is related to an inhibition of norepinephrine transmission through activation of dopamine D2 receptors, some of which are located in the spinal cord and some of which are located in the peripheral circulation. The central pressor component, which became manifest after peripheral dopamine D2 receptor blockade, appears to be related to an increase in vasopressin release and sympathetic tone through activation of brain dopamine D2 receptors.     

INHIBITORY EFFECT OF FRUSEMIDE ON SYMPATHETIC VASOCONSTRICTOR RESPONSES: DEPENDENCE ON A RENAL HORMONE AND THE VASCULAR ENDOTHELIUM

1. Mesenteric perfusion pressure was measured in the in situ mesentery perfused at a constant rate with blood drawn from the carotid artery of the same anaesthetized rat. Increases in perfusion pressure were produced by mesenteric periarterial electrical stimulation. These responses were measured before and 30 min after the administration of frusemide (5 mg/kg i.v.) to the rat. Loss of volume due to the frusemide-induced diuresis was prevented by a urinary bladder-venous extracorporeal circuit. 2. Responses to stimulation were reduced after frusemide and were not increased by the subsequent administration of indomethacin (2 mg/kg i.v.). This indomethacin treatment rapidly and completely prevented the fall in blood pressure produced by i.v. arachidonic acid. 3. In rats where the renal papilla had been ablated by treatment with bromoethylamine (200 mg/kg i.p.) 5 weeks previously, frusemide administration did not reduce sympathetic responses in the in situ blood-perfused mesentery. 4. A segment of rat tail artery, cannulated at both ends was mounted in an organ bath and perfused with blood withdrawn from, and returned to, an anaesthetized rat. Increases in perfusion pressure produced by periarterial electrical stimulation of this ex vivo blood perfused tail artery segment were reduced by frusemide administration to the anaesthetized rat. 5. When the endothelium was removed from the tail artery segment, frusemide administration did not lead to any reduction of vasoconstrictor responses. 6. Frusemide may lead to the release of a non-prostanoid hormone from the renal medulla which results in inhibition of peripheral sympathetic vasoconstrictor responses. The release of the hormone may involve intra-renal prostaglandins. The final antivasoconstrictor effect requires an intact vascular endothelium.