Blood Pressure In Pithed Rats Research Articles

Selective peripheral regulation of noradrenaline and adrenaline release by nitric oxide.

1. Nitric oxide (NO) has complex effects on the sympathoadrenal and cardiovascular systems and may act at both central and peripheral loci. Nitric oxide appears to act directly on blood vessels and indirectly by modulating the sympathoadrenal system. In the present study, we investigated the contribution of catecholamine release from peripheral vascular and adrenal sympathetic nerves to the cardiovascular effects of the NO synthesis inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg). Our experiments were performed in pithed vagotomized rats to remove the influence of central and baroreflex pathways. 2. Spinal cord stimulations for 30 s periods at 1, 2, 5 and 10 Hz using pulses of 1 msec at 10 V caused marked increases in plasma adrenaline and noradrenaline. N(G)-Nitro-L-arginine methyl ester did not alter resting plasma catecholamine concentrations. However, L-NAME generally more than doubled stimulation-evoked release of adrenaline while reducing the extent of noradrenaline release relative to vehicle (saline)-treated controls. 3. N(G)-Nitro-L-arginine methyl ester significantly enhanced the vasopressor responses to spinal cord stimulation. The alpha1-adrenoceptor antagonist prazosin (0.2 mg/kg) reduced the pressor responses of electrically stimulated L-NAME-treated rats to levels below those of vehicle-treated control rats. 4. In the absence of electrical stimulation, L-NAME raised the blood pressure of pithed rats without altering plasma catecholamines and the pressor effect was briefly attenuated by L-arginine, but was unaffected by prazosin. 5. We conclude that the augmented pressor response to sympathetic stimulation in L-NAME-treated pithed rats is due largely to enhanced adrenal adrenaline release mediated by a peripheral mechanism. Stimulation of alpha(1)-adrenoceptors plays a major role in the pressor response to electrical stimulation of L-NAME-treated rats, but this is not due to L-NAME augmentation of noradrenaline release from vascular sympathetic nerves.

In vivo effects of the NMDA receptor agonist tetrazolyl-glycine related to the function of small-diameter primary afferents.

The NMDA receptor agonist tetrazolyl-glycine (TG; 100 microg kg(-1), i.v.) caused a depressor reflex in anaesthetized rats. The NMDA receptor antagonist MK-801 (300 microg kg(-1), i.v.) inhibited this depressor reflex, but not that induced by pentylenetetrazol (PTZ; 100 mg kg(-1), i.v.), indicating a selective effect of TG on NMDA receptors in vivo. Capsaicin pretreatment, which excludes the function of small-diameter primary afferent fibres, caused only a reduction of the TG-induced depressor reflex, suggesting a reduction of NMDA receptors. The absence of effects of TG and PTZ on the blood pressure in pithed rats excluded any peripheral vascular actions of TG and PTZ. The depressor reflex evoked by afferent nerve stimulation was also inhibited by MK-801 (300 microg kg(-1), i.v.), but not by the tachykinin antagonist L-742694 (10 mg kg(-1), i.v.), confirming the essential role of glutamate in the neurotransmission of signals at central terminals of small-diameter afferent neurons. Plasma protein extravasation in the rat hind paw, induced by neurotransmitters released at peripheral terminals of small diameter afferent neurons by antidromic nerve stimulation, was not influenced by MK-801, indicating that glutamate is either not released or has no effect there. It is concluded that the NMDA agonist TG is a valuable tool to study the functions of primary afferents in vivo.

Diphenylpropionic acids as new AT1 selective angiotensin II antagonists.

The synthesis and pharmacological evaluation of a new series of potent AT1 selective diphenylpropionic acid nonpeptide angiotensin II receptor antagonists are reported. The new compounds were evaluated for in vitro AT1 (rat liver) and AT2 (rat adrenal) binding affinity as well as for in vivo inhibition of angiotensin II-induced increase in mean arterial blood pressure in pithed rats. Unsaturation of the diphenylpropionic acids as well as substitution or replacement by alkyl groups of the pendant phenyl ring resulted in a decrease of potency. On the other hand, the presence of small alkyl groups in the alpha-position to the carboxylic acid was important for activity, with one of the resultant diastereoisomers (R*,R*) being ca. 10-fold more active than the other (R*,S*). Oral evaluation of the most active compounds in a furosemide-treated sodium-depleted rat model showed that compound 36g (UR-7198) reduced blood pressure dose dependently. This compound showed in vitro and iv potencies similar to that of the reference compound losartan but faster onset of action and somewhat greater oral activity, presumably due to its improved bioavailability.

Facilitation by procaterol, a β‐adrenoceptor agonist, of noradrenaline release in the pithed rat independently of angiotensin II formation

1. The effects of the beta 2-adrenoceptor agonist, procaterol, on sympathetic neuroeffector transmission were studied in the pithed adrenal demedullated rat to determine if generation of angiotensin II was involved in its effect. Pressor responses were elicited by either electrical stimulation (20 V, 2 Hz) of the entire spinal sympathetic outflow or methoxamine (0.1 mg kg-1, i.v.). 2. Sodium nitroprusside (3 and 5 micrograms kg-1 min-1, i.v.) produced hypotension and the pressor responses to both sympathetic nerve stimulation and methoxamine were reduced. This indicates that decreasing blood pressure in pithed rats reduces pressor responses. Procaterol (10 and 30 ng kg-1 min-1, i.v.) also produced hypotension but did not alter pressor responses to sympathetic nerve stimulation. Nevertheless, procaterol (10 and 30 ng kg-1 min-1, i.v.) did reduce pressor responses to to methoxamine. Together these results suggest that procaterol may have enhanced sympathetic neurotransmitter release. This was confirmed in another series of experiments where procaterol (30 ng kg-1 min-1, i.v.) increased plasma noradrenaline levels during sympathetic nerve stimulation. 3. Captopril (5 mg kg-1, i.v.) produced hypotension and as expected reduced pressor responses to sympathetic nerve stimulation. When the hypotensive effect of captopril was abolished by concomitant vasopressin infusion (1.5-4.5 i mu kg-1 min-1, i.v.), pressor responses to sympathetic nerve stimulation were restored to pre-captopril levels. In this situation procaterol (10 and 30 ng kg-' min', i.v.) reduced basal blood pressure and did not alter pressor responses to sympathetic nerve stimulation whereas the pressor responses were reduced by an equihypotensive infusion of sodium nitroprusside (3 and 5 jig kg-' min' , i.v.). The lack of reduction of pressor responses after procaterol in the presence of captopril is indirect evidence that procaterol may have enhanced noradrenaline release independently of angiotensin II.4. In another series of experiments, plasma noradrenaline levels elicited by sympathetic nerve stimulation were not altered by captopril (5 mg kg', i.v.). In the presence of captopril (5 mg kg-', i.v.),procaterol (30 ng kg- min-1, i.v.) no longer enhanced plasma noradrenaline levels during sympathetic nerve stimulation. However, since the dose of captopril is well above that required to block angiotens in converting enzyme (ACE) the effect may be non-specific. Therefore, the selective AT, receptor antagonist, losartan (10mgkg'1, i.v.), was also used. Losartan (10mgkg'1, i.v.) did not alter plasma noradrenaline levels during sympathetic nerve stimulation, and in the presence of losartan procaterol(30 ng kg-I min-', i.v.) enhanced plasma noradrenaline levels during sympathetic nerve stimulation. This result further suggests that 1-adrenoceptor facilitation of noradrenaline release from sympathetic nerves in the pithed rat occurs by a mechanism independent of angiotensin II generation.

Direct effects of indorenate and 8‐OH‐DPAT on the blood pressure of pithed rats

AbstractIndorenate is a 5‐HT1A receptor agonist with antihypertensive properties. This study was aimed to determine if indorenate, like other 5‐HT1A receptor agonists, may also interact with α‐adrenoceptors. Therefore, the effects of indorenate and 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT; which has affinity for 5‐HT1A receptors and, to a lesser extent, for α1‐adrenoceptors) on the blood pressure of pithed rats were compared. Both compounds produced dose‐dependent increases in blood pressure; 8‐OH‐DPAT was the most potent whereas indorenate produced a higher maximum effect. Metitepine (a mixed 5‐HT1/5‐HT2 receptor antagonist), but not pindolol (a β‐adrenoceptor and 5‐HT1 receptor blocker), antagonized the pressor responses produced by both agonists; only the pressor effects of 8‐OH‐DPAT, however, were antagonized by prazosin (an α1‐adrenoceptor antagonist). Interestingly, ketanserin (a 5‐HT2 and α1‐adrenoceptor blocker) strongly antagonized the pressor responses to indorenate whereas only a slight inhibition of 8‐OH‐DPAT responses was observed. Further, in pithed rats intravenously infused with norepinephrine (NE), 8‐OH‐DPAT, but not indorenate, produced dose‐dependent hypotensive effects and both compounds were inactive in rats infused with quipazine. In conclusion, 8‐OH‐DPAT behaved as a partial agonist at α1‐adrenoceptors whereas indorenate produced pressor effects probably due to stimulation of 5‐HT2 receptors. Thus, 8‐OH‐DPAT, but not indorenate, showed activity at α1‐adrenoceptors in the pithed rat. © 1994 Wiley‐Liss, Inc.

Opening of ATP-sensitive K + channels responsible for adenosine A 2 receptor-mediated vasodepression does not involve a pertussis toxin-sensitive G protein

Whether the opening of ATP-sensitive K + channels responsible for adenosine A 2 receptor-mediated vasodepression involves a pertussis toxin (PTX)-sensitive G protein was investigated in pithed rats. Adenosine and levcromakalim were used as reference substances. The blood pressure of pithed rats was kept elevated with an i.v. infusion of methoxamine. 2-(1-Octynyl)-adenosine (YT-146; 0.1–10 μg/kg i.v.), a selective adenosine A 2 receptor agonist, produced a dose-dependent and long-lasting decrease in mean blood pressure (MBP) scarcely affecting heart rate (HR). Levcromakalim (0.3–10 μg/kg per min i.v. for 20 min) produced a dose-dependent and slowly developing decrease in MBP. The vasodepressor effects of YT-146 and levcromakalim were antagonized by glibenclamide (20 mg/kg i.v.), a blocker of ATP-sensitive K + channels; the ED 50 values for YT-146 and levcromakalim both increased about 2.5-fold. In rats pretreated with PTX (10 μg/kg i.v.), in which vagally induced bradycardia was nearly abolished, the vasodepressor effects of YT-146 and levcromakalim were slightly enhanced. Adenosine (0.3–10 mg/kg per min i.v. for 1 min) produced a dose-dependent and long-lasting decrease in MBP accompanied by a transient decrease in HR. The vasodepressor effect of adenosine was antagonized by glibenclamide; the ED 50 value for adenosine increased about 3.2-fold, but not after PTX pretreatment. In contrast, the transient bradycardia was antagonized by PTX pretreatment but not by glibenclamide. These results suggest that the opening of ATP-sensitive K + channels in vascular smooth muscle following stimulation of adenosine A 2 receptors by YT-146 and adenosine does not involve a PTX-sensitive G protein. The opening of ATP-sensitive K + channels by levcromakalim also appears not to involve a PTX-sensitive G protein.

CGP 35348 blocks noradrenaline-release-inhibiting GABAB receptors in the pig retina, rat vena cava and pithed rat vasculature.

In superfused pig retina discs, preincubated with 3H-noradrenaline, the electrically (3 Hz) evoked tritium overflow was inhibited by gamma-aminobutyric acid (GABA) and the GABAB receptor agonist R-(-)-baclofen but was not affected by the GABAA receptor agonist 3-amino-1-propanesulphonic acid. The effect of GABA was counteracted by the GABAB receptor antagonist CGP 35348 [P-(3-aminopropyl)-P-diethoxymethylphosphinic acid] but was not influenced by the GABAA receptor antagonist SR 95531 [2-(3-carboxypropyl)-3-amino-6-paramethoxyphenylpyridazinium bromide]. Furthermore, CGP 35348 antagonized the inhibitory effect of R-(-)-baclofen on the electrically (0.66 Hz) evoked tritium overflow in superfused rat vena cava segments, preincubated with 3H-noradrenaline, and on the electrically (0.5 Hz) induced rise in diastolic blood pressure in pithed rats. The present results suggest that GABA is capable of inhibiting noradrenaline release (most likely from vascular sympathetic nerve endings) in the pig retina via GABAB receptors and that CGP 35348 is a valuable tool for the characterization of GABAB receptors in vitro and in situ.

Bolus intravenous administration of bisphosphonates produce a transient fall in blood pressure of pithed rats

Bolus intravenous administration of bisphosphonates produce a transient fall in blood pressure of pithed rats

Anti-Hypotensive Effects of M6434, an Orally Active α1-Adrenoceptor Agonist, in Rats

The anti-hypotensive effects of M6434 were evaluated and compared with those of other orally active sympathomimetics in rats. Oral administration of M6434 (0.5–2.0 mg/kg) and midodrine (1.0–5.0 mg/kg) also produced a dose-related increase in mean arterial pressure in normotensive rats. The pressor effect of M6434 was about 4 times more potent than that of midodrine. Both M6434 and midodrine caused a dose-dependent decrease in heart rate. The pressor effect of M6434 (1.0 mg/kg) did not diminish after its repeated administration for 7 days. The pretreatment with M6434 (0.5–1.0 mg/kg) and midodrine (2.0–5.0 mg/kg) improved the orthostatic index in the experimental model of postural hypotension in rats. The effect of M6434 on postural hypotension was about 5 times more potent than that of midodrine. Intravenously injected M6434 (3–300 μg/kg) produced a dose-dependent increase in the blood pressure of pithed rats. These results suggest that M6434 possesses a potent antihypotensive activity which is superior to that of midodrine, and M6434 may be useful in the treatment of essential and postural hypotension.

Actions of L- And D-Arginine and NG-Monomethyl-l-Arginine on the Blood Pressure of Pithed Normotensive and Spontaneously Hypertensive Rats

We have examined the depressor effects of L- and D-arginine on the diastolic blood pressure of pithed normotensive Wistar (NW), Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats after the administration of a single bolus injection of the nitric oxide synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). A single bolus intravenous injection of L-NMMA, 30 mg/kg, produced an increase in both the systolic and diastolic blood pressure of pithed rats. Injections of bolus doses, 1-300 mg/kg, of D-arginine did not lead to sustained reductions of the blood pressure in pithed NW rats although slight decreases in the blood pressure of WKY and SH rats were observed, and these transient effects of D-arginine appeared to be more pronounced in the WKY strain. Immediately following the bolus injections of the higher doses of D-arginine a transient decrease in both the systolic and diastolic pressure occurred. In contrast to the actions of D-arginine single bolus injections of L-arginine, 1-300 mg/kg, produced a dose-dependent sustained reduction in both the systolic and diastolic blood pressures of all rats. The threshold for the depressor actions of L-arginine was the same for NW, WKY and SH rats. The final dose of L-arginine (300 mg/kg), produced a significantly greater depressor effect in WKY and SH rats as compared to NW rats. The blood pressure remained elevated after the dose-response curve to D-arginine and, in order to determine whether D-arginine-treated rats are sensitive to the effects of other vasodilators and whether differences in vasoactive actions exist for vasodilators acting other than via nitric oxide synthesis, a dose-response curve to the calcium channel antagonist verapamil was constructed. Injections of verapamil, 0.1-1000 micrograms/kg, produced a dose-dependent reduction in blood pressure with no difference in either threshold or sensitivity to the actions of verapamil among the three strains of rats. Our results suggest that strain differences exist between the depressor actions of L-arginine and that it is possible that these differences may be due to an alteration in the endogenous levels of nitric oxide synthase and/or the activity of guanylate cyclase, however, no relationship to the hypertensive state of the spontaneously hypertensive rats was apparent.

Effects of endothelin 3 on diastolic blood pressure of pithed Sprague–Dawley, Wistar–Kyoto, and spontaneously hypertensive rats before and after pretreatment with nifedipine

Pressor actions of endothelin 3 (ET3) were examined in pithed Sprague-Dawley (SD), Wistar-Kyoto (WKY), and spontaneously hypertensive (SH) rats before and after the administration of the calcium channel antagonist, nifedipine. Systolic and diastolic blood pressures were recorded via an intra-arterial catheter from sodium pentobarbital anaesthized rats prior to pithing. The systolic and diastolic blood pressures recorded from SH rats were significantly greater than those of SD and WKY rats; however, after pithing there were no significant differences between the diastolic blood pressures among the various strains. Administration of nifedipine significantly reduced the diastolic blood pressure of pithed rats to an equal extent in all three strains. The infusion of ET3 produced a dose-dependent increase in diastolic blood pressure of SD, WKY, and SH rats, but neither vascular sensitivity nor reactivity to ET3 was altered in SH rats. Nifedipine was more effective at inhibiting the vasoactive actions of ET3 in SD and WKY than in SH rats. It was therefore concluded that the pressor actions of ET3 in SH rats may be less dependent on the influx of calcium through a dihydropyridine-sensitive calcium channel as compared with WKY and SD rats.

Effects of Staurosporine on the Pressor Responses to Alpha-Adrenoceptor Agonists in Pithed Rats: A Comparison with Nifedipine

The effects of the calcium channel antagonist nifedipine and the protein kinase C (PKC) inhibitor, staurosporine were examined on the pressor actions of a full, cirazoline, and a partial, St587, alpha 1-adrenoceptor agonist as well as the alpha 2-adrenoceptor agonist B-HT 920 in the pithed rat preparation. Administration of nifedipine or staurosporine significantly reduced the diastolic blood pressure of pithed rats. Staurosporine displaced the dose-diastolic pressure response curves for B-HT 920 and St587 to the right in a dose-dependent manner. The ED50 value for the dose-response curves to B-HT 920 and St587 were found to be significantly increased after the administration of staurosporine. Staurosporine also caused a depression of the maximum response to B-HT 920 and St587. The presence of nifedipine resulted in an increase in the ED50 value of the dose-response curve to B-HT 920 and St587, and this was accompanied by significant reductions of the maximum response, whereas the administration of either staurosporine or nifedipine did not significantly affect the calculated ED50 value of the dose-response curve to cirazoline. In the presence of the calcium channel antagonist but not the PKC inhibitor the maximum response to cirazoline was significantly depressed. As judged from the slope function of the dose-response curves the nature of the inhibition produced by nifedipine compared to staurosporine also appeared to differ. Thus, with nifedipine as the antagonist, the slope function of the dose-response curve for alpha-agonists was significantly reduced. Moreover, in contrast to the actions of staurosporine, nifedipine reduced the maximum response to cirazoline in a dose-independent manner. This study supports the hypothesis that activation of alpha-adrenoceptors that have a substantial dependence on extracellular calcium for vasoconstriction are susceptible not only to the action of calcium channel antagonists but also to the actions of the PKC inhibitor staurosporine, thus suggesting that PKC may modulate directly/indirectly calcium channel activity in vascular smooth muscle.

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.

Presynaptic muscarinic receptors mediating inhibition of neurogenic contractions in rabbit vas deferens are of the ganglionic M 1-type

The present study was designed to further characterize the presynaptic muscarinic M 1-receptor responsible for the inhibition of neurogenic contractions in the isolated rabbit vas deferens. Electrically induced twitch contractions of this preparation were inhibited by the M 1-agonist, McN-A-343, and by some of its analogs: 4-chloro-phenyl derivative > McN-A-343 > trans-olefinic analog > cis-olefinic analog. The same rank order of potency was observed for these agonists to raise the blood pressure of pithed rats by stimulation of M 1-receptors in sympathetic ganglia. A highly significant correlation was found between the antimuscarinic potencies of atropine, pirenzepine and a series of 9 antagonists structurally related to the ganglionic M 1β-receptor selective compounds, hexocyclium and hexahydro-difenidol, to antagonize the McN-A-343-induced inhibition of twitch contractions in rabbit vas deferens or the muscarine-induced depolarization in rat isolated superior cervical ganglia. It is suggested that the presynaptic muscarinic receptor that mediates inhibition of neurogenic contractions in rabbit vas deferens is of the ganglionic M 1β-type.

Interaction of calmodulin antagonists with α-adrenergic responses in pithed rats and in the perfused hindquarters of the rat

The effect of calmodulin antagonists was studied on the α 1- and α 2-adrenoceptor-mediated increase in diastolic blood pressure in pithed rats and on the α 1-adrenoceptor-mediated reduction of flow in the perfused hindquarters of the rat. B-HT 920 was used as a selective α 2-adrenoceptor agonist in the pithed rat experiments, whereas cirazoline was used as a selective agonist for α 1-adrenoceptors. The latter was used after pretreatment with nifedipine (1 mg/kg) or phenoxybenzamine (30 μg/kg), revealing calcium influx-insensitive and -sensitive mechanisms of vasoconstriction, respectively. Papaverine, calmidazolium and W-7 did not influence the dose-response curves for the agonists in the pithed rat experiments. The modest effects of high doses of flunarizine and bepridil on the dose-response curve for B-HT 920 and of trifluoperazine on the dose-response curve for cirazoline can be explained by the well-known calcium entry (flunarizine) and α 1-adrenoceptor-blocking (bepridil) effects of these drugs. Bepridil and calmidazolium caused an elevation of the cirazoline dose-response curves in the perfused rat hindquarters; flunarizine and trifluoperazine showed a parallel and dose-dependent displacement of the cirazoline dose-response curve to the right, whereas W-7 was inactive. Our results do not implicate calmodulin-associated effects in the α-adrenoceptor-mediated vasoconstriction in pithed rats and in the perfused rat hindquarters.

Presynaptic inhibition by dihydroergotoxine of the response to peripheral sympathetic nerve stimulation in rats

Dihydroergotoxine decreased the heart rate in both intact and pithed rats but increased blood pressure in pithed rats only. Dihydroergotoxine did not inhibit the postsynaptic effect of isoprenaline and noradrenaline but reduced the neurally induced pressor responses and tachycardia in the rat. The first effect was antagonized by sulpiride, and the second by yohimbine. It was concluded that dihydroergotoxine stimulates presynaptic α 2-adrenoceptors at the cardioaccelerator nerve endings, and presynaptic dopamine receptors at the sympathetic terminations innervating the vascular bed.

Calcium Antagonist Properties of Diclofurime Isomers. I. Functional Aspects

Trans-diclofurime has been shown to be a potent calcium antagonist which resembles verapamil in vitro and in vivo. Trans-diclofurime was a potent antagonist of Ca2+-induced contractions in K+-depolarized taenia preparations from the guinea pig caecum (pA2 = 8.3 +/- 0.2), whereas the cis isomer was 50 times less active (pA2 = 6.6 +/- 0.1); the inhibitory effects of trans-diclofurime were reversed noncompetitively by the Ca2+ channel activator Bay K 8644. Trans-diclofurime and verapamil were equipotent inhibitors of electrically evoked contractions of guinea pig left atria preparations; the inhibitory effects were frequency dependent and cis-diclofurime was 10 times less effective. Both diclofurime isomers prolonged the effective refractory period at high concentrations, indicating that they also possess local anaesthetic properties. Trans-diclofurime and verapamil reduced blood pressure in pithed rats infused with angiotensin II. Hypotensive effects were accompanied by bradycardia and prolongation of PR intervals, leading to second-degree atrioventricular block. The cis isomer was less potent. Diclofurime is thus a very potent calcium antagonist in heart and smooth muscle and has some additional membrane-stabilizing properties.

An in vivo pharmacological method for the quantitative evaluation of the central effects of alpha 1 adrenoceptor agonists and antagonists

A new in vivo pharmacological method for the quantitative evaluation of α 1-adrenoceptor agonists and antagonists has been developed. It consists of recording the myoclonic twitch activity (MTA) of the suprahyoideal muscle of rats anesthetized with urethane. In these animals, the isomers of amphetamine elicited myoclonic twitch activity; their effects were dose-related and the d-isomer was approximately 3.5 times more effective than the l-isomer. While pimozide did not block this response, the postsynaptic α 1-antagonist prazosin fully blocked the myoclonic twitch activity induced by d-amphetamine. Other postsynaptic α 1-antagonists, such as haloperidol, phenoxybenzamine and clozapine, were also effective in blocking this response to d-amphetamine. Since d-amphetamine elicited myoclonic twitch activity in rats pretreated with reserpine and α-methyl- p-tyrosine, it was concluded that d-amphetamine exerted a direct α 1-adrenoceptor stimulation. In rats pretreated with nialamide and pimozide, l-DOPA elicited myoclonic twitch activity which was dose-related. This effect of l-DOPA was promptly and fully blocked by prazosin. It was concluded that this response to l-DOPA resulted from stimulation of α 1-adrenoceptors. The relative potencies of four α 1-adrenoceptor stimulants, namely, cirazoline, St-587, (−)SKF 89748A and Sgd 101 75 were determined using this method. The results correlated very well with their relative potencies to increase the diastolic blood pressure of pithed rats. Evidence that myoclonic twitch activity is a centrally-mediated response has also been presented. It appears that the method is a simple, sensitive, versatile and easily quantifiable procedure for the evaluation of the central effects of α 1-adrenoceptor agonists and antagonists.

α-Blockade and Vasodilatation Induced by Nipradilol, Arotinolol and Labetalol in Pithed Rats

In pithed rats two recently-introduced beta-blockers, nipradilol and arotinolol, as well as labetalol shifted the pressor dose-response curve for phenylephrine to the right. Labetalol and arotinolol did not modify the pressor dose-response curve for clonidine, while nipradilol induced a definite rightward shift. These results indicate that labetalol and arotinolol are selective alpha 1-blockers, while nipradilol is a non-selective one. In addition, all the three beta-blockers produced complex changes in the blood pressure in pithed rats. A fall of the diastolic blood pressure induced by labetalol and nipradilol was preceded by a slight rise, while arotinolol produced a fall at lower doses and a rise at higher ones. The hypotension by labetalol was abolished after propranolol, while the hypertension was suppressed by prazosin, indicating that labetalol has an intrinsic beta- and alpha 1-sympathomimetic effect. The hypertension and the hypotension produced by nipradilol and arotinolol persisted even in the presence of propranolol and prazosin or propranolol and yohimbine.

Selectivity and potency of 2-alkyl analogues of the alpha 2-adrenoceptor antagonist idazoxan (RX 781094) in peripheral systems.

The profiles of four analogues of idazoxan have been examined at alpha-adrenoceptors and the results compared to those obtained with idazoxan and yohimbine. The compounds possessed either a methyl (RX 801079), ethyl (RX 811033), n-propyl (RX 811054) or isopropenyl (RX 811005) group at the two position of idazoxan. The rank order of antagonist potency against UK-14,304 at prejunctional alpha 2-adrenoceptors of the rat isolated vas deferens was RX 811054 greater than RX 811033 greater than idazoxan greater than RX 811005 greater than yohimbine = RX 801079. All compounds were competitive antagonists. The rank order of antagonist potency against noradrenaline at postjunctional alpha 1-adrenoceptors of the rat isolated anococcygeus muscle was RX 811054 = RX 811033 = idazoxan = yohimbine greater than RX 811005 = RX801079. All compounds were competitive antagonists. The rank order of alpha-adrenoceptor selectivity (alpha 2/alpha 1) was RX 811005 greater than RX 801079 greater than RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine. In pithed rats, intravenous administration of all compounds fully reversed the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. In pithed rats the rank order of antagonist potency against UK-14,304 at cardiac prejunctional alpha 2-adrenoceptors was RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine greater than RX 811005 greater than RX 801079. In contrast, the rank order of antagonist potency against cirazoline pressor effects (vascular postjunctional alpha 1-adrenoceptors) was RX 811054 greater than RX 811033 greater than yohimbine greater than idazoxan greater than RX 811005 greater than RX 801079. The rank order of alpha 2-adrenoceptor selectivity was RX 811033 = RX 801079 = RX 801005 greater than RX 811054 greater than idazoxan greater than yohimbine. Although idazoxan produced contractions of the anococcygeus muscle and increased blood pressure in pithed rats, three of the analogues (RX 811005, RX 801079 and RX 811033) were inactive. In conclusion, alkyl substitution in the 2-position of idazoxan can enhance either alpha 2-adrenoceptor antagonist potency or selectivity or both and furthermore, the weak partial alpha 1-adrenoceptor agonist properties of idazoxan can be removed.