Pharmacological, hemodynamic and autonomic nervous system mechanisms responsible for the blood pressure and heart rate lowering effects of pergolide in rats

In conscious spontaneously hypertensive rats, pergolide (50.0 micrograms/kg s.c.) produced a sustained decrease in tail artery pressure which was blocked by haloperidol (1.0 mg/kg s.c.) pretreatment. In anesthetized spontaneously hypertensive rats this effect was accompanied by a fall in total peripheral resistance inasmuch as pergolide did not significantly change cardiac output. In anesthetized normotensive rats, pergolide (30.0 micrograms/kg i.v.) also lowered blood pressure. This effect was not significantly modified by adrenalectomy, methysergide, idazoxan (alpha-2 adrenoceptor antagonist), vagotomy alone or plus ligation of carotid arteries or plus atenolol, but was entirely prevented by domperidone or sulpiride pretreatment and was reverted to a pressor response (due to stimulation of alpha adrenoceptors and 5-hydroxytryptamine receptors) by blockade of ganglionic transmission with chlorisondamine. Pergolide given either i.v. or into the cisterna magna or the lateral cerebral ventricle produced changes in blood pressure of the same magnitude. In intact or adrenalectomized rats, i.v. pergolide significantly lowered plasma norepinephrine concentration. Furthermore, in saline but not sulpiride-pretreated pithed rats, pergolide reduced the pressor responses and the accompanying increases in plasma norepinephrine evoked by electrical stimulation of the spinal cord. However, pergolide failed to modify the vascular reactivity to several pressor agents and lacked beta-2 and DA-1 dopamine receptor agonist properties. These results indicate that the decrease in blood pressure produced by pergolide can be accounted for by an inhibition of sympathetic tone resulting from stimulation of peripheral neuronal dopamine receptors. A possible central contribution remains to be substantiated. The pronounced bradycardia produced by pergolide (30.0 micrograms/kg i.v.) in anesthetized intact rats was partly reduced by vagotomy, methylatropine, domperidone, sulpiride, idazoxan, phentolamine or atenolol. The effects of pergolide in vagotomized rats were further diminished by domperidone but they were blocked by the combination of phentolamine or idazoxan plus domperidone. In rats pretreated with atenolol or in rats with the cervical section of spinal cord and the low level of heart rate increased with an isoprenaline infusion, the decrease in heart rate produced by pergolide was abolished by domperidone, methylatropine or idazoxan. In pithed rats, pergolide changed neither the base-line heart rate nor the tachycardia to exogenous norepinephrine nor the bradycardia evoked by carbachol or electrical stimulation of the peripheral cervical vagus.(ABSTRACT TRUNCATED AT 400 WORDS)     

Cardiovascular responses to the stimulation of alpha-1 and alpha-2 adrenoceptors in the conscious dog

Hemodynamic responses to the selective stimulation of alpha-1 and alpha-2 adrenoceptors were examined in chronically instrumented, conscious dogs. Norepinephrine (0.02-0.1 micrograms/kg/min), a mixed alpha-1/alpha-2 adrenoceptor agonist, phenylephrine (0.2-1.0 micrograms/kg/min), a selective alpha-adrenoceptor agonist and B-HT 920 (0.5-2.0 micrograms/kg/min), a selective alpha-2 adrenoceptor agonist, were infused i.v. after ganglionic (hexamethonium, 30 mg/kg i.v.), beta adrenoceptor (propranolol, 1, mg/kg i.v.) and muscarinic receptor (atropine methylbromide, 0.1 mg/kg i.v.) antagonism. Each of the alpha adrenoceptor agonists increased mean arterial pressure and total peripheral resistance but had no significant effect on cardiac output, stroke volume or heart rate. Equipressor doses of the alpha adrenoceptor agonists caused similar increases in left ventricular systolic and end-diastolic pressure, but there were no significant changes in left ventricular dP/dt or heart rate with any of the alpha adrenoceptor agonists. Selective antagonism of alpha-1 adrenoceptors with prazosin (1 mg/kg i.v.) abolished the pressor and vasoconstrictor responses to phenylephrine but had a lesser effect on the response to B-HT 920. Antagonism of alpha-2 adrenoceptors with rauwolscine (0.1 mg/kg i.v.) caused a significantly greater attenuation of the pressor and vasoconstrictor responses to B-HT 920 than to phenylephrine. The responses to norepinephrine were significantly attenuated by antagonism of either alpha-1 or alpha-2 adrenoceptors. Thus, in the conscious dog with reflex pathways blocked, selective stimulation of either postsynaptic alpha-1 or alpha-2 adrenoceptors increases arterial pressure and total peripheral resistance but does not significantly change heart rate, left ventricular dP/dt, stroke volume or cardiac output.     

Smooth muscle alpha-2 adrenoceptors mediate vasoconstrictor responses to exogenous norepinephrine and to sympathetic stimulation to a greater extent in spontaneously hypertensive than in Wistar Kyoto rat tail arteries

The alpha adrenoceptor-mediated vasoconstriction in isolated perfused tail arteries from spontaneously hypertensive (SHR) and age matched Wistar Kyoto (WKY) normotensive rats has been examined. Responses induced by periarterial field stimulation, exogenous norepinephrine or the selective alpha-1 adrenoceptor agonist methoxamine were preferentially antagonized by prazosin in both SHR or WKY tail arteries. However, in SHR only, the alpha-2 adrenoceptor antagonist idazoxan (RX 781094) at low concentrations, significantly antagonized responses to periarterial field stimulation and to exogenous norepinephrine. Except at rather high concentrations, idazoxan was inactive as an antagonist of responses induced by methoxamine. The alpha-1 adrenoceptor blocking agent prazosin was a very potent antagonist of the responses induced by periarterial field stimulation and by methoxamine. These results indicate that alpha-2 adrenoceptors predominate in both SHR and WKY tail arteries, but a significant subpopulation of smooth muscle alpha-2 adrenoceptors is present in tail arteries of SHR but not of WKY rats. In contrast to WKY normotensive rats, postjunctional alpha-2 adrenoceptors may also be involved in the vasoconstrictor responses to sympathetic nerve stimulation in tail arteries of SHR.     

Urethane inhibits cardiovascular responses mediated by the stimulation of alpha-2 adrenoceptors in the rat

Clonidine and oxymetazoline (4.0 microgram/kg i.v. or i.a.) evoked a marked bradycardia in either methylatropine-pretreated conscious or pentobarbital-anesthetized (55 mg/kg i.p.), vagotomized rats. Urethane (1.2 g/kg i.p.) inhibited by more than 50% this effect which is mediated through the stimulation of peripheral and/or central neuronal alpha-2 adrenoceptors. However, in adrenalectomized rats only the inhibition of oxymetazoline by urethane was significantly less pronounced. In pithed rats in which the adrenal glands were either left untouched or surgically removed, urethane significantly attenuated the clonidine or oxymetazoline-induced decreases in experimental neural sympathetic tachycardia although it neither changed the base-line nor the experimentally elevated heart rate. Urethane, in contrast to pentobarbital, increased plasma epinephrine concentrations in intact but not in adrenalectomized or in pithed rats. Elevation of plasma epinephrine did not result from the low arterial pressure level associated with urethane anesthesia since the increase of this parameter with vasopressin did not abolish the effect of urethane. Furthermore, guanethidine-pretreated rats, when anesthetized with urethane, exhibited a higher heart rate and plasma adrenaline value than those anesthetized with pentobarbital. The elevated heart rate was decreased by either propranolol or adrenalectomy. The bradycardia produced by injecting clonidine into the lateral cerebral ventricles of either intact or adrenalectomized rats was markedly less in urethane- than in pentobarbital-anesthetized animals. Whereas in pentobarbital-anesthetized rats the peak heart rate effects of i.v. or i.c.v. clonidine were similar, in urethane-anesthetized animals the effects of clonidine were more inhibited when it was given centrally than when it was given peripherally. In pithed rats, the cumulative dose-pressor response curves elicited by the relatively selective alpha-2 adrenoceptor agonists, B-HT 930 and M-7, were depressed by urethane significantly more than those produced by the relatively selective alpha-1 adrenoceptor agonists, phenylephrine and cirazoline, or by angiotensin II. Urethane also decreased the pressor responses evoked by clonidine, oxymetazoline and norepinephrine which stimulate both alpha-1 and alpha-2 adrenoceptors. However, the extent of this inhibition was less than that of B-HT 920 and M-7 but greater than that of cirazoline and phenylephrine. These results show that urethane inhibits cardiovascular responses that are mediated by peripheral and central alpha-2 adrenoceptors. Furthermore, urethane increases the central drive to the adrenal medulla and this leads to the secretion of epinephrine. This may be partly responsible for the inhibitory activity of urethane on oxymetazoline-induced bradycardia. Although the basic mechanism by which urethane impairs responses mediated by alpha-2 adrenoceptors remains to be determined, it is advised that urethane anesthesia should be avoided, particularly for cardiovascular studies.     

Central alpha-2 adrenoceptor-mediated hypertensive response to clonidine in conscious, normotensive rats

Possible involvement of central alpha-2 adrenoceptors in the hypertensive response to i.c.v. injected clonidine was investigated in free-moving, normotensive rats. Clonidine (2-50 micrograms) injected i.c.v. produced a dose-dependent and long-lasting pressor response associated with bradycardia in conscious rats, but a long-lasting depressor response in anesthetized rats. The pressor response to clonidine (20 micrograms i.c.v.) was antagonized in a dose-dependent manner by central (i.c.v.) pretreatment with yohimbine (20-100 micrograms) and was abolished by a high dose (100 micrograms), whereas the same dose of yohimbine injected i.v. had less effect on the response. Central pretreatment with prazosin (10 and 20 micrograms) inhibited, but did not abolish, the pressor response to clonidine. However, systemic (i.v.) pretreatment with the same dose of prazosin (10 and 20 mu) was more effective in reducing the clonidine-induced pressor response than central pretreatment with the drug. The pressor response to clonidine (20 micrograms i.c.v.) was not significantly modified by central pretreatment with pyrilamine (50 and 100 micrograms), cimetidine (50 and 100 micrograms), ketanserin (50 and 100 micrograms) or procaine (100 micrograms). The selective alpha-2 adrenoceptor agonist, BHT-920, injected i.c.v. (5-50 micrograms) also produced a dose-dependent pressor response which was abolished by either anesthesia or central pretreatment with yohimbine, but not with prazosin, whereas the selective alpha-1 adrenoceptor agonist, methoxamine (10-100 micrograms i.c.v.), caused a slight increase in mean blood pressure only at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heterogeneity of smooth muscle alpha adrenoceptors in rat tail artery in vitro

Vascular smooth muscle alpha adrenoceptors in the proximal end of the rat isolated tail artery have been classified by determining pA2 values and -log KB values for the antagonists prazosin, corynanthine and idazoxan (RX 781094, a new synthetic alpha-2 adrenoceptor antagonist) against norepinephrine. The effects of the antagonists on responses to intramural sympathetic nerve stimulation were also assessed. Artery segments were perfused and superfused with Krebs' solution containing cocaine (4 microM) and propranolol (1 microM). Maximum responses to KCl, norepinephrine and nerve stimulation were not significantly different from one another. Corynanthine (0.1-100 microM), prazosin (10 nM-1 microM) and idazoxan (1-100 microM) caused competitive antagonism of norepinephrine responses with pA2 values consistent with the presence of alpha-1 adrenoceptors. However, idazoxan (10-100 nM) also caused parallel shifts in the concentration-response curves to norepinephrine with -log KB values higher than those consistent with the presence of alpha-1 adrenoceptors. The results have been interpreted to suggest a predominance of smooth muscle alpha-1 adrenoceptors in addition to a subpopulation of smooth muscle alpha-2 adrenoceptors which also contribute to vasoconstrictor responses to norepinephrine. In contrast to the results obtained with exogenous norepinephrine, responses to electrical stimulation were exquisitely sensitive to blockade by prazosin but resistant to idazoxan , suggesting an involvement of an alpha-1 adrenoceptor in these responses. It is concluded that idazoxan may be used to distinguish alpha-1 and alpha-2 adrenoceptors on vascular smooth muscle in vitro and that the results favor the existence of alpha-1 and alpha-2 adrenoceptors in terms of the existing subclassification scheme for alpha adrenoceptor subtypes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effect of alpha-1 adrenoceptor stimulation on cardiac sympathetic neurotransmission in pithed normotensive rats

In the present study we investigated the inhibitory effect of the selective alpha-1 adrenoceptor agonists cirazoline, amidephrine and St 587 on the cardiac sympathetic neurotransmission in pithed normotensive rats. Increases in heart rate were elicited by electrical stimulation of the cardiac sympathetic nerves or by i.v. administration of norepinephrine, isoproterenol or tyramine. Intravenous pretreatment of the animals with cirazoline, amidephrine or St 587 diminished the heart rate response to sympathetic stimulation significantly. However, the tachycardia produced by norepinephrine, isoproterenol or tyramine was also inhibited significantly by the selective alpha-1 adrenoceptor agonists. The selective alpha-1 antagonist prazosin blocked the sympathoinhibitory effect to alpha-1 adrenoceptor stimulation significantly. However, the inhibitory effect of cirazoline and St 587 was not suppressed completely by a maximally effective dose of prazosin. In contrast, the sympathoinhibitory action of amidephrine was antagonized completely by prazosin. However, the selective alpha-2 antagonist rauwolscine also produced a significant, albeit modest, attenuation of the sympathoinhibitory effect to amidephrine. The results of the present study indicate that alpha-1 adrenoceptor agonists, at relatively high doses, inhibit the sympathetic neurotransmission in rat heart. This sympathoinhibitory effect is mediated largely by alpha-1 adrenoceptors which are localized postjunctionally rather than prejunctionally.     

Undifferentiated effects of calcium antagonists on pressor responses to selective alpha-1 and alpha-2 adrenoceptor agonists in anesthetized, spinal dogs

Whether pressor responses mediated by alpha-2 adrenoceptors are more susceptible to calcium antagonists than those mediated by alpha-1 adrenoceptors was investigated in anesthetized, spinal dogs. All drugs were administered i.v. Methoxamine (3-100 mu/kg) or xylazine (3-300 micrograms/kg) produced a sustained increase in mean arterial pressure but almost no effect on heart rate. Both the initial and the sustained phase of the pressor response to methoxamine were selectively antagonized by prazosin, whereas those to xylazine were selectively antagonized by yohimbine. These results indicate that the peripheral arterial bed of the dog comprises alpha-1 and alpha-2 adrenoceptors and that both the initial and sustained phases of the pressor response to methoxamine are predominantly mediated by alpha-1 adrenoceptors, whereas those to xylazine are mediated by alpha-2 adrenoceptors. The calcium antagonists, i.e., nifedipine (0.3-3 micrograms/kg), diltiazem (10-100 micrograms/kg) and KB-944 (10-100 micrograms/kg), administered during the sustained phase of the pressor responses to equieffective doses of methoxamine (100 micrograms/kg) and xylazine (1000 micrograms/kg), lowered mean arterial pressure. The three calcium antagonists in these doses also lowered the baseline mean arterial pressure but to a lesser extent than the elevated one. These results altogether indicate that the calcium antagonists were more effective in lowering mean arterial pressure elevated by either an alpha-1 or alpha-2 adrenoceptor agonist than the base-line mean arterial pressure and that the sustained phase of the pressor response mediated by alpha-1 adrenoceptors would involve Ca++ influx as much as or more than those mediated by alpha-2 adrenoceptors.     

Differential antagonism of alpha-1 and alpha-2 adrenoceptor-mediated pressor responses by urotensin I, a selective mesenteric vasodilator peptide

In order to characterize the hemodynamic actions of urotensin I, a vasodilator peptide with selectivity for the mesenteric vascular bed, we studied its hypotensive effects and interference with alpha-1 and alpha-2 adrenergic vasoconstrictor responses in the rat. After i.v. administration in anesthetized rats, urotensin I (0.06-6 nmol/kg) produced a dose-dependent lowering of arterial blood pressure. At hypotensive doses, urotensin I was about 3 times more potent in antagonizing systemic pressor responses to the selective alpha-1 adrenoceptor agonist, phenylephrine, than responses to the nonselective adrenoceptor agonist, norepinephrine. Additional studies were performed on the blood-perfused mesenteric bed of the anesthetized rat and on the isolated rat superior mesenteric artery, using as tools phenylephrine, norepinephrine and the relatively selective alpha-2 adrenoceptor agonist, alpha-methylnorepinephrine. The selectivity of the three agonists for vascular alpha-1 and alpha-2 adrenoceptors in the blood-perfused mesenteric bed was confirmed using prazosin and yohimbine as selective antagonists of alpha-1 and alpha-2 adrenoceptors, respectively. Urotensin I diminished the maximum increase in perfusion pressure and shifted the log dose-response curves to the right for all three agonists. A marked selectivity of urotensin I for alpha-1 adrenoceptor-mediated responses was observed: IC30 values of the peptide for pressor responses to phenylephrine, norepinephrine and alpha-methylnorepinephrine were 0.05, 0.83 and greater than 6 nmol/kg, respectively. A less pronounced selectivity of urotensin I for alpha-1 adrenoceptor-mediated contractions could be demonstrated in isolated strips of the superior mesenteric artery of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)     

Analysis of the presence of postjunctional alpha-2 adrenoceptors in the rat anococcygeus muscle

When the tone is raised by guanethidine, rat anococcygeus muscle produces inhibitory responses to field stimulation, whose mechanism is not understood properly. The present study is an attempt to investigate the role of alpha adrenoceptors in the field stimulation-induced relaxations in isolated rat anococcygeus muscle. When the tissues are contracted with clonidine, UK-14,304 and low doses of oxymetazoline, field stimulation produced relaxations at lower frequencies, but not in the tissues precontracted with phenylephrine and norepinephrine. Relaxations induced by low frequencies were blocked by idazoxan, but not by phentolamine, prazosin, indomethacin, N-methyl-hydroxylamine, ouabain or 3,4-diminopyridine. When the tone of the muscle is raised by norepinephrine, prazosin reversed the field stimulation-induced contractions to relaxation responses. The data of the present study suggested the possible involvement of alpha-2 adrenoceptors during the field stimulation-induced relaxations of the rat anococcygeus muscle. To analyze and quantitate the alpha-2 adrenoceptor antagonism in the rat anococgygeus muscle, Schild analyses of clonidine-induced contractions against idazoxan were conducted either for idazoxan alone or after partially alkylating the alpha-1 adrenoceptors with phenoxybenzamine and by pharmacologic resultant analysis by blocking the alpha-1 adrenoceptors with prazosin. The Schild regression for idazoxan and pharmacologic resultant analysis suggested that the rat anococcygeus muscle responds to alpha-2 agonists with alpha-1-mediated contractions and idazoxan competes with alpha-1 antagonists for the same site, i.e., alpha-1 adrenoceptor site. However, the atypical Schild regression of idazoxan after partial alkylation with phenoxybenzamine indicated the existence of a second alpha adrenoceptor site in the rat anococcygeus muscle.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of quinpirole, a specific dopamine DA2 receptor agonist on the sympathoadrenal system in dogs

The effects of quinpirole, a specific dopamine DA2 receptor agonist, were investigated on both cardiovascular responses in conscious dogs and catecholamine release from the adrenal medulla in anesthetized dogs. In conscious normal dogs, i.v. quinpirole (30 micrograms/kg) elicited a decrease in blood pressure and a marked increase in heart rate associated with a rise in plasma catecholamine levels. The increase in heart rate is due to both baroreflex and central mechanisms because a slight but significant positive chronotropic effect persists in sinoaortic denervated dogs (i.e., animals deprived of baroreflex pathways). The central origin of this excitatory effect was confirmed by two subsequent protocols: intracisterna magna injection of quinpirole (5 micrograms/kg) increased blood pressure, heart rate and plasma catecholamines; i.v. domperidone reversed the hypotensive effect of i.v. quinpirole into a pressor response. The rise in plasma catecholamines was associated with an increase in plasma vasopressin levels. In anesthetized dogs, i.v. quinpirole (10 micrograms/kg/min during 12 min), which also decreased blood pressure, failed to modify epinephrine (and norepinephrine) release from the adrenal medulla whatever the stimulation frequencies (1, 3 and 5 Hz) of the sectioned splanchnic nerve. Similar results were obtained with apomorphine (5 micrograms/kg/min during 12 min). These results show that two mechanisms are involved in the action of quinpirole: first, a peripheral depressor action (which elicits the decrease in blood pressure) and secondly, a central pressor component involving an increase in both sympathetic tone and vasopressin release. They also demonstrate clearly that peripheral DA2 receptors are not involved in the control of catecholamine release from the adrenal medulla under in vivo conditions.     

SL 84.0418: a novel, potent and selective alpha-2 adrenoceptor antagonist: in vitro pharmacological profile.

One novel, potent and selective alpha-2 adrenoceptor antagonist is 2-(4,5-dihydro-1H-imidazol-2-yl)-1,2,4,5-tetrahydro-2- propylpyrrolo[3,2,1-hi]-indole hydrochloride (SL 84.0418). It inhibits with high affinity the radioligand binding to rat cortical alpha-2 adrenoceptors, as well as to human platelet alpha-2 adrenoceptors labeled with [3H]idazoxan (Ki = 7 nM). SL 84.0418 has low affinity for alpha-1 adrenoceptors labeled with [3H]prazosin (Ki = 3.3 microM). In vitro, SL 84.0418 has no alpha agonist properties, whereas it is a potent alpha-2 adrenoceptor antagonist at both pre- and postsynaptic alpha-2 adrenoceptors. In contrast, it possesses low potency as an antagonist at postsynaptic alpha-1 adrenoceptors demonstrating a more than 1000-fold selectivity toward alpha-2 compared with alpha-1 adrenoceptors. In the same tests, the alpha-2 adrenoceptor antagonist idazoxan had a selectivity ratio of 200. SL 84.0418 is the racemic mixture of two enantiomers, SL 86.0715 [(+) enantiomer] and SL 86.0714 [(-) enantiomer]. The alpha-2 adrenoceptor blocking activities reside with SL 86.0715. Similar to idazoxan, SL 84.0418 increases in a concentration-dependent manner the electrically evoked release of [3H]norepinephrine from rat hypothalamic slices through the blockade of the presynaptic inhibitory alpha-2 adrenoceptors. In isolated hamster adipocytes, SL 84.0418 potently antagonizes the inhibition of lipolysis induced by UK 14,304. In addition, SL 84.0418 inhibits epinephrine-induced aggregation of rabbit platelets, effects mediated by postsynaptic alpha-2 adrenoceptors. SL 84.0418 does not inhibit (IC50 > 1,000 nM) radioligand binding to other receptors or recognition sites, nor does it inhibit calcium, sodium or potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)     

An investigation of the effects of intravenous injection of the 5-hydroxytryptamine 2 receptor antagonists ketanserin and LY 53857 on blood pressure in anesthetized spontaneously hypertensive rats

The mode of action of i.v. injected ketanserin, LY 53857 and other 5-hydroxytryptamine (5-HT2) receptor antagonists in lowering blood pressure was examined in anesthetized and pithed spontaneously hypertensive rats (SHR). In pithed SHR, LY 53857 (1 mg kg-1) had no effect on alpha-1 or alpha-2 adrenoceptors, but ketanserin (1 mg kg-1) had some potency as an alpha-1 adrenoceptor antagonist, being approximately 100 times less potent than prazosin. Both ketanserin and LY 53857 (0.01 mg kg-1) markedly antagonized the pressor response to 5-HT. In pentobarbitone-anesthetized SHR, ketanserin and LY 53857 (1 mg kg-1) were equieffective at lowering diastolic blood pressure (DBP) subsequent to prazosin (1 mg kg-1), although ketanserin (1 mg kg-1) was more effective at lowering DBP in the absence of prazosin. The blood pressure lowering effects of LY 53857 were unaffected by the peripherally acting 5-HT2 receptor antagonist BW 501C. Neither LY 53857 nor ketanserin lowered DBP in pithed rats. It is concluded that ketanserin in high doses lowers DBP in anesthetized SHR partly by alpha-1 adrenoceptor blockade, but that ketanserin and LY 53857 in high doses have additional blood pressure lowering properties, unrelated to peripheral 5-HT2 receptor blockade.     

Evidence for alpha adrenoceptor modulation of the nociceptive jaw-opening reflex in rats and rabbits

The jaw-opening reflex (JOR) in anesthetized rats and rabbits was the pain paradigm studied. The JOR was elicited by the electrical intrapulpal (left maxillary) stimulation and quantified by the measurement of threshold values for eliciting electromyograms (dEMGs) from the ipsilateral digastric muscle which served as the experimental nociceptive index. In both species, the threshold for the JOR was significantly elevated by the systemic administration of clonidine (12.5-50 micrograms/kg i.v.) and these JOR thresholds were inversely correlated with the frequency of stimulation. The analgesia elicited by clonidine was antagonized by pre- and postdrug treatment with the alpha-2 adrenoceptor antagonist yohimbine (1 mg/kg i.v.) but not the alpha-1 adrenoceptor antagonist prazosin (1 mg/kg i.v.) or the opiate receptor antagonist naloxone (1 mg/kg i.v.). The lipophilic alpha-1 adrenoceptor agonist St587 (100-400 micrograms/kg i.v.) had no significant effect on dEMG. Yohimbine did not antagonize the increase in dEMG elicited by morphine or pentobarbital. There was no direct correlation between the antinociceptive and cardiovascular effects of clonidine. Our results suggest that in the JOR nociceptive paradigm, clonidine elicits potent analgesia by activation of alpha-2 and not alpha-1 adrenoceptors.     

Additional evidence for functional subclassification of alpha-2 adrenoceptors based on a new selective antagonist, SK&F 104856.

SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4-methyl-thieno[4,3,2ef][3] benzazepine) shows a similar selectivity profile to the previously reported alpha adrenoceptor antagonist, SK&F 104078 (6-chloro-9-[(3-methyl-2-butenyl)oxy]-3-methyl-1H-2,3,4,5-tetrahydro-3- benzazepine), having the ability to block alpha-1 and postjunctional alpha-2 adrenoceptors, although having little or no activity at most prejunctional alpha-2 adrenoceptors. SK&F 104856 is more potent than SK&F 104078, and lacks the 5-hydroxytryptamine receptor antagonist activity associated with the earlier compound. The postjunctional vs. prejunctional selectivity of SK&F 104856 at alpha-2 adrenoceptors in the same tissue preparation was demonstrated in both canine and human saphenous vein. Concentrations substantially higher than those required to block postjunctional alpha-2 adrenoceptor-agonist induced vasoconstriction had no effect on the ability of norepinephrine, acting on prejunctional alpha-2 adrenoceptors, to inhibit stimulation evoked transmitter overflow in the human tissue, and only a small effect in the canine vein. As observed with SK&F 104078, SK&F 104856 has some prejunctional alpha-2 adrenoceptor antagonist activity in the rat vas deferens, although the receptor dissociation constant is nearly 50-fold higher than that at the postjunctional alpha-2 adrenoceptor in the canine saphenous vein. The results obtained with SK&F 104856 provide additional evidence to support the premise that alpha-2 adrenoceptors can be functionally differentiated. Because SK&F 104856 can selectively antagonize certain alpha-2 adrenoceptor-mediated responses, this agent may be a useful tool to evaluate the functional roles of the multiple alpha-2 adrenoceptor subtypes that have been identified in biochemical and molecular studies.     

Role of vasopressin in the cardiovascular effects of LY171555, a selective dopamine D2 receptor agonist: studies in conscious Brattleboro and Long-Evans rats

To elucidate the role of central and peripheral arginine vasopressin (AVP) in the cardiovascular action of LY171555 in conscious rats, we have examined the effects of LY171555 on mean arterial pressure, heart rate, plasma AVP and catecholamine levels in conscious, congenitally AVP-deficient Brattleboro (DI) rats and Long-Evans (LE) control rats. Administration of LY171555 (1 mg/kg i.v.) increased heart rate without altering mean arterial pressure in DI rats but increased both mean arterial pressure and heart rate in LE rats. After pretreatment with domperidone, LY171555 induced both a pressure response and a tachycardia in DI rats. Domperidone pretreatment enhanced the pressor action of LY171555 and attenuated the LY171555-induced tachycardia in LE rats. After pretreatment with phenoxybenzamine, LY171555 induced a depressor and bradycardic response that could be blocked by pretreatment with domperidone in DI rats. Pressor and bradycardic responses to LY171555 were attenuated by phenoxybenzamine pretreatment in LE rats. LY171555 administration increased plasma norepinephrine and epinephrine levels in both DI and LE rats but increased plasma AVP only in LE rats. The vasopressor effect of the alpha-1 adrenoceptor agonist phenylephrine was significantly attenuated in DI rats compared with LE rats, whereas the pressor action of angiotensin II was similar in both groups. These results suggest that the pressor action of LY171555 in conscious LE rats is mediated by an increase in plasma AVP and by activation of sympathetic outflow through the central D2 dopaminergic system but not through the central vasopressinergic system.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antinociceptive effects of intrathecal adrenoceptor agonists in a rat model of visceral nociception

Intrathecal administration of alpha adrenoceptor agonists in rats produces a significant elevation of nociceptive thresholds as measured by hot-plate and tail-flick latencies. That these antinociceptive effects were antagonized by alpha adrenoceptor antagonists suggests that spinal adrenoceptors modulate the rostrad transmission of nociceptive information. The role of spinal adrenoceptors in the modulation of nociception in visceral pain tests has in the past been examined primarily in the writhing model of visceral pain. Recently, however, a new model of visceral pain has been developed which utilizes colorectal distension (CRD) as the noxious visceral stimulus in awake, unanesthetized animals. CRD produces a pressor response and contraction of the abdominal and hindlimb musculature (a visceromotor response), both of which are readily quantifiable. Inhibition of both of these pseudoaffective reflexes is indicative of antinociception. The effects of intrathecally administered adrenoceptor agonists on the responses to CRD were examined in conscious rats. The visceromotor and pressor responses to CRD were dose-dependently inhibited by the alpha-2 adrenoceptor agonists clonidine and ST-91 and the nonselective alpha adrenoceptor agonist norepinephrine (NE), but not by the alpha-1 adrenoceptor agonist methoxamine or the alpha adrenoceptor agonist isoproterenol. Tizanidine, an alpha-2 adrenoceptor agonist, dose-dependently inhibited the pressor response to CRD but failed to significantly elevate the visceromotor threshold in response to CRD. The effects produced by clonidine, NE and ST-91 were antagonized by pretreatment with yohimbine. The effects produced by tizanidine were antagonized by idazoxan.(ABSTRACT TRUNCATED AT 250 WORDS)     

Mechanisms mediating the positive inotropic and chronotropic changes induced by dopexamine in the anesthetized dog

Mechanisms contributing to the increments in heart rate (HR) and cardiac contractile force (CCF) produced by dopexamine (DPX) were studied in anesthetized dogs. Intravenous infusions of DPX (4.0 micrograms/kg/min) produced increments in HR, CCF and renal blood flow and decrements in mean arterial pressure (MAP). The sequential administration of atenolol (0.5 mg/kg i.v.) administered at a dose selective for beta-1 adrenoceptors, propranolol (2.5 mg/kg i.v.) and the DA1 dopamine receptor antagonist, SCH 23390 (10 micrograms/kg i.v.) blocked the DPX-induced changes in HR, CCF, MAP and renal blood flow, respectively. After ganglionic blockade, the increments in HR and CCF produced by DPX (4.0 and 16.0 micrograms/kg i.v.) were reduced 90 and 76%, respectively, with little or no change in its hypotensive effect. In separate dogs, administration of the beta-2 adrenoceptor agonist salbutamol (0.55 microgram/kg i.v.) produced a comparable decrement in MAP but smaller increments in HR and CCF than produced by DPX (16.0 micrograms/kg i.v.). DPX (64 micrograms/kg i.v.) also produced greater increments in HR during cardioaccelerator nerve stimulation (1 Hz, 0.5 msec, supramaximal voltage) than before nerve stimulation. Therefore, we tested the effect of DPX (1.0, 4.0 and 8.0 micrograms/kg/min i.v.) on the increments in HR, CCF and MAP produced by norepinephrine (0.25 microgram/kg i.v.) and the indirect acting sympathomimetic amine, tyramine (60 micrograms/kg i.v.). DPX potentiated the increments in HR, CCF and MAP produced by norepinephrine and suppressed those produced by tyramine. Thus, the positive inotropic and chronotropic effects of DPX in the intact dog are due primarily to baroreceptor-mediated stimulation and inhibition of neuronal uptake of norepinephrine.     

A study of the selectivity and potency of rauwolscine, RX 781094 and RS 21361 as antagonists of alpha-1 and alpha-2 adrenoceptors

In a comparative study using various in vivo and in vitro models, the alpha-1/alpha-2 adrenoceptor blocking potencies and selectivities were quantitatively assessed for the purported alpha-2 adrenoceptor selective antagonists rauwolscine, RX 781094 and RS 21361. In pithed normotensive rats, RX 781094 showed direct agonist activity at postjunctional alpha-1 and alpha-2 adrenoceptors and had an indirect tachycardic effect. RS 21361 exhibited but minor actions on diastolic pressure and did not influence heart rate. Rauwolscine, RX 781094 and RS 21361 caused rightward parallel displacements of the log dose-response curve to the increase in diastolic pressure of methoxamine (alpha-1 agonist) and B-HT 920 (alpha-2 agonist) as well as to the B-HT 920-induced reduction in stimulation-evoked tachycardia. Schild plots afforded straight lines with slopes not significantly different from unity. Rauwolscine was more potent than RX 781094 in blocking these alpha-2 adrenoceptors in vivo, whereas both compounds were equipotent at alpha-1 adrenoceptors. RS 21361 possessed moderate in vivo blocking potencies at either subtype. All three antagonists had high blocking selectivity for alpha-2 adrenoceptors in vivo. Rauwolscine was found about 25 times more selective than RX 781094 and 2 times more selective than RS 21361. RX 781094 was approximately 3 times more effective than rauwolscine in antagonizing the centrally mediated alpha-2 adrenoceptor-induced hypotension and sedation of clonidine in rats and mice, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic epinephrine treatment fails to alter prejunctional adrenoceptor modulation of sympathetic neurotransmission in the rat mesentery.

Rats were treated chronically with epinephrine (EPI-T; 100 micrograms/kg/hr, s.c.) for 6 days. On day 6 of treatment, the rats were anesthetized and the mesenteric vascular bed was isolated and perfused with Krebs' bicarbonate buffer containing cocaine (10 microM) and corticosterone (40 microM). Stimulus-induced (2 Hz, 120 pulses) overflow of neurotransmitter and its modulation by prejunctional adrenoceptors was studied. After chronic exposure to EPI, 50% of the mesenteric catecholamine stores consisted of EPI with no increase in total catecholamine content as compared to the control group (C). Absolute and fractional overflows of catecholamines upon periarterial nerve stimulation (2 Hz, 1 min) were not significantly different in the two groups. Beta adrenoceptor blockade by propranolol (10(-10) to 10(-6) M) did not alter the overflow of catecholamines. Alpha adrenoceptor blockade by phentolamine (10(-5) M) increased neurotransmitter overflow in both EPI-T and C groups. However, there was no significant difference in total catecholamine overflows between the two groups. Moreover, in the presence of phentolamine, propranolol (10(-6) M) remained without effect on overflow in both groups. These data suggest that EPI-T did not significantly increase the stimulus-induced overflow of catecholamines in the rat mesentery, nor did EPI-T result in prejunctional beta adrenoceptor modulation of neurotransmitter release in the mesenteric vascular bed.