Alpha adrenoceptor subtypes involved in the emetic action in dogs.

In order to assess the involvement of alpha-1 and alpha-2 adrenoceptors in emesis, the emetic effect of eight alpha agonists was studied in dogs. The i.m. administration of each agonist elicited dose-dependent emesis. The order of potency in inducing emesis was: clonidine greater than oxymetazoline greater than tramazoline greater than naphazoline greater than xylazine greater than epinephrine greater than methoxamine = phenylephrine. The clonidine-induced emesis was antagonized by adrenoceptor antagonists showing alpha-2 blocking activity, yohimbine, tolazoline and phentolamine. Among these antagonists, yohimbine was the most effective. The alpha-1 and beta adrenergic, cholinergic, dopaminergic, histaminergic, serotonergic and opioid receptor antagonists did not prevent the clonidine-induced emesis. The emesis induced by oxymetazoline, tramazoline, xylazine, naphazoline and epinephrine was also antagonized by a selective alpha-2 adrenoceptor antagonist, yohimbine, but not by a selective alpha-1 adrenoceptor antagonist, prazosin. In contrast, methoxamine and phenylephrine-induced emesis was antagonized by prazosin, but not by yohimbine. Neither yohimbine nor prazosin prevented the morphine- and histamine-induced emesis. These results indicate that alpha-2 adrenoceptors are involved in the mediation of emetic action, and that the alpha adrenoceptor-mediated emesis does not involve beta adrenergic, cholinergic, dopaminergic, histaminergic, serotonergic and opioid receptors in the emetic pathway. This study further suggests that alpha adrenoceptors involved in the emesis are mainly of the alpha-2 type, although the involvement of alpha-1 adrenoceptors cannot be ruled out.     

Interaction of imidazolines with alkylation-sensitive and -resistant alpha-1 adrenoceptor subtypes.

The interaction of imidazolines with alpha-1 adrenoceptor subtypes sensitive and resistant to inactivation by SZL-49 and chlorethylclonidine (CEC) has been evaluated. Clonidine, oxymetazoline, phentolamine and naphazoline or the phenethylamine, phenylephrine, interacted with high- and low-affinity sites labeled by [3H]prazosin. SZL-49 (1-1000 nM) eliminated the high-affinity sites and caused a significant reduction of the low-affinity sites. CEC (1-100 microM) reduced the number of low-affinity sites, while the effect on high-affinity sites was dependent on the route of administration. In control aortic rings the dose-response curves for either clonidine or naphazoline were biphasic, consisting of high- and low-affinity components. Only the high-affinity component was blocked by prazosin. SZL-49 was more potent than CEC at inhibiting agonist-induced contraction of rat aortic rings. The agonist responses obtained after treatment with either SZL-49 or CEC were only weakly antagonized by prazosin. The combination of SZL-49 and CEC produced no greater inhibition of muscle contraction than did SZL-49 alone. These data show that 1) imidazolines interact with different affinity at sites labeled by [3H]prazosin and these sites correspond to the alpha-1a and alpha-1b adrenoceptor subtype designation; 2) imidazolines induce smooth muscle contraction by interacting at high- and low-affinity sites; 3) these low-affinity sites do not appear to have properties of an alpha-1 adrenoceptor; 4) there may be three sites of interaction for imidazolines on the aorta, the alpha-1a and alpha-1b adrenoceptors and a site that does not have alpha-1 adrenoceptor characteristics.     

An in vitro quantitative analysis of the alpha adrenoceptor partial agonist activity of dobutamine and its relevance to inotropic selectivity

In rat anococcygeus muscle, dobutamine produced concentration-related submaximal contractions which were antagonized competitively by phentolamine (pKB = 8.3) and dobutamine antagonized norepinephrine-induced contractions in a competitive manner with an equilibrium dissociation constant for the alpha adrenoceptor of 20 nM (pKB = 7.7). Therefore, dobutamine satisfied criteria for a partial agonist of alpha adrenoceptors having an affinity for alpha adrenoceptors 25 times that of norepinephrine (pKA = 6.3) in this tissue. An estimate of the relative efficacy of dobutamine showed one-fortieth the the efficacy of norepinephrine at the alpha adrenoceptors. Dobutamine contracted rabbit aorta and produced concentration-related relaxations at 1000 times greater concentrations after alkylation of alpha adrenoceptors by phenoxybenzamine. In noncontracted canine saphenous vein, dobutamine had no visible agonist activity but did produce contractions after propranolol. In partially contracted saphenous vein, dobutamine produced a small contraction which was converted to a propranolol-sensitive relaxation of tone after phentolamine. Dobutamine was a full beta adrenoceptor agonist in guinea-pig trachea under spontaneous tone but a partial agonist after strong contraction by bethanechol. This allowed measurement of the pKB of dobutamine at beta adrenoceptors (pKB = 5.35) and estimation of efficacy at beta adrenoceptors relative to isoproterenol (eDob/eIso = 1/20). No evidence for beta adrenoceptor selectivity was found in studies of potency ratios and relative efficacy using isoproterenol for comparison. Dobutamine showed a slight (2-fold) selectivity for inotropy in vitro when compared to isoproterenol in guinea-pig right and left atria. This selectivity was removed by phentolamine suggesting a cardiac alpha-like adrenoceptor effect; this finding was confirmed in propranolol-treated guinea-pig left atria. These results are discussed in terms of the in vivo effects of dobutamine and its use as a tool for classification of beta adrenoceptors, particularly the putative presynaptic beta adrenoceptor.     

Imidazoline desensitization of epinephrine responses in rat vas deferens.

Repeated exposure of the rat vas deferens to the imidazoline oxymetazoline (OXY) results in a progressive loss of response which can appear selective for imidazoline agonists. The present study tests the hypothesis that imidazolines produce desensitization through prolonged blockade or inactivation of alpha-1 adrenoreceptors. Repeated exposure to OXY, naphazoline (NPZ) or tetrahydrozoline (THZ) produces a concentration- and time-dependent rightward shift and depression of the (-)-epinephrine concentration-effect curve, suggesting a mechanism of prolonged receptor blockade or inactivation. (-)-Epinephrine Kd values were similar when estimated after either receptor inactivation with phenoxybenzamine or repeated exposure to imidazolines. The differences in the ability of individual imidazolines to produce desensitization (order of potency: OXY greater than NPZ greater than or equal to THZ) do not follow their intrinsic activity (NPZ approximately THZ approximately OXY) or affinity (OXY greater than or equal to NPZ greater than THZ). The ability of individual imidazoline and phenethylamine agonists to produce a response in imidazoline-desensitized rat vas deferens reflects agonist intrinsic efficacy. Desensitization by imidazoline exposure does not affect contraction produced by either KCl or neurokinin A. Imidazolines produce effects similar to receptor inactivation and their desensitization in vas deferens can be explained without invoking an imidazoline subtype of alpha-1 adrenoreceptor.     

Vascular alpha-1 antagonistic and agonistic effects of beta adrenoceptor agonists in rabbit common carotid arteries.

The stainless-steel cannula-inserting method was used to observe vascular effects of mixed and selective beta adrenoceptor agonists, isoproterenol, procaterol and denopamine, on isolated, perfused rabbit common carotid arteries. In phenylephrine-preconstricted preparations, the three beta agonists induced a dose-dependent vasodilation which was not suppressed by treatment with beta antagonists, atenolol, a selective beta-1 antagonist and ICI 118551, a selective beta-2 antagonist. On the other hand, in prostaglandin F2 alpha-preconstricted preparations, these agonists produced no vasodilation and revealed weak vasoconstrictions which were readily suppressed by bunazosin, a selective alpha-1 antagonist. Moreover, these agonists caused a shift of the dose-response curve for phenylephrine to the right in a parallel fashion in non-preconstricted preparations. The relative pA2 values for isoproterenol, procaterol and denopamine calculated from the displacement curve were 7.47, 7.59 and 8.17, respectively. Thus, it is concluded that 1) there are little functional beta adrenoceptors in the rabbit common carotid arteries, 2) beta adrenoceptor agonists have both antagonistic and agonistic properties for alpha-1 adrenoceptor activation, 3) denopamine possesses a higher potency as an alpha-1 antagonist and 4) beta agonists generally act as vasodilators in rabbit cerebral circulation.     

Pharmacological characterization of alpha-2 adrenergic receptor subtype involved in the release of insulin from isolated rat pancreatic islets

Alpha-2 adrenoceptors are involved in the inhibition of insulin release induced by sympathetic nerve stimulation. To test the possibility that one of the postulated subtypes of alpha-2 adrenoceptors is differentially implicated in the inhibition of insulin release, we compared the effects of several agonists and antagonists with preferential selectivity for the alpha-2 adrenoceptor subtypes on the release of insulin induced by glucose in rat isolated islets. Similar to the inhibition of glucose-evoked release of insulin by the alpha-2 agonist (nonsubtype selective) UK 14.304, the alpha-2A preferential agonist oxymetazoline, concentration-dependently inhibited the release of insulin. Glucose-evoked insulin release was similarly inhibited by other alpha-2 adrenoceptor agonists such as clonidine, p-aminoclonidine, epinephrine and norepinephrine. However, neither the alpha-1 selective agonist cirazoline, nor the beta adrenoceptor agonist isoproterenol affected glucose-evoked insulin release, thus suggesting that this inhibitory effect is mediated by alpha-2 adrenoceptors, possibly of the alpha-2A subtype. The inhibition of glucose-evoked insulin release induced by the alpha-2 adrenoceptor agonists was concentration-dependently inhibited by the alpha-2 antagonists yohimbine, phentolamine, rauwolscine and idazoxan. However, neither the alpha-1 selective antagonist prazosin, nor the beta selective antagonist propranolol attenuated the inhibition of insulin release induced by alpha-2 adrenoceptor agonists. Furthermore, the inhibition of insulin release induced by UK 14.304 was concentration-dependently antagonized by the alpha-2A preferential antagonist WB-4101.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alpha‐adrenoceptor agonistic activity of oxymetazoline and xylometazoline

Oxymetazoline and xylometazoline are both used as nasal mucosa decongesting α‐adrenoceptor agonists during a common cold. However, it is largely unknown which of the six α‐adrenoceptor subtypes are actually present in human nasal mucosa, which are activated by the two alpha‐adrenoceptor agonists and to what extent. Therefore, mRNA expression in human nasal mucosa of the six α‐adrenoceptor subtypes was studied. Furthermore, the affinity and potency of the imidazolines oxymetazoline and xylometazoline at these α‐adrenoceptor subtypes were examined in transfected HEK293 cells. The rank order of mRNA levels of α‐adrenoceptor subtypes in human nasal mucosa was: α_2A > α_1A ≥ α_2B > α_1D ≥ α_2C >> α_1B. Oxymetazoline and xylometazoline exhibited in radioligand competition studies higher affinities than the catecholamines adrenaline and noradrenaline at most α‐adrenoceptor subtypes. Compared to xylometazoline, oxymetazoline exhibited a significantly higher affinity at α_1A‐ but a lower affinity at α_2B‐adrenoceptors. In functional studies in which adrenoceptor‐mediated Ca²⁺ signals were measured, both, oxymetazoline and xylometazoline behaved at α_2B‐adrenoceptors as full agonists but oxymetazoline was significantly more potent than xylometazoline. Furthermore, oxymetazoline was also a partial agonist at α_1A‐adrenoceptors; however, its potency was relatively low and it was much lower than its affinity. The higher potency at α_2B‐adrenoceptors, i.e. at receptors highly expressed at the mRNA level in human nasal mucosa, could eventually explain why in nasal decongestants oxymetazoline can be used in lower concentrations than xylometazoline.     

Involvement of adrenergic and angiotensinergic receptors in the paraventricular nucleus in the angiotensin II-induced vasopressin release.

The role of hypothalamic paraventricular adrenoceptors and angiotensin II (ANG II)-AT 1 receptors in mediating the vasopressin (AVP) release into the plasma in response to i.c.v. and local paraventricular ANG II injections was investigated in conscious chronically instrumented rats. Noradrenaline (NA) administered bilaterally into the paraventricular nucleus (PVN) dose-dependently stimulated AVP release. Bilateral PVN microinjections of the alpha 1 adrenoceptor agonists methoxamine and phenylephrine, or of the alpha2 adrenoceptor agonist clonidine, did not affect plasma AVP when given alone, but increased plasma AVP when methoxamine and clonidine were given in combination. In contrast, PVN microinjections of both the beta 1 adrenoceptor agonist dobutamine and the beta 2 adrenoceptor agonist salbutamol significantly reduced basal plasma AVP. Bilateral PVN pretreatment with the alpha 1 and alpha 2 adrenergic antagonists prazosin, idazoxan and rauwolscine, but not of the beta 1 and beta 2 adrenoceptor antagonists atenolol and ICI 118 551, significantly attenuated the i.c.v. ANG II-induced AVP release. ANG II injected bilaterally into the PVN dose-dependently increased plasma AVP. Bilateral PVN pretreatment with the specific ANG II-AT 1 receptor antagonist losartan partially inhibited the i.c.v. ANG II-induced AVP release. We conclude: 1) Beta 1 and beta 2 adrenoceptors in the PVN exert an inhibitory action on basal AVP secretion. 2) ANG II can release AVP by directly stimulating its ANG II-AT 1 receptors in the PVN. 3) PVN mediated AVP release in response to periventricular ANG II-AT 1 receptor stimulation is at least partially effected through ANG II-AT 1 receptors in the PVN impinging on alpha adrenergic terminals.     

Variation in the interaction of some phenylethylamine and imidazoline derivatives with alpha-1 adrenoceptors in rabbit arteries: further evidence for the variable receptor affinity hypothesis.

This study was undertaken to determine whether the variation in the affinity of the alpha-1 adrenoceptors previously found for norepinephrine and phenylephrine in different arteries is also seen with other alpha-1 adrenoceptor agonists, and if so, if one part of the structure is particularly responsible for the variation. The potency and dissociation constants of eight agonists, both phenylethylamines and imidazolines, were determined in five rabbit arteries. In each artery the rank order of phenylethylamine agonist potency was epinephrine greater than norepinephrine greater than phenylephrine greater than deoxyepinephrine greater than methoxamine greater than dopamine. The same rank order of dissociation constants was found. For the imidazolines, the potency order was oxymetazoline greater than clonidine. For each agonist, there was a linear correlation between artery sensitivity and receptor affinity. None of the regression line slopes differed from each other. For each artery there was a linear correlation between phenylethylamine sensitivity and affinity. With the exception of the ovarian, which was lower, slopes of the regression lines in each group do not differ from each other. There were differences in the spread of the dissociation constants of the phenylethylamine derivatives among the arteries. The range of affinities was most marked with norepinephrine (greater than 40-fold) and least with epinephrine (approximately 4-fold). They suggest that agonist affinity governs the biological activity of at least the phenylethylamines on rabbit arteries mediated by the alpha-1 adrenoceptor. Variation in agonist affinity can explain the extent of the biological response. Differences in range of amine affinities in different arteries suggest that the agonist recognition site, although similar in the different arteries, is not identical and may be related particularly to some variation of the amine attachment site of the molecule. The results provide further support for the variable receptor affinity hypothesis.     

Specialization in beta-1 and beta-2 adrenoceptor distribution in veins of the rabbit face: relationship to myogenic tone and sympathetic nerve innervation

Studies were performed on several superficial veins from the rabbit face to examine the relationship between beta adrenoceptor subtype distribution, intrinsic myogenic tone and sympathetic nerve innervation. Experiments using selective beta adrenoceptor agonists and antagonists indicate that the dorsal nasal and angularis oculi veins possess a homogeneous population of beta-2 adrenoceptors. Sympathetic nerve stimulation in these segments results only in contraction mediated through postjunctional alpha adrenoceptors. These segments are devoid of intrinsic myogenic tone. In the facial vein, of which both veins are tributaries, both beta-1 and beta-2 adrenoceptors are found. Studies with the beta-1 adrenoceptor antagonist, betaxolol, and beta-2 adrenoceptor antagonist, ICI 118,551, indicate that the prominent relaxation observed in this tissue to sympathetic nerve stimulation is mediated through postjunctional beta-1 adrenoceptors. At physiological temperatures, the facial vein possesses a marked intrinsic myogenic tone that is inhibited by this beta-1 adrenoceptor-mediated sympathetic activity. Considering the anatomical relationship between these vessels and the unique association between beta adrenoceptor subtype, intrinsic myogenic tone and sympathetic innervation, it is possible that facial blood redistribution in the rabbit can be markedly affected by sympathetic nerve stimulation. Such a process could have an important role in cranial thermoregulation.     

Rat jugular vein relaxes to norepinephrine, phenylephrine and histamine.

Circular muscle of the rat external jugular vein contracted to serotonin, angiotensin and potassium chloride but not to norepinephrine, phenylephrine, histamine or carbamylcholine. In contrast, rabbit and guinea-pig jugular veins contracted to norepinephrine, phenylephrine and histamine, although contractions to norepinephrine were small in guinea-pig jugular veins. Norepinephrine, phenylephrine and histamine produced a concentration-dependent sustained relaxation of serotonin-induced contractions in the rat jugular vein, as did isoproterenol, nitroglycerin and papaverine. Propranolol blocked relaxation to norepinephrine, phenylephrine and isoproterenol whereas metiamide, a H2 receptor antagonist blocked relaxation to histamine. alpha adrenergic receptor blockade with phentolamine or prazosin resulted in greater relaxation to norepinephrine whereas cocaine did not enhance norepinephrine-induced vasodilation. This study supports the premise that norepinephrine may exert prominent beta adrenergic receptor stimulation in some blood vessels and that this effect may be more apparent in veins than arteries.     

Catecholamine modulation of spinal sympathetic reflexes

Sympathetic reflexes in an in vitro frog spinal cord appeared to be qualitatively similar to those observed in cats in vivo. The present study ws conducted to determine whether or not this similarity extended to catecholamine effects on spinal sympathetic reflexes and to examine the adrenoceptor mechanisms responsible for these effects. Norepinephrine inhibited spinal sympathetic reflexes elicited by supramaximal electrical stimulation of the second spinal nerve in a concentration-dependent manner. This inhibition could be mimicked by other alpha adrenoceptor agonists and was antagonized by phentolamine. No effect of norepinephrine was observed when submaximal stimuli were employed. Epinephrine facilitated reflex activity elicited by both submaximal and supramaximal stimulation; however, in the presence of propranolol, an inhibitory effect of epinephrine was observed. At high concentrations, dopamine inhibited spinal sympathetic reflex activity and this inhibition was antagonized by phentolamine. l-Dopa produced a slow-onset, long-lasting inhibition which could be blocked by pretreatment with a decarboxylase inhibitor. It is concluded that alpha adrenoceptor agonists acting on alpha receptors can inhibit spinal sympathetic reflex activity and that the inhibition is dependent on the intensity of stimulation. Activation of beta adrenoceptors facilitates, whereas activation of dopamine receptors has no effect on, spinal sympathetic reflexes. These alpha and beta adrenoceptor mechanisms may function in the modulation of sympathetic preganglionic activity in the intact animal.     

Depression of contractile responses in rat aorta by spontaneously released endothelium-derived relaxing factor

Removal of endothelial cells on rings of rat aorta increased the sensitivity to the selective alpha-1 adrenoceptor agonist phenylephrine, to the nonselective alpha adrenoceptor agonist norepinephrine and to the selective alpha-2 adrenoceptor agonist clonidine. In the case of the first two, which are strong agonists for the alpha-1 adrenoceptor-mediating contraction, removal of endothelium increased sensitivity 4- and 6-fold at the EC30 level, but produced little or no increase in maximum. In the case of clonidine, a partial agonist for the alpha-1 adrenoceptor, which gave only about 15% of the maximum given by phenylephrine on endothelium-containing rings, removal of the endothelium not only shifted the curve to the left but also increased the maximum to about 50% of that given by phenylephrine. The depression of sensitivity to these agonists in rings with endothelium appeared to be due to the vasodepressor action of endothelium-derived relaxing factor (EDRF), as hemoglobin, a specific blocking agent of EDRF, abolished this depression. It is unlikely that the endothelium-dependent depression was due to stimulation of release of EDRF, because clonidine did not produce endothelium-dependent relaxation in precontracted rings even when its contractile action was blocked by the alpha-1 adrenoceptor antagonist prazosin. Further evidence against alpha adrenoceptor agents stimulating release of EDRF was that neither phenylephrine nor clonidine induced a rise in cyclic GMP in aortic rings, whereas acetylcholine, which does release EDRF, caused a large rise in cyclic GMP content. The possibility that the muscle cells of intact rat aortic rings were under the tonic influence of released EDRF was supported by the finding that, in the absence of any contractile agent, hemoglobin induced a fall in the basal level of cyclic GMP in endothelium-containing rings. Also consistent with EDRF being released spontaneously was the finding that contraction induced by 5-hydroxytryptamine, like that by alpha-adrenergic agonists, was also depressed in endothelium-containing rings of aorta. When the efficacy of phenylephrine as an alpha-1 agonist was reduced to about the initial efficacy of clonidine by irreversible inactivation of a very large fraction of alpha-1 adrenoceptors of the smooth muscle cells by pretreatment with dibenamine, the concentration-contraction curves for phenylephrine for both endothelium-containing rings and for endothelium-denuded rings now became very similar to the corresponding curves obtained for clonidine before receptor inactivation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Pharmacologic characterization of SK&F 104078, a novel alpha-2 adrenoceptor antagonist which discriminates between pre- and postjunctional alpha-2 adrenoceptors

SK&F 104078 has been reported to be a moderately potent antagonist at postjunctional alpha-2 adrenoceptors in canine saphenous vein, rabbit saphenous vein and canine saphenous artery (KB = 76-150 nM). In contrast, SK&F 104078 has been found to have essentially no affinity for prejunctional alpha-2 adrenoceptors in the guinea pig atrium. To characterize further the pharmacology of SK&F 104078 we have examined its effects in several additional alpha-2 adrenoceptor models and on several non alpha adrenoceptor-mediated vascular responses. SK&F 104078 does not block the neuroinhibitory effect of alpha methylnorepinephrine in the guinea pig ileum. In contrast, in the rat vas deferens, high concentrations of SK&F 104078 (3-30 microM) antagonized the neuroinhibitory effect of UK 14,304; however, the antagonism was not competitive. At concentrations up to 1 microM, SK&F 104078 did not potentiate [3H]overflow from guinea pig vas deferens or guinea pig atrium prelabeled with [3H]norepinephrine, indicating no prejunctional alpha-2 adrenoceptor blocking activity in these tissues. SK&F 104078 is a competitive antagonist at alpha-1 adrenoceptors, and at 5-hydroxytryptamine2 receptors, as demonstrated by blockade of norepinephrine- and serotonin-induced contraction in the rabbit aorta, with KB values of 155 and 20 nM, respectively. At concentrations up to 10 microM, SK&F 104078 does not depress angiotensin II-induced contraction of rabbit aorta. At 1 microM, no depression of the response to Ca++ in depolarized rabbit aorta is observed, although a significant inhibition of this response is seen at 10 microM.(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)     

Involvement of alpha-2 adrenergic receptor subtypes in hyperglycemia

Alpha-2 adrenoceptor stimulation induces in the mouse a hyperglycemic response which is accompanied by a concomitant inhibition of insulin secretion. To test the possibility that one of the postulated subtypes of alpha-2 adrenoceptors is preferentially implicated in this response, we compared the interaction of several drugs with known selectivity toward alpha-2A or alpha-2B adrenoceptor subtypes in our model. The alpha-2A preferential agonist oxymetazoline induced in the mouse a hyperglycemic response similar to that of the nonselective alpha-2 adrenoceptor agonist UK 14.304. This hyperglycemic response to oxymetazoline was accompanied by a concomitant inhibition of insulin release. Both the effect on glycemic level and the inhibition of insulin release by oxymetazoline were antagonized by the alpha-2 adrenoceptor antagonist idazoxan. The alpha-2B preferential antagonists ARC-239, prazosin or chlorpromazine failed to block the modifications in both glycemic and insulin levels induced by alpha-2 adrenoceptor stimulation. The nonselective antagonists rauwolscine, yohimbine, WY 26703, phentolamine and corynanthine, as well as the receptor antagonists with alpha-2A selectivity like WB 4101, idazoxan and tolazoline, dose-dependently antagonized both the glycemic and the insulin responses to UK 14.304. A positive correlation was obtained between the potencies of these drugs in antagonizing the hyperglycemic response to UK 14.304 and their affinities for alpha-2A adrenergic receptors (r = 0.918, P less than .001) but no correlation was obtained with their affinities for alpha-2B adrenergic receptors (r = 0.048, P = N.S.)(ABSTRACT TRUNCATED AT 250 WORDS)     

Spinal cord pharmacology of adrenergic agonist-mediated antinociception

Intrathecal administration of norepinephrine (NE) and alpha adrenergic agonists in rats with chronic spinal catheters produced a significant elevation of the nociceptive threshold as measured by hot plate and tail flick. The intrathecal NE effect was dose-dependent and antagonized in a competitive fashion by pretreatment with phentolamine (alpha antagonist) but not by propranolol (beta antagonist). Intrathecal administration of isoproterenol (beta agonist) did not alter the nociceptive threshold. Effective doses of intrathecal NE did not produce demonstrable motor effects. Doses 20 times greater than the maximum analgesic dose produced marked weakness of the hindlimbs and tails. The intrathecal NE effect was not antagonized by intrathecal papaverine of bradykinin (vasodilators) or mimicked by angiotensin-II (vasoconstrictor). The intrathecal NE effect was not altered by intrathecal administration of subconvulsant doses of either picrotoxin (gamma-aminobutyric acid antagonist) or strychnine (glycine antagonist) or by i.p. administration of either naloxone (opiate antagonist) or methysergide (serotinin antagonist). The nociceptive threshold was significantly decreased 1 week after intrathecal administration of 6-hydroxydopamine, which depleted spinal cord NE by 85%. Intrathecal administration of tyramine (indirectly acting sympathomimetic amine) produced an elevation of the nociceptive threshold in a control group of animals but was less effective in animals pretreated with intrathecal 6-hydroxydopamine. The tyramine effect was antagonized by intrathecal phentolamine. Intravenous administration of aminophylline (phosphodiesterase inhibitor) did not potentiate the intrathecal NE effect. The relative antinociceptive potencies of alpha adrenergic agonists after intrathecal administration were: l-norepinephrine = dl-epinephrine greater than dl-alpha-methyl norepinephrine greater than clonidine greater than or equal to l-phenylephrine greater than or equal to 3,4-dihydroxytolazoline greater than or equal to oxymetazoline. The relative potencies of intrathecally administered alpha antagonists in antagonizing the intrathecal NE effect were: phentolamine greater than phenoxybenzamine greater than tolazoline greater than or equal to yohimbine.     

Cardiac inotropic beta adrenoceptors are fully active at low temperature.

The purpose of this study was to test the adrenoceptor interconversion hypothesis of Kunos and Nickerson (Brit. J. Pharmacol. 59: 603--614, 1977) which claims that lowering temperature from 31 to 17 degrees C converts inotropic beta adrenoceptors in rat atria to alpha adrenoceptors. If lowering temperature transforms the adrenoceptor from a beta type to an alpha type, one should expect that the sympathomimetic drug phenylephrine would be more potent at the low than at the high temperature, that the reverse would be true for the sympathomimetic drug isoproterenol, and that the blocking ability of the beta adrenoceptor blocking drug propranolol might be reduced and that of the alpha adrenoceptor blocking drug phentolamine increased by lowering temperature. This was not observed. It was impossible to obtain satisfactory inotropic effects at 17 degrees C and the calcium concentration in the incubation medium had to be reduced, which lowered contractility and permitted strong inotropic effects. At 17 degrees C the sympathomimetic drug effects were inhibited only by propranolol and not by phentolamine, and there was no evidence of "adrenoceptor interconversion."     

Dopamine receptor stimulating and alpha adrenoceptor blocking actions of trans (CS-265) and cis (CS-263) isomers of nonhydroxylated N-propyl octahydrobenzo[F]quinoline

Experiments were designed to determine the dopaminergic and alpha adrenergic receptors involvement of cis (CS-263) and trans (CS-265) isomers of nonhydroxylated N-propyl octahydrobenzo[f]quinoline. Both compounds caused competitive blockade of presynaptic alpha-2 adrenoceptors of guinea-pig ileum and rat vas deferens. Postsynaptic alpha-1 adrenoceptors of rabbit aorta was inhibited. In the guinea-pig ileum, these compounds were found to be as active as yohimbine. In the rabbit aorta, they were weaker antagonists of phenylephrine than prazosin. CS-compounds reversed epinephrine-induced pressor responses and inhibited reflex hypertensive responses to stimulation of the central stump of sciatic nerve in anesthetized cats. Only CS-265 inhibited reflex tachycardia of sciatic nerve stimulation. In isolated cat right atria, CS-265 inhibited stimulation-induced tachycardic response through stimulation of presynaptic dopamine receptors in contrast to CS-263 that produced potentiation of stimulation-induced tachycardia. The results suggest that CS-265 is an unusual compound having dopamine receptor stimulating activity and alpha adrenoceptor blocking properties. These divergent properties provide direct evidence that presynaptic alpha-2 adrenoceptors and dopamine-receptors are different entities on the sympathetic nerve terminal.     

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.