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Results for “Adrenergic alpha-2 Receptor Agonists”

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PubMed1992

The role of adrenergic receptors in the initiation of vomiting and its gastrointestinal motor correlates.

We investigated the role of adrenergic receptors in the mechanisms of initiation of vomiting and its gastrointestinal (GI) motor correlates. The effects of clonidine, UK-14304, St-91, naphazoline, phenylephrine and isoproterenol were examined for their ability to initiate vomiting and its GI motor correlates. Only the alpha-2 adrenoceptor agonists UK-14304, clonidine, St-91 and naphazoline activated vomiting and its GI motor correlates. Tolerance of vomiting, but not its GI motor correlates, readily developed to all alpha-2 adrenergic receptor agonists but St-91. The responses to UK-14304 or clonidine were blocked by idazoxan, yohimbine, clonidine tolerance or high doses of phenoxybenzamine, but not by propranolol or prazosin. The responses to UK-14304 or clonidine were also blocked by fentanyl, 1-(1-naphthyl) piperazine, methysergide, SCH 22390 or scopolamine, but not by haloperidol, sulpiride, domperidone or naloxone. Adrenoceptor antagonists, clonidine tolerance or sympathetic blockade did not block vomiting or its GI motor correlates activated by apomorphine, CuSO4 or cholecystokinin-octapeptide. We concluded that alpha-2 adrenergic receptors of the chemoreceptive trigger zone can initiate vomiting and its GI motor correlates, but these receptors do not mediate vomiting induced by another chemoreceptive trigger zone stimulant, apomorphine, or stimulation of the GI tract using CuSO4. However, 5-hydroxytryptamine-2 serotonergic, muscarinic cholinergic and opiate receptors within the central nervous system participate in controlling emesis activated by alpha-2 adrenergic agonists. Peripheral adrenergic receptors do not mediate the GI motor correlates of vomiting.

Adrenergic alpha-Agonists↗

PubMed1992

Phorbol ester and staurosporine modulation of antagonist and agonist binding to alpha-2 adrenergic receptors: differential influence on Na+ versus guanylylnucleotide regulation.

The modulatory influence of the protein kinase C (PKC) activator phorbol dibutyrate (pDBu) and the PKC inhibitor staurosporine on the binding of the antagonist rauwolscine and the agonist (-)-epinephrine to alpha-2 adrenergic receptors was studied in plasma membranes from bovine aorta. In control membranes [3H]rauwolscine binding exhibited high (KDH = 110 pM) and low (KDL = 2.4 nM) affinity components. The addition of 0.1 mM 5'-guanylylimidodiphosphate [Gpp(NH)p] reduced binding to a single component (KD = 1.3 nM) and the addition of 140 mM NaCl increased the proportion of high affinity sites from 7 to 15%, whereas the combination of both Gpp(NH)p and NaCl did not differ from values for NaCl alone. PDBu pretreatment had little effect on [3H]rauwolscine binding with the exception of a small increase in KD in the presence of Gpp(NH)p. Staurosporine pretreatment, however, eliminated the high-affinity component in the absence of Gpp(NH)p or NaCl and rendered Gpp(NH)p ineffective. NaCl was able to restore two components of [3H]rauwolscine binding to the same extent as in untreated membranes. Epinephrine displaced [3H]rauwolscine in a biphasic manner (KDH = 93 nM, KDL = 3.5 microM; %RH = 42). In untreated membranes Gpp(NH)p reduced epinephrine affinity, but did not alter the %RH. NaCl alone increased KDL and caused a partial decrease in %RH, whereas the combination of Gpp(NH)p and NaCl was required to produce a single, low-affinity state (KD = 11.9 microM). PDBu pretreatment reduced epinephrine affinity and blocked the effectiveness of Gpp(NH)p, but the action of NaCl was more pronounced than in untreated membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkaloids↗

PubMed1992

Influence of age on control of norepinephrine release from the rat tail artery.

Stimulation-evoked norepinephrine release from the rat tail artery increases with age; therefore, the sensitivity of prejunctional alpha-2 adrenergic receptors to antagonists and agonists was compared in perfused tail arteries from Fischer-344 rats, aged 6 and 20 months. The increase in endogenous fractional norepinephrine release produced by blockade of alpha-2 adrenergic receptors with submaximal concentrations of either yohimbine or idazoxan was significantly greater in 6-month-old animals as compared to 20 months; however, the effect of a maximal concentration of idazoxan was not significantly different. Inhibition of norepinephrine release by the alpha-2 receptor agonist UK14304 was reduced in 20-month-old animals compared to 6 months. In contrast, there were no age-related differences in inhibition of contractile responses to nerve stimulation by the prejunctionally acting dopamine D2 agonist, N-0923. These data suggest that age-related changes in the sensitivity of prejunctional alpha-2 receptors to agonists and antagonists may not reflect any fundamental alteration in the function of this receptor system, but may be related to competition between alpha-2 agonists or antagonists and increased biophase concentrations of norepinephrine. This conclusion is supported by lack of an age-related change in function of prejunctional dopamine D2 receptors. Persistence of age-related increases in norepinephrine release when alpha-2 adrenergic receptors are fully blocked may reflect an alteration in other fundamental mechanisms that control norepinephrine release.

Adrenergic beta-Agonists↗

PubMed1992

[Imidazoline-guanidine site: a subtype of imidazoline receptors].

Since the demonstration that imidazoline and guanidinium alpha-2 adrenergic agonists induce some of their functional effects by a "nonadrenergic" mechanism, many efforts have been done to identify an imidazoline receptor. Binding studies have allowed to characterize two classes of potential imidazoline receptors: the "(p-amino)clonidine" and the "idazoxan" binding sites. These last, that we named "imidazoline-guanidinium receptive sites" (IGRS) on the basis of their ligand-recognition properties, have been identified, for the first time, in the proximal tubule from rabbit and human kidney. In the present report we will summarize the studies that led us to the characterization of IGRS.

Animals↗

PubMed1992

Platelet alpha-2 adrenergic receptor binding and plasma free 3-methoxy-4-hydroxyphenylethylene glycol in depressed patients before and after treatment with mianserin.

To examine the noradrenergic function in endogenous depression, binding of a selective agonist radioligand, 3H-UK14304, to platelet alpha 2-adrenergic receptors and plasma free 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured in untreated depressed patients. The effects of an antidepressant, mianserin, on these parameters were also assessed. The Bmax and Kd values for 3H-UK14304 binding in 26 untreated depressed patients were significantly higher (p less than 0.05, p less than 0.01) than those in 26 normal controls. On the other hand, there were no significant differences in plasma free MHPG levels between 12 untreated depressed patients and 12 normal controls. Chronic administration of mianserin to 8 depressed patients slightly increased the Bmax and Kd values. However, plasma free MHPG levels did not change after treatment. These findings suggest that depression is related to the subsensitivity of alpha 2-receptors as indicated by a decreased affinity of platelet alpha 2-receptors. In addition, chronic administration of mianserin further decreased the affinity of alpha 2-receptors. This suggests that mianserin acts not only on alpha 2-receptors but also on the other neurotransmitter systems.

Aged↗

PubMed1992

Desensitization and down-regulation of the 5-hydroxytryptamine1B receptor in the opossum kidney cell line.

In the opossum kidney cell line the 5-hydroxytryptamine (serotonin; 5-HT)1B receptor is negatively coupled to adenylyl cyclase via a Gi protein. Preincubation of opossum kidney cell line cell monolayers with 5-HT resulted in 5-HT1B receptor-mediated desensitization expressed as a 4-fold rightward shift of the dose-response curve and a 10 to 29% decrease of maximal inhibition of forskolin-stimulated cyclic AMP production. These moderate decreases in potency and efficacy were concentration- and time-dependent. Maximal desensitization occurred with 3 hr of 5-HT preincubation. Preincubation with 5-HT caused no change in the potency or efficacy of alpha-2 adrenergic agonist-mediated inhibition of forskolin-stimulated cyclic AMP production. Therefore, the desensitization caused by 5-HT preincubation appears to be homologous. Down-regulation of the 5-HT1B receptor, assessed with the high affinity radioligand [125I]iodocyanopindolol, also occurred, and was concentration- and time-dependent. Maximum down-regulation of 40% occurred after 20 hr of exposure to 10 microM 5-HT. These results demonstrate that, like other receptors coupled to the inhibition of adenylyl cyclase, exposure of 5-HT1B receptors to an agonist causes desensitization of the functional response followed by down-regulation of the receptor.

Animals↗

PubMed1992

Activation of alpha-1 adrenergic receptors modulates the control of left/right sidedness in rat embryos.

Presomite stage rat embryos were cultured for 45-49 hr with medium containing various adrenergic agonists and antagonists. L-Norepinephrine but not D-norepinephrine (several orders of magnitude less potent than the L-isomer at alpha-1 adrenergic receptors) resulted in a dose-dependent increase of situs inversus similar to that found for phenylephrine, an alpha-1 adrenergic agonist. Prazosin, an alpha-1 adrenergic antagonist, inhibited phenylephrine-induced situs inversus in a dose-dependent manner. Neither dexmedetomidine, an alpha-2 adrenergic agonist, nor isoproterenol, a beta adrenergic agonist, caused situs inversus. These results provide pharmacological evidence that stimulation of alpha-1 but not of alpha-2 and beta adrenergic receptors modulates the control of left/right sidedness in rat embryos.

Adrenergic alpha-Agonists↗

PubMed1992

Characterization of prejunctional alpha-2 adrenergic receptors involved in modulation of adrenergic transmitter release in the isolated perfused rat kidney.

The subclassification of alpha-2 adrenergic receptors into A and B subtypes is based on radioligand binding and functional studies. Radioligand binding studies also have suggested the existence of C and D subtypes, which have only been described as binding sites. This study was designed to determine the subtype of prejunctional alpha-2 adrenergic receptor involved in inhibition of norepinephrine release from sympathetic nerves in the rat kidney. Electrically induced (0.25 Hz, 50 V, 0.5 msec, 10 pulses) fractional tritium overflow was measured in kidneys isolated from male Sprague-Dawley rats and prelabeled with [3H]norepinephrine. The alpha-2 receptor antagonists rauwolscine and yohimbine did not enhance fractional tritium overflow, suggesting the lack of autoinhibition at this frequency of stimulation. The alpha-2 receptor agonist, UK-14,304, inhibited electrically stimulated fractional tritium overflow with an ED50 of 4.85 +/- 0.35 nM. pA2 values for various alpha receptor antagonists against UK-14,304-induced inhibition of fractional tritium overflow were: rauwolscine, 8.8; yohimbine, 8.1; prazosin, 7.4; BAM 1303, 7.5; SKF 104078, 6.4; phentolamine, 8.7; WB 4101, 8.1; corynanthine, 6.1; and ARC-239, 7.2. The correlation coefficients and slopes of the regression lines between pA2 values of alpha receptor antagonists at the prejunctional alpha-2 adrenergic receptor and the reported pKi values obtained from radioligand binding studies were: 0.48 and 0.82; 0.61 and 0.58; 0.53 and 0.85; and 0.89 and 1.05 for the alpha-2A, B, C and D adrenergic receptors, respectively. These data suggest that the prejunctional alpha-2 adrenergic receptor modulating [3H]norepinephrine release in the rat kidney most closely resembles the alpha-2D adrenergic receptor characterized by radioligand binding studies.

Adrenergic alpha-Antagonists↗

PubMed1992

Characterization of the pharmacology of intrathecally administered alpha-2 agonists and antagonists in rats.

To examine the pharmacology of the spinal alpha receptor which modulates nociceptive transmission, the antinociceptive effects (52.5 degrees C hot plate; HP) of three i.t. administered alpha-2-preferring agonists [dexmedetomidine (DMET); clonidine (CLON) and ST-91] were determined. The antagonist potency of atipamezole (ATI), idazoxan (IDAZ), yohimbine (YOH) and prazosin (PRA), adrenergic antagonists with differing alpha-2-preferring profiles, were then examined for each of the three agonists. The three agonists produced a dose-dependent block of the HP response with the ED50 and the dose which was just maximally effective being DMET (3.2 and 10 micrograms); CLON (27 and 100 micrograms) and ST-91 (6.1 and 20 micrograms). After determining the time of peak antagonist effect, studies were run in which the just maximally effective dose of each agonist was given in conjunction with one of several doses of the several antagonists. The rank order of potency (and ID50 in microgram) for the several antagonists against each of the three agonists was: DMET = [IDAZ (1.9); ATI (4.1); YOH (70); PRA (greater than 100)]; CLON = [ATI (2.7); IDAZ (23); YOH (52); PRA (greater than 100)]; ST-91 = [PRA (38); YOH (69); ATI (greater than 100); IDAZ (greater than 100)]; where antagonists joined by a common line display overlapping 95% confidence intervals and greater than (greater than) indicates failure to achieve a 50% reversal at the highest antagonist dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

L-dopa is protective against indomethacin-induced small intestinal ulceration in the rat: possible role of an alpha-2-adrenergic mechanism.

Dopaminergic agents ameliorate experimentally induced gastroduodenal mucosal injury, but there is no information about their effect on small intestinal mucosa. We studied the effect of L-dopa and related substances on indomethacin-induced intestinal ulceration in the rat. Ulceration was produced by s.c. injection of 30 mg/kg indomethacin, 30 min after refeeding fasted rats. Total ulcer area was measured 24 hrs after indomethacin administration. L-dopa, 5 mg/kg given in two divided doses 5 h apart, starting 30 minutes before administration of indomethacin, was found to protect the small bowel mucosa against indomethacin- induced damage (ulcer area 122 +/- 5.5 vs 224.2 +/- 5.4 mm2, mean +/- SEM, p less than 0.006). Administration of 5 mg/kg haloperidol, a dopa antagonist, did not abolish the protective effect of L-dopa. On the other hand, yohimbine, an alpha-2-adrenoreceptor antagonist, almost completely abolished the protective effect (180.4 +/- 5.3 vs 122 +/- 5.5, p less than 0.004). Clonidine 20 micrograms/kg, an alpha-2-adrenoreceptor agonist, closely mimicked the protective effect of L-dopa (141.5 +/- 10.9 vs 224.2 +/- 5.4, p less than 0.006). All drugs were give i.p. in two divided doses, at the same schedule as described for L-dopa. The results demonstrate that L-dopa has a protective effect on indomethacin-induced small bowel injury in the rat. The protective effect is probably mediated through stimulation of alpha-2-adrenoreceptors.

Animals↗

PubMed1992

The insulin-secreting cell line, RINm5F, expresses an alpha-2D adrenoceptor and nonadrenergic idazoxan-binding sites.

The pharmacological properties of alpha-2 adrenoceptors and the existence of nonadrenergic idazoxan-binding sites (NAIBS) were investigated in the insulin-secreting cell-line, RINm5F, using [3H]RX821002 and [3H]idazoxan. Analysis of [3H]RX821002 saturation isotherms revealed the presence of a single class of binding sites (Bmax = 47.5 +/- 3.5 fmol/mg protein) having high affinity (Kd = 1.26 +/- 0.18 nM). Inhibition of [3H]RX821002 binding by adrenergic compounds showed that the labeled sites displayed the properties expected for an alpha-2 adrenoceptor. Based on competition data with drugs having alpha-2 adrenoceptor subtype selectivity, the receptor from RINm5F is neither an alpha-2B nor an alpha-2C. It resembles the alpha-2A, but deviates from this subtype because of a weak affinity for yohimbine and rauwolscine. In this respect, RINm5F alpha-2 adrenoceptor is identical to the receptor previously described in rat intestinal mucosa and corresponds to a fourth subtype: alpha-2D. Agonist inhibition curves were better fitted by a two-site model and indicated that about half of the receptor population was under a high-affinity state corresponding to G protein-coupled receptors. [32P]ADP-ribosylation with pertussis toxin and immunodetection with specific antibodies permitted the identification of three distinct G proteins: Gi2, Gi3 and G0. Binding experiments with [3H]idazoxan showed that this imidazoline labeled two types of sites corresponding to alpha-2 adrenoceptors and NAIBS. Analysis of saturation isotherms under binding conditions allowing to discriminate between the two site populations indicated that the density of NAIBS (44 +/- 2 fmol/mg protein) was fairly identical to that of alpha-2 adrenoceptors. The pharmacological properties of NAIBS, as assessed by determining the relative affinity of imidazolinic and nonimidazolinic compounds, reasonably matched that reported in other tissues. Taken together, these data make the RINm5F cell-line 1) the first model in permanent culture known as expressing an alpha-2 adrenoceptor of the alpha-2D subtype; 2) a good system for studying in vitro the respective role of alpha-2 adrenoceptors and NAIBS in the regulation of insulin secretion by beta cells.

Adenosine Diphosphate↗

PubMed1992

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.

Adrenergic alpha-Agonists↗

PubMed1992

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)

Adrenergic alpha-Antagonists↗

PubMed1992

Opposite rank order of potency for alpha-2 adrenoceptor agonists on water and solute excretion in the rat: two sites and/or receptors?

Preliminary studies determined that, unlike other purported alpha-2 adrenoceptor agonists, 2,6-dimethyl clonidine (2,6-DMC) increased urine flow rate independent of vasopressin. We therefore compared the dose-response curves of three alpha-2 adrenoceptor agonists, clonidine, UK 14,304 and 2,6-DMC. Unilaterally nephrectomized Sprague-Dawley rats were anesthetized and the left kidney was exposed and the ureter cannulated. A 31-gauge needle was advanced into the renal artery to permit direct intrarenal infusion of the study drugs. All three agonists produced a dose-related increase in urine flow rate and sodium excretion. A clear opposite rank order of potency was observed when the urine flow rate was analyzed as free water and osmolar clearance. For free water clearance, clonidine much greater than UK 14,304 much greater than 2,6-DMC, with 2,6-DMC producing little change. The effect on osmolar clearance was opposite with 2,6-DMC much greater than clonidine = UK 14,304. The V2 antagonist [1-(beta-mercapto-beta,beta-pentamethylene-proprionic acid), 2-d-isoleucine,4-isoleucine]arginine-vasopressin blocked the effects of clonidine but not 2,6-DMC. In a water-loaded rat model, 2,6-DMC but not clonidine increased the delivery of filtrate out of the proximal segments of the nephron. These results are consistent with the postulate that lower doses of 2,6-DMC increase solute excretion independent of vasopressin, possibly in proximal segments of the nephron. Clonidine on the other hand increases free water clearance and this effect is mediated through an interaction with the renal actions of vasopressin. Whether these disparate effects represent two distinct receptors or two sites of alpha-2 adrenoceptors in the kidney is not known.

Adrenergic alpha-Agonists↗

PubMed1992

Comparison of signal transduction mechanisms of alpha-2C and alpha-1A adrenergic receptor-stimulated prostaglandin synthesis.

Prostaglandin (PG) synthesis elicited by adrenergic transmitter in the vascular smooth muscle cells (VSMC) of rabbit aorta is primarily mediated through activation of alpha-2C and alpha-1A adrenergic receptors (ARs). We have now investigated and compared the signal transduction mechanisms involved in alpha-2C and alpha-1A AR-stimulated prostacyclin (PGI2) production, measured as 6-keto-PGF1 alpha, in vascular smooth muscle cells. Norepinephrine, methoxamine (an alpha-1 AR agonist) and UK-14304 (an alpha-2 AR agonist) enhanced 6-keto-PGF1 alpha production. UK-14304 and norepinephrine (in the presence of propranolol), but not methoxamine, reduced basal adenosine 2':3'-cyclic monophosphate (cyclic AMP) as well as forskolin- and isoproterenol-stimulated cyclic AMP accumulation. Forskolin and isoproterenol did not alter basal 6-keto-PGF1 alpha production and alpha AR agonist-induced 6-keto-PGF1 alpha production. Alpha-2C and alpha-1A AR-stimulated 6-keto-PGF1 alpha production was independent of cyclic AMP levels in vascular smooth muscle cells. Both alpha-2C and alpha-1A AR-stimulated 6-keto-PGF1 alpha production required extracellular Ca++. Pertussis toxin prevented inhibition of cyclic AMP accumulation and reduced 6-keto-PGF1 alpha production in response to AR agonists. Guanosine 5'-O-(3-thiotriphosphate) potentiated 6-keto-PGF1 alpha production induced by norepinephrine and UK-14304 but not by methoxamine, whereas at a higher Mg++ concentration (4 mM), guanosine 5'-O-(3-thiotriphosphate) potentiated 6-keto-PGF1 alpha production by all three agonists. In contrast, the effect of UK-14304 on cyclic AMP was prevented in the presence of 4 mM Mg++. These data suggest that the pertussis toxin-sensitive G protein(s) mediated the stimulation of PG synthesis by alpha-1A and alpha-2C AR activation and the decrease in cyclic AMP accumulation by alpha-2C AR activation.

6-Ketoprostaglandin F1 alpha↗

PubMed1992

[Na+/H+ exchangers, alpha-2-adrenergic receptors, sodium sensitivity and arterial hypertension].

Existing evidences indicate that a crossed regulation between alpha 2-adrenergic receptors and Na+/H+ exchanger(s) exists, that Na decreases the affinity of alpha 2-adrenergic receptors for agonists and antagonists, that intracellular Na+ and H+ ion concentrations regulate Na+/H+ exchanger activity, that intracellular pH controls the affinity of the alpha 2-adrenergic receptors for their agonists and antagonists. Alterations of alpha 2-adrenergic receptor densities and allosteric regulation by sodium have been demonstrated in sodium-dependent hypertension in rats. Increased Na+/H+ exchanger activity has been reported in genetic hypertension. Nevertheless, cosegregation experiments and human genetic polymorphism suggest that the exchanger could not be related to hypertension. We propose the following hypothesis: the increased Na+/H+ exchanger characteristic of hypertension could be secondary to the abnormalities of the alpha 2-adrenergic receptors found in hypertension, probably through the alteration of the sodium allosteric effect on these receptors.

Animals↗

PubMed1992

Suppression by spinal alpha-2 agonists of motor and autonomic responses evoked by low- and high-intensity thermal stimuli.

In halothane (0.9%)-anesthetized rats, the immersion of the tail in 52.5 degrees C or 60 degrees C water for 15 sec resulted in a short-latencied tail jerk and a subsequent tachycardia and elevation in blood pressure. The i.t. administration of the alpha-2 agonists, dexmedetomidine (DMET), clonidine (CLON) and ST-91, resulted in a dose-dependent increase in the somatomotor reflex latency and a reduction in the magnitude of the increase in the magnitude of the cardiovascular response, with the ordering of activity on all endpoints at all temperatures being: DMET greater than CLON greater than or equal to ST-91. Increasing the stimulus intensity from 52.5 to 60 degrees C resulted in right shifts in the dose-response curves for all agents with the magnitude of shift being: 1) greatest on the blood pressure and least on the tail flick, and 2) greatest for ST-91 and CLON and least for DMET. Thus, the dose ratio (ED50 at 60 degrees C/ED50 at 52.5 degrees C) for these three agents on the tail flick and blood pressure response was, respectively, 1.1 and 1.8 for DMET, 1.1 and 4.3 for CLON and 4.8 and 9.7 for ST-91 (mean +/- S.E.). On resting blood pressure, i.t. DMET and CLON produced a dose-dependent hypotension and bradycardia. ST-91 had no consistent dose-dependent effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Prostaglandin synthesis elicited by adrenergic stimuli is mediated via alpha-2C and alpha-1A adrenergic receptors in cultured smooth muscle cells of rabbit aorta.

This study was performed to characterize the subtype of adrenergic receptor(s) (AR) involved in prostacyclin synthesis [measured as 6-keto-prostaglandin (PG)F1 alpha] elicited by AR agonists in cultured vascular smooth muscle cells of rabbit aorta. Both alpha-1 and alpha-2 AR agonists enhanced 6-keto-PGF1 alpha synthesis in a dose-dependent manner with the following order of potency: norepinephrine greater than BHT 933 greater than UK 14304 greater than xylazine greater than phenylephrine greater than or equal to methoxamine greater than cirazoline. Isoproterenol and oxymetazoline did not alter 6-keto-PGF1 alpha synthesis. Methoxamine-induced 6-keto-PGF1 alpha synthesis was not reduced by the alpha-2 AR antagonist rauwolscine. The affinities of AR antagonists (PA2 value) in inhibiting methoxamine-induced 6-keto-PGF1 alpha synthesis were of the following order: prazosin greater than WB 4101 greater than corynanthine greater than yohimbine. Administration of WB 4101 and the irreversible alpha-1B AR antagonist chloroethylclonidine reduced norepinephrine (in the presence of rauwolscine, 10(-8) M)- or methoxamine-induced 6-keto-PGF1 alpha synthesis; WB 4101 was more potent than chloroethylclonidine. UK 14304-induced 6-keto-PGF1 alpha synthesis was not reduced by chloroethylclonidine or BRL 44408, a selective alpha-2A AR antagonist, but it was inhibited by other alpha AR antagonists. The affinities of AR antagonists (PA2 values) in inhibiting UK 14304-induced 6-keto-PGF1 alpha synthesis were of the following order: rauwolscine greater than yohimbine greater than BAM 1303 greater than BRL 41992 greater than WB 4101 greater than ARC 239 greater than or equal to prazosin greater than SKF 104078 greater than or equal to corynanthine. The order of affinity of alpha-2 AR antagonists in inhibiting UK 14304-induced 6-keto-PGF1 alpha synthesis in vascular smooth muscle cells was similar to that derived from radioligand binding studies in opossum kidney cell line receptors classified as alpha-2C receptors. These data suggest that 6-keto-PGF1 alpha synthesis elicited by adrenergic stimuli in cultured vascular smooth muscle cells of rabbit aorta is mediated primarily via alpha-2C and to a lesser extent alpha-1A receptors.

6-Ketoprostaglandin F1 alpha↗