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J Giraldo

Publications and source records attributed to J Giraldo.

At least 19 recordsLinked to original sources
PubMed2005

Ageing affects nitric oxide synthase, cyclooxygenase and oxidative stress enzymes expression differently in mesenteric resistance arteries.

1 Our aim was to study the role of nitric oxide (NO) and arachidonic acid pathways in the alpha(1)-adrenoceptor-mediated vasoconstriction in mesenteric resistance arteries from 3--4 and 22 to 23-month-old Sprague-Dawley rats. 2 The expression of NO synthase (NOS), cyclooxygenase (COX) isoforms, soluble guanylate cyclase, superoxide dismutase and the NAD(P)H oxidase subunits p22(phox) and p 47(phox) were determined. 3 The N(G)-nitro-l-arginine methyl ester, a non-selective NOS inhibitor, shifted to the left but indomethacin and NS 398, non-selective and selective COX-2 inhibitors, shifted to the right the concentration-response curve for the vasoconstriction by phenylephrine in both age groups. 4 Ageing up-regulated endothelial NOS and p22(phox) expression but did not modify COX, soluble guanylate cyclase, superoxide dismutase and p 47(phox) expression. 5 These data suggest that the observed enhancement of eNOS protein expression could constitute a compensatory mechanism to counter-regulate a chronic loss of NO possibly through increased superoxide anion production from NAD(P)H oxidase induced by age.

Acetylcholine↗
PubMed2001

Colon epithelial cellular protein induces oral tolerance in the experimental model of colitis by trinitrobenzene sulfonic acid.

Rectal administration of trinitrobenzene sulfonic acid (TNBS) produces chronic colitis in experimental animals. However, the role of epithelial cellular protein(s) in this model is unknown. We examined whether oral tolerance can be induced in this model with colon epithelial cell proteins and whether it is organ specific. Rats were fed five times with extracts of LS-180 human colon cancer cells or HT 1080 human fibroblast cells. Syngeneic normal rat colon or small intestinal extracts were fed to separate groups of rats. After oral feedings, each rat received TNBS by enema. Rats were killed 15 days later, and the following were measured: gross and histologic disease score, weight, thickness, and myeloperoxidase values of colon and serum interferon-gamma (IFN-gamma) and transforming growth factor-beta (TGF-beta) levels. Rectal TNBS alone produced severe colitis with a 26% mortality rate. Rats fed LS-180 or rat colon extract before TNBS enema were protected, as evidenced by reductions in mortality rate, disease scores, and myeloperoxidase values. However, rats fed HT 1080 or small intestine extract lacked such protection. To examine the possible mechanism of the oral tolerance, T lymphocytes from mesenteric lymph nodes and spleen of LS-180 extract-fed rats were passively transferred to naive rats, and this was followed by TNBS enema. These rats showed clear protection. Protected animals had low IFN-gamma and high TGF-beta levels. This study demonstrates that cellular protein(s) from human colon epithelial cells, but not from human fibroblasts, can induce oral tolerance in experimental colitis. This oral tolerance is mediated by primed mesenteric and splenic T lymphocytes.

Administration, Oral↗
PubMed2000

Secretion of inhibin B during ovarian stimulation is decreased in infertile women with endometriosis.

OBJECTIVE(S): To determine the levels and pattern of inhibin B secretion during ovarian stimulation in patients with endometriosis and to evaluate the correlation between inhibin B levels and variables of follicular and oocyte development. DESIGN: Retrospective cohort study. SETTING: IVF center. PATIENT(S): Women with endometriosis (n = 20) and tubal factor (n = 10) as the only cause of infertility. INTERVENTION(S): Inhibin B levels were measured during gonadotropin stimulation on day 1, days 8-11, day of hCG administration, and oocyte retrieval. MAIN OUTCOME MEASURE(S): Patterns and levels of inhibin B secretion were compared in the two groups. Other variables analyzed were age, days of gonadotropin stimulation and total ampules used, oocytes retrieved, and the fertilization and pregnancy rate. RESULT(S): Inhibin B levels and number of oocytes retrieved were significantly lower in patients with endometriosis than in the control group. Two patterns of inhibin B secretion were noted: It peaked in the midfollicular phase or on the day of hCG administration. In contrast, E2 levels peaked on the day of hCG administration. Inhibin B in the midfollicular phase in both groups correlated positively with number of oocytes retrieved. In addition, E2 and inhibin B levels in the midfollicular phase correlated positively. CONCLUSION(S): Decreased inhibin B secretion in patients with endometriosis suggests impaired granulosa cell function. Inhibin B may serve as an alternate marker to assess follicular development or to predict the number of oocytes retrieved.

Adult↗
PubMed1999

A pH-dependent model of the activation mechanism of the histamine H2 receptor.

A pH-dependent model of agonist action for the histamine H2 receptor was developed by taking into account the different ionic states of the amino acid residues that constitute the agonist-binding pocket of the receptor. The model offers the possibility of examining diverse mechanistic pathways to yield the active form of the receptor according to the molecular structure of the ligand. The rationale is valid for either tautomeric or non-tautomeric agonists and provides new insight into the mechanism of receptor activation. The subsequent application of the operational model of agonism allows one to derive agonist concentration- effect relationships that may prove useful for both the simulation of agonist profiles under different physiological conditions and the estimation of the pharmacologic parameters of efficacy and potency. General principles involved in the formulation are expected to be valid for other G-protein-coupled receptors.

Histamine Agonists↗
PubMed1999

Adrenergic and purinergic components in bisected vas deferens from spontaneously hypertensive rats.

1. Purinergic and adrenergic components of the contractile response to electrical field stimulation (EFS) have been investigated in epididymal and prostatic portions of Wystar Kyoto (WKY) and spontaneously hypertensive rat (SHR) vas deferens. 2. In both halves of SHR and WKY vas deferens, EFS (40 V, 0.5 ms for 30 s, 0.5-32 Hz) evoked frequency-related contractions. The neurogenic responses were biphasic, consisting of a rapid non-adrenergic response, dominant in the prostatic portion, followed by a slow tonic adrenergic component, dominant in the epididymal half. 3. Phasic and tonic components of the frequency-response curves evoked by EFS were significantly higher in the epididymal but not in the prostatic portion of vas deferens from SHR compared to WKY rats. 4. The alpha1-adrenoceptor antagonist prazosin (0.1 microM) was more effective against both components of the contractile response in the epididymal end of SHR than in WKY rats. 5. Inhibition by alpha, beta-methylene adenosine 5'-triphosphate (alpha,beta-meATP 3 and 30 microM) was higher in both components of the contractile responses in WKY preparations than in SHR. 6. Combined alpha1-adrenoceptor and P2x-purinoceptor antagonism virtually abolished the EFS-evoked contractile response in both strains. The degree of inhibition by prazosin (0.1 microM) after P2x-purinoceptor blockade was higher in SHR than in WKY rats. 7. These results demonstrate a modification in the purinergic and noradrenergic contribution to neurogenic responses in SHR and WKY animals besides a co-participation of ATP and noradrenaline in both contractile components of the response to EFS.

Adenosine Triphosphate↗
PubMed1999

Modelling the changes due to the endothelium and hypertension in the alpha-adrenoreceptor-mediated responses of rat aorta.

The present study focuses on the role of endothelium on alpha1-adrenoceptor-mediated vasoconstriction in aorta from Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR). To define and quantify changes in the parameters governing agonism at alpha1-adrenoceptor by hypertension and/or endothelium, the operational model of analysis was used. In either endothelium intact or denuded aorta, the sensitivity (P < 0.001) and the maximum contraction (P < 0.05) to phenylephrine were smaller in SHR than in WKY. However, in each strain of rats, removal of endothelium increased the sensitivity (P < 0.001) to phenylephrine but reduced (P < 0.05) KCl-evoked vasoconstriction, suggesting a modulation of these responses by the endothelium. The observed differences in sensitivity and maximum contraction are interpreted in terms of the operational parameters: Em, the maximum possible effect; pK(A), the agonist affinity; alpha, the agonist efficacy and n, the slope for the function relating receptor occupancy to pharmacological effect. The estimated parameters reflected differences, between strains, in the signal transduction processes linked to alpha1-adrenoceptor stimulation ascribed to the presence of the endothelium. N(G)-nitro-L-arginine methyl ester (L-NAME), enhanced to a similar extend in both rat strains the sensitivity (P < 0.001) and the maximum contraction to phenylephrine. Indomethacin reduced the maximum contraction to phenylephrine by 56.85% in SHR and by 11.80% in WKY suggesting that contracting prostanoids play a more major role in this response in SHR than in WKY. Nevertheless, these inhibitors were without effect on denuded vessels from both strains suggesting that NO and cyclooxygenase products from the media or the adventitia do not play a role on the phenylephrine-mediated responses. The studied endothelial factors partially explain the observed differences in modulation of alpha1-adrenoceptor responses by the endothelium but suggest the participation of other compounds released by the endothelium.

Adrenergic alpha-Agonists↗
PubMed1998

Conformational analysis of GpA and GpAp in aqueous solution by molecular dynamics and statistical methods.

Barnase, an extracellular endoribonuclease from Bacillus amyloliquefaciens, hydrolyses single-stranded RNA. Its very low catalytic activity toward GpN dinucleotides, where N stands for any nucleoside, is markedly increased when a phosphate is added to the 3'-end, as in GpNp. Here we investigate the conformational properties of GpA and GpAp in solution, in order to determine whether differences in these properties may be related to the changes in enzymatic activity. Two independent 1.3 ns molecular dynamics trajectories are generated for each dinucleotide in the presence of explicit water molecules and counter ions. These trajectories are analysed by monitoring molecular properties, such as the solvent accessible surface area, the distance and orientation between the bases, the behaviour of torsion angles and formation of intramolecular H-bonds. To identify relevant correlations between these parameters, statistical techniques, comprising multiple regression, clustering and discriminant analysis are used. Results show that GpA has a significant propensity to form folded conformations (approximately 50%), fostered by a small number of intramolecular H-bonds, whereas GpAp remains essentially extended. The latter behaviour seems to be due to an H-bond between the terminal phosphate and adenosine ribose group, which restricts rotation about the adenine Agamma angle. We also find that GpA folding is induced by a concerted motion of specific torsion angles, which is closely coupled to the formation of a network of flexible hydrogen bonds. Finally, on the basis of an expression for barnase KM, which incorporates the folded/extended conformational equilibria of the dinucleotide substrates, it is argued that our findings on the differences between these equilibria, can qualitatively rationalize the experimentally measured differences in enzymatic properties.

Bacterial Proteins↗
PubMed1997

The effect of the molecular mechanism of G protein-coupled receptor activation on the process of signal transduction.

A thermodynamic model of signal transduction that incorporates the possibility of multiple conformational states between the inactive and the active forms of the receptor was developed. The obtained equilibrium model is equivalent to the extended ternary complex of Samama et al. (J. Biol. Chem. 268 (1993) 4625-4636) if only two states of the receptor exist. These multiple equilibria between receptor states are modeled by two sets of equilibrium constants: K(piAR) and K(sigma piAR), in the presence of the ligand; and K(piR) and K(sigma piR), in the absence of the ligand. The higher the value of these constants, the more efficiently the active form of the receptor is generated. Intrinsic efficacy of the agonist is defined in the present formulation as the molecular processes induced by ligands in the receptor that lead to the active form of the receptor. Both the energetics (associated to K[piAR]) and mechanism of the process of receptor activation (associated to K[sigma piAR]) are important in eliciting the maximum response. Moreover, analytical expressions of basal activity, potency and maximum response were obtained. These definitions were used to classify the extra cellular ligand as agonists (K[sigma piAR] > K[sigma piR]), inverse agonists (K[sigma piR] > K[sigma piAR] > 0), neutral antagonists (K[sigma piAR] = K[sigma piR]), and pure antagonists.

Computer Simulation↗
PubMed1997

Use of the operational model of agonism and [3H]prazosin binding to assess altered responsiveness of alpha1-adrenoceptors in the vas deferens of spontaneously hypertensive rat.

Changes in functional responsiveness to alpha1-adrenoceptor activation with noradrenaline and in [3H]prazosin binding in the epididymal portion of vas deferens from normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) were investigated. The operational model fitting and the nested hyperbolic method were used to analyze the effects of irreversible receptor alkylation by phenoxybenzamine (0.1 microM) on the alpha1-adrenoceptor mediated contractile responses to noradrenaline of vasa deferentia from SHR and WKY rats. Saturation isotherms for [3H]prazosin revealed a significant increase (P < 0.05) in the Bmax in SHR vas deferens (145 +/- 19 fmol/mg protein) compared with vas deferens from normotensive controls (75 +/- 12 fmol/mg protein) without changes in the K(D). No differences in the proportion of high and low affinity binding sites for WB-4101 and 5-methylurapidil were observed. The maximum contractile response, alpha, (P < 0.001) and the pEC50 (P < 0.05) values for noradrenaline were greater for SHR than for WKY rat tissues. The apparent affinity (pK(A)) determined by the nested hyperbolic method and by the operational model of agonism was found to be similar in the two strains. In agreement with relative pEC50, the efficacy (tau) value for SHR was greater than for WKY rats. However, the difference in the tau estimates did not reach statistical significance. In summary, in the epididymal portion of SHR vas deferens, the increased maximum contractile response to noradrenaline is due to an increase of Em. Taken together, the tau values and the results from binding experiments lead to the assumption that the transducer constant K(E) must be greater in SHR than in WKY rats, suggesting a deterioration in the transduction of the stimulus provided by the agonist in hypertensive animals.

Adrenergic alpha-Agonists↗
PubMed1997

Effects of L-NG-nitro-arginine on noradrenaline induced contraction in the rat anococcygeus muscle.

1. The influence of L-NG-nitro-arginine (L-NOARG, 30 microM) on contractile responses to exogenous noradrenaline was studied in the rat anococcygeus muscle. 2. Noradrenaline (0.1-100 microM) contracted the muscle in a concentration-dependent manner. L-NOARG (30 microM) had no effect on noradrenaline responses. 3. Phenoxybenzamine (Phz 0.1 microM) depressed by 46% (P < 0.001) the maximum response and shifted to the right (P < 0.001) the E/[A] curve to noradrenaline (pEC50 control: 6.92 +/- 0.09; pEC50 Pbz: 5.30 +/- 0.10; n = 20). 4. The nested hyperbolic null method of analysing noradrenaline responses after phenoxybenzamine showed that only 0.61% of the receptors need to be occupied to elicit 50% of the maximum response, indicating a very high functional receptor reserve. 5. Contractile responses to noradrenaline after partial alpha 1-adrenoceptor alkylation with phenoxybenzamine (0.1 microM) were clearly enhanced by L-NOARG. 6. The potentiating effect of L-NOARG on noradrenaline responses after phenoxybenzamine was reversed by (100 microM) L-arginine but not by (100 microM) D-arginine. 7. These results indicate that spontaneous release of NO by nitrergic nerves can influence the alpha -adrenoceptor-mediated response to exogenous noradrenaline.

Adrenergic alpha-Agonists↗
PubMed1997

Alpha 1-adrenoceptor vasoconstriction in the tail artery during ageing.

1. We have studied the alpha 1-adrenoceptor-mediated responses in intact tail artery rings from 3-4 and 20-22 months old Sprague-Dawley rats, focusing on possible endothelial alterations. The influence of nitric oxide released by the endothelium, the number of alpha 1-adrenoceptors and the functional receptor reserve were evaluated to determine their contribution to the contractile response mediated by this receptor. The state of the endothelial layer was assessed by confocal microscopy. 2. Noradrenaline (1 nM-100 microM) induced concentration-dependent vasoconstriction. The maximum contractions to noradrenaline (P < 0.05) and to 75 mM KCl (P < 0.01) were higher in young than in old animals. 3. The density (Bmax) of alpha 1-adrenoceptors and the dissociation constant (KD) obtained in [3H]-prazosin binding experiments were unchanged by age. 4. The apparent affinity (pKA) and the percentage of functional receptors (qx 100) remaining after phenoxybenzamine (0.03 microM) were similar in both age groups. 5. After partial alpha 1-adrenoceptor inactivation with phenoxybenzamine, NG-nitro-L-arginine methylester (30 microM) significantly potentiated the E/[A] curve to noradrenaline in young rats. However, only responses to 0.1 to 1 microM noradrenaline were significantly potentiated in old animals. In addition, 94% of the vessels from young, but only 52% from old rats were relaxed by 80-100% of the noradrenaline (0.03 microM) contraction, with 1 microM acetylcholine. 6. No modifications in the area (micron2) or in the number of endothelial nuclei (per mm2) were observed between age groups. An elongation of the nuclei of endothelial cells was observed in the old animals. 7. These data suggest that the noradrenaline-induced contraction is decreased in old rats probably due to differences in either the contractile machinary or postreceptor mechanisms. These alterations may be accompanied by an impairment of the release or production of NO from endothelial cells.

Adrenergic alpha-1 Receptor Agonists↗
PubMed1996

Effect of nucleotide substrate binding on the pKa of catalytic residues in barnase.

A thermodynamic cycle is used to describe barnase catalysis, which considers explicitly the presence of different ionic states of the catalytic residues Glu-73 and His-102 in barnase during the enzyme-substrate recognition process. Reinterpretation of published experimental data using rate equations derived from this cycle provides estimates of the ionization constants of these catalytic side chains, in the free enzyme and in the barnase-GpA complex. In addition, the electrostatic properties of the barnase-d(CGAC) crystal complex and of a barnase-5'3'(AAGAAp)-O-methyl ester modeled complex are investigated by means of a continuum approach to account for solvent polarization effects. Taking GpA as a reference substrate, it is shown that increasing the length of the bound nucleotide induces pKa shifts in the catalytic side chains, which modulate the fraction of enzyme in the correct ionic form for achieving the transesterification reaction. The computed results are in good agreement with the experimental variation of the optimum pH of barnase activity. The present analysis underscores the influence of pH effects on the kcat and KM kinetic constants of barnase and provides the basic formalism for linking the effective kinetic parameters, which usually depend on the pH, to the theoretical estimates of the true kinetic constants.

Bacterial Proteins↗
PubMed1996

Effect of NG-nitro-L-arginine methylester (L-NAME) on functional and biochemical alpha 1-adrenoceptor-mediated responses in rat blood vessels.

1. The modulation by NG-nitro-L-arginine methylester (L-NAME) of alpha 1-adrenoceptor-mediated contraction was investigated on isolated segments of rat tail artery and aorta. The influence of L-NAME on inositol phosphates accumulation by alpha 1-adrenoceptor agonists was also investigated to elucidate the intracellular mechanism responsible for this modulation. 2. In aorta but not in tail artery L-NAME (30 microM) enhanced the sensitivity (3.3 times) and the maximum contraction (Emax) induced by the full agonist, phenylephrine. 3. St-587, a partial alpha 1-adrenoceptor agonist, behaved as a weak agonist in the aorta (22.2% of phenylephrine Emax). However, when the same agonist was studied in tail artery rings a maximum contraction that was 78.4% of the phenylephrine induced Emax was reached. 4. L-NAME increased (3.3 times) the Emax for St-587 contraction in the aorta but not in the tail artery. Sensitivity to St-587 was slightly but significantly (P < 0.001) enhanced (1.9 times) by L-NAME in tail artery segments. 5. Contractile responses to phenylephrine after partial alkylation with phenoxybenzamine were analyzed by the nested hyperbolic null method. To elicit 50% of Emax for contraction only 1.1% of the receptors in the tail artery and 21% of the receptors in the aorta need to be occupied. These results indicate a higher receptor reserve for the tail artery than the aorta. 6. In the tail artery but not in the aorta, St-587 activates phosphoinositide turnover. The presence of L-NAME was without effect on inositol phosphates accumulation induced by this partial alpha 1-adrenoceptor agonist. 7. The maximum contraction induced by phenylephrine, after partial alpha-adrenoceptor alkylation, was enhanced by L-NAME in tail artery rings. However, the NO synthase inhibitor was unable to modify the phenylephrine-induced accumulation of inositol phosphates in the presence of phenoxybenzamine. 8. These results indicate that the differences in St-587-induced contraction and the modulation by L-NAME of alpha 1-adrenoceptor-mediated contraction observed between the tail artery and aorta are associated with differences in receptor reserve. In addition, our biochemical studies indicate that the potentiating effect of L-NAME is independent of intracellular calcium release via phosphatidylinositol turnover.

Adrenergic alpha-Agonists↗
PubMed1996

Endothelial modulation of alpha 1-adrenoceptor contractile responses in the tail artery of spontaneously hypertensive rats.

1. Vascular contraction induced by phenylephrine was studied in tail artery rings from spontaneously hypertensive (SHR) and Wistar Kyoto rats (WKY) with particular focus on the role of endothelium. The influence of receptor reserve and the density of alpha 1-adrenoceptors on the possible differences observed were also analysed. 2. Phenylephrine (0.01-100 microM) induced concentration-dependent vasoconstrictions. The maximum response (alpha, P < 0.001) was greater but the pEC50 (P < 0.05) smaller in rings from SHR than from WKY rats irrespective of the presence or absence of endothelium. 3. Removal of endothelial cells resulted in a decrease of the maximum contraction with no modification in the pEC50 in arteries from both WKY and SHR. 4. The density of alpha 1-adrenoceptors (Bmax) and the dissociation constant (KD) were found to be the same for preparations from SHR and WKY rats in [3H]-prazosin binding experiments. 5. The apparent affinity (pKA) determined by the nested hyperbolic method and the operational model was similar in tail arteries from the two rat strains, irrespective of the presence or absence of endothelium. However, in endothelium-denuded rings, the pKA value was enhanced when compared with intact rings, in both SHR and WKY rats. 6. In rings from hypertensive rats, the operational parameter maximum possible effect (Em) was greater and the agonist efficacy (tau) was smaller than in rings from normotensive rats. When the endothelium was removed log tau and Em diminished in preparations from both rat strains. 7. In summary, the increased maximum responsiveness to phenylephrine in rings from SHR could be due to enhancement in Em. The log tau values indicate a deterioration in the transduction of the stimulus provided by the agonist in tail arteries from hypertensive animals. This study also suggests that the absence of endothelium modifies the alpha 1-adrenoceptor-mediated vasoconstriction probably by altering the transduction signalling mechanisms. The importance of analysing the degree of endothelium functionality when comparing results from different groups of rats is stated.

Adrenergic alpha-Agonists↗
PubMed1996

Modelling the changes induced by chronic desipramine treatment on the factors governing the agonism at prejunctional alpha 2-adrenoceptors.

1. The adaptational changes induced after chronic desipramine treatment on functional responsiveness of alpha 2-adrenoceptor activation were investigated in prostatic portions of the rat vas deferens. 2. For this purpose, clonidine and xylazine were studied for their effects on twitch contractions elicited by electrical field stimulation of prostatic portions removed 48 h after the last injection to the animals of vehicle or desipramine (10 mg kg-1, i.p.; 14 days). Operational model-fitting and the nested hyperbolic method were used to analyse the effects of irreversible receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ, 300 nM) on the alpha 2-adrenoceptor-mediated effects of clonidine, either in vehicle- or in desipramine-treated animals. 3. Treatment with desipramine decreased the potency (increased the EC50) of clonidine and xylazine by about 12 and 9 fold respectively. However, the treatment did not modify the maximal effect (alpha) elicited by either agonist. The estimates of apparent affinity for clonidine did not depend on the method of calculation as the 'null' method and the 'operational' method gave similar answers. Estimates of tau values for both agonists revealed that chronic desipramine treatment resulted in significant decreases in the efficacy of agonists. However, desipramine treatment was not associated with significant changes in the affinity constant for clonidine while for xylazine, the operational model provided a higher estimate of KA (lower affinity) after desipramine treatment. 4. The results indicate a large receptor reserve at prejunctional alpha 2-adrenoceptors which is modulated by chronic desipramine treatment. 5. The comparison of results obtained after chronic desipramine exposure with those by using EEDQ suggests that chronic desipramine treatment is not a useful experimental intervention for the purpose of estimating agonist affinities and efficacies.

Adrenergic Uptake Inhibitors↗
PubMed1994

Analysis of agonism at functional prejunctional alpha 2-adrenoceptors of rat vas deferens using operational and null approaches.

The alpha 2-adrenoceptors located prejunctionally on the postganglionic neurons that innervate the smooth muscle of the prostatic portion of the rat vas deferens were examined. For this purpose, three imidazolidine derivatives (structurally related to clonidine) were studied for their effects on twitch contractions elicited by electrical field stimulation of this tissue. In this study, operational model-fitting and the nested hyperbolic method were used to analyse the effects of irreversible receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) on the alpha 2-adrenoceptor-mediated effects of clonidine (2-[2,6-dichlorophenylimino]imidazolidine) in stimulated vas deferens. The operational model provided an estimate of KA for clonidine which was not significantly different from the estimate obtained by using the nested hyperbolic method (null approach). The data indicate a large receptor reserve at prejunctional alpha 2-adrenoceptors for clonidine. The estimates of apparent affinity for St-587 (2-[2-chloro-5-trifluoromethylphenylimino]imidazolidine) and St-591 (2-[2-chloro-5-methylphenylimino]imidazolidine) did not depend on the method of calculation as the 'null' method and the 'operational' method gave similar answers. Further, estimates of the ratio of tau values for these partial agonists with respect to clonidine were numerically the same as those of their relative efficacies. Therefore, no limitations in the ability of the operational model to fit experimental data and provide reproducible estimates of affinity and efficacy have been revealed for agonists acting at prejunctional alpha 2-adrenoceptors.

Adrenergic alpha-Agonists↗