Search

On the isolated papillary muscle of the rabbit experiments were performed in order to study whether β-and/or α-adrenoceptors mediate the positive inotropic effect of phenylephrine and, for comparison, of other sympathomimetic drugs. [ABSTRACT FROM AUTHOR]

Nine patients on maintenance hemodialysis and transfusion-demanding renal anemia (group A) were treated with rHuEPO 120 IU/kg i.v. three times per week. Hemoglobin-content was raised from 7.2±0.9 to 10.4±0.8 g/dl. In all patients blood pressure rose, three patients developed arterial hypertension. Mean diastoloic blood pressure was 66±12 and 78±16 mmHg ( p<0.001) before and after rHuEPO. Rise in blood pressure was accompanied by a significant fall in plasma-noradrenaline-levels (from 498±100 to 383±75 pg/ml; p<0.05) and alpha-adrenoceptor-density (from 574±76 to 384±49; p<0.05). Compared to nine patients on maintenance hemodialysis and hematocrit over 30% (group B), patients with severe renal anemia (group A before treatment) had higher densities of alpha-adrenoceptors (574±76 vs. 218±32; p<0.001) despite higher plasma-noradrenaline-levels (498±100 vs. 399±63; n.s.). We suppose a anemia-related disturbance of alpha-receptor-function with the result of abolished receptor down-regulation and impaired vascular reagibility to vasoconstricting stimuli. With the correction of anemia receptor-function improves, receptor down-regulation as well as vascular reagibility is re-established resulting in augmented vascular resistance and higher blood pressure. [ABSTRACT FROM AUTHOR]

Both Shy-Drager syndrome and pheochromocytoma are characterized by an abnormal catecholamine secretion, e.g. a reduced secretion in Shy-Drager syndrome, and an excessive stimulation in pheochromocytoma resulting in adrenergic dysfunction and in adrenergic hyperactivity, respectively. The relationship between extreme variations in circulating catecholamines and β-adrenergic receptor activity was studied in two patients with severe orthostatic hypotension (Shy-Drager syndrome) and in a patient with pheochromocytoma with excessive spontaneous catecholamine increases using the lymphocyte β-adrenoceptor assay. In both patients with Shy-Drager syndrome, basal plasma concentrations of epinephrine and dopamine were low under resting conditions and could not be stimulated in the upright position. Norepinephrine was low in the first patient, and could not be stimulated; whereas the second patient had a normal basal concentration of norepinephrine, which could be moderately stimulated. There was no β-adrenoceptor abnormality in the first patient; however, in the second patient, there were no measurable β-adrenoceptors on membrane fractions, whereas a population of receptors only in the low affinity state could be identified on intact cells. Alpha-adrenoceptor density on thromboycte membranes was slightly increased in both patients with Shy-Drager syndrome and showed no substantial change during upright posture. Catecholamine increases in the pheochromocytoma patient were accompanied by a rise in blood pressure, bradycardia, and an acute up-regulation of β-adrenoceptors. Plasma concentrations of cAMP paralleled the increase in receptor density and blood pressure. The findings in pheochromocytoma add support to the theory that an acute catecholamine stimulation gives rise to an acute β-adrenergic sensitization leading to blood pressure elevation. In Shy-Drager syndome, we found no β-adrenoceptor up-regulation in the orthostatic position (first patient) since catecholamines were not stimulated. Although there was an acute up-regulation due to a moderate norepinephrine stimulation (second patient) during posture orthostatic hypotension could not be prevented. Alpha-adrenoceptor expression was normal in both patients. Thus, in orthostatic hypotension the function of the β-adrenoceptor system seems to be disturbed since either norepinephrine is not secreted in sufficient amounts to induce β-receptor up-regulation or the β-receptor is in a low affinity (uncoupled) state. From these observations in Shy-Drager syndrome and in pheochromocytoma, it is concluded that adrenergic blood pressure regulation is dependent on a normal catecholamine secretion, alpha-adrenoceptor function, and a normal β-adrenoceptor population, as well as affinity with an intact β-adrenergic regulation. [ABSTRACT FROM AUTHOR]

The effect of a long-term administration of furosemide (2×30 mg/day for 3 weeks) on platelet α-adrenoceptor density and the fraction of high-affinity binding sites, as well as on platelet aggregation induced by adrenaline and ADP, was studied ex vivo in 8 normotensive volunteers. For comparison the in vitro effect of furosemide on platelet aggregation was also evaluated. Furosemide decreased α-adrenoceptor-density ( P<0.01) and the fraction of high-affinity binding sites ( P<0.05). Adrenaline-induced platelet aggregation was not altered ex vivo and in vitro. Furosemide inhibited ADP-induced platelet aggregation ex vivo ( P<0.05) and in parallel in vitro ( P<0.01) in a dose-dependent manner. The reduction of the density of α-adrenoceptors in the high affinity state may be of functional importance for the hemodynamic effects of furosemide. The inhibitory effect of furosemide on ADP-induced platelet aggregation ex vivo and in vitro, which is not related to the effects on adrenoceptors, seems to involve direct effects of furosemide on platelet function. It remains to be seen whether the latter effect is of clinical importance. [ABSTRACT FROM AUTHOR]

Neuroprotective effect of epinephrine is revealed against the background of prazosin, β-antagonists and their combinations protect against cerebral ischemia. α2-Antagonists (but not α1) block the neuroprotective effect of these combinations, methyldopa, guanabenz, clonidine, and oxymetazoline and decrease brain resistance to ischemia. α2-Adrenoreceptors participate in the endogenic mechanism of brain resistance to ischemia and in the neuroprotective effect. [ABSTRACT FROM AUTHOR]

Oestrogen and progesterone influence myometrial and cervical responses at different levels of the mechanisms regulating uterine contractility. One of these mechanisms could involve alterations in the adrenoceptor concentrations. This study was undertaken to assess the effects of treatment with the antiprogestogen RU-486 on the concentrations of α-and β-adrenoceptors in pregnant rabbit myometrial and cervical membranes by means of a radioligand binding technique. The probable relative oestrogen dominance due to the antiprogestogen treatment selectively decreased the α-adrenoceptor subtype in the cervix, where an α-adrenoceptor dominance was found on day 27 of pregnancy. The results indicate a heterologous regulation of α-adrenoceptors by sex steroids, i.e. suppression of the α-adrenoceptor concentration by antiprogestogen treatment. [ABSTRACT FROM PUBLISHER]

Pharmacological characterization of adrenoceptors mediating smooth muscle contraction was performed in isolated preparations from the human uterine artery. The mixed alpha 1- and alpha 2-adrenergic agonist, noradrenaline (NA) and the selective alpha 1-agonists, phenylephrine and methoxamine, all contracted the smooth muscle preparations in a concentration-dependent manner. The responses were antagonized competitively by the selective alpha 1-antagonist, prazosin, yielding pA2 values for the three agonists (8.33-9.08) typical for an interaction with alpha 1-receptors. The alpha 2-selective receptor agonists, clonidine and BHT 920, did not exert any contractile effects in the isolated uterine arteries, and the alpha 2-adrenergic antagonist, yohimbine, counteracted the contractile effect of NA only at high concentrations. The concentration-response curve for NA was unaffected by the alpha 2-selective antagonists, rauwolscine and idazoxan. The results suggest that the postjunctional contractile receptors in the human uterine artery primarily are of the alpha 1 type, and give no evidence for any substantial involvement of alpha 2-receptors in this important tributary vessel of the human female reproductive tract. [ABSTRACT FROM AUTHOR]

P19 embryonal carcinoma cells were differentiated via embryolike aggregates (embryoid bodies) into spontaneously beating myocytes. During the whole process of differentiation the functional expression of cardiac-specific receptors and ionic channels was characterized by measuring the chronotropic reactivity, action potentials, and ionic currents in response to various cardioactive drugs. Positive chronotropic effects obtained at different maximal effective concentrations of adrenoceptor-mediated agonists indicated differential adrenoceptor expression during the in vitro development of cardiomyocyte-like cells. No cardiac-specific response was obtained with the muscarinic cholinoceptor agonist carbachol. Single beating cells were enzymatically isolated and investigated by the patch-clamp technique. Pacemaker action potentials similar to those of embryonal cardiomyocytes exhibited amplitudes ranging from 50 to 85 mV. The action potentials were synchronous to the mechanical contractions and, comparable to the chronotropic effects, were modulated by BayK 8644, isradipine, and adrenaline. The functional expression of L-type Ca channels was demonstrated by the Ca channel blockers isradipine, nisoldipine, gallopamil, and diltiazem causing negative chronotropic responses, as well as by the Ca channel activator BayK 8644 causing positive chronotropic responses. These effects gradually increased with time of differentiation. The expression of L-type Ca channels and of nicotinic acetylcholine receptors was confirmed in voltage-clamp experiments. The study demonstrates that P19 embryonal carcinoma cells can be induced to differentiate into cardiomyocyte-like cells comparable to embryonal and neonatal heart cells lacking the muscarinic cholinoceptor response only. [ABSTRACT FROM AUTHOR]

The density and subtype pattern of β-adrenoceptors in equine tracheal epithelium, tracheal smooth muscle and heart from 6–9 horses were investigated by radioligand binding studies using the non-selective β-adrenoceptor antagonist 125I-cyanopindolol (ICYP). The specific binding of ICYP was 341±162 fmol/mg protein (mean±SD) for epithelium, 42±13 fmol/mg for smooth muscle and 124±39 and 101±19 fmol/mg for the cardiac atrium and ventricle, respectively. The Kd value of ICYP was 6.7–10.2 pmol/L. In competition studies, different concentrations of either the β2-selective drug ICI 118551 or the β1-selective CGP 20712A competed with 25 pmol/L ICYP for the binding sites. The competition curves for tracheal smooth muscle and epithelium were monophasic with an approximate Kd value for ICI 118551 of 1 nmol/L and for CGP 20712A of 10 000 nmol/L. This corresponds to known Kd values for these substances binding to β2-adrenoceptors. β2-Adrenoceptors were also found in the heart, most pronounced in the atrium, where the density was 29%±6% (mean±SD) of the total receptor density. CGP 20712A and ICI 118551 bound to the dominating binding site of β1-adrenoceptors in the heart with Kd values of approximately 1 nmol/L and 100 nmol/L, respectively. [ABSTRACT FROM AUTHOR]

Muscarinic and β-adrenoceptors were identified in airway epithelium, smooth muscle and lung parenchyma from Holstein-Friesian calves and cows and were characterized with [H]quinuclidinyl benzilate and [H]dihydroalprenolol, respectively. The muscarinic receptor density in the smooth muscle of cows ( B=4803±245 fmol/mg protein) was 33% greater ( p<0.01) than in calves. Low receptor numbers were detected in the epithelium and parenchyma. In both calves and cows, the density of epithelial β-adrenoceptors was twice as high as in smooth muscle and parenchyma. The quantity of β-adrenoceptors in the tracheal epithelium ( B=994±83 fmol/mg protein) and smooth muscle ( B=492±41 fmol/mg protein) in cows was respectively 37% ( p<0.001) and 35% ( p<0.01) lower than in calves. Adenylate cyclase (AC) assays indicated that the basal and the (−)-isopropylnoradrenaline- (ISO-) stimulated cAMP production were not significantly different between the calves and cows. After stimulation with NaF, significantly higher cAMP production was found in all tissues from cows. Significant correlations were found between absolute AC responses to NaF and β-adrenoceptor density in epithelium ( r=−0.75, p<0.001) and smooth muscle ( r=−0.63, p<0.01). It seems that, in older animals, the production of cAMP is independent of the number of receptors, indicating the presence of fully active compensatory mechanisms. [ABSTRACT FROM AUTHOR]

The aim of this study, carried out in six elder healthy volunteers (mean age: 61 years), was to determine the influence of muscarinic receptor blockade with atropine (15 µg/kg i.v. loading dose followed by 0.15 µg/kg/min by i.v. infusion) on the effects of i.v. infusions of noradrenaline (5 incremental doses of 10-120 ng/kg/min) or tyramine, that releases endogenous noradrenaline (4 incremental doses of 5-20 µg/kg/min), on blood pressure, heart rate and systolic time intervals (STI’s, as a measure of positive inotropism). These results were compared with those recently published for young healthy volunteers (mean age: 26 years; Schäfers et al. 1997). Noradrenaline caused increases in systolic and diastolic blood pressure, decreases in heart rate and a shortening of STI’s that were not different from those in young volunteers. Atropine did not significantly affect these hemodynamic responses to noradrenaline, while in young volunteers it significantly enhanced noradrenaline-induced blood pressure increases and converted the heart rate decrease into an increase. In the present study in elder volunteers, tyramine caused a smaller increase in systolic blood pressure than in the previous study in young volunteers; in addition, it slightly increased diastolic blood pressure while it decreased diastolic blood pressure in young volunteers. Atropine did not significantly affect the hemodynamic effects of tyramine in the elder volunteers, while in the young volunteers it enhanced the increase in systolic blood pressure and converted the decreases in diastolic blood pressure and heart rate into increases. These results indicate a) that ageing is accompanied by a blunted baroreflex-mediated parasympathetic activation resulting in reduced cholinergic vasodilation and decreases in heart rate, and b) that ageing is associated with a decreased responsiveness of (cardiac) β-adrenoceptors and (vascular) α1-adrenoceptors which is only unmasked when the counterregulatory action of parasympathetic activation is removed. [ABSTRACT FROM AUTHOR]

The effects of free radicals, generated by electrolysis of a physiological salt solution, on various inotropic responses to drugs in isolated rat left atria were studied. Evidence for the generation of hydroxyl radicals was obtained from an appropriate fluorimetric assay. The amount of free radicals produced by electrolysis of the medium proved current-dependent. Exposure of isolated rat left atria to the medium which had been subjected to electrolysis caused a current-dependent decrease in contractile force. Oxidative stress, as a result of the electrolysis of the medium, caused altered inotropic responses to extra cellular Ca2+ (pD2 control group: 2.62 ± 0.06 vs. 2.44 ± 0.07 electrolysis group), sodium withdrawal (rise in contractile force control group: 1.73 ± 0.19 mN vs. 0.48 ± 0.21 mN electrolysis group) and lowering of stimulation frequency. The response to isoprenaline was diminished in atria subjected to oxidative stress and led to a rightward shift of the concentration response curves (pD2 control group: 7.56 ± 0.10 vs. 6.77 ± 0.11 electrolysis group). In addition, the inotropic responses to forskolin (pD2 control group: 6.17 ± 0.12 vs. < 4.5 electrolysis group) and dibutyryl cAMP (rise in contractile force caused by 1 × 10–5 M db-cAMP in control group: 2.15 ± 0.01 mN vs. 1.21 ± 0.10 mN electrolysis group) proved blunted as well. Measurement of the adenylyl cyclase activity revealed that free radicals attenuated the basal (by 11.1%) and forskolin stimulated (155.0 ± 5.1 vs. 48.0 ± 1.8 pmol cAMP/mg prot./min for control and electrolysis group respectively) activity of the adenylyl cyclase. DMSO, a well known hydroxyl radical scavenger, was able to abolish the free radical-induced decrease in the response to isoprenaline. Surprisingly, addition of α-adrenoceptor agonists to atria subjected to electrolysis-generated free radicals led to a rapid decrease in contractile force. DMSO was unable to counteract the negative intropic effect of methoxamine in atria subjected to oxidative stress. This negative inotropic response to α-adrenoceptor agonists in atria subjected to electrolysed medium is unlikely to be the direct result of phospholipase C or protein kinase C activation. Angiotensin II (which stimulates PLC as well) did not reduce contractile force and chelerythrine (a PKC inhibitor) was unable to counteract the negative inotropic effect of the adrenoceptor agonists. In addition, the negative inotropic effect of methoxamine proved insensitive to 10–6 M phentolamine and 10–5 M doxazosin, which indicates an α-adrenoceptor independent mechanism. From this study we conclude that free radicals alter responses to various inotropic stimuli. These alterations may be the result of injured contractile elements, transporter molecules and molecules involved in signal transduction. Addition of α-adrenoceptor agonists after oxidative stress leads to a α-adrenoceptor, PLC and PKC independent decrease in contractile force. [ABSTRACT FROM AUTHOR]

This study aimed firstly to compare the in vivo cardiovascular effects of exogenously administered and of endogenously released noradrenaline; secondly to characterize the adrenoceptors mediating these responses; thirdly to assess the influence of parasympathetic tone on the cardiovascular effects of noradrenaline. In two randomised placebo-controlled studies, healthy, young, male volunteers received intravenous (i.v.) infusions of noradrenaline at six incremental doses of 10–160 ng/kg/min and – in order to release endogenous noradrenaline – tyramine at four incremental doses of 5–20 μg/kg/min. Noradrenaline and tyramine were administered in the absence and presence of α1-adrenoceptor blockade with doxazosin (2 mg p.o.), α2-adrenoceptor blockade with yohimbine (15 mg p.o.), selective β1-adrenoceptor blockade with bisoprolol (15 mg p.o.) and muscarinic receptor blockade with atropine (15 μg/kg i.v. loading dose followed by 0.15 μg/kg/min by i.v. infusion). Vasoconstrictor effects were assessed by measurement of diastolic blood pressure (Pdiast) and myocardial effects by measurement of systolic time intervals, namely the duration of electromechanical systole corrected for heart rate (QS2c). I.v. noradrenaline increased Pdiast (Δmax 17 mmHg) and this was nearly completely suppressed by doxazosin but only slightly blunted by yohimbine. Noradrenaline also slightly shortened QS2c (Δmax –22 ms), and this was potentiated by both doxazosin and yohimbine and completely blocked by bisoprolol. I.v. tyramine reduced Pdiast (Δmax –7 mmHg), which was not affected by α1-adrenoceptor blockade, and profoundly shortened QS2c (Δmax -104 ms) which was significantly correlated with a marked increase in systolic blood pressure (Psyst) (Δmax 57 mmHg). The shortening of QS2c and the rise in Psyst were not influenced by α-adrenoceptor blockade but were antagonized by bisoprolol. Atropine potentiated the blood pressure rise and the shortening of QS2c induced by i.v. noradrenaline and converted the fall in Pdiast induced by i.v. tyramine into an increase. Thus the cardiovascular effects of exogenous noradrenaline are mainly characterized by α1-adrenoceptor-mediated vasoconstriction and the actions of endogenous noradrenaline (released by i.v. tyramine) by β1-adrenoceptor-mediated positive inotropic effects. The rise in Psyst with i.v. tyramine most likely reflects positive inotropism and not a vascular ‘pressor’ response. [ABSTRACT FROM AUTHOR]

Meningeal fibroblasts express the proenkephalin gene during embryonal development but terminate the expression shortly before birth. When brought into primary culture at postnatal day 1, the fibroblasts again express the gene. Activation of protein kinase A reduces this expression and thus may contribute to its prenatal termination. Since the noradrenergic innervation of the meninges begins around the time of birth, it was investigated in the present study, how adrenergic agonists affected the levels of proenkephalin mRNA in cultured fibroblasts. The β-adrenoceptor agonists salbutamol and procaterol increased the levels of endogenous cAMP and diminished the concentration of proenkephalin mRNA indicating that the cultured fibroblasts possessed this β-subtype. In contrast, noradrenaline increased the level of proenkephalin mRNA in a concentration-dependent manner. This effect was independent of endogenous cAMP and was mediated by α-adrenoceptors. The data indicate that the noradrenergic innervation of the meninges at the time of birth is not responsible for the termination of the proenkephalin gene expression. [ABSTRACT FROM AUTHOR]

In order to clarify whether adrenoceptors in the guinea-pig distal colon are under sympathetic control, we assessed possible variations in the sensitivity to adrenoceptor agonists after blockade of neuronal catecholamine uptake mechanisms by desipramine (DMI). First, experiments were carried out to investigate the effects of DMI added in the organ bath on propulsion velocity, endogenous and [H] prelabelled acetylcholine overflow, electrically evoked noradrenaline overflow and longitudinal smooth muscle tone. Secondly, we studied the effects of adrenoceptor agonists on the above parameters in untreated animals and in animals chronically treated with DMI. DMI added in the organ bath at concentrations equal to or higher than 30 nM inhibited all the parameters under study. Thus, when evaluating the effect of DMI on concentration-response curves to adrenoceptor agonists, concentrations which were per se inactive were used. DMI added in the organ bath at concentrations up to 30 nM potentiated the inhibitory effects of exogenous noradrenaline on propulsion velocity and acetylcholine overflow, but it did not affect the concentration-response curve to exogenous noradrenaline on longitudinal smooth muscle tone. Furthermore, 30 nM DMI inhibited propulsion velocity during sympathetic nerve stimulation. In preparations obtained from animals chronically treated with DMI, no significant change of propulsion velocity, endogenous and [H] prelabelled acetylcholine overflow was found with respect to untreated animals. Nevertheless, in such preparations subsensitivity to isoprenaline (acting mainly on muscular β-adrenoceptors) and clonidine (acting on neuronal α-adrenoceptors) and supersensitivity to phenylephrine were observed. Electrically evoked noradrenaline overflow was enhanced, in a frequency-dependent way, by yohimbine and inhibited by clonidine. We conclude that in the guinea-pig colon: 1) α- and β-adrenoceptors are under tonic neuronal control, as indicated by the sensitivity changes to α- and β-adrenoceptor agonists after chronic DMI treatment; 2) exogenous NA reaching neuronal, but not muscular adrenoceptors, is affected by neuronal uptake mechanisms; 3) NA released by adrenergic terminals undergoes neuronal uptake and is controlled by α-autoreceptors. [ABSTRACT FROM AUTHOR]

Isolated perfused spontaneously beating rabbit hearts were treated with increasing concentrations of norepinephrine (0.01, 0.1, 0.5 μmol/l) either alone or in presence of propranolol (0.1 μmol/l). For analysis of the epicardial activation and repolarization process and epicardial mapping (256 unipolar leads) was performed. For each electrode the activation and repolarization time was determined. From these data the 'breakthrough-points' (BTP) of epicardial activation were determined. At each electrode an activation vector (VEC) was calculated giving direction and velocity of the local excitation wave. The beat similarity of various heart beats (under NE) compared to control was evaluated by determination of the percentage of identical BTP and of similar VEC (deviation ≤5°). Moreover at each electrode the local activation recovery interval (ARI) and its standard deviation (of 256 leads, dispersion, DISP) were determined. Norepinephrine alone (0.01, 0.1, 0.5 μmol/l) led to an increase in left ventricular pressure, heart rate and DISP with concomittant frequency dependent reduction in ARI, and to changes in the epicardial activation pattern (reduction in BTP, VEC). We found that in the presence of propranolol (0.1 μmol/l) norepinephrine prolonged ARI and reduced ARI-dispersion. This effect was not due to changes in heart rate. The disturbing effects on the activation pattern were dimished. These effects could be prevented by pretreatment with 1 μmol/l prazosine. From these results we conclude, that norepinephrine prolongs the relative action potential duration via stimulation of α-adrenoceptor and enhances cellular coupling. Thus, the antiarrhythmic properties of propranolol may at least in part be due to an unmasking of class III like norepinephrine effects and additional reduction in dispersion. [ABSTRACT FROM AUTHOR]

Potencies of new aromatic substituted fluoro or iodo analogues of catecholimidazolines on functional responses in rat aorta (α) and platelets (α) were quantified. (1) When compared either on the basis of EC or the dissociation constant (K), 5-fluorocatecholimidazoline was as potent as the reference α-adrenoceptor agonist, phenylephrine in the vascular tissue. The maximum contraction of aorta produced by the fluoro analogue was, however, 17% higher than that of phenylephrine. The time required for 1/2 relaxation of the tissue after 5-fluoro hydroxy imidazoline was at least twice as long as that of the phenylephrine. The catechol moiety as well as fluorine substitution at the critical 5-position of the aromatic ring is essential for higher α adrenoceptor-mediated potency. (2) As compared to the fluoro analogues, the adrenoceptor-mediated potencies of iodo-analogues were relatively weak on vascular tissue. Naphazoline and its analogues were partial agonists on vascular tissue with dissociation constants which ranged from 110 to 2600 nmol/l. (3) Imida zole analogues were generally less potent agonist than the imida zolines by one order of magnitude. (4) The vascular effects of all agonists were competitively blocked by prazosin with K values which ranged from 0.04 to 0.48 nmol/l. Since the variation in K values were within normal limits, the action of new imidazolines on rat aorta appears to be mediated mainly by the activation of the α-adrenoceptor. Prazosin 10 nmol/l abolished the vascular response of some partial agonists. This indicates a slightly different mode of interaction of agonists with the transduction process. (5) Carbon 4-substituted imidazolines produced little or no α adrenoceptor-mediated intrinsic activity, but competitive receptor blocking potency was comparable to that of phentolamine. (6) Medetomidine was a partial agonist on the rat aorta with a K of 260 nmol/l. When investigated as a blocker, the K of medetomidine against phenylephrine was approximately 5600 nmol/l. The variation in the latter value was high. (7) In acetylsalicylic acid-treated human platelets, the α-adrenoceptor-mediated aggregatory effect of all fluoro analogues was weak. lodo or naphazoline analogues did not initiate platelet aggregation but blocked the aggregation induced by epinephrine. The affinity of naphazoline for the α-adrenoceptor was 1100 nmol/l. The IC of medetomidine for platelet anti-aggregatory effect was 3300 nmol/l, which compares favorably with other imidazoline type of blockes of platelet aggregation. (8) Sympathomimetic vasoconstrictor actions and platelet aggregation effects of these compounds can be dissociated. Some vasoconstrictors were antiaggregatory. The structure-activity relationships of the two receptor systems, namely rat aorta (α) and platelets (α), are discussed. [ABSTRACT FROM AUTHOR]

We have investigated the proposed postjunctional selectivity of the a2-adrenoceptor antagonist SK & F 104078 employing the pithed rat, rat isolated atrium and human saphenous vein preparations. In the pithed rat, SK & F 104078 (5 mg kg) produced a 20-fold shift in the prejunctional ID (concentration of agonist producing 50% inhibition of the cardioacceleration to a single stimulus) and a 3-fold shift in the postjunctional ED (concentration producing 50% of maximum rise in diastolic blood pressure) of the α-adrenoceptor agonist xylazine. However, the α-adrenoceptor antagonist yohimbine also showed apparent selectivity for prejunctional receptors in the pithed rat. In the rat isolated atrium, yohimbine was approximately 10 times more potent than SK & F 104078 at enhancing the stimulation-evoked release of tritium in tissues preincubated with (H)-noradrenaline. In the human saphenous vein, yohimbine and SK & F 104078 had pA values of 7.40 and 6.33, respectively, against contractions to noradrenaline, so that yohimbine was again approximately ten times more potent than SK & F 104078. In conclusion, SK & F 104078 behaved like yohimbine in its relative potencies at pre- and postjunctional α-adrenoceptors both in vivo and in vitro, so that we fail to find any selectivity of SK & F 104078 for postjunctional α-adrenoceptors. [ABSTRACT FROM AUTHOR]

In the pithed normotensive rat the intravenous administration of increasing doses of angiotensin II caused an increase in heart rate by a maximum of 93 ± 6 beats/min. This increase in heart rate was diminished dose-dependently by the concomitant infusion of the angiotensin II analogue saralasin. It was not affected by acute bilateral adrenalectomy but strongly reduced by pretreatment with reserpine. By using the selective antagonists of α-, α-, β- or β-adrenoceptors prazosin, yohimbine, atenolol and ICI 118,551, respectively, it was shown that this tachycardia was mediated by stimulation of cardiac β-adrenoceptors. Moreover, the high endogenous angiotensin II level following pithing contributed to the basal heart rate in the pithed rat model. From our experiments it may be concluded that angiotensin II induces tachycardia in the pithed rat primarily by stimulating the sympathetic ganglia leading to the release of noradrenaline, which subsequently activates cardiac β-adrenoceptors. [ABSTRACT FROM AUTHOR]

Chronic activation of opioid receptors results in the development of tolerance and dependence. Tolerance may be confined to a single receptor type and thus has been termed 'selective tolerance'. The present investigation reveals that prolonged activation of an inhibitory acting receptor type not only results in dependence associated with this receptor but also brings about cross-dependence. Cross-dependence involves both opioid receptors as well as non-opioid receptors, e. g. adrenoceptors. The experimental design employed did not permit conclusions to be drawn about whether those receptors exhibiting cross-dependence also developed tolerance. Regardless of the receptors and their specific subsequent transduction systems, all the receptors which showed dependence and cross-dependence proved sensitive to pertussis toxin, suggesting a critical function of GTP-binding proteins for the development of not only opioid dependence but also for drug dependence in general. Since multiple transmitter receptors may converge on the same ion channel, the concept of 'convergent dependences' may be linked to GTP-binding proteins. However, no conclusions can be drawn with regard to the precise biochemical mechanisms underlying dependence. [ABSTRACT FROM AUTHOR]

Antagonism of reserpine-induced hypothermia is an animal model used in the screening of antidepressants. The activity of imipramine on this test is partly impaired by propranolol. This effect of imipramine was analyzed using specific adrenoceptor and 5-HT receptor blocking drugs in order to determine the nature of this effect of propranolol. The non-selective beta 1-beta 2 adrenoceptor antagonist, propranolol as the specific beta 1 adrenoceptor antagonist betaxolol, but not the specific beta 2 blocking drug d l,-erythro-3-isopropylamino-1-(7-methyl-4-indanyloxy)-2-butanol hydrochloride 313.9 (ICI 118 551), partly antagonized the effect of imipramine at 30 min. None of the serotonin (5-HT) receptor antagonists, methysergide, metergoline, ritanserin and buspirone, impaired the effect of imipramine. On the contrary, methysergide alone antagonized reserpine-induced hypothermia and methysergide or metergoline increased the action of imipramine. Propranolol impaired neither the hypothermia induced by an agonist at the 5-HT 1 A receptors: 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) nor the increase in spontaneous motor activity induced by an agonist at the 5-HT 1B receptors: 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1-Hindole (Ru 24 969). It is concluded that the effect of propranolol is not the result of a blockade of 5-HT 1 A, 5-HT 1B or 5-HT 2, but is in part due to blockade of beta 1 adrenoceptors. [ABSTRACT FROM AUTHOR]

The mode of action of (-) norepinephrine (NE) and UK-14,304-18 has been investigated using the chohnergically-evoked 'twitch' response of the electrically stimulated guinea-pig ileum. St 587 and benextramine were employed as antagonists. St 587 acted as a competitive antagonist toward UK-14,304-18, yielding an apparent pA value of 7.3. In contrast, St 587 failed to act competitively toward NE. Similarly, benextramine (1×10 mol/l) blocked the inhibitory responses to UK-14,304-18 but was considerably less active toward NE. Remaining responses to NE after benextramine were not antagonized by St 587, even at a concentration of 3×10 mol/l. It is postulated that NE acts to inhibit the 'twitch' response be evoking two different receptor-mediated events: 1. agonism at the alpha-adrenoceptor and 2. agonism at a site which is distinct from the alpha- and beta-subtypes. In the concentrations studied, UK-14,304-18, St 587 and benextramine age postulated to lack affinity for the proposed site. The effect of NE and UK-14,304-18 was also investigated on the contractile responses to exogenously applied histamine. These experiments were done in the presence of muscarinic cholinergic and adrenoceptor blockade. NE inhibited responses to histamine but UK-14,304-18 was inactive. Furthermore, the inhibitory action of NE was stereoselective with the (-) form being 25 times more potent than the (+) enantiomer. These findings suggest the presence of a receptor site for NE which is distinct from cholinergic mechanisms and established alpha and beta-adrenoceptors. [ABSTRACT FROM AUTHOR]

Stimulation of the renal nerves to the perfused toad kidney produced an increase in intravascular pressure. This response was always abolished by bretylium, indicating that it was mediated by adrenergic nerves. The response was usually reduced by tubocurarine, indicating that some of the fibres in the renal nerve trunks were preganglionic. The vasoconstrictor response was abolished by treatment with yohimbine or phenoxybenzamine, but was only partially reduced by phentolamine. It is postulated that adrenaline released from nerve terminals acts primarily on 'junctional' adrenoceptors which are not antagonised by phentolamine. However, part of the vasoconstrictor response appears to be due to occupation of nearby 'extra-junctional' receptors by neurally-released adrenaline: only this part of the response can be antagonised by phentolamine. The vasoconstrictor response was enhanced by propranolol in both summer and winter. This indicates that neurally-released adrenaline can occupy β-adrenoceptors, to antagonise the effects of α-receptor occupation, at both times of the year. In this respect, the β-receptors mediating the effects of renal nerve stimulation are different from those acted upon by perfused adrenaline. A non-adrenergic vasodilatation was sometimes revealed after abolition of the vasoconstrictor response, but the nature of the nerve fibres mediating this response could not be determined. [ABSTRACT FROM AUTHOR]

Adrenoceptor-mediated effects of the enantiomers of the optically active imidazoline, 2-(3,4,α-trihydroxybenzyl)imidazoline, and the corresponding desoxy derivative, 2-(3,4-dihydroxybenzyl)imidazoline, have been investigated in the pithed rat. The enantiomers and desoxy derivative were potent pressor agents with a direct action mediated predominantly via postsynaptic vascular α-adrenoceptor. These compounds were significantly less potent at presynaptic α-adrenoceptor in rat heart. The rank order of potency for the two enantiomers and desoxy derivative at postsynaptic vascular α- and presynaptic cardiac α-adrenoceptor in pithed rat were: desoxy≥R(−) >(+), consistent with our previous findings in vitro. This order of potency is not in agreement with the rank order of R(−)>S(+)=desoxy which is predicted by the Easson-Stedman Hypothesis. The β-adrenoceptor-mediated chronotropic and β-adrenoceptor-mediated vasodepressor effects of these imidazolines were also investigated in pithed rat and found to be weaker than either the α- or α-adrenoceptor-mediated effects. However, the rank order of potency of the enantiomers and corresponding desoxy derivative for β- and β-adrenoceptor-mediated effects was found to be similar to that order predicted by the Easson-Stedman Hypothesis. Studies with these optically active imidazoline enantiomers and corresponding desoxy derivativative indicate that quantitative as well as qualitative differences exist in the stereochemical requirements of α- and β-adrenoceptor. The results also support our previous observations which suggest that phenethylamines and imidazolines may interact differently with α-adrenoceptor since the former adhere strictly to the Easson-Stedman Hypothesis whereas the latter do not. [ABSTRACT FROM AUTHOR]

Adrenaline and noradrenaline produced both constriction and dilatation of the toad renal vasculature: constrictor effects were mediated by α-adrenoceptors; dilator effects were mediated by β-adrenoceptors. Vasoconstriction was the predominant response to these amines. Dilatation was only revealed after blockade of α-adrenoceptors and constriction of the vasculature. There was a marked seasonal variation in the constrictor responses to adrenaline, but not to noradrenaline. The maximal increase in renal vascular resistance produced by adrenaline in summer was greater, by a factor of three, than the maximum constrictor response in winter. The response to adrenaline in summer was also significantly greater than the responses to noradrenaline in both summer and winter. However, after treatment with propranolol there was no difference between the maximum vasoconstrictions to these two amines, in summer or in winter. Determination of dissociation constants for phentolamine indicated that adrenaline and noradrenaline acted on the same population of α-adrenoceptors in both summer and winter. The enhanced vasoconstriction to adrenaline in summer appears to be due to a reduced potency of adrenaline on renal vascular β-adrenoceptors. The reduction in potency may be caused by a subtle configurational change in the β-adrenoceptors, perhaps induced by hormonal changes associated with the onset of breeding. [ABSTRACT FROM AUTHOR]

Stimulation of sympathetic nerves to the toad heart produced increases in both the rate and force of cardiac beat. Although these responses were abolished by treatment with bretylium (10 mol ·l) or 6-hydroxydopamine (100 mg·kg), and surgical sympathetic denervation, they were not abolished by treatment with propranolol (10 mol·l) and phentolamine (3×10 mol·l), either alone or in combination. The responses remaining after adrenoceptor blockade could not be ascribed to the effects of neurally released dopamine, ATP, adenosine, histamine or a variety of neuropeptides, although the participation of an as yet unidentified co-transmitter cannot be ruled out. Quantitative analysis of the interactions between propranolol and adrenaline on cardiac adrenoceptors, after blockade of α-receptors and amine uptake mechanisms, revealed that these interactions do not comply with the conditions for simple competitivity. Therefore, in addition to its action on β-receptors, adrenaline seems to be producing excitation of the toad heart by acting on adrenoceptors which cannot be classified as either α-or β-receptors. These results, together with the existence of close neuromuscular gaps (<50nm) in the toad heart, are consistent with the hypothesis that sympathetic excitation of the toad heart is mediated by both 'extra-junctionl' β-adrenoceptors, and 'junctional' adrenoceptors which are neither α-nor β-receptors. [ABSTRACT FROM AUTHOR]

To study the distribution of α-and β-adrenoceptors dog saphenous vein strips were electrically stimulated (2 ms, 30 V, 0.25-20 Hz). The strips either had spontaneous tone (contraction experiments) or were contracted by 0.28 μM prostaglandin F2 α in the presence of 7 μM phentolamine (relaxation experiments). In strips without preloading or in strips preloaded with (−)-noradrenaline α-adrenoceptor-mediated excitatory responses were readily evoked (contraction experiments) but not β-adrenoceptor-mediated inhibitory responses (relaxation experiments). In strips preloaded with (−)-adrenaline both α-(contraction experiments) and β-effects (relaxation experiments) were readily elicited by electrical stimulation and by tyramine. Thus, strips preloaded with (−)-adrenaline were used to compare α-with β-effects. In these strips the latency between the beginning of the electrical stimulation and the onset of the response was longer for β-than for α-responses. The same applies to responses to exogenous (−)-adrenaline. However, the ratio 'latency for β-/latency for α-response' was 3.6±0.2 ( n=8) for responses to electrical stimulation and 1.8±0.1 ( n=12) for responses to (−)-adrenaline ( P<0.001). Cocaine (12μM) enhanced the α-effect elicited by electrical stimulation 2.8±0.2 ( n=7) times but did not change the β-effect, whereas U-0521 (50 μM) enhanced the β-effect 3.4±0.2 ( n=8) times without changing the α-effect. In strips preloaded with (−)-adrenaline also tyramine caused concentration-dependent β-responses (relaxation experiments). The concentration of phentolamine and prazosin required to inhibit contractions caused by electrical stimulation were about 5-7 times higher than those required to inhibit contractions caused by exogenous adrenaline or noradrenaline, whereas propranolol was equipotent in reducing β-responses to adrenaline released by electrical stimulation and to exogenous adrenaline. Our results strongly support the view that α-adrenoceptors are in close contact with the nerve endings and β-adrenoceptors are in close proximity of COMT in a vessel with the nerve endings evenly distributed throughout the media. [ABSTRACT FROM AUTHOR]

β-Adrenoceptors were identified and characterized by [H]dihydroalprenolol ([H]DHA) binding experiments in muscle membrane preparations from piglets. The [H]DHA binding was rapid, reversible and stereoselective. Catecholamines competed for specific binding with a rank order of potency (-)-isopropylnoradrenaline > (-)-epinephrine » (-)-norepinephrine, indicating a β-subtype of adrenoceptor. Saturation binding experiments with [H]DHA showed no significant difference for either the number of binding sites or the equilibrium dissociation constants in normal and splayleg pigs. Adenylate cyclase assays indicated that the basal adenylate cyclase activity and the prostaglandin E (PGE)-, (-)-isopropylnoradrenaline (ISO)-, 5′-guanylyl-imidodiphosphate (GppNHp)- and sodium fluoride (NaF)-stimulated values were not significantly different in normal and splayleg pigs. In both groups, PGE did not affect basal activity, whereas ISO and GppNHp stimulated adenylate cyclase activity significantly ( p<0.001) to about 40% above basal level. NaF induced a significant ( p<0.001) increase of cAMP in normal and splayleg pigs amounting to 48% and 61% respectively. Significant correlations between absolute adenylate cyclase responses to ISO ( r=0.83), NaF ( r=0.72) and GppNHp ( r=0.61) and basal activity in the splayleg pigs were the most striking findings. In contrast, these correlations could not be detected in the normal pigs. Whether or not this observation reflects an alteration in the signal transduction system needs to be further investigated. To the best of our knowledge this is the first biochemical study which relates an altered β-adrenoceptor function and porcine splayleg. [ABSTRACT FROM AUTHOR]

Objective: Although the haemodynamic effects of catecholamines on the rat left ventricle have been investigated extensively, only few systematic in vivo studies have been performed on the right ventricle. The aim was to examine the acute effects of noradrenaline and isoproterenol on rat right ventricular function. Methods: Haemodynamic variables were measured during acute, 20 minute infusion of noradrenaline (0.1 mg·kg−1·h−1) or isoproterenol (12 μg·kg−1·h−1) in female Sprague Dawley rats. To estimate the contribution of α and β receptor stimulation to these effects, eight rats each were infused with prazosin (0.1 mg·kg−1·h−1), metoprolol (1.0 mg·kg−1·h−1), or the α and β antagonist carvedilol (0.5 and 1.0 mg·kg−1·h−1) alone and in combination with noradrenaline or isoproterenol. Results: Noradrenaline and isoproterenol increased right ventricular systolic pressure (RVSP) from 30.3(SEM 0.5) (n = 32) to 72.7(2.7) (n = 24) and 72.3(4.4) (n = 8) mm Hg, right ventricular (RV) dP/dtmax from 1848(70.3) to 4058(301) and 3612(366) mm Hg·s−1, and heart rate from 329(6) to 371(6) and 420(8) beats·min−1, respectively. Metoprolol completely prevented the isoproterenol induced haemodynamic changes, but neither metoprolol nor prazosin was able to significantly affect the pressure effect of noradrenaline (noradrenaline + metoprolol: 67.3(6.9) mm Hg, noradrenaline + prazosin: 67.0(3.8) mm Hg). The combination of both blockers, however, prevented the noradrenaline induced rise in RVSP (noradrenaline + metoprolol + prazosin: 36.5(5.1), and noradrenaline + prazosin + metoprolol: 30.0(1.2) mm Hg). Carvedilol (1.0 mg·kg−1·h−1) significantly attenuated the noradrenaline induced RVSP increase (39.1(3.0) mm Hg), but not to the control range. Metoprolol or carvedilol completely prevented the noradrenaline elicited increases in heart rate (254(7) and 287(20) min−1) and RVdP/dtmax, but prazosin alone had no effect on the heart rate and RVdP/dtmax increase. Thus β receptor blockade alone failed to significantly influence the noradrenaline induced increase of RVSP despite prevention of the increase in heart rate and RVdP/dtmax. Prazosin had a significant effect on RVSP only in combination with metoprolol. Conclusions: The combined effect of both α and β blockade exceeds the pure addition of the single effects in the rat right ventricle. Moreover, we speculate that the failure to reduce the noradrenaline induced increase in RVSP by either α or β blockade alone is due to the stimulation of the receptor that is not affected by the respective blocker.Cardiovascular Research 1993;27:2146-2151 [ABSTRACT FROM PUBLISHER]

Study objective – The aim was to determine the receptors involved in the antiaggregatory effects of adrenaline in the rat.Design – The 111indium oxine technique was used to evaluate ADP induced pulmonary accumulation of 111In labelled platelets in adrenalectomised rats (ie, no endogenous adrenaline) in the absence of anticoagulants. Adrenaline was infused (10, 20 and 40 μg·kg−1·h−1) and ADP aggregation measured. Adrenoceptor agonists, isoprenaline, methoxamine, and BHT 933, were given to evaluate whether they mimic the adrenaline effects. Adrenoceptor antagonists, yohimbine, propranolol, prazosin, and WY 26392, were given to assess whether they block the adrenaline effects.Measurements and main results – In all cases, pulmonary accumulation of platelets was measured in response to ADP. Adrenaline dose dependently inhibited platelet aggregation. BHT 933 (1.5 μg·kg−1·min−1) mimicked, while phentolamine (1 mg·kg−1), yohimbine (2.5 mg·kg−1), and WY 26392 (0.1, 1.0, 5.0 mg·kg−1) blocked, the adrenaline effects. Methoxamine (3.3 μg·kg−1·min−1) produced a relatively weak non-specific inhibition of ADP aggregation. Isoprenaline (33 ng·kg−1·min−1) did not mimic the effects of adrenaline, neither did propranolol (1 mg·kg−1) affect the adrenaline inhibition of the aggregatory responses to ADP. Indomethacin (3 mg·kg−1) blocked the inhibitory effects of adrenaline.Conclusions – Adrenaline stimulates α receptors on platelets but inhibits platelet aggregation. There is no evidence to suggest that β receptors participated in the effects produced by adrenaline. There is a role for cyclo-oxygenase products in the inhibitory effects of adrenaline on aggregation. [ABSTRACT FROM PUBLISHER]

Study objective – The aim was to identify the role of the endothelium in mediating the responses to acetylcholine in the rabbit coronary artery, and to determine whether α or β adrenergic stimulation may cause relaxation via endothelial receptors in the coronary arteries of this species.Design – Responses to acetylcholine and adrenoceptor agonists were compared in isolated ring preparations with and without endothelium. The adrenoceptor agonists were examined in the presence of phentoiamine or propranolol to block α and β adrenoceptors, respectively.Experimental material – 30 New Zealand white rabbits (2.3–3.4 kg) were killed by an overdose of barbiturate and exsanguination, and the left epicardial coronary artery was dissected free. Ring preparations were suspended in organ baths under isometric tension and, where required, the tone of the preparations was raised by KC1.Measurements and main results – Concentrations of acetylcholine up to 1−6 mol·litre−1 produced dose dependent relaxation of the preparations with endothelium intact, but no relaxation in preparations denuded of endothelium. At higher concentrations, a marked vasoconstrictor response was seen in all preparations regardless of the presence of endothelium. At basal tone, acetylcholine produced vasoconstriction which reached a maximum of 1.0 (SEM 0.14) g tension in preparations with endothelium and 1.74(0.27) g tension in those without endothelium (p≪0.05). In coronary arteries pretreated with 50 (μmol·litre−1 phenoxybenzamine to block α adrenoceptors, noradrenaline, isoprenaline, and salbuta-mol produced dose dependent relaxation of the preparations; this was unaffected by the absence of endothelium. In vessels not pretreated with phenoxybenzamine, propranolol inhibited the relaxation to noradrenaline and isoprenaline but again there was no difference between vessels with and without endothelium.Conclusions – In the rabbit isolated epicardial coronary artery, acetylcholine produces an endothelium dependent relaxant response over a limited concentration range; a vasoconstrictor response via smooth muscle dominates at higher concentrations. (β Adrenoceptors mediating relaxation are present on the smooth muscle, but there was no evidence for either α or β adrenoceptor mediated responses via the endothelium. Important differences with coronary arteries from other species are discussed. [ABSTRACT FROM PUBLISHER]

The effects of an alpha2 adrenoceptor blocker, yohimbine, and an alpha1 adrenoceptor blocker, phenoxybenzamine, and the central alpha2 adrenoceptor agonist, clonidine, on changes in arterial blood pressure and heart rate were studied during fatiguing muscular contractions to determine whether an adrenergic-opioidergic system might be involved in the mediation of cardiovascular function. Fatiguing contractions of the gastrocnemius and plantaris muscles of cats caused an increase in mean arterial blood pressure to 150-170 mmHg from resting values of 110-120 mmHg. Injection of clonidine into the cerebral aqueduct eliminated the increase in blood pressure; this effect was dose dependent. Naloxone antagonised the effects of the highest dose of clonidine (5 μg). Injections of yohimbine (1 μg) into the cerebral aqueduct had no significant effect on this pressor response. Yohimbine (1 μg) effectively counteracted the antipressor effects of clonidine when the two drugs were injected together until higher doses of clonidine (2-5 μg) were used. Phenoxybenzamine had no effect on the pressor response itself but unlike yohimbine was able to attenuate the effects of clonidine only when injected together. These data suggest that activation of muscle ergoreceptor afferent nerve fibres (group III and IV fibres) during muscular contractions may cause an increase in arterial blood pressure by interfering with an inhibitory adrenergic-endorphinergic pathway in the medullary region of the brainstem. [ABSTRACT FROM PUBLISHER]

alpha- and beta-Adrenoceptors have each been divided into two subgroups (alpha 1, alpha 2, beta 1 and beta 2). The basic mechanisms underlying the adrenoceptor/effector coupling are complex and vary for the alpha-, but not for the beta-subpopulations. Adrenoceptors of the bronchi and the lung show a special pattern of distribution and response, ensuring that the airway system works as a functionary unit. Dysfunctions of adrenoceptor-mediated effects have been suggested to contribute to some important paediatric disorders such as hyaline membrane syndrome, wet lung, bronchial asthma, cystic fibrosis, and pertussis. Drugs which act on the adrenergic system influence some of these disorders directly. Further studies applying modern techniques to receptor research are needed in order to clarify the basic mechanisms involved in receptor-mediated lung disorders and the activity of drugs in lung tissue. [ABSTRACT FROM AUTHOR]

Isolated helical strips from coronary arteries of pigs or cattle were activated by potassium-rich solutions. The ED for potassium was calculated by means of an exponential function of the dose-response curve. After blockade of the alpha-adrenoceptors by 1.4 μg/ml of phenoxybenzamine the ED was not changed (37.4 and 37.2 mval K, respectively), but decreased to 29.4 mval K after blockade of the beta-adrenoceptors by 6.3 μg/ml of propranolol. - The maximum dilating concentration of noradrenaline for the polarized preparation was about 1 μg/ml. Noradrenaline relaxed the depolarized, contracted preparation in potassium-rich solution (135 mval K), too. Therefore, it seems that changes of the membrane potential are not required for the coronary dilatation elicited by stimulation of betaadrenoceptors. After blockade of the alpha-adrenoceptor the dilatory effect of noradrenaline was enhanced, whereas after blockade of the beta-adrenoceptors noradrenaline induced a contraction. Concerning physiological concentrations at the vascular smooth muscle of coronary arteries both adrenotropic receptors were activated by noradrenaline. The changes of contractile tension observed were discussed with respect to variations of intracellular calcium ion concentration. [ABSTRACT FROM AUTHOR]

The mechanisms that sense alterations in total body sodium content to facilitate sodium homeostasis in response to an acute sodium challenge that does not increase blood pressure have not been fully elucidated. We hypothesized that the renal sympathetic nerves are critical to mediate natriuresis via α 1 - or β-adrenoceptors signal transduction pathways to maintain sodium balance in the face of acute increases in total body sodium content that do not activate the pressure-natriuresis mechanism. To address this hypothesis, we used acute bilateral renal denervation (RDNX), an anteroventral third ventricle (AV3V) lesion and α 1 - or β-antagonism during an acute 1M NaCl sodium challenge in conscious male Sprague Dawley rats. An acute 1M NaCl infusion did not alter blood pressure and evoked profound natriuresis and sympathoinhibition. Acute bilateral RDNX attenuated the natriuretic and sympathoinhibitory responses evoked by a 1M NaCl infusion [peak natriuresis (μeq/min) sham 14.5 ± 1.3 vs. acute RDNX: 9.2 ± 1.4, p < 0.05; plasma NE (nmol/L) sham control: 44 ± 4 vs. sham 1M NaCl infusion 11 ± 2, p < 0.05; acute RDNX control: 42 ± 6 vs. acute RDNX 1M NaCl infusion 25 ± 3, p < 0.05]. In contrast, an AV3V lesion did not impact the cardiovascular, renal excretory or sympathoinhibitory responses to an acute 1M NaCl infusion. Acute i.v. α 1 -adrenoceptor antagonism with terazosin evoked a significant drop in baseline blood pressure and significantly attenuated the natriuretic response to a 1M NaCl load [peak natriuresis (μeq/min) saline 17.2 ± 1.4 vs. i.v. terazosin 7.8 ± 2.5, p < 0.05]. In contrast, acute β-adrenoceptor antagonism with i.v. propranolol infusion did not impact the cardiovascular or renal excretory responses to an acute 1M NaCl infusion. Critically, the natriuretic response to an acute 1M NaCl infusion was significantly blunted in rats receiving a s.c. infusion of the α 1 -adrenoceptor antagonist terazosin at a dose that did not lower baseline blood pressure [peak natriuresis (μeq/min) sc saline: 18 ± 1 vs. sc terazosin 7 ± 2, p < 0.05]. Additionally, a s.c. infusion of the α 1 -adrenoceptor antagonist terazosin further attenuated the natriuretic response to a 1M NaCl infusion in acutely RDNX animals. Collectively these data indicate a specific role of a blood pressure-independent renal sympathetic nerve-dependent α 1 -adrenoceptor-mediated pathway in the natriuretic and sympathoinhibitory responses evoked by acute increases in total body sodium., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Frame, Nist, Kim, Kuwabara and Wainford.)

Purpose: Perivascular adipose tissue (PVAT) exerts an anti-contractile effect which is vital in regulating vascular tone. This effect is mediated via sympathetic nervous stimulation of PVAT by a mechanism which involves noradrenaline uptake through organic cation transporter 3 (OCT3) and β 3 -adrenoceptor-mediated adiponectin release. In obesity, autonomic dysfunction occurs, which may result in a loss of PVAT function and subsequent vascular disease. Accordingly, we have investigated abnormalities in obese PVAT, and the potential for exercise in restoring function., Methods: Vascular contractility to electrical field stimulation (EFS) was assessed ex vivo in the presence of pharmacological tools in ±PVAT vessels from obese and exercised obese mice. Immunohistochemistry was used to detect changes in expression of β 3 -adrenoceptors, OCT3 and tumour necrosis factor-α (TNFα) in PVAT., Results: High fat feeding induced hypertension, hyperglycaemia, and hyperinsulinaemia, which was reversed using exercise, independent of weight loss. Obesity induced a loss of the PVAT anti-contractile effect, which could not be restored via β 3 -adrenoceptor activation. Moreover, adiponectin no longer exerts vasodilation. Additionally, exercise reversed PVAT dysfunction in obesity by reducing inflammation of PVAT and increasing β 3 -adrenoceptor and OCT3 expression, which were downregulated in obesity. Furthermore, the vasodilator effects of adiponectin were restored., Conclusion: Loss of neutrally mediated PVAT anti-contractile function in obesity will contribute to the development of hypertension and type II diabetes. Exercise training will restore function and treat the vascular complications of obesity., (© 2020. The Author(s).)

Adrenoceptors (ARs) mediate the effects of the sympathetic neurotransmitters norepinephrine (NE) and epinephrine (E) in the human body and play a central role in physiologic and pathologic processes. Therefore, ARs have long been recognized as targets for therapeutic agents, especially in the field of cardiovascular medicine. During the past decades, the contribution of the sympathetic nervous system (SNS) and particularly of its major peripheral catecholamine NE to the pathogenesis of osteoarthritis (OA) attracted growing interest. OA is the most common degenerative joint disorder worldwide and a disease of the whole joint. It is characterized by progressive degradation of articular cartilage, synovial inflammation, osteophyte formation, and subchondral bone sclerosis mostly resulting in chronic pain. The subchondral bone marrow, the periosteum, the synovium, the vascular meniscus and numerous tendons and ligaments are innervated by tyrosine hydroxylase-positive (TH+) sympathetic nerve fibers that release NE into the synovial fluid and cells of all abovementioned joint tissues express at least one out of nine AR subtypes. During the past decades, several in vitro studies explored the AR-mediated effects of NE on different cell types in the joint. So far, only a few studies used animal OA models to investigate the contribution of distinct AR subtypes to OA pathogenesis in vivo. This narrative review shortly summarizes the current background knowledge about ARs and their signalling pathways at first. In the second part, we focus on recent findings in the field of NE-induced AR-mediated signalling in different joint tissues during OA pathogenesis and at the end, we will delineate the potential of targeting the adrenergic signalling for OA prevention or treatment. We used the PubMed bibliographic database to search for keywords such as 'joint' or 'cartilage' or 'synovium' or 'bone' and 'osteoarthritis' and/or 'trauma' and 'sympathetic nerve fibers' and/or 'norepinephrine' and 'adrenergic receptors / adrenoceptors' as well as 'adrenergic therapy'. • Sympathetic nerve fibers and neurotransmitters have been detected in almost all joint tissues. • All joint tissues express at least one adrenoceptor subtype. • α2a- and β2-adrenoceptors are most abundant in healthy and osteoarthritic joints • Adrenoceptor-mediated effects on joint cells during osteoarthritis pathogenesis are mainly catabolic • Targeting adrenoceptors in the joint represents a promising therapeutic strategy for osteoarthritis treatment [ABSTRACT FROM AUTHOR]

Background: Alpha 2A -adrenergic (α 2A -AR) and cannabinoid CB 1 (CB 1 -R) receptors exert their functions modulating multiple signaling pathways, including MEK-ERK (extracellular signal-regulated kinases) and FADD (Fas-associated protein with death domain) cascades. These molecules are relevant in finding biased agonists with fewer side effects, but the mechanisms involving their modulations by α 2A -AR- and CB 1 -R in vivo are unclear. This study investigated the roles of Gαi 2 and Gαz proteins in mediating α 2A -AR- and CB 1 -R-induced alterations of MEK-ERK and FADD phosphorylation (p-) in mouse brain cortex., Methods: Gαi 2 or Gαz protein knockdown was induced in mice with selective antisense oligodeoxinucleotides (ODNs; 3 nmol/day, 5 days) prior to UK-14,304 (UK or brimonidine; 1 mg/kg) or WIN55212-2 (WIN; 8 mg/kg) acute treatments. Inactivated (p-T 286 ) MEK1, activated (p-S 217/221 ) MEK1/2, activated (p-T 202 /Y 204 ) ERK1/2, p-S 191 FADD, and the corresponding total forms of these proteins were quantified by immunoblotting., Results: Increased (+ 88%) p-T 286 MEK1 cortical density, with a concomitant reduction (-43%) of activated ERK was observed in UK-treated mice. Both effects were attenuated by Gαi 2 or Gαz antisense ODNs. Contrastingly, WIN induced Gαi 2 - and Gαz-independent upregulations of p-T 286 MEK1 (+ 63%), p-S 217/221 MEK1/2 (+ 86%), and activated ERK (+ 111%) in brain. Pro-apoptotic FADD was downregulated (- 34 to 39%) following UK and WIN administration, whereas the neuroprotective p-S 191 FADD was increased (+ 74%) in WIN-treated mice only. None of these latter effects required from Gαi 2 or Gαz protein integrity., Conclusion: The results indicate that α 2A -AR (UK), but not CB 1 -R (WIN), agonists use Gαi 2 and Gαz proteins to modulate MEK-ERK, but not FADD, pathway in mouse brain cortex., (© 2021. Maj Institute of Pharmacology Polish Academy of Sciences.)

We have demonstrated that 5-methoxycarbonylamino-N-acetyltryptamine (5-MCA-NAT), reduces intraocular pressure (IOP) in rabbits. In addition, we have reported a link between hypotensive effect of 5-MCA-NAT and sympathetic nervous system. Moreover, it is known that aqueous humour production is controlled by the activation of adrenoceptors (ADRs) present in the ocular ciliary epithelium. Thus, the aim of this study is to investigate if the hypotensive effect of 5-MCA-NAT is due to a regulation of ciliary ADR genes expression. To confirm this we followed the effect of 5-MCA-NAT on rabbit IOP for 144 consecutive hours. A sustained IOP reduction for up to 72 h (P<0.01) was seen. In addition, changes in ADRB2 and ADRA2A mRNA were measured in cultured rabbit nonpigmented ciliary epithelial cells. After 5-MCA-NAT treatment, a significant downregulation of ADRB2 and upregulation of ADRA2A was observed. These results provide the regulation of ADRs mRNA by 5-MCA-NAT. [ABSTRACT FROM AUTHOR]

Segment-specific characteristics of the reactions of pial arteries of different generations to intravenous injection of norepinephrine were studied under conditions of instrumental stabilization of systemic blood pressure in rats with blocked α- and β-adrenoceptors. [ABSTRACT FROM AUTHOR]

We found that exogenous and endogenous cAMP induces changes in the spectrum and amount of intraerythrocytic peptides in human erythrocytes of different age. Activation of cAMP formation with epinephrine leads to the appearance of peptides of the other type and to an increase in their total amount in young cells, while blockade of these β-adrenoreceptors with propranolol eliminates these effects. Inhibition of cAMP phosphodiesterase with imidazole in the absence of hormonal signals elevates the content of longer peptides in erythrocytes compared to the effect of exogenous cAMP. The degree of this elevation depends on erythrocyte age. [ABSTRACT FROM AUTHOR]

Healthy and degenerating intervertebral discs (IVDs) are innervated by sympathetic nerves, however, adrenoceptor (AR) expression and functionality have never been investigated systematically. Therefore, AR gene expression was analyzed in both tissue and isolated cells from degenerated human IVDs. Furthermore, human IVD samples and spine sections of wildtype mice (WT) and of a mouse line that develops spontaneous IVD degeneration (IVDD, in SM/J mice) were stained for ARs and extracellular matrix (ECM) components. In IVD homogenates and cells α1a-, α1b-, α2a-, α2b-, α2c-, β1-, and β2-AR genes were expressed. In human sections, β2-AR was detectable, and its localization parallels with ECM alterations. Similarly, in IVDs of WT mice, only β2-AR was expressed, and in IVDs of SM/J mice, β2AR expression was stronger accompanied by increased collagen II, collagen XII, decorin as well as decreased cartilage oligomeric matrix protein expression. In addition, norepinephrine stimulation of isolated human IVD cells induced intracellular signaling via ERK1/2 and PKA. For the first time, the existence and functionality of ARs were demonstrated in IVD tissue samples, suggesting that the sympathicus might play a role in IVDD. Further studies will address relevant cellular mechanisms and thereby help to develop novel therapeutic options for IVDD. [ABSTRACT FROM AUTHOR]