Effects Of Adrenoceptor Agonists Research Articles

Effects of clonidine in the isolated rat testicular capsule

The testicular capsule contracts in response to noradrenaline and adrenaline, but the effects of adrenoceptor agonists, as for instance clonidine, had not yet been thoroughly evaluated. The testicular capsule from adult male Wistar rats was isolated and mounted in organ bath and cumulative concentration curves were performed for clonidine and other adrenergic agonists in the absence or presence of α-adrenoceptors antagonists. The order of potency for agonists (pD2) was clonidine=adrenaline>UK 14,304>noradrenaline>phenylephrine>methoxamine. The consecutive curves for clonidine showed desensitization with 3-fold rightward shift and Emax reduction of 40%. The noradrenaline curves were 4.5, 19 and 190-fold less potent after clonidine pretreatment at 10−5, 10−4 or 10−3M for 10min, respectively, added to Emax decrease by about 20%. Clonidine (10−5M for 10min) was unable to alter the noradrenaline curves if the treatment was made in the presence of idazoxan (α2-adrenoceptor antagonist) whereas prazosin (α1-adrenoceptor antagonist) was ineffective. The effect of idazoxan 3×10−7M on noradrenaline curves was decreased by 50% after clonidine pretreatment, as reflected by the concentration ratio of 5.2±1.2 (treated tissue) and 10.1±1.0 (untreated tissue). However, the concentration ratio for prazosin 3×10−8M was unchanged. After phenoxybenzamine (irreversible antagonist of α1-adrenoceptor) pretreatment, the residual noradrenaline contraction was antagonized by idazoxan or prazosin with pKB values of 7.8 and 5.1, respectively. The results indicate the presence of α2-adrenoceptors in testicular capsule. Furthermore, these receptors may be desensitized by clonidine, causing a decreased potency of noradrenaline.

Functional antagonism of β‐adrenoceptor subtypes in the catecholamine‐induced automatism in rat myocardium

Myocardial automatism and arrhythmias may ensue during strong sympathetic stimulation. We sought to investigate the relevant types of adrenoceptor, as well as the role of phosphodiesterase (PDE) activity, in the production of catecholaminergic automatism in atrial and ventricular rat myocardium. The effects of adrenoceptor agonists on the rate of spontaneous contractions (automatic response) and the amplitude of electrically evoked contractions (inotropic response) were determined in left atria and ventricular myocytes isolated from Wistar rats. Catecholaminergic automatism was Ca(2+) -dependent, as it required a functional sarcoplasmic reticulum to be exhibited. Although both α- and β-adrenoceptor activation caused inotropic stimulation, only β(1) -adrenoceptors seemed to mediate the induction of spontaneous activity. Catecholaminergic automatism was enhanced and suppressed by β(2) -adrenoceptor blockade and stimulation respectively. Inhibition of either PDE3 or PDE4 (by milrinone and rolipram, respectively) potentiated the automatic response of myocytes to catecholamines. However, only rolipram abolished the attenuation of automatism produced by β(2) -adrenoceptor stimulation. α- and β(2) -adrenoceptors do not seem to be involved in the mediation of catecholaminergic stimulation of spontaneous activity in atrial and ventricular myocardium. However, a functional antagonism of β(1) - and β(2) -adrenoceptor activation was identified, the former mediating catecholaminergic myocardial automatism and the latter attenuating this effect. Results suggest that hydrolysis of cAMP by PDE4 is involved in the protective effect mediated by β(2) -adrenoceptor stimulation.

Effects of adrenoceptor agonists and antagonists on morphine-induced Straub tail in mice

Straub-tail behavior was induced by subcutaneous injection of different doses (10–60 mg/kg) of morphine to mice. The maximum response was obtained with 20–40 mg/kg of the drug. The response induced by morphine (40 mg/kg) was decreased by intraperitoneal administration of different doses of clonidine (0.05–0.1 mg/kg). Pretreatment of animals with yohimbine (1–4 mg/kg ip) reversed the inhibitory action of clonidine. Yohimbine did not elicit any response by itself. Administration of prazosin (0.25, 0.5, and 1 mg/kg) reduced the morphine response. The combination of prazosin with yohimbine (1 mg/kg), but not with clonidine (0.05 mg/kg), caused a potentiated inhibition of the morphine effect. Phenylephrine (2–6 mg/kg ip) did not elicit any effect by itself and also did not alter the response induced by morphine or morphine plus clonidine. Dobutamine (2.5–10 mg/kg ip), atenolol (2.5–10 mg/kg ip), salbutamol (2.5–10 mg/kg ip), and propranolol (2.5–10 mg/kg ip) did not alter morphine-induced Straub-tail behavior in mice. In conclusion, activation of α 2-adrenergic pathways contributes to morphine-induced Straub tail, while α 1- and β 2-adrenergic may not be involved in this phenomenon.

Effect of α-adrenoceptor agents on imipramine-induced antinociception in nerve-ligated mice

In this study, the effects of adrenoceptor agonists and antagonists on antinociception induced by imipramine in sciatic-nerve-ligated mice were investigated. The response of different doses of morphine, imipramine and adrenoceptor agonists and antagonists was examined 14 days after unilateral nerve-ligation in the hot-plate test. Intraperitoneal injection of different doses of morphine (3, 6 and 9 mg/kg), imipramine (10, 20 and 40 mg/kg), the α 2-adrenoceptor agonist, clonidine (0.05, 0.1 and 0.2 mg/kg) or the α 1-adrenoceptor agonist, phenylephrine (2, 4 and 8 mg/kg) induced dose-related antinociception in both intact and nerve-ligated mice. The antinociception induced by morphine but not that of imipramine, clonidine or phenylephrine, in nerve-ligated mice was significantly less than that induced in intact animals. Imipramine in combination with clonidine tends to induce a higher response, but the combination of imipramine with phenylephrine did not lead to significant potentiation. The α 2-adrenoceptor antagonist, yohimbine, reduced the response induced by imipramine or imipramine plus clonidine in intact and nerve-ligated animals. However, the α 1-adrenoceptor antagonist, prazosin, did not alter imipramine response. It may be concluded that imipramine induced antinociception in both intact and nerve-ligated mice through an α 2-adrenoceptor mechanism(s).

Influence of Different Adrenoceptor Agonists and Antagonists on Physostigmine-Induced Yawning in Rats

In the present study, effects of adrenoceptor agonists and antagonists on physostigmine-induced yawning was investigated. Intraperitoneal (IP) injection of different doses of physostigmine (0.03, 0.05, 0.1, and 0.2 mg/kg) induced yawning in rats. The maximum response was obtained by 0.2 mg/kg of the drug. The α1-adrenoceptor agonist, phenylephrine, and the α2-adrenoceptor agonist, clonidine, decreased yawning induced by physostigmine. Prazosin and higher doses of phenoxybenzamine reduced the inhibitory effect of phenylephrine. Higher doses of yohimbine also reduced the clonidine response. The adrenoceptor antagonists, prazosin, phenoxybenzamine, and propranolol, did not significantly alter the physostigmine response. However, yohimbine, or lower doses of prazosin, decreased the physostigmine response. It may be concluded that α1- and α2-adrenoceptor stimulation decreases the physostigmine-induced yawning behavior in rats.

Alpha1-adrenoceptors antagonize activated chloride conductance of amphibian skin epithelium.

The effects of adrenoceptor agonists on the transepithelial Cl- conductance (GCl) in the skin of several amphibian species, both toads and frogs, were studied. Epinephrine (Epi) from the serosal side selectively and reversibly inhibited the voltage-activated GCl in toad skin and the short-circuit GCl in frog skin. The main effects of activation of the adrenoceptors must reside in the skin epithelium and not in the glands, since measurements were made both from intact skins and split epithelia with essentially the same results. Effective concentrations of Epi were variable among individual tissues. GCl was reduced to 34+/-17% (n=46) with 1 micromol/l Epi, but in some tissues 0.1 micromol/l inhibited more than 80% of GCl, whereas some preparations were little influenced at >3 micromol/l Epi. The affected receptor type was identified by the use of the alpha1-agonist phenylephrine, which mimicked the response of Epi at concentrations above 30 micromol/l, whereas the alpha2-agonists xylazine and iodoclonidine had no effect at supramaximal concentrations. Prazosin, a specific alpha1-antagonist, reduced or eliminated the inhibition by Epi, but the response pattern suggests a low affinity. The alpha2-antagonist yohimbine, at concentrations </=0.3 micromol/l, had a minimal effect, but reduced the inhibition by Epi at concentrations of 1-10 micromol/l. This might indicate affinity to alpha1-adrenoceptors in amphibian skin. Activation of beta-adrenoceptors by isoproterenol (0.1-5 micromol/l) led to a transient increase of the baseline inactivated component of GCl with a slight reduction of the voltage-activated GCl at the higher concentrations, but the inhibitory effect of Epi was not altered. Epi, on the other hand, neither prevented nor reversed the induction of a voltage-insensitive GCl in toad skin caused by application of cAMP at supramaximal concentrations (>100 micromol/l CPT-cAMP). Preincubation of the serosal medium with Ca2+-free solution (in the presence of 2 mmol/l EGTA) for extended periods of time (>30 min) eliminated the response to Epi. It is concluded that alpha1-adrenoceptors participate in the physiological control of voltage-activated Cl- conductance in amphibian skin epithelium via modulation of intracellular Ca2+, presumably by efflux from intracellular stores.

Opposite influences of different adrenoceptors on baclofen-induced antinociception in mice.

In the present study, the effects of adrenoceptor agonists and antagonists on baclofen-induced antinociception was investigated. Intraperitoneal administration of different doses of baclofen (2.5, 5 and 10 mg/kg) induced antinociception in the tail-flick test. The response was dose-dependent. The alpha 2-adrenoceptor agonist, clonidine, increased, while the alpha 1-adrenoceptor agonist, phenylephrine, decreased the baclofen response. In reserpine-treated animals, alpha 2-adrenoceptor, clonidine, induced antinociception and increased that of baclofen. Yohambine and propranolol but not prazosin decreased the baclofen effect. Although phenoxybenzamine itself induced antinociception it did not alter the baclofen response significantly. Reserpine treatment decreased the response induced by single administration of baclofen or phenoxybenzamine and that induced by a combination of baclofen with either phenoxybenzamine or prazosin. It may be concluded that alpha 2-adrenoceptor stimulation increases, while alpha 1-adrenoceptor activation decreases the baclofen-induced antinociception, and aminergic mechanism(s) may have a positive influence on baclofen response.

Central catecholaminergic neurons are involved in expression of the 10-Hz rhythm in SND

We studied the effects of adrenoceptor agonists and antagonists on sympathetic nerve discharge (SND) of urethan-anesthetized, baroreceptor-denervated cats. In cats in which a 10-Hz rhythm coexisted with irregular 2- to 6-Hz oscillations in SND, intravenous clonidine, an alpha 2-adrenoceptor agonist, blocked the 10-Hz rhythm without affecting power at lower frequencies. In contrast, power at frequencies < or = 6 Hz was depressed by clonidine in cats in which the 10-Hz rhythm was absent. These effects were reversed by intravenous administration of alpha 2-adrenoceptor antagonists, idazoxan and rauwolscine. Rauwolscine is devoid of affinity for imidazoline receptors. Furthermore, in cats untreated with clonidine, idazoxan and rauwolscine enhanced or induced the 10-Hz rhythm without affecting power at lower frequencies. Prazosin, an alpha 1-adrenoceptor antagonist, selectively blocked the 10-Hz rhythm in SND. Finally, the 10-Hz rhythm in SND was blocked by microinjection of clonidine into the rostral or caudal ventrolateral medulla. The results support the view that central catecholaminergic neurons play a role in expression of the 10-Hz rhythm in SND.

Effect of desipramine-induced blockade of neuronal uptake mechanisms on adrenoceptor-mediated responses in the guinea-pig colon

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 [3H] 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 [3H] prelabelled acetylcholine overflow was found with respect to untreated animals. Nevertheless, in such preparations subsensitivity to isoprenaline (acting mainly on muscular beta-adrenoceptors) and clonidine (acting on neuronal alpha 2-adrenoceptors) and super-sensitivity to phenylephrine were observed. Electrically evoked noradrenaline overflow was enhanced, in a frequency-dependent way, by yohimbine and inhibited by clonidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of adrenoceptor agonists on striated muscle strips of the canine oesophagus

1. Acute psychological stress, which could be related to the release of a large amount of catecholamines, may cause oesophageal motility disorders. Therefore, the aim of our study was to elucidate the influence of adrenoceptor agonists on the striated muscle portion of the oesophagus by use of isolated strips from dogs. 2. Contractions were evoked in isolated striated muscle strips by electrical field stimulation (1 pulse min-1, 1 ms/pulse, submaximal voltage). The effects induced by administration of adrenoceptor agonists alone or in the presence of antagonists were tested to determine the nature of the adrenoceptors on this muscle preparation. 3. The administration of both the natural adrenoceptor agonists, adrenaline and noradrenaline, and the synthetic beta-adrenoceptor agonists, isoprenaline (beta 1 + beta 2), dobutamine (beta 1) or ritodrine (beta 2), enhanced the amplitude of the contractions induced by electrical stimulation in a concentration-dependent manner. The maximum responses were 82.6 (adrenaline), 66.2 (noradrenaline), 86.2 (isoprenaline), 34.6 (dobutamine) and 80.8% (ritodrine). The EC20 values obtained were respectively 2 nM, 0.2 microM, 0.91 nM, 3 microM and 80 nM. The administration of the alpha 1-adrenoceptor agonist, phenylephrine, also enhanced the contractile response in a concentration-dependent manner (EC20 value = 0.3 microM) and the maximum response was 64.6%, but the administration of the alpha 2-adrenoceptor agonist, clonidine, did not influence the contractile response. These data suggest the involvement of beta 2- and possibly alpha 1-adrenoceptors in the responses of these adrenoceptor agonists. 4 The selective P2-adrenoceptor antagonist ICI 118551 (3-100nM) shifted the concentration-effect curves for noradrenaline, phenylephrine and ritodrine to the right in a concentration-dependent manner.ICI 118551 (3 nM) also shifted the concentration-effect curves for adrenaline and isoprenaline to the right, but increasing the concentration of ICI 118551 did not cause any further antagonist activity until a concentration of 100 nM, when a further rightward shift was obtained.5. The selective alpha 1-adrenoceptor antagonist, prazosin (30-300 nM), did not affect the increased contractile responses induced by adrenaline, noradrenaline, phenylephrine, isoprenaline or ritodrine.6. In conclusion, it appears that beta2-adrenoceptors are present in the striated muscle portion of the canine oesophagus, where they mediate an enhancement of contractile responses evoked by electrical stimulation. The alpha l-agonist, phenylephrine, appears to interact with beta2-adrenoceptors on this preparation.beta 3-Adrenoceptors have already been demonstrated in smooth muscle from various parts of the gastrointestinal tract, and our study does not exclude the possibility that there is an additional population of beta 3-receptors in the canine striated muscle part of the oesophagus.

Effects of adrenoceptor agonists and antagonists on cardiovascular functional parameters in rats.

The effects of intravenous administration of adrenoceptor agonists and antagonists on electrocardiographic or blood pressure (BP) functional parameters were assessed in urethane-anesthetized rats. The responses of cardiovascular functional parameters produced by these drugs included: (1) isoproterenol decreased the duration of a whole BP cycle (Wd), duration of the diastolic wave (Dd), peak amplitude of the systolic wave (SYa), amplitude of the diastolic notch (DNa), amplitude of the diastolic wave (DWa), pulse pressure (dp) and mean arterial pressure (mp) but increased the heart rate (HR) accompanied by prolonged R-R (RR) or P-P interval (PP) (2) propranolol decreased SYa, DNa, dp, mp, HR, the amplitude of the P wave (Pa) and amplitude of the S wave (Sa) but increased the duration of the QRS wave, P-R interval, duration of the R wave (Rd) and duration of the P wave (Pd); (3) adrenaline decreased HR (accompanied by prolonged RR and PP), Rd, Pa and amplitude of the T wave (Ta) but increased Pd, Wd, Dd, DNA, the time interval between aortic valve opening and closure (Dw), dp, mp, amplitude of the Q wave and amplitude of the R wave (Ra); (4) noradrenaline decreased HR (accompanied by prolonged RR and PP) and Pa but increased Wd, Pd, SYa, DNa, Dw, dp, mp, Ra and Ta; (5) phenylephrine decreased HR (accompanied by prolonged RR and PP) and Pa but increased Wd, Dd, DNa, mp and Ra; (6) phentolamine decreased SYa, DNa, DWa, Dw, dp and mp. This study illustrates the utility of the automated electrocardiogram (ECG) and BP analysis system for investigation of adrenoceptor agonists and antagonists. The use of this methodology not only reproduced most of cardiovascular functional parameter effects produced by these drugs using the conventional methodology but also realizes some new information about the drug-induced ECG or BP waveform effects.

Catecholaminergic projections to tuberoinfundibular neurones of the paraventricular nucleus: III. Effects of adrenoceptor agonists and antagonists

Stimulation of the ventral noradrenergic ascending bundle (VNAB) at low frequencies ( 0.5 5 Hz) excited the majority ( 37 46 , 80%) of single paraventricular nucleus (PVN) tuberoinfundibular neurones, with high frequency (50 Hz) trains of stimuli reversing the direction of the response to inhibition for 7 16 (44%) of these excited cells. Iontophoretic application of noradrenaline, or the α1-adrenoceptor agonist 1-phenylephrine, increased the spontaneous electrical activity of most of the cells tested (94% and 72%), whilst application of the α1-antagonist, ergotamine reduced the spontaneous activity of 44% of the cells tested and prevented the excitation following VNAB stimulation for 84% of the cells examined. Application of the β-adrenoceptor antagonist, propranolol, increased the spontaneous activity of 77% of cells and prevented the inhibitory PVN neuronal responses following high frequency VNAB stimulation of 94% of the cells, often reversing the response to excitation similar to that observed following low frequency VNAB stimulation. The α2-adrenoceptor antagonist, tolazoline, was found to evoke mixed responses from the cells examined but a trend towards a suppression of spontaneous activity and potentiation of VNAB stimulation-evoked responses was observed. The α2-adrenoceptor agonist, clonidine, elicited an initial excitation from the majority of cells tested, with most of the cells then exhibiting an inhibition, either with or without continued application. Excitatory responses following stimulation of the sciatic nerve were recorded from the majority of cells (82.5%) and ergotamine was able to suppress this response for all four cells so tested. The results of this study extend the previous data demonstrating that the VNAB provides an excitatory input to the PVN, indicating that this input is primarily regulated by α1-adrenoceptors and that there is a tonic stimulation of such receptors. In addition, the increased spontaneous activity and blockade of inhibitory responses (following high frequency VNAB stimulation) during iontophoretic application of propranolol indicate the involvement of an inhibitory β-adrenoceptor mechanism mediating a tonic down-regulation of PVN neuronal activity and the inhibitory responses recorded following high frequency VNAB stimulation. The data are discussed in the context of the neural regulation of hypothalamo-pituitary-adrenocortical regulation.

Effects of adrenoceptor agonists and antagonists on Ca ++ ATPase activities of rabbit aorta microsomal fraction

Effects of adrenoceptor agonists and antagonists on Ca ++ ATPase activities of rabbit aorta microsomal fraction

ALTERATIONS OF “SLEEPING TIME” IN THE RAT INDUCED BY DRUGS WHICH MODULATE CENTRAL MONOAMINERGIC SYSTEMS

The effects of adrenoceptor agonists and antagonists have been determined on "sleeping time" in the rat--that is, with the animal immobile and adopting a sleeping posture. Alterations in their gross behaviour patterns were assessed also. The specific alpha 2-adrenoceptor agonists (yohimbine, WY 26393, RX 781094 and RS 21361) decreased sleeping time, as did the beta-adrenoceptor agonist clenbuterol. The specific alpha 2-adrenoceptor agonist clonidine gave a large increase in sleeping time at doses in excess of 25 micrograms kg-1. The same effect was seen with the beta-antagonist propranolol and the specific beta 2-antagonist ICI 118551.

Effects of adrenoceptor agonists and antagonists on sulfobromophthalein disposition in mice

The effects of α 2-adrenoceptor agonists on sulfobromophthalein (BSP) disposition in mice were studied. It was found that agents with both central and peripheral activities (clonidine, guanabenz, B-HT 920 and methyldopa) as well as peripherally acting α 2-adrenoceptor agonists (para amino-clonidine and St 91) inhibited sulfobromophthalein disposition in the mouse, and also caused substantial hypothermia. The effects of these agonists were inhibited by yohimbine, a specific α 2-antagonist, except for those of para amino-clonidine where only partial reversal was achieved. The effects of clonidine on BSP disposition were also reversed by piperoxan but not by the α 1-adrenoceptor antagonists, prazosin and phenoxybenzamine, nor by the β-blocker, propranolol. These results suggest that, in mice, peripheral α 2-adrenoceptors are involved in the effects of the α-agonists on BSP disposition.

Effects of adrenoceptor agonists and antagonists on the firing of neurons in the rat A1 noradrenergic region.

Noradrenaline (NA), but not clonidine applied microiontophoretically, inhibited the firing of neurons in the rat A1 noradrenergic region, whereas intravenous clonidine dose-dependently inhibited their firing (ED50 = 18.3 micrograms/kg). The NA-induced inhibition was blocked by the beta-antagonist timolol, but not by the alpha-antagonists phentolamine or piperoxane. These results suggest that neurons in the A1 region possess beta-adrenoceptors rather than alpha-adrenoceptors near their cell bodies, and that systemically administered clonidine acts indirectly on these cells.

The effects of adrenoceptor agonists and antagonists on plasma potassium concentration in anaesthetized guinea‐pigs, rabbits and rats

An intravenous K+-sensitive electrode has been used to monitor plasma [K+] changes induced by alpha- and beta-adrenoceptor agonists in anaesthetized guinea-pigs, rabbits and rats. The effects of phentolamine and propranolol on these responses were studied. In the guinea-pig both alpha- and beta-adrenoceptor agonists produced a biphasic response consisting of an initial rapid increase in [K+] which was followed, within 1 min, by a fall below baseline. The antagonist studies indicated that in this species both phases of the response could be elicited by either alpha- or beta-adrenoceptor activation. In the rabbit the responses were both slower and smaller than those seen in the guinea-pig and required larger agonist doses. In addition it was found that the increase in plasma [K+] was alpha-adrenoceptor-mediated while the subsequent fall was seen only with beta-adrenoceptor activation. In the rat triphasic changes in plasma [K+] were seen consisting of an initial decrease which was alpha-adrenoceptor-mediated, followed by an increase and then a second fall which was elicited by beta-adrenoceptor stimulation. The increase in plasma [K+] was only slightly reduced by either alpha- or beta-adrenoceptor antagonists. Apamin, a toxin from bee venom which blocks Ca2+-activated K+-channels, was found to block the hyperkalaemic phase of the response in the guinea-pig and rabbit but had no effect in the rat. It is concluded that there are marked species differences in the effects of adrenoceptor agonists on plasma [K+] in vivo.

Effects of adrenoceptor agonists and antagonists on smooth muscle cells and neuromuscular transmission in the guinea‐pig renal artery and vein

In the guinea-pig renal artery and vein, the membrane potential was -66.8 mV and -46.8 mV, the length constant 0.54 mm and 0.43 mm, and the time constant 240 ms and 98 ms, respectively. The maximum slope of the depolarization produced by a 10 fold increase [K]o was 46 mV in the renal artery and 39 mV in the renal vein. Noradrenaline (NA over 5 X 10(-7)M in the artery and over 10(-7)M in the vein) depolarized the membrane and slightly reduced the membrane resistance, assessed from relative changes in the amplitude of electrotonic potential. The action of NA was suppressed by prazosin in the artery but by yohimbine in the vein, i.e. the alpha 1-adrenoceptor is present in the extrajunctional muscle membrane in the renal artery while the alpha 2-adrenoceptor is present in the renal vein. Dopamine and isoprenaline did not modify the membrane properties. In the renal artery, repetitive perivascular nerve stimulation (0.1 ms, 50 Hz, 5 shocks) evoked excitatory junction potential (e.j.p.). Applications of guanethidine (10(-6) M) or tetrodotoxin (3 X 10(-7) M) abolished the generation of the e.j.p.. Low concentrations of phentolamine (5 X 10(-7) M), prazosin (10(-7) M) and yohimbine (5 X 10(-7) M) enhanced the e.j.p. amplitude, while high concentrations of phentolamine (10(-5) M) and prazosin (greater than 10(-5) M) reduced the amplitude of e.j.p.s. NA, dopamine and clonidine consistently suppressed the amplitude of e.j.ps, at any given concentration over 10(-7) M. Spontaneous generated miniature e.j.ps (m.e.j.ps) were recorded on rare occasions. Phentolamine and yohimbine both at 5 x 10(-7) M and prazosin 10(-7) M increased the appearance of m.e.j.ps. 5 In the renal vein, repetitive nerve stimulation failed to generate the e.j.p. Sympathetic innervation to this tissue seems to be sparse. 6 Specificity of innervation and adrenoceptors present on smooth muscle cells in both the renal artery and vein are discussed, and the presynaptic regulation ofNA release is compared with findings in other vascular tissues.

Effect of noradrenaline and vanadate on sodium, potassium-activated ATPase of human brain cortical homogenate

Human brain cortical homogenate derived from surgical operations exhibited Na(+), K(+)-ATPase and K-p-nitrophenylphosphatase activity values of 2.12 +/- 0.08 ?mol P(i)/mg protein/15 min and 0.38 +/- 0.01 ?mol p-nitrophenol/mg protein/15 min, respectively which is in the range of those observed in rat brain cortical homogenates. Vanadate concentration dependently inhibited the activity of both enzymes. Noradrenaline, dopamine and isoprenaline reversed the inhibitory effect of vanadate in the presence of EDTA (0.2 mM). When Mg(2+) concentration was enhanced from 4 to 24 mM, the inhibitory effect of vanadate (1 ?M) was significantly potentiated. Evidence has been obtained that the effect of catecholamines is not a receptor mediated process; antagnoists such as phentolamine, phenoxybenzamine, propranolol, haloperidol failed to prevent the effect of adrenoceptor agonists. It is concluded that there is an interaction between vanadate and noradrenaline on human brain Na, K-ATPase.

HOMOGENEOUS AND NON‐HOMOGENEOUS DISTRIBUTION OF INHIBITORY AND EXCITATORY ADRENOCEPTORS IN THE LONGITUDINAL MUSCLE OF THE GUINEA‐PIG ILEUM

1 The effects of adrenoceptor agonists and antagonists on spontaneous and evoked membrane activities of longitudinal muscle cells from different parts of the guinea-pig ileum were observed, using microelectrode methods.2 Isoprenaline inhibited the generation of spikes in cells in the terminal (0-3 cm from the ileocaecal valve) and proximal (more than 50 cm from the ileocaecal valve) regions of the ileum, with no change on the membrane potential and ionic conductance of the membrane. These actions of isoprenaline were abolished by propranolol.3 Noradrenaline and phenylephrine depolarized the membrane and increased both the spike frequency and ionic conductance of cell membranes of the terminal ileum, whereas noradrenaline and clonidine hyperpolarized the membrane, increased the ionic conductance of the membrane and inhibited the spontaneously generated spikes from cells of the proximal ileum. The excitatory effect of phenylephrine in the cells of the proximal ileum and the inhibitory effect of clonidine on cells of the terminal ileum were less pronounced.4 The excitatory actions of noradrenaline or phenylephrine were antagonized by prazosin and phentolamine, but not by yohimbine, whereas the inhibitory actions of noradrenaline or clonidine were antagonized by yohimbine and phentolamine but not by prazosin.5 The cholinergic e.j.ps evoked by field stimulation to the tissue were not affected by isoprenaline or phenyleprine but were inhibited by noradrenaline and clonidine, in both the terminal and proximal regions of the ileum. These actions of noradrenaline and clonidine were antagonized by yohimbine but not by prazosin.6 The results indicate that in the myenteric plexus and longitudinal muscle tissues of the guinea-pig ileum there are prejunctional inhibitory (alpha(2)), postjunctional inhibitory (alpha(2) and beta) and postjunctional excitatory (alpha(1)) adrenoceptors. The homogeneous distributions of prejunctional alpha(2)- and postjunctional beta-adrenoceptors in the ileum are responsible for inhibitions of cholinergic excitatory junction potentials (e.j.ps) and spontaneous spike activities, respectively. The density of distribution of the postjunctional alpha(1)-adrenoceptors is higher in the terminal than in the proximal regions, and these distributions are reversed in the case of the postjunctional alpha(2)-adrenoceptors. The postjunctional alpha(1)-adrenoceptors are probably responsible for the membrane depolarization and alpha(2)-adrenoceptors for the hyperpolarization induced by catecholamines.