Calcium antagonists and sympathetic neuroeffector function.
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Neuroeffector mechanisms in the voiding cycle of the guinea-pig urinary bladder.
1. The effect of drugs expected to modify cholinergic (atropine, physostigmine) or GABA-ergic (GABA, picrotoxin, bicuculline methiodide, BMI) neurotransmission were investigated on the voiding cycle of the urinary bladder in urethane-anaesthetized guinea-pigs. 2. Transvesical saline infusion elicited a series of regular voiding cycles which were abolished by topical tetrodotoxin as well as by topical or intravenous (i.v.) hexamethonium, thus indicating their reflex neurogenic origin. 3. Either i.v. or topical atropine decreased amplitude and duration of micturition contraction, reduced efficiency of bladder voiding and, in about 30% of preparations, suppressed micturition (overflow incontinence). Either topical or i.v. physostigmine potentiated, in an atropine-sensitive manner, voiding efficiency. 4. GABA was administered during the ascending limb of the voiding cycle: i.v. GABA inhibited while topical GABA increased efficiency of the first voiding cycle. Both direction and intensity of the effect of GABA were dependent upon initial pressures. The second and following voiding cycles after GABA administration were inhibited transiently. 5. Either topical or i.v. picrotoxin or BMI potentiated the efficiency of the voiding cycle of the guinea-pig bladder. In these preparations either i.v. or topical GABA (administered during the ascending limb of the voiding cycle) produced only inhibitory effects on voiding efficiency. 6. These findings indicate that, in guinea-pigs, bladder voiding is largely dependent upon an intact cholinergic neurotransmission. Although amplitude of the initial voiding contraction is largely atropine-resistant, its duration and, consequently, degree of bladder voiding, are strongly influenced by blockade (atropine) or potentiation (physostigmine) of cholinergic neurotransmission. Endogenous GABA-ergic mechanism modulate, possibly at peripheral level, the voiding efficiency of the guinea-pig bladder. GABA exerts a complex neuromodulatory influence on voiding function, its overall effect being mainly influenced by resting parameters.
Animals↗
Relaxation of smooth muscle following contraction elicited by sympathetic nerve stimulation in vivo.
1. A method for studying in vivo the process of neuroeffector transmission in the nictitating membrane and nasal blood vessels of the cat is described. 2. Administration of desmethylimipramine or cocaine caused increases in both the amplitude and duration of the nasal and membrane responses which may be explained by inhibition of neuronal uptake of noradrenaline. 3. Phenoxybenzamine depressed the responses to nerve stimulation, but had little effect on the relationship between response amplitude and rate of recovery. 4. The relationship between response amplitude and rate of recovery is discussed and related to the sigmoid shape of a log concentration-response curve.
Animals↗
Effects of magnesium on contractile responses induced by electrical transmural stimulation and noradrenaline in rabbit thoracic aorta.
1 In rabbit isolated thoracic aortae, effects of magnesium ions on the contraction and (3)H-efflux in response to electrical transmural stimulation and on the contractile responses induced by noradrenaline and KCl were investigated.2 Addition of magnesium (1.2, 3.6, 12.0 and 24.0 mM) to the bathing solution inhibited the electrically induced contractions in a dose-related manner; the inhibition was complete with a concentration of 24.0 mM.3 The increase in (3)H-efflux induced by electrical transmural stimulation was inhibited by the addition of magnesium to the superfusing fluid, but a complete block was not obtained even in high concentrations of magnesium.4 Magnesium ions (1.2, 3.6, 12.0 and 24.0 mM) inhibited the contractile responses induced by low concentrations of noradrenaline (2 x 10(-8)M) and KCl (2 x 10(-2)M). However, the responses induced by higher concentrations of noradrenaline (5 x 10(-7) and 10(-5)M) and KCl (3 and 4 x 10(-2)M) were enhanced by low concentrations of magnesium.5 Magnesium ions affect both presynaptic and effector sites in rabbit thoracic aortae but in a different manner; magnesium manifests only an inhibitory effect on noradrenaline release from the adrenergic nerves, but dual effects on reactivity of vascular smooth muscle, depending on concentrations of magnesium and stimulants; it is suggested that the change in vascular reactivity is more important than the reduction in transmitter release when magnesium inhibits the response to nerve stimulation.
Animals↗
Effects of end-tidal concentrations of cyclopropane, halothane and diethyl ether on peripheral autonomic neuroeffector systems in the rat.
The effects of the inhalation anaesthetics, cyclopropane, halothane and diethyl ether were examined on peripheral neuroeffector systems in the pithed and in the conscious rat. 2 In the absence of a suitable means of accurately quantifying doses of inhalation anaesthetics given to small animals, an apparatus was constructed whereby end-tidal gas samples were collected semi-automatically from the mechanically ventilated rat. 3 Cyclopropane (15.3 and 29.3% end-tidal), halothane (0.20, 0.52 and 0.83% end-tidal) and diethyl ether (2% and 4% end-tidal) lowered the arterial pressure of the pithed rat. Heart rate was increased by diethyl ether 4%, decreased by halothane and unchanged by cyclopropane. 4 While each anaesthetic depressed the pressor responses to sympathetic nerve stimulation, cyclopropane increased and halothane and diethyl ether depressed the pressor responses to exogenous noradrenaline. 5 Each anaesthetic reduced the motor responses of the smooth muscle of the colon to parasympathetic stimulation. 6 The significance of the effects on peripheral neuroeffector systems is discussed in relation to the overall circulatory changes produced by these anaesthetics in the whole animal.
Animals↗
Effects of clonidine on canine cardiac neuroeffector structures controlling heart rate.
1 In intact dogs anaesthetized with pentobarbitone, clonidine (10 mug/kg, i.v.) produced a sustained decrease in heart rate. This effect was significantly smaller in vagotomized dogs in which the sympathetic drive to the heart was either left intact or experimentally created by continuous electrical stimulation of the decentralized cardioaccelerator nerve. In the latter preparation, the negative chronotropic action of clonidine was reversed by an intravenous injection of phentolamine, whereas in the former experimental situation it was antagonized only by an intravenous plus an intravertebral artery injection of phentolamine.2 In dogs with denervated hearts the tachycardia produced by electrical stimulation of the cardioaccelerator nerve was accompanied by a rise in noradrenaline overflowing into the coronary sinus plasma. Clonidine inhibited both these effects and phentolamine restored them to pre-clonidine levels.3 Clonidine decreased heart rate in dogs with an intact parasympathetically innervated heart and decentralized stellate ganglia. When the low basal heart rate of this preparation was elevated by electrical stimulation of the cardioaccelerator nerve, clonidine had a negative chronotropic effect, the degree of which was similar to that observed in intact dogs.4 Clonidine neither modified baseline heart rates of dogs with denervated hearts nor the levels of heart rate which in this preparation were reduced by a sustained electrical stimulation of the right vagus or increased by intravenous infusions of either isoprenaline or noradrenaline.5 These findings indicate that in the intact dog, bradycardia induced by clonidine resulted both from a reduction of sympathetic drive and from a concomitant increase in parasympathetic tone. The latter action did not occur at the level of cardiac neuroeffector structures since it was observed only in the presence of centrally connected vagal pathways. The inhibition of cardiac sympathetic tone was of both peripheral and central origin. Clonidine, in fact, diminished the quantity of noradrenaline overflowing into the coronary sinus plasma in cardiac denervated dogs with a tachycardia elicited by electrical stimulation of the decentralized cardioaccelerator nerve. This peripheral effect was probably due to an activation of alpha-adrenoceptors located on sympathetic nerve terminals since it was antagonized by phentolamine. However, in vagotomized dogs (intact sympathetic pathways) intravenous phentolamine failed to antagonize the heart rate effects of clonidine which were abolished by a subsequent injection of phentolamine into the vertebral artery. Thus, the clonidine-induced inhibition of both the peripheral and central sympathetic drive to the heart would appear to be mediated via alpha-adrenoceptors.
Animals↗
Spontaneous activity in the trachea of dogs treated with indomethacin: an experimental model for aspirin-related asthma.
1 Electrical and mechanical properties of smooth muscle cells or of neuro-effector transmission in the smooth muscle layer of the dog trachea, were studied after treatment with indomethacin, by means of the double sucrose gap, microelectrode or tension recording methods. 2 After several subcutaneous injections of indomethacin (1.0 mg/kg daily), 6 out of 12 dogs were coughing and wheezing. 3 Smooth muscle tissues dissected from the trachea of the coughing dog showed spontaneous electrical and mechanical activities at the frequency of 8-15 per min. These spontaneous electrical and mechanical activities were completely suppressed by treatment with atropine (10(-6) M), isoprenaline (5 X 10(-7) M) or prostaglandin E2 (10(-9) M) but not by tetrodotoxin (1.5 X 10(-6) M). 4 Direct muscle stimulation induced oscillatory potential changes followed by tension development in the trachea of the indomethacin-treated dog. 5 In the indomethacin-treated dog, mean membrane potential of the tracheal smooth muscle cells was -52.4 mV, and in the control trachea, the potential was -59.0 mV. 6 In the trachea from control dogs, the amplitude of test e.j.ps after conditioning e.j.ps was always smaller than the conditioning e.j.p., at any time interval between the two stimuli. In the trachea from indomethacin-treated dogs, facilitation phenomena were observed. 7 In the trachea from the indomethacin-treated dog, prostaglandin E1 (PGE1) or PGE2 (10(-10)-10(-9) M) markedly suppressed the amplitude of the e.j.p. but did not affect the facilitation phenomenon. 8 These results indicate that endogenous prostaglandins play important physiological roles in the feed-back inhibitory mechanisms for acetylcholine release from the nerve terminals during the resting and active states. 9 The results are also discussed in relation to the genesis of aspirin-induced asthma in man.
Animals↗
An examination of the pre- and postsynaptic alpha-adrenoceptors involved in neuroeffector transmission in rabbit aorta and portal vein.
1 The alpha-adrenoceptor agonists, clonidine and xylazine, reduced and the alpha-antagonists, yohimbine an rauwolscine, increased the stimulation-evoked tritium overflow from rabbit aorta and portal vein pre-incubated with [3H]-noradrenaline. 2 Based on an order of agonist potency of clonidine greater than xylazine greater than phenylephrine and antagonist potency of rauwolscine = yohimbine greater than prazosin, the presynaptic receptor mediating these effects is of the alpha 2 type. 3 In the aorta, stimulation-evoked contractions were abolished by prazosin (0.1 micrometers) and potentiated by rauwolscine and yohimbine in concentrations that increased the stimulation-evoked overflow tritium. 4 In the portal vein, prazosin was less potent in reducing, and rauwolscine and yohimbine failed to potentiate, the stimulation-evoked contraction. 5 In experiments in which tissues were pre-exposed to phenoxybenzamine (30 nM) to block some of the postsynaptic alpha-receptors, rauwolscine in concentrations that increased stimulation-evoked tritium overflow, reduced the evoked contraction in the portal vein but not in the aorta. 6 It is concluded that presynaptic alpha 2-autoreceptors are present in both tissues and that the postsynaptic alpha-receptors which mediate nerve stimulation-evoked contractions are alpha 1 in the aorta but a mixture of alpha 1 and alpha 2 in the portal vein.
Animals↗
The use of neurally released agonist in the measurement of antagonism at alpha-adrenoceptors.
Graded contractile responses of the rat vas deferens were obtained to trains containing varying numbers of pulses delivered transmurally at 500 Hz, allowing construction of pulse-response curves. In the presence of postjunctional adrenoceptor blocking drugs, these curves were displaced to the right in a parallel manner, allowing the estimation of pA2 values for the drugs. Activity of drugs at prejunctional adrenoceptors was estimated from the reduction of inhibition of the response to a second pulse delivered 3 s after trains containing different numbers of pulses. It is suggested that the technique is more physiological than others used to determine the antagonistic activity of drugs at adrenoceptors.
Adrenergic alpha-Antagonists↗
Post-natal development of functional neurotransmission in rat vas deferens.
Responses of the rat vas deferens to drugs and to field stimulation were examined in sexually immature rats. The vasa from immature rats often exhibited spontaneous contractions and displayed greater sensitivity to the contractile effects of alpha-adrenoceptor agonists. The responses of the vasa from immature rats to single pulse field stimulation lacked the adrenergic component of the response although the non-adrenergic component was present. The responses were antagonized by alpha 2-adrenoceptor agonists. In the presence of cocaine, an adrenergic component of the response did appear. During trains of pulses the pre- and postjunctional effects of adrenergic transmission which are found in adult rats were absent in vasa from immature rats. Electron microscopic studies showed no qualitative differences in adrenergic innervation in vasa from immature and adult rats. It is concluded that a state of 'pre-innervation supersensitivity' associated with a lack of functional adrenergic transmission exists in the vas deferens of immature rats. The supersensitivity disappears and functional transmission develops during the period in which testosterone secretion increases in the rat. The reason for the lack of functional transmission at a time when the innervation appears to be morphologically mature is not clear but may be due to the noradrenaline release mechanism not being fully operative.
Adrenergic alpha-Agonists↗
Evidence for neuro-effector transmission through postjunctional alpha 2-adrenoceptors in human saphenous vein.
The effects of the alpha 1-adrenoceptor antagonist prazosin and the alpha 2-adrenoceptor antagonist yohimbine were examined against stimulation-evoked contractions in human isolated saphenous veins. The concentration of yohimbine producing 30% inhibition of stimulation-evoked contractions (IC30) was 13.2 nM, whereas the IC30 of prazosin was greater than 250 nM. The inhibition of stimulation-evoked contractions by yohimbine was not prejunctionally mediated since yohimbine (0.01-0.1 microM) significantly potentiated the stimulation-evoked overflow of tritium in tissues pre-incubated with [3H]-noradrenaline. The high potency of yohimbine and the low potency of prazosin indicate that neuro-effector transmission in human saphenous vein is mediated predominantly by postjunctional alpha 2-adrenoceptors.
Adult↗
Electrophysiology of neuroeffector transmission in the isolated, innervated trachea of the guinea-pig.
Intracellular recordings were made from cells of the guinea-pig trachealis muscle. Some cells were electrically quiescent while others exhibited spontaneous slow waves. In quiescent cells, stimulation of the cervical vagus nerve evoked transient depolarization. Occasionally there was a single depolarization, but more often there were several fluctuations in potential. In spontaneously active cells, vagal stimulation induced a transient increase in amplitude of the slow waves without affecting their frequency. Depolarizing responses could be obtained with a single pulse applied to the vagus nerve, and responses increased in amplitude with number of pulses (up to 16 pulses), and with frequency of stimulation (up to 20 Hz). Depolarization did not give rise to spike discharge. Responses to vagal stimulation were blocked by atropine. In the presence of neostigmine, vagally-mediated depolarization was augmented and abortive spikes were observed in a number of cells. In quiescent cells, repetitive stimulation of the sympathetic stellate ganglion evoked slight hyperpolarization. In spontaneously active cells, sympathetic stimulation evoked attenuation, or temporary cessation of slow wave discharge, with or without hyperpolarization. Sympathetic-induced hyperpolarization and suppression of slow waves were both blocked by propranolol, but unaffected by phentolamine. Electrical changes associated with sympathetic stimulation may be of minor importance in the initiation of relaxation.
Animals↗
Effect of chlorpromazine on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta.
1. The effects of chlorpromazine on sympathetic neuroeffector transmission have been studied in the rabbit isolated pulmonary artery and aorta. 2. Chlorpromazine (10(-8)-10(-5) M), prazosin (10(-9)-10(-7) M) and phentolamine (3 x 10(-8)-3 x 10(-5) M) decreased the contractions of pulmonary artery evoked by electrical field stimulation (150 pulses; 3 Hz). The rank order of inhibitory potency (ID50) was prazosin greater than chlorpromazine greater than phentolamine. 3. Rauwolscine (3 x 10(-9) M-4 x 10(-6) M) enhanced the neurogenic response by up to 201%. However, higher concentrations (6 x 10(-6)-3 x 10(-5) M) reduced the contractions evoked by transmural stimulation. 4. The inhibitory effect of prazosin (10(-6) M) was reversible, while that of chlorpromazine (10(-8) M) was not. 5. Chlorpromazine (10(-8)-10(-4) M), desmethylimipramine (3 x 10(-9)-10(-5) M), cocaine (10(-7)-3 x 10(-4) M) and phentolamine (10(-5)-3 x 10(-4) M) reduced the accumulation of [3H]-noradrenaline ([3H]-NA, 10(-8) M) by aorta. The rank order of inhibitory potency (ID50) was: desmethylimipramine greater than chlorpromazine greater than cocaine greater than phentolamine. Prazosin (10(-7)-10(-5) M) and rauwolscine (10(-8)-10(-4) M) did not reduce [3H]-NA accumulation. 6. Chlorpromazine (10(-8)-10(-6) M) and prazosin (3 x 10(-9)-10(-7) M) antagonized the contractions of aorta evoked by exogenous noradrenaline (10(-9)-3 x 10(-4) M) and phenylephrine (10(-9)-3 x 10(-3) M). The pA2 values for chlorpromazine on the alpha 1-adrenoceptors were 8.24 (noradrenaline) and 8.27 (phenylephrine). The corresponding values for prazosin were 8.64 and 8.57, respectively. 7. It is concluded that chlorpromazine and prazosin are potent inhibitors of postsynaptic alpha 1-adrenoceptors. Chlorpromazine and phentolamine, unlike prazosin and rauwolscine, are also inhibitors of Uptake.
Adrenergic alpha-Antagonists↗
Neuroeffector actions of thromboxane B2 in dog isolated mesenteric arteries.
1. Thromboxane (TX) B2 and epithiomethano (sTXA2), in concentrations that were insufficient to alter the basal tone, potentiated contractile responses of helical strips of dog mesenteric arteries to transmural electrical stimulation. The potentiating effect of TXB2 (up to 10(-6) M) was not abolished by diphloretin phosphate (DPP), a prostaglandin antagonist, whereas the potentiation by sTXA2 was abolished by the antagonist. 2. sTXA2 and TXB2 (3 x 10(-6) M or higher) potentiated the responses to noradrenaline, the potentiation being antagonized by DPP. 3. 3H-overflow evoked by transmural stimulation in superfused arterial strips previously soaked in medium containing [3H]-noradrenaline was increased by TXB2, but not altered by sTXA2. 4. TXB2 in low concentrations potentiated the contractile response to adrenergic nerve stimulation, possibly by increasing the release of noradrenaline, while the potentiation by the TXA2 analogue appears to be due to increased sensitivity of the arteries to noradrenaline. Prejunctional effects of TXB2 may be mediated by receptor sites functionally different from those located postjunctionally.
Animals↗
Effects of omega-conotoxin GVIA on autonomic neuroeffector transmission in various tissues.
1. The effects of omega-conotoxin GVIA (conotoxin), a potent inhibitor of neuronal N-type Ca2+ channels, have been examined on responses to stimulation of noradrenergic, cholinergic and non-adrenergic, non-cholinergic (NANC) nerves in a range of isolated tissues to investigate the role of conotoxin-sensitive Ca2+ channels in neurotransmission. 2. Contractions elicited by field stimulation of noradrenergic nerves in rat and mouse anococcygeus muscles, rabbit ear artery and rat vas deferens (epididymal portion) were inhibited by conotoxin. Responses to noradrenaline, and to adenosine triphosphate in the vas deferens, were not affected. 3. Positive chronotropic responses to field stimulation of noradrenergic nerves were inhibited by conotoxin in rat and mouse atria, but responses to noradrenaline and tyramine were not affected. 4. The stimulation-induced release of noradrenaline was inhibited by conotoxin in the rabbit ear artery and in rat and mouse atria. 5. Relaxations in response to stimulation of the noradrenergic perivascular mesenteric nerves were reduced or abolished by conotoxin in rat and rabbit jejunum. The response to noradrenaline in rat jejunum was not affected. 6. Contractions elicited by stimulation of cholinergic nerves were inhibited by conotoxin in rat jejunum and mouse ileum (perivascular mesenteric nerves), and in guinea-pig taenia caeci (field stimulation). Responses to acetylcholine in rat jejunum and mouse ileum were not affected. 7. Contractions elicited by stimulation of the cholinergic plus NANC pelvic nerves were inhibited by conotoxin in rabbit colon, and to a lesser extent in guinea-pig colon. The stimulation-induced contraction of the guinea-pig colon was inhibited by conotoxin by a greater proportion in the presence than in the absence of atropine. Responses to acetylcholine were not affected in the rabbit colon but were slightly reduced in the guinea-pig colon. 8. Relaxations in response to field stimulation of NANC nerves were inhibited by conotoxin in guinea-pig taenia caeci and rat gastric fundus strips, and in rat anococcygeus muscle when the tone was raised by guanethidine but not when it was raised by carbachol. The relaxations produced by sodium nitroprusside in the rat gastric fundus and anococcygeus were not affected. 9. Contractions of the rat bladder elicited by stimulation of the peri-urethral nerves, which are NANC- and cholinergically mediated, were relatively insensitive to inhibition by conotoxin. The response were almost completely abolished by tetrodotoxin. 10. The conotoxin-induced inhibitions of responses to nerve stimulation developed slowly and persisted after removal of conotoxin. The responses were almost completely abolished by tetrodotoxin. 10. The conotoxin-induced inhibitions of responses to nerve stimulation developed slowly and persisted after removal of conotoxin. 11. The inhibitory effect of conotoxin was inversely proportional to the frequency of stimulation (in several preparations) and to the Ca2+ concentration in the bathing solution (in rat vas deferens). These observations suggest that the inhibition by conotoxin of the Ca2+ influx required for excitation-secretion coupling in autonomic nerve terminals is not absolute, and can be overcome by repeated stimulation or by raising the Ca2 + concentration.
Animals↗
Neuropeptide Y inhibits Ca2+ influx into cultured dorsal root ganglion neurones of the rat via a Y2 receptor.
1. The identity of the neuropeptide Y (NPY) receptor associated with the observed inhibition of neuronal Ca2+ currents (ICa) in rat dorsal root ganglion (DRG) cells has been established on the basis of agonist responses to analogues and carboxy terminal (C-terminal) fragments of the NPY molecule. 2. Whole cell barium currents (IBa) in DRG cells were reversibly inhibited by 100 nM NPY, 100 nM PYY and C-terminal fragments of NPY in a manner that correlated with the length of the NPY fragments (for inhibition of the IBa NPY = PYY greater than NPY2-36 greater than NPY13-36 greater than NPY16-36 greater than NPY18-36 much greater than NPY25-36). 3. C-terminal fragments of NPY were also effective in reversibly reducing the ICa, the associated increase in the intracellular Ca2+ concentration [( Ca2+]i) and the increased [Ca2+]i produced by evoked action potentials in the DRG cells. In addition, a Ca(2+)-activated Cl- conductance was also reversibly reduced by NPY fragments only when accompanied by a reduction in Ca2+ entry. 4. We conclude that the Y2 receptor for neuropeptide Y is coupled to inhibition of Ca2+ influx via voltage-sensitive calcium channels in DRG cells.
Action Potentials↗
Evidence for the involvement of different receptor subtypes in the pre- and postjunctional actions of angiotensin II at rat sympathetic neuroeffector sites.
1. The effects of the nonpeptide angiotensin II receptor (AT) antagonists losartan and PD 123319 on actions of angiotensin II in the rat caudal artery and rat vas deferens preparations were investigated. 2. Angiotensin II (1.0 microM) increased perfusion pressure in isolated segments of the rat caudal artery. This increase in perfusion pressure was prevented by the AT1-antagonist, losartan (0.1 microM) but was not affected by the AT2-antagonist, PD 123319 (0.1 microM). 3. Angiotensin II (0.1-3.0 microM) produced a concentration-dependent enhancement of the stimulation-induced (S-I) efflux of [3H]-noradrenaline from isolated segments of rat caudal artery in which the noradrenergic transmitter stores had been labelled with [3H]-noradrenaline. The maximum enhancement of S-I efflux was approximately 60% with 1.0 microM angiotensin II. 4. Losartan (0.01 and 0.1 microM) reduced the enhancement of S-I efflux produced by 1.0 microM angiotensin II in the caudal artery. 5. PD 123319 (0.01 microM) did not affect the enhancement of S-I efflux produced by angiotensin II (1.0 microM) in the caudal artery. However, in a higher concentration (0.1 microM), PD 123319 reduced the enhancement of S-I efflux produced by 1.0 microM angiotensin II. 6. Angiotensin II produced concentration-dependent enhancement of the purinergic twitch responses (1 pulse/60 s) in the rat vas deferens. 7. Losartan (0.03 microM) and PD 123319 (0.03 microM) each reduced the angiotensin II-induced enhancement of the twitch responses in the rat vas deferens. 8. These findings indicate that the enhancement of sympathetic neuroeffector transmission in both the caudal artery and vas deferens of the rat involves angiotensin receptor subtype(s) sensitive to both losartan and PD 123319. In contrast, the direct vasoconstrictor effect of angiotensin II in the rat caudal artery involves activation of a receptor subtype sensitive only to losartan.
Angiotensin II↗
The ontogenetic profiles of the pre- and postjunctional adenosine receptors in the rat vas deferens.
1. The ontogenetic profiles of the prejunctional A1 and postjunctional A1 and A2 receptors on the rat vas deferens were investigated, using a combination of functional and radioligand binding assays to follow the A1 receptors and functional assays alone to follow the development of the A2 receptors. 2. The prejunctional A1 receptor, assessed by the inhibitory action of N6-cyclopentyladenosine (CPA) (3 nM-3 microM) on nerve-mediated contractions, was present from day 15 onwards, day 15 being the earliest age at which nerve-mediated contractions could be detected. The potency of CPA was constant across the ages studied, with pD2 values ranging from 6.4-7.1, not significantly different from that previously observed in adult rat vas deferens. 3. The postjunctional A2 receptors, assessed by the inhibitory action of 5'-N-ethylcarboxamidoadenosine (NECA) (10 nM-30 microM) on KCl-induced contractions were present from day 10 onwards, day 10 being the earliest age at which responses to KCl could be observed. The potency of NECA remained constant with an increase in age, with potency values, expressed as pEC25 values, ranging from 6.5-7.0. 4. The postjunctional A1 receptor displayed a different development profile from that of the prejunctional A1 and postjunctional A2 receptors. Postjunctional A1 receptors were identified by the enhancement of KCl-induced contractions by CPA (10 nM-0.3 microM). At 10 and 15 days, CPA failed to enhance KCl-induced contractions. From day 20 to day 40, this enhancement increased with an increase in age and the level of enhancement achieved statistical significance from day 30. 5. Radioligand binding studies using 1,3-[3H]-dipropyl-8-cyclopentylxanthine ([3H]-DPCPX) revealed binding sites characteristic of A1 receptors on the vas deferens from rats aged 20 days onwards. The density (Bmax) of A1 receptors expressed relative to protein content was greatest at day 20 (153 +/- 33 fmol mg-1 protein) and declined at day 30 (43.9 +/- 3.7 fmol mg-1 protein) to a level commensurate with that previously determined in adult rat vas deferens (43.3 +/- 12 fmol mg-1 protein). However, when expressed relative to tissue wet weight little variation in receptor density was observed between these ages (Bmax 0.13 +/- 0.02 fmol mg-1 wet weight at 20 days; 0.17 +/- 0.01 fmol mg-1 wet weight at 30 days). The binding affinity (KD) remained constant with an increase in age and was similar to the KD value previously generated for adult rat vas deferens (approximately 1 nM). At ages 10 and 15 days no reproducible binding could be detected. 6. These results show the differential development of the adenosine receptors on the rat vas deferens with postjunctional A1 receptors demonstrating delayed development, while prejunctional A1 and postjunctional A2 receptors were present from the earliest ages studied. In addition, comparison of binding studies and functional studies suggests that the binding studies detect only the A1 receptors present on the smooth muscle and not those present on the nerve terminals.
Adenosine↗