Stimulation-induced Responses Research Articles

Pelvic nerve stimulation-induced pressor responses in corpus cavernosum of anesthetized dogs.

To analyze the mechanism of penile erection and pathogenesis of impotence, pressures in the corpus cavernosum in anesthetized dogs were measured. Pelvic nerve stimulation produced pressor responses in a frequency-dependent manner. Intravenous injections of NG-nitro-L-arginine, a nitric oxide (NO) synthase inhibitor, dose dependently attenuated the response, and the inhibition was reversed by intravenous injection of L-arginine but not of D-arginine. The response was also inhibited by NG-nitro-L-arginine injected into the corpus cavernosum, the potency being approximately 10 times of that applied intravenously. The intracavernous injection of L-arginine restored the response. NG, NG-dimethylarginine, an endogenous NO synthase inhibitor, dose dependently attenuated the stimulation-induced response, which was restored by an intracavernous injection of L-arginine. An intravenous injection of hexamethonium abolished the pressor response to nerve stimulation, whereas phentolamine and atropine did not significantly alter the response. These findings suggest that an increase in intracavernous pressure caused by pelvic nerve stimulation in anesthetized dogs is mediated by NO liberated from postganglionic neurons that originate in the ganglion located in the vicinity of corpus cavernosum.

Potentiation by vasopressin of adrenergic vasoconstriction in the rat isolated mesenteric artery.

1. The aim of the present study was to investigate in rat mesenteric artery rings whether low concentrations of vasopressin could modify the contractile responses to noradrenaline and electrical stimulation of perivascular nerves. 2. Vasopressin (10[10]-10[-7] M) caused concentration-dependent contractions (pD2 = 8.36+/-0.09). The V1-receptor antagonist d(CH2)5Tyr(Me)AVP (10[-9]-10[-8] M) produced parallel rightward shifts of the control curve for vasopressin. Schild analysis yielded a pA2 value of 9.83 with a slope of 1.10+/-0.14. 3. Vasopressin (3 x 10[-10] and 10[-9] M) caused concentration-dependent potentiation of the contractions elicited by electrical stimulation (2-8 Hz; 0.2 ms duration for 30 s) and produced leftward shifts of the concentration-response curve for noradrenaline. The V1-receptor antagonist induced concentration-dependent inhibitions of potentiation induced by vasopressin. The selective V1-receptor agonist [Phe2, Orn8]-vasotocin (3 x 10[10] and 10[-9] M) induced potentiation of electrical stimulation-evoked responses which was also inhibited in the presence of the V1 antagonist (10[-8] M). In contrast, the V2-receptor agonist deamino-8-D-arginine vasopressin (desmopressin 10[-8]-10[-7] M) did not modify the electrical stimulation-induced responses and the V2-receptor antagonist [d(CH2)5, D-Ile2, Ile4, Arg8]-vasopressin (10[-8]-10[-7] M) did not affect the potentiation evoked by vasopressin. 4. In artery rings contracted by 10(-6) M noradrenaline in the presence of 10(-6) M guanethidine and 10(-6) M atropine, electrical stimulation (2, 4 and 8 Hz) produced frequency-dependent relaxations which were unaffected by 10(-9) M vasopressin but abolished by 10(-6) M tetrodotoxin. 5. Vasopressin also potentiated contractions elicited by KCl and contractions induced by addition of CaCl2 to KCl depolarized vessels. The augmenting effects were inhibited by the V1 antagonist. 6. In the presence of the calcium antagonist nifedipine (10[-6] M), vasopressin failed to enhance the contractile responses to electrical stimulation, noradrenaline and KCl. 7. The results demonstrate that low concentrations of vasopressin strongly potentiate the contractions to adrenergic stimulation and KCl depolarization. This effect appears to be mediated by V1 receptor stimulation which brings about an increase in calcium entry through dihydropyridine-sensitive calcium channels.

Study of paired-pulse inhibition of transcallosal response in the pyramidal tract neuron in vivo

The effects of a specific GABA B receptor antagonist, p-(3-aminopropyl)- p-diethoxymethyl-phosphonic acid (CGP 35348), on pyramidal tract neuron responses to transcallosal stimulation were investigated in the cat motor cortex in vivo. The paired-pulse method was used to obtain more insight into the role of GABA B receptors. At a 200-ms inter-stimulus interval the spike response was inhibited in 75% of the neurons. There was an approximately 40% depression of the mean spike value in the control. CGP 35348 reduced paired-pulse inhibition, while (−)-baclofen increased it. Stronger drug effects on the second stimulation-induced response possibly indicate their presynaptic action on GABA B receptors.

Glutamatergic and GABAergic postsynaptic responses of striatal spiny neurons to intrastriatal and cortical stimulation recorded in slice preparations.

Glutamatergic and GABAergic responses of the neostriatal spiny neurons to intrastriatal and cortical stimulation were characterized by intracellular recording in brain slice preparations. This study also demonstrated the role of each response in the spike activity of the spiny neuron. Single neostriatal stimulation induced postsynaptic potentials consisting of multiple components. The early part of the postsynaptic potential, which was isolated by the GABAA antagonist bicuculline methiodide and the N-methyl-D-aspartate antagonist 3-(2-carboxypiperzin-4-yl)-propyl-1-phosphonic acid (CPP), was mainly an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor-mediated response. Perfusion of magnesium-free medium containing bicuculline methiodide and the AMPA/kainate antagonist 3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline (NBQX) disclosed a large, slow N-methyl-D-aspartate receptor-mediated response. The N-methyl-D-aspartate response in magnesium-containing perfusing medium was small in neurons at the resting membrane potential, but became a significant component when the neurons were depolarized to subthreshold membrane potential. The duration of the N-methyl-D-aspartate response was over 300 ms. The nicotinic antagonists dihydro-beta-erythroidine hydrobromide and mecamylamine failed to change responses to single stimulation. Repetitive intrastriatal stimulation induced a large, long-duration depolarization with action potentials in the spiny neurons. This stimulation-induced response resembles that of the depolarization stage observed in anesthetized animals. Bicuculline methiodide increased the response amplitude. In contrast, CPP reduced the amplitude of the response to the below the spike generation threshold. The CPP-sensitive N-methyl-D-aspartate response was large and lasted several hundred milliseconds after the termination of repetitive stimulation. Responses of the neostriatal neurons to cortical stimulation were similar to those induced after intrastriatal stimulation. CPP greatly reduced both the response amplitude and the number of spikes triggered from the response. Bicuculline methiodide, on the other hand, greatly increased the response amplitude and the number of spikes. The AMPA/kainate response alone, which was isolated by application of bicuculline methiodide and CPP, did not induce sustained depolarization in spiny neurons to repetitive cortical stimulation. Application of NBQX diminished GABAA response to cortical stimulation. This observation indicates that, for neostriatal spiny neurons to respond with GABAA response after cortical stimulation, the AMPA/kainate response must be induced in the GABAergic secondary neurons in the neostriatum. This study indicates that the main synaptic driving forces of neostriatal spiny neurons include AMPA/kainate, N-methyl-D-aspartate and GABAA responses. Although AMPA/kainate response is the main synaptic input, the generation of the action potentials in neostriatal neurons is greatly influenced by both GABAA and N-methyl-D-aspartate responses.

Role of nitric oxide and neuropeptides in neurogenic vasodilatation of the guinea pig mesenteric artery

Although dense networks of adrenergic nerves are present and noradrenaline causes vasoconstriction, electrical field stimulation failed to elicit any constriction of the isolated ring preparation of the guinea pig mesenteric artery. In the presence of an active tone, a vasodilator response was elicited by electrical field stimulation in endothelium-removed tissues. Nonadrenergic, noncholinergic nerves mediate the electrical field stimulation-induced vasodilator response, since guanethidine and atropine did not affect while tetrodotoxin abolished it. Multiple mediators seem to participate in this vasodilatation. NADPH-diaphorase-positive nerves, calcitonin gene-related peptide (CGRP)- and vasoactive intestinal peptide (VIP)-immunoreactive nerves were present in the mesenteric artery. Nitro- l-arginine but not nitro- d-arginine suppressed the electrical field stimulation-induced vasodilator response with rapid onset and l-arginine restored it. VIP and CGRP relaxed the tissue in a dose-dependent manner. Pretreatment of the animals with capsaicin partly reduced the electrical field stimulation-induced vasodilator response. CGRP-(8-37), a CGRP antagonist, slightly attenuated the vasodilator response induced by both electrical field stimulation and CGRP. Glibenclamide, an inhibitor of ATP-sensitive K + channels, decreased the nitro- l-arginine- and capsaicin-insensitive component of the electrical field stimulation-induced vasodilator response. Zinc protoporphyrin IX, an inhibitor of CO formation, did not affect the electrical field stimulation-induced response. In the presence of nitro- l-arginine without an active tone, electrical field stimulation induced a vasoconstrictor response that was sensitive to bunazosin and guanethidine. The results show that the electrical field stimulation-induced vasodilator response of the mesenteric artery of guinea pigs is mediated by nitric oxide (NO), CGRP and some yet unidentified substance(s). Elimination of the vasodilator response unmasked the adrenergic vasoconstrictor response to electrical field stimulation.

Acute and Chronic Effects of Losartan (Dup 753) on Blood Pressure and Vascular Reactivity in Normotensive Rats

The effects of in vivo treatment with the nonpeptide subtype 1 angiotensin II receptor antagonist, losartan, on blood pressure and vascular reactivity in normotensive male Sprague-Dawley rats were studied. Initial acute experiments demonstrated that blood pressure was significantly decreased six hours following a single injection of losartan (10 mg/kg, sc), but returned to control levels by 24 hours post-injection. Pressor responses to angiotensin II (0.1 ug/kg, iv) in these rats were significantly attenuated 2 and 24 hours following losartan injection. For chronic studies, rats were injected once daily for 21 days with either the same dose of losartan or saline vehicle. Blood pressure and pressor responses to angiotensin II were assessed at the end of the 21 day treatment period. A significant decrease in blood pressure was observed in chronic losartan treated rats 6 hours after the last injection on day 21; however, as in the acute studies, blood pressure had returned to control values by 24 hours post-injection. Although blood pressure had returned to normal, pressor responses to angiotensin II were significantly attenuated in chronic losartan treated rats 24 hours after the last injection. Following the in vivo studies, aortae and tail arteries were removed for experiments on vascular reactivity. Acute and chronic losartan treatment had no effect on KCl and norepinephrine reactivity. Endothelial-dependent and independent relaxation responses were also unaltered. A significant decrease in the maximal contractile response to angiotensin II was observed in aorta from acute and chronic losartan treated rats. Electrical stimulation-induced responses were unaltered in tail arteries from rats acutely treated with losartan but were potentiated in rats chronically treated with losartan. Exogenously applied angiotensin II, in concentrations which did not elicit contractile responses, potentiated electrical stimulation-induced responses of tail arteries from control rats but did not influence responses in arteries from acute and chronic losartan treated rats. These results demonstrate that losartan has significant blood pressure lowering effects in normotensive rats. Interestingly, although blood pressure returns to normal by 24 hours post-injection, pressor responses to angiotensin II remain attenuated in acute and chronic losartan treated rats. Finally, losartan treatment results in specific alterations in vascular reactivity associated with the actions of angiotensin II.

Effect of neuropeptide Y on adrenergic and non-adrenergic, non-cholinergic responses in the rat anococcygeus muscle.

1. The effects of neuropeptide Y (NPY) were examined on adrenergic and non-adrenergic, non-cholinergic (NANC) neurotransmission in the rat anococcygeus muscle. 2. NPY (0.1-0.3 microM) greatly potentiated the contractile responses induced by field stimulation. Prazosin (0.1 microM) completely abolished the stimulation-induced responses either in the absence or presence of NPY. 3. NPY (0.1-0.3 microM) enhanced only the contractile responses to low doses of noradrenaline (NA, 0.003-0.01 microM). Responses to tyramine were unaffected by the same concentrations of NPY. 4. In superfused anococcygeus, previously loaded with [3H]-NA, NPY (0.1-0.3 microM) failed to modify the basal, as well as the stimulation-evoked, release of tritium at 2 and 4 Hz. 5. NANC relaxations induced by electrical stimulation were significantly reduced, in a concentration-related manner, by 0.1-0.3 microM NPY. 6. L-NG-nitro-arginine (L-NOARG, 30 microM) enhanced the stimulation (0.25-1 Hz)-induced motor responses. In the presence of L-NOARG (30 microM), NPY (0.1 microM) did not modify the motor responses induced by field stimulation (0.25-0.5 Hz). L-Arginine did not reverse the NPY-induced potentiation of stimulation-induced motor responses. 7. The relaxations of anococcygeus muscle induced by sodium nitroprusside (SNP, 0.01-0.3 microM) were diminished by NPY (0.1-0.3 microM). 8. Our study suggests that NPY, at concentrations devoid of contractile effect, potentiates the motor responses of rat anococcygeus muscle as a consequence, at least in part, of the inhibition of NANC relaxing responses by a different mechanism from L-NOARG.

Autonomic mechanisms underlying area postrema stimulation-induced cardiovascular responses in rats

Experiments were designed to examine the autonomic mechanisms underlying the decreases in blood pressure and heart rate elicited by electrical stimulation in the rat area postrema (AP). Vagotomy was found to significantly reduce the bradycardia observed in response to AP stimulation (control -123.5 +/- 23.5 beats/min; vagotomized -7 +/- 5.4 beats/min; P less than 0.001) but was without significant effect on blood pressure responses. Hexamethonium significantly reduced both heart rate (control -225.5 +/- 11.9 beats/min; hexamethonium -5.5 +/- 2.8 beats/min; P less than 0.001) and depressor (control -35.4 +/- 4.7 mmHg; hexamethonium -6.4 +/- 0.8 mmHg; P less than 0.001) responses to such stimulation, whereas combined alpha- and beta-adrenergic blockade was without effect. The muscarinic blocking agent atropine also abolished both blood pressure (control -22.0 +/- 4.3 mmHg; atropine 2.8 +/- 4.4 mmHg; P less than 0.01) and heart rate (control -187.0 +/- 41.9 beats/min; atropine 8.8 +/- 2.6 beats/min; P less than 0.01) responses to AP stimulation. These data suggest that AP stimulation influences two separate neural pathways eliciting distinct cardiovascular responses. It would appear that activation of one of these pathways results in activation of vagal efferents to the heart and thus bradycardia. A second parallel pathway influenced by AP stimulation apparently elicits depressor response through actions on cholinergic muscarinic receptors.

Multifactorial Analysis of Epidural Spinal Cord Stimulation

In order to provide a data bank to allow a more precise and effective implementation of spinal cord stimulation, a computerized analysis of 1,375 combinations obtained from electrode arrays located in the thoracic and cervical epidural area was performed. 67 electrode arrays implanted in 34 subjects were subjected to analysis. During the stimulation trial, all the available combinations were systematically tested and the results entered into a computerized database. The study was not meant to analyze the clinical results or the indications of epidural spinal cord stimulation. Parameters studied include position of each electrical contact as related to midline, vertebral level of each contact, distribution of stimulation-induced paresthesiae, and electrical parameters (voltage, rate, pulse width, perception threshold, discomfort threshold, usage range). Analysis of the data allow the surgeon (1) to define the characteristics of the stimulation-induced paresthesiae; (2) to define the spectrum of the electrical parameters used to stimulate the spinal cord; (3) to define the population of implanted electrode arrays/contacts; (4) to study objectively how the position of the electrodes within the spinal canal, their vertebral level and the interelectrode distance affect the electrical parameters and the stimulation-induced responses. The multifactorial systematic analysis of such a large number of combinations provides the basis for further developments in the area of electrical stimulation of the nervous system.

Endothelin-1 enhances responses to sympathetic nerve stimulation in endothelium-denuded and endothelium-intact rabbit ear arteries

In the rabbit isolated and endothelium-denuded ear artery, endothelin-1 (1-10 nM) elicited concentration-dependent vasoconstrictor responses. Lower concentrations of endothelin-1 (0.1, 0.3 and 1 nM) with little or no direct vasoconstrictor action significantly enhanced responses to sympathetic nerve stimulation in both endothelium-denuded and endothelium-intact arteries. The vasoconstrictor action of endothelin-1 and its enhancing effect on stimulation-induced responses were significantly decreased by the presence of the dihydropyridine-type calcium channel antagonist nicardipine (10 nM). The enhancing effect of low concentrations of endothelin-1 on responses to sympathetic nerve stimulation may play a role in the regulation of vascular tone.

The Role of Protein Kinase C and Calcium in the Regulation of Norepinephrine Release From the Vascular Adrenergic Neurons in Hypertension

This study was designed to investigate the role of protein kinase C and calcium in vascular adrenergic transmission in hypertension. In perfused mesenteric vasculatures of spontaneously hypertensive rats (SHR, 7 to 10 weeks old) and age-matched Wistar-Kyoto rats (WKY), we have examined the effects of the protein kinase C inhibitor H-7 on endogenous norepinephrine release and vascular responsiveness during nerve stimulation. Endogenous norepinephrine release and pressor responses during periarterial nerve stimulation were significantly greater in SHR than in WKY. The protein kinase C inhibitor H-7 inhibited the stimulation-induced norepinephrine release and pressor responses in a dose-dependent manner. The magnitude of these suppressive responses were more pronounced in SHR than in WKY. Calcium removal from extracellular fluid also reduced the norepinephrine release more strongly in SHR than in WKY. These results demonstrate that the regulation of norepinephrine release might be more dependent on protein kinase C and calcium in the blood vessels of SHR, which could contribute, at least partially, to the pathogenesis of this form of hypertension.

Effect of Enflurane on Contractile Reactivity in Isolated Canine Mesenteric Arteries and Veins

The effects of enflurane on responses of isolated canine mesenteric arteries and veins to transmural nerve stimulation and to exogenously administered norepinephrine (a mixed alpha 1- and alpha 2-adrenoceptor agonist), phenylephrine (a selective alpha 1-adrenoceptor agonist), and tyramine were studied. The contractile responses of the arteries and the veins to transmural nerve stimulation and to norepinephrine were attenuated by exposure to enflurane; the responses to phenylephrine were decreased more than those to norepinephrine. When compared with the effect of enflurane on transmural nerve stimulation-induced responses, exposure to enflurane resulted in slight attenuation of the contractile responses caused by tyramine, suggesting that enflurane may inhibit the responses to tyramine by interfering with an interaction between released norepinephrine and postjunctional alpha 1-adrenoceptors rather than with tyramine-induced norepinephrine release. The data are also consistent with the view that enflurane acts on sympathetic nerve endings to inhibit release of norepinephrine associated with electrical stimulation-induced nerve membrane depolarization.

Hydrogen peroxide-induced potentiation of contractile responses in isolated rat airways

We hypothesized that metabolites of O2 may play a role in the development of airway hyperreactivity and undertook this study to examine the effects of one of these metabolites, hydrogen peroxide (H2O2), on electrical field stimulation-induced contractile responses of isolated rat intrapulmonary bronchi. Exposure to H2O2 (1 mM) elicited a transient contractile response with a peak response equivalent to 18.1 +/- 2.0% of the reference contraction obtained to electrical stimulation. The H2O2-induced contraction was attenuated by pretreatment of tissues with indomethacin and superoxide dismutase, but abolished by catalase and mianserin. Subsequent to H2O2 exposure, electrical field stimulation-induced contractile responses were potentiated (P less than 0.0001), whereas acetylcholine-induced contractions were not. The potentiating effects of H2O2 were inhibited by catalase and mianserin. Addition of 5-hydroxytryptamine (5-HT) to the bath similarly potentiated contractions to electrical stimulation (P less than 0.0001). Together, these results are consistent with a role for 5-HT in H2O2-induced contraction and the subsequent potentiation of airway smooth muscle contraction elicited by cholinergic nerve activation. Thus endogenous metabolites of O2 may be important in modulating airway smooth muscle tone.

Adrenomedullary pressor responses to stimulation of the rostral hypothalamus in the rat: influence of adrenaline-induced vasodilation and reflex cardioinhibition.

Electrical stimulation (100 Hz, 1 ms, 150 microA, 10 s) of the anterior hypothalamus in chloralose-anesthetized rats evoked a biphasic pressor response consisting of an initial sharp rise in arterial pressure at the onset of stimulation, followed by a second elevation after cessation of the stimulus. This response was accompanied by an increase in plasma noradrenaline and adrenaline levels. Peripheral sympathectomy with guanethidine selectively abolished the primary phase of the biphasic pressor response, while bilateral removal of the adrenal medulla eliminated only the secondary component. After alpha-adrenergic blockade with phentolamine, the primary phase of the stimulation-induced response was reduced while the secondary pressor component was blocked and replaced by a significant hypotension. The intravenous administration of sotalol enhanced the secondary pressor component without affecting the stimulation-induced plasma noradrenaline and adrenaline responses. After treatment with atropine, the secondary pressor effect was also potentiated, as the reflex bradycardia normally associated with the response was eliminated. A subsequent administration of sotalol in these rats further potentiated the secondary pressor component to stimulation. In rats treated with atropine and sotalol, the sympathetic vasomotor and the adrenomedullary pressor responses could be dissociated according to thresholds and stimulus frequency or current-response characteristics. The results suggest that in intact rats, adrenaline-induced vasodilation and reflex cardiac inhibition contribute to either reduce or mask the adrenomedullary component of the biphasic pressor response evoked by stimulation of the anterior hypothalamus. The study also raises the hypothesis of a dual regulation of both components of the sympathetic system in the anterior hypothalamic region.

A note on responses of isolated guinea-pig tracheal strip preparation to electrical stimulation.

Authors observed the mechanical response of the tracheal muscle to electrical stimulation using only one transverse strip preparation of isolated guinea-pig trachea, 4-5 mm in width, which included only one tracheal muscle strip. The effects of various pharmacological agents on these responses were also investigated. A biphasic response which is a contractile response followed by a relaxing response usually appeared when the preparation was stimulated with rectangular pulses (50 volt, 0.5 msec) at 40 Hz for a period of 5 sec. A monophasic contractile response also appeared, only rarely but this response was shifted to the biphasic response as the resting tonus level of the preparation gradually increased in the course of the experiment. When the preparation was stimulated electrically at intervals of 15 min, the resting tonus level of the preparation gradually decreased and it subsequently reached a stable state. Then the amplitude of contractile response and depth of relaxing response in the biphasic response evoked by electrical stimulation of constant condition were, respectively, almost constant, whenever the preparation was stimulated at intervals of 15 min. The amplitude of monophasic contractile response which appeared only rarely was relatively constant to every trial of electrical stimulation throughout the experiment. The amplitude of contractile response and depth of relaxing response in the biphasic response were 283 +/- 65 mg (mean +/- SD, n = 10) and 293 +/- 93 mg (mean +/- SD, n = 10), respectively. The monophasic contractile response was abolished by atropine (5 X 10(-7) g/ml) or tetrodotoxin (2 X 10(-7) g/ml). The contractile response in the biphasic response was abolished by atropine (5 X 10(-7) g/ml). In the presence of atropine (5 X 10(-7) g/ml), therefore, only the relaxing response appeared. This relaxing response was respectively reduced by guanethidine (1 X 10(-5) g/ml-1 X 10(-6) g/ml) and propranolol (1 X 10(-5) g/ml-1 X 10(-6) g/ml), but complete inhibition was never seen. These findings suggest that the excitatory innervation is cholinergic and the inhibitory innervation is both adrenergic and non-adrenergic. In addition, from the results of this work it is clear that the preparation used by the authors are good enough to observe the electrical stimulation-induced response of the preparation.

Effects of bromocriptine on catecholamine receptors mediating cardiovascular responses in the pithed rat.

The interaction of bromocriptine with several catecholamine receptors that control the sympathetic responses at cardiac and vascular level has been studied in pithed adrenalectomized and vagotomized normotensive rats. Bromocriptine (30 and 100 micrograms/kg) inhibited the stimulation-induced pressor responses in the pithed rat without modifying the pressor responses induced by noradrenaline. Sulpiride (0.3 mg/kg) abolished the effects of bromocriptine (30 micrograms/kg) but only partially prevented the effects of bromocriptine (100 micrograms/kg) on the stimulation-induced pressor responses. Yohimbine (0.3 mg/kg) partially antagonised the inhibitory effect of bromocriptine on stimulation-induced pressor responses. Combination of yohimbine and sulpiride abolished attenuation of the stimulation-induced pressor responses by bromocriptine (100 micrograms/kg). Bromocriptine (0.3 and 1 mg/kg) shifted to the right the frequency-response curve of increases in heart rate. This effect was prevented by yohimbine (0.3 mg/kg) but not by sulpiride (0.3 mg/kg). The same doses of bromocriptine were ineffective on heart rate increases induced by noradrenaline. Bromocriptine (0.3 and 1 mg/kg) shifted to the right the increases in diastolic blood pressure induced by methoxamine without modifying those induced by xylazine and noradrenaline. These results suggest that bromocriptine acts on the peripheral sympathetic nervous system of the pithed rat as an agonist of presynaptic dopamine receptors and alpha 2-adrenoreceptors and as an antagonist of postsynaptic alpha 1-adrenoreceptors.

Facilitation by beta-adrenoreceptors of stimulation-induced vasoconstriction in pithed spontaneously hypertensive rats.

In pithed bilateral adrenal demedullated spontaneously hypertensive rats, slow i.v. infusion of adrenaline (500 ng/min) significantly increased pressor responses to the electrical stimulation of the entire sympathetic outflow, but had little effect on pressor responses induced by bolus injections of noradrenaline. After pretreatment with timolol (1 mg/kg, i.v., 30 min) adrenaline infusion enhanced noradrenaline-induced pressor effects, but not stimulation-induced responses. Salbutamol (50-500 ng/min, i.v.) and procaterol (2.5 ng/min, i.v.) infusions significantly potentiated stimulation-induced pressor effects without affecting noradrenaline-induced responses. Higher rates of salbutamol (5 micrograms/min, i.v.) and procaterol (25 ng/min, i.v.) infusion significantly depressed noradrenaline-induced pressor effects and attenuated those induced by sympathetic nerve stimulation. It is concluded that the potentiation of stimulation-induced pressor responses by adrenaline salbutamol and procaterol, involves a beta-adrenoreceptor mediated facilitation of sympathetic neurotransmission.

Effect of desipramine on the effects of alpha-adrenoceptor inhibitors on pressor responses and release of norepinephrine into plasma of pithed rats.

The role of neuronal uptake inhibition on the efficiency of alpha 1- and alpha 2-antagonists in inhibiting pressor responses and the release of plasma catecholamines in pithed rats were studied. Prazosin, in doses which selectively blocked alpha 1-adrenoceptors (0.01-0.1 mg/kg), was more effective than yohimbine, a relatively selective alpha 2-antagonist, in inhibiting stimulation-induced pressor responses. Yohimbine (0.1-1 mg/kg) potentiated or did not alter the pressor responses to stimulation, whereas it blocked pressor responses to administered norepinephrine (NE) more effectively than did prazosin. Inhibition of uptake by desipramine (DMI), 0.3 mg/kg, did not affect prazosin inhibition of stimulation-induced pressor responses though it increased NE overflow into circulation. In yohimbine-treated rats, DMI potentiated significantly (p less than 0.001) both pressor and NE responses to stimulation. DMI partially reversed prazosin inhibition of pressor response to administered NE (p less than 0.001) and potentiated the response in yohimbine-treated rats (p less than 0.01). The results are consistent with the view that endogenously released NE acts at intrajunctional alpha 1-adrenoceptors, whereas exogenous NE acts predominantly at extrajunctional alpha 2-adrenoceptors. The neuronal uptake site appears to be functionally (and perhaps anatomically) located outside the synaptic cleft, between intrajunctional alpha 1-postsynaptic receptors and extrajunctional alpha 2-adrenoceptors.

Field stimulation-induced responses of circular smooth muscle from guinea-pig stomach. Characterisation of the receptor mechanisms involved.

Field stimulation of circular smooth muscle of guinea-pig stomach from the regions of the cardia and fundus caused contraction responses at low stimulation frequencies (0.25–1 Hz) with relaxation at higher frequencies (1–10 Hz), whilst tissues of the body and antrum responded with contraction throughout the frequency range. Atropine (10−9–10−8 M) antagonised the contraction responses of all tissues, with relaxation developing at higher concentrations (except for antral tissue). In contrast, metoclopramide (10−8–10−6 M) caused modest (cardia, fundus) or marked (body, antrum) enhancement of contractions to field stimulation, whilst domperidone (10−8–10−7 M), haloperidol (10−8–10−6 M), prazosin, propranolol and methysergide (10−8–10−6 M) failed to modify the contraction responses. However, whilst yohimbine and guanethidine failed to modify the contractions of the cardia, fundus and body tissues, those of the antral preparations were antagonised by nanomolar concentrations of yohimbine and by guanethidine (10−6–5×10−5 M). To optimise the relaxation responses for study, atropine was included in the physiological solution. Relaxation to field stimulation of preparations from the body and cardia, but not the fundus, was antagonised by reserpine pretreatment (5 mg/kg i.p., 24h), addition of guanethidine (10−5–10−4 M), phentolamine, prazosin or propranolol (10−7–10−6 M) (the effects of prazosin and propranolol being additive). Higher concentrations of haloperidol and domperidone antagonised the relaxation responses of the body preparations only. Metoclopramide, yohimbine and methysergide (10−8–10−6 M) were ineffective. Thus, it is concluded that the contractile effects of the 4 stomach areas to field stimulation reflects a major cholinergic involvement, with an additional α2-adrenoceptor contractile component in antral tissue. Relaxation responses of cardia and body tissue involve α2- and β-adrenoceptors plus a further, unidentified, non-adrenergic component; the latter represents the total relaxation response of the fundic preparation.

EFFECTS OF NARCOTIC AND NON-NARCOTIC ANALGESICS ON THE ABDOMINAL OR TAIL STIMULATION-INDUCED STRUGGLING IN RATS

AbstractAs a model, we used struggling induced by a repetitive stimulation of the tail or abdomen and two types of pseudoaffective responses were evoked in rats. The effects of narcotic and non-narcotic analgesics on these responses were alternately assessed. Narcotics were markedly effective in inhibiting struggling elicited by tail stimulation and slightly less effective in suppressing the abdominal stimulation-induced struggling. These effects on two types of struggling differed quantitatively but not qualitatively. On the other hand, non-narcotics such as aspirin (200 mg/ kg, i.p.), aminopyrine (160 mg/kg, i.p.) and indomethacin (20 mg/kg, i.p.) had an inhibitory action on the struggling elicited by the tail stimulation but showed equivocal and far less inhibition on the abdominal stimulation-induced response. These two effects were quantitatively and qualitatively different because the slope of the dose-response curves were not in parallel. The action of baclofen appears to be ambiguous since it had distinctive inhibitory actions on both types of struggling. However, baclofen can be classified into the latter group in that it exerted an inhibitory action on two types of struggling, in a quantitatively different manner. These results suggest that two types of struggling in rats provide a convenient means to assess the potency of analgesics.