[Effect of beta-adrenoceptor agonists on vascular smooth muscle contraction and transmitter release in the portal vein from spontaneously hypertensive rats].
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Adrenergic beta-Agonists↗
Biomedical subjects
T C Westfall
Publications and source records attributed to T C Westfall.
The nicotinic-induced release of endogenous dopamine from rat striatal slices from animals chronically exposed to dimethylphenylpiperazinium (DMPP).
The effect of the nicotinic agonist, dimethylphenylpiperazinium (DMPP), to release endogenous dopamine (DA) from striatal slices obtained from animals chronically treated with the nicotinic agonist for 7 or 14 days was determined. Endogenous DA was measured by high pressure liquid chromatography coupled to electrochemical detection. There was no difference in the DMPP concentration-effect curve for DA release from slices obtained from untreated rats or rats treated with saline. Treatment with DMPP for 7 days did not change the DMPP concentration-effect curve when compared to saline treatment. In contrast, treatment of rats with DMPP for 14 days resulted in a significant attenuation of the DMPP-induced release of DA. These studies support the hypothesis that chronic treatment with nicotinic agonists results in a functional uncoupling of cholinergic nicotinic receptors facilitating DA release in the striatum.
Animals↗
3H-norepinephrine release in hypothalamus and brainstem of Dahl-salt sensitive and resistant rats in vitro.
Electrically evoked 3H-norepinephrine release was measured in slices of hypothalamus and brainstem of Dahl-salt sensitive (Dahl-S) and Dahl-salt resistant (Dahl-R) rats on both high and low sodium chloride diets. Only those Dahl-S rats fed a high sodium chloride diet became hypertensive, systolic blood pressure above 150 mmHg, although the Dahl-S rats on a low sodium diet, and Dahl-R rats fed a high sodium diet, both had blood pressures that were elevated compared to the Dahl-R rats maintained on a low sodium diet, when measured at the time of sacrifice. The Dahl-S rats on a high sodium diet also showed an enhancement in the field-stimulation induced release of 3H-norepinephrine in the posterior hypothalamus. Evoked 3H-norepinephrine release was not altered in low sodium diet Dahl-S rats or in low or high sodium salt Dahl-R rats. The stimulation induced 3H-norepinephrine release was also not different in the anterior hypothalamus or the A2 region of the nucleus tractus solitarius in either Dahl-S or Dahl-R animals on either sodium chloride diet. These results suggest that the alteration of evoked 3H-norepinephrine release, specifically in the posterior hypothalamus may play a role in the development and/or maintenance of hypertension.
Animals↗
Comparison of norepinephrine release in hypertensive rats: I. Hypothalamic and brainstem tissues.
Stimulation induced 3H-norepinephrine release was measured in hypothalamus and brainstem of spontaneously hypertensive (SHR) and normotensive (WKY) rats. Age dependent changes in 3H-norepinephrine release were shown to occur in the anterior and posterior hypothalamus and the A2 region of the nucleus tractus solitarius (NTS). In an attempt to determine whether these changes in 3H-transmitter release were causal or merely secondary to the increase in blood pressure, similar release studies were carried out in DOCA-salt and one kidney-one clip hypertensive animals with similar levels of systolic blood pressure. The changes in stimulus-induced 3H-norepinephrine release seen in the SHR were not observed in the other two models of hypertension, suggesting that one: they were not secondary to an increase in systolic blood pressure; and two that the changes observed in the SHR may possibly play a role in the development and/or maintenance of the hypertension.
Age Factors↗
Comparison of norepinephrine release in hypertensive rats: II. Caudal artery and portal vein.
It was observed that there was a significantly greater field-stimulation induced release of norepinephrine from the portal vein and caudal artery obtained from 28 week old SHR compared to WKY. The greater field-stimulation induced release of norepinephrine observed in the blood vessels of the SHR compared to WKY was not seen in DOCA-salt and one kidney-one clip hypertensive animals with similar elevations of systolic blood pressure. It was also observed that there was an attenuation of the effect of the prejunctional alpha 2-adrenoceptor antagonist, yohimbine to enhance the field-stimulation induced release of norepinephrine from blood vessels of the 28 week old SHR. There was no attenuation of the yohimbine effect in the other two models of hypertension. It is concluded that there is an alteration in the release of norepinephrine from blood vessels of SHR, resulting in a greater evoked release of the transmitter. A decrease in the functional activity of prejunctional alpha 2-adrenoceptor may contribute to the enhanced release of norepinephrine from the blood vessels of the SHR.
Animals↗
Cholecystokinin octapeptides alter the release of endogenous dopamine from the rat nucleus accumbens in vitro.
Sulfated cholecystokinin octapeptide (CCK-8S) has been reported to be extensively colocalized with dopamine in the posterior, but not the anterior, portion of the nucleus accumbens (NAc). The hypothesis tested in the present study was that CCK-8S alters the release of dopamine in this structure and the actions it produces are dependent on the extent of colocalization with dopamine. We observed in vitro that CCK-8S enhanced the resting release of dopamine from the posterior, but not anterior, NAc. It was also found that CCK-8S attenuated the release of dopamine induced by potassium-evoked depolarization in both regions of the NAc, although the concentration-release curves for the two areas differed. In the posterior NAc, a biphasic response was seen whereas, in the anterior NAc, there was a monophasic attenuation. Proglumide, a putative CCK-8S antagonist, was found to antagonize the action of a low concentration of CCK-8S on 40 mM K+-induced dopamine release from slices of the posterior, but not anterior, NAc. Unsulfated CCK-8 had mixed action on K+-evoked dopamine release, as it enhanced this form of release in the posterior NAc but attenuated it in the anterior NAc. Additionally, we found no effect of sulpiride on the actions of CCK-8S with respect to evoked release, suggesting that CCK-8S is not acting to alter dopamine autoreceptor function, as has recently been hypothesized. In summary, our results demonstrate that the observed effects of CCK-8S on dopamine release are dependent upon the region of the NAc studied, and there appear to be different subtypes of CCK-8S receptors present in the two regions.
Animals↗
Modulation of terminal excitability of mesolimbic dopaminergic neurons by D-amphetamine and haloperidol.
Electrophysiological techniques were used to study the changes in the terminal excitability of mesolimbic DA and non-DA neurons following the infusion of D-amphetamine (D-AMP) and haloperidol (HAL) into the nucleus accumbens (NAc) of rats. The amount of current needed to evoke antidromic spikes by electrical stimulation of the NAc was used as an index of the excitability of axon terminals of these neurons. The excitability of DA neurons was decreased by D-AMP and increased by HAL. In addition, the effect produced by D-AMP was reversed by HAL. By contrast, these drugs either induced an opposite effect or were ineffective in inducing changes on the excitability of nerve terminals of mesolimbic non-DA neurons. Infusion of the vehicle or saline produced no effect. D-AMP and HAL were still effective in modulating the excitability of mesolimbic DA nerve terminals after the destruction of NAc neurons by ibotenic acid. The results suggest that the effects seen after D-AMP and HAL are mediated primarily by DA autoreceptors. It is likely that the increase in the current needed for evoking antidromic spikes after infusion of D-AMP into the terminal region is the consequence of DA autoreceptor-mediated hyperpolarization of terminal membranes. On the other hand, HAL could exert its actions by blocking autoreceptor-mediated hyperpolarization.
Animals↗
Alterations in the release of norepinephrine at the vascular neuroeffector junction in hypertension.
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Animals↗
Effect of low sodium diet on the facilitatory effect of angiotensin on 3H-norepinephrine release in the rat portal vein.
The ability of angiotensin to enhance the field-stimulation induced release of 3H-norepinephrine from the superfused rat portal vein was examined in vessels obtained from animals fed a normal (0.5% Na+) or low sodium diet (0.05% Na+). Angiotensin was seen to enhance the field-stimulation (480 pulses, 2 Hz, 1 ms duration, supramaximal voltage) induced release of 3H-norepinephrine from vessels obtained from Sprague-Dawley, Wistar, Wistar-Kyoto (WKY) and the spontaneously hypertensive rats (SHR) maintained on a normal sodium diet. The effect of angiotensin was attenuated when examined in vessels obtained from animals maintained on the low sodium diet. The selectivity of the low sodium diet for angiotensin was demonstrated by a lack of effect of the low sodium diet in altering the facilitatory effect of isoproterenol on the release of 3H-norepinephrine and an enhanced response to the alpha 2-adrenoceptor-selective antagonist, yohimbine. The simultaneous treatment of rats with a low sodium diet plus captopril (estimated to be approximately 50 mg/kg/day for 7 days) prevented the attenuation of the angiotensin-induced enhancement of the release of 3H-norepinephrine seen by sodium alone. These results are consistent with the hypothesis that low sodium treatment increases circulating angiotensin levels which lead to a down-regulation of the angiotensin receptors located on adrenergic nerve varicosities.
Angiotensin II↗
The effects of cholecystokinin on the in vivo release of newly synthesized [3H]dopamine from the nucleus accumbens of the rat.
It has been reported that in the medial nucleus accumbens (NAc) there are nerve terminals which contain either the neuropeptide cholecystokinin (CCK) or the catecholamine dopamine (DA), as well as terminals which contain both. In this study, we have examined the action of CCK-peptides on the basal and potassium-evoked release of [3H]DA within this structure. The in vivo release of [3H]DA, newly synthesized from [3H]tyrosine, was measured by using the push-pull cannula perfusion technique. It appeared that a large percentage of the [3H]DA released under resting conditions was dependent upon nerve impulse activity as it was found that tetrodotoxin, absence of extracellular Ca2+, and the inhibition of DA synthesis by alpha-methyl-p-tyrosine all decreased [3H]DA release by more than 50%. In addition, the potassium-evoked release of [3H]DA was found to be almost completely dependent upon extracellular Ca2+. When sulfated CCK-octapeptide was administered into the NAc, it was found to increase the basal levels of [3H]DA released at concentrations of 2 X 10(-8) and 2 X 10(-7) M. However, at 2 X 10(-6) M there was no longer an effect by this peptide. The unsulfated form was found to have no effect at a concentration which was maximally effective for the sulfated form. In contrast to its effects on the basal release of [3H]DA, sulfated CCK-octapeptide was found to attenuate the potassium-evoked release of [3H]DA from the NAc in a concentration-dependent fashion from 2 X 10(-9) to 2 X 10(-6) M. The unsulfated form of the octapeptide had no effect on evoked release. Our results suggest that CCK acts to modulate the release of DA within the NAc in vivo in a complex manner, as it appears that the action of CCK depends not only on the concentration tested but also on the excitation state of the tissue during the testing period.
Animals↗
Evidence that noradrenergic transmitter release is regulated by presynaptic receptors.
A review is provided of the evidence in support of the existence of prejunctional alpha adrenoceptors on noradrenergic nerve terminals as well as the evidence for their physiological importance. The use of alpha-adrenoceptor agonists and antagonists has provided convincing data in support of the presynaptic receptor hypothesis. Moreover, there is ample evidence for the location of alpha adrenoceptors on nerve terminals. This evidence has often been forgotten in arguments opposing the presynaptic alpha-adrenoceptor hypothesis. The precise physiological role of presynaptic alpha adrenoceptors is still an open question, but there is support from a wide range of experiments in favor of a physiological role. Although it is not known which of these functions is most important, presynaptic alpha adrenoceptors may: regulate the pulse-to-pulse regulation of norepinephrine release during nerve stimulation, prevent noise, and protect the neuroeffector cell from excessive activation by transmitter during periods of rest or as physiological antagonists to the facilitation of transmitter release. In summary, evidence reviewed here strongly supports the existence of presynaptic alpha adrenoceptors. These receptors are clearly important pharmacologically and may play a physiological role in noradrenergic transmission. The exact physiological function must await further experimentation.
Adrenergic alpha-Agonists↗
The effect of opioid drugs on the release of dopamine and 5-hydroxytryptamine from rat striatum following activation of nicotinic-cholinergic receptors.
The effect of (Met5)enkephalin, (D-Ala2,D-Met5)enkephalin, (Leu5)enkephalin, (D-Ala2,D-Met5)enkephalin and morphine on the release of [3H]dopamine, endogenous dopamine and [3H]5-hydroxytryptamine produced by the nicotinic-cholinergic agonist, dimethylphenyl piperazinium iodide (DMPP), was examined in rat striatal slices. The DMPP-induced release of [3H]dopamine and endogenous dopamine was reduced by the presence of (Met5)enkephalin, (D-Ala2,D-Met5)enkephalin (1-10 microM) or morphine (10 microM) but not by (Leu5)enkephalin or (D-Ala2,D-Leu5)enkephalin. The DMPP-induced release of [3H]5-hydroxytryptamine was reduced by (Leu5)enkephalin, (D-Ala2,D-Leu5)enkephalin, (Met5)enkephalin, (D-Ala2,D-Leu5)enkephalin (1-10 microM), and morphine (10 microM). All three opioids failed to alter the release of [3H]dopamine induced by field stimulation or potassium depolarization (30 microM). The inhibitory effects of opioid peptides and morphine demonstrated in the present study appear to be due to an initial interaction with nicotinic-cholinergic receptors in the striatum.
Animals↗
Further evidence for an opioid receptor complex.
We recently presented evidence that distinct morphine and enkephalin receptors coexist in an opioid receptor complex. These studies used membranes prepared from whole rat brain. In this paper the receptor complex is demonstrated to occur in membranes prepared from rat striatum, cortex, and pooled nonstriatal-noncortical regions of the brain. The observation that morphine masks enkephalin receptors is confirmed using 3H-methionine enkephalin to label the enkephalin receptor. These data further support the hypothesis that populations of morphine and enkephalin receptors coexist in an opioid receptor complex.
Animals↗
Multiple opioid receptors: an examination of the dissociation of [3H]leucine enkephalin from rat brain membranes.
The experiments reported in this paper address the hypothesis that [3H]leucine enkephalin labels both mu and delta receptors. As reported by other workers, this peptide dissociates from rat brain membranes in a biphasic manner. This is consistent with a two site binding model which hypothesizes that the peptide labels both opioid mu and delta receptors from which it dissociates at different rates. To test this hypothesis, we determined the dissociation of bound ligand from rat brain membranes incubated to equilibrium with [3H]leucine enkephalin in the absence and presence of 100 nM morphine. The data were not significantly different. We conclude that the biphasic off-kinetics of [3H]leucine enkephalin is not evidence for a two-site binding model.
Animals↗
Interaction of leucine enkephalin with (3H)naloxone binding in rat brain: evidence for an opioid receptor complex.
We recently presented evidence that distinct morphine and enkephalin receptors coexist in an opioid receptor complex (Mol. Pharmacol. 21:548-557, 1982). In this paper, we present data which demonstrate that in the presence of sodium leucine enkephalin noncompetitively inhibits the binding of [3H]naloxone to a crude particulate fraction of rat brain. Since the binding site labeled by [3H]naloxone in the presence of sodium may be an alternate conformation of the morphine receptor, these data provide further evidence that morphine and enkephalin receptors are allosterically coupled.
Animals↗
Release of dopamine and 5-hydroxytryptamine from rat striatal slices following activation of nicotinic cholinergic receptors.
1. The administration of the nicotinic cholinergic agonists dimethylphenylpiperazinium iodide (DMPP) or nicotine caused a concentration dependent release of [3H] dopamine, [3H]5-hydroxytryptamine as well as endogenous dopamine and 5-hydroxytryptamine from superfused slices of rat striatum. 2. Release of both labelled and non-labelled transmitter was antagonized by the nicotinic antagonist, hexamethonium but not the muscarinic antagonist, atropine. 3. The present study provides additional evidence that nicotinic-cholinergic receptors are present in the mammalian central nervous system. 4. Activation of these nicotinic-cholinergic receptors in the striatum results in the release of both dopamine and 5-hydroxytryptamine.
Animals↗
Relative potency of dopamine agonists on autoreceptor function in various brain regions of the rat.
The effect of six dopamine agonists including apomorphine, epinine, dopamine, piribedil, lergotrile and bromocriptine on the incorporation of [3H]tyrosine into dopamine was studied in slices and synaptosomes prepared from various brain areas containing dopamine terminals including striatum, nucleus accumbens, olfactory tubercle and medial basal hypothalamus. It was observed that all of these drugs were active in causing a decrease in dopamine synthesis in these various brain areas. The catecholamine agonists apomorphine, epinine and dopamine were more potent in inhibiting dopamine synthesis in the mesolimbic structures than in the striatum. On the other hand, apomorphine and epinine were less potent while dopamine was more potent in the medial basal hypothalamus. The ergoline drugs were weak agonists in all structures studied. It is concluded that autoreceptor regulation of dopamine synthesis is more active in the mesolimbic compared with the nigrostriatal dopamine pathway while autoreceptors may be absent in the median eminence.
Animals↗
Mu and delta receptors: their role in analgesia in the differential effects of opioid peptides on analgesia.
Utilizing the mouse tail-flick assay, the rank order of analgesic potency for various opioids (i.c.v.) is beta h-endorphin greater than D-Ala2-D-Leu5-enkephalin greater than morphine greater than D-Ala2-met-enkephalinamide much greater than met-enkephalin much greater than leu-enkephalin. Assuming mu receptor mediation of analgesia, there is an affinity and analgesic potency (ie: D-Ala2-Leu5-enkephalin has 1/7 the affinity of morphine for the mu receptor but is 18X more potent as an analgesic). Additionally, sub-analgesic doses of various opioid peptides have opposite effects on analgesic responses. Leu-enkephalin, D-Ala2-D-Leu5-enkephalin or beta h-endorphin potentiate morphine or D-Ala2-met-enkephalinamide analgesia whereas met-enkephalin or D-Ala2-met-enkephalinamide antagonize opioid-induced analgesia. Using the enkephalins as the prototypic delta ligands (100 fold selective) and based on their effects on analgesia, we suggest that Leu-enkephalin-like peptides interact with the delta receptor as an "agonist" to facilitate and met-enkephalin-like peptides as an "antagonist" to attenuate analgesia. Given the biochemical evidence of a coupling between mu and delta receptors, we suggest that the mechanism of facilitation or attenuation of analgesia by the enkephalins is a direct in vivo consequence of this coupling. Further, the analgesic potencies of various opioid ligands can be better correlated to the combination of their simultaneous occupancy of mu and delta receptors.
Animals↗