3H Overflow Research Articles

Effects of Bay K 8644 on the electrically evoked and KCl-evoked norepinephrine release and the corresponding contraction in isolated canine saphenous veins.

Bay K 8644 caused no significant effects on the 3H overflow and contraction evoked by electrical stimulation in the canine saphenous vein preloaded with [3H]norepinephrine. Bay K 8644 significantly enhanced the 3H overflow evoked by 40 mM KCl in a concentration-dependent manner, which was antagonized by nisoldipine. Bay K 8644 failed to significantly augment the KCl-evoked contraction. These results suggest that there is a difference between the modes of action of Bay K 8644 on norepinephrine releases evoked by electrical stimulation and KCl.

Effects of Bay K 8644 on the Electrically Evoked and KCI-Evoked Norepinephrine Release and the Corresponding Contraction in Isolated Canine Saphenous Veins

Bay K 8644 caused no significant effects on the 3H overflow and contraction evoked by electrical stimulation in the canine saphenous vein preloaded with [3H]norepinephrine. Bay K 8644 significantly enhanced the 3H overflow evoked by 40 mM KCl in a concentration-dependent manner, which was antagonized by nisoldipine. Bay K 8644 failed to significantly augment the KCI-evoked contraction. These results suggest that there is a difference between the modes of action of Bay K 8644 on norepinephrine releases evoked by electrical stimulation and KCl.

Effects of Bay K 8644 on the Electrically Evoked and KCI-Evoked Norepinephrine Release and the Corresponding Contraction in Isolated Canine Saphenous Veins

Bay K 8644 caused no significant effects on the 3H overflow and contraction evoked by electrical stimulation in the canine saphenous vein preloaded with [3H]norepinephrine. Bay K 8644 significantly enhanced the 3H overflow evoked by 40 mM KCI in a concentration-dependent manner, which was antagonized by nisoldipine. Bay K 8644 failed to significantly augment the KCI-evoked contraction. These results suggest that there is a difference between the modes of action of Bay K 8644 on norepinephrine releases evoked by electrical stimulation and KCI.

Subendothelial beta 2-adrenoceptors in the rat vena cava: facilitation of noradrenaline release via local stimulation of angiotensin II synthesis.

Preparations of the cranial segment of the rat inferior vena cava preincubated with 3H-noradrenaline were superfused in the presence of desipramine and corticosterone. Tritium overflow was stimulated electrically (2 Hz). The experiments were carried out in spirally cut strips with or without intima or in segments ligated at both ends and superfused either on the adventitial side ("conventionally") or "inside out". In spirally cut strips electrically evoked 3H overflow was increased by isoprenaline and procaterol, but much less so by prenalterol. Adrenaline 1 nmol/l increased overflow, but at high concentrations it reduced it, just as noradrenaline did at all concentrations. The concentration-response curve for isoprenaline was shifted to the right by propranolol (apparent pA2:8.29) and even more so by ICI 118-551, whereas atenolol was less potent (apparent pA2:6.42). Rauwolscine which, given alone, increased the evoked 3H overflow antagonized the inhibitory effect of noradrenaline (apparent pA2:7.58). These findings indicate that beta 2- and alpha 2-adrenoceptors mediating facilitation and inhibition of noradrenaline release, respectively, are present in the vena cava. The response to isoprenaline (at all concentrations) was considerably lower in segments superfused "conventionally" than in spirally cut strips, but no difference was observed with respect to the effects of noradrenaline, rauwolscine and angiotensin II. The effect of isoprenaline was clearly more pronounced in segments superfused "inside out" than in segments superfused "conventionally". In spirally cut strips angiotensin II increased 3H overflow. This effect was antagonized by saralasin, suggesting the involvement of facilitatory angiotensin receptors. In spirally cut strips or segments superfused "inside out", saralasin or captopril considerably attenuated the facilitatory effect of isoprenaline on 3H overflow. Conversely, in the presence of isoprenaline, captopril inhibited the electrically evoked 3H overflow in spirally cut strips, whereas in the absence of isoprenaline, captopril was ineffective. In conclusion, angiotensin receptors and alpha 2-adrenoceptors appear to be located on the sympathetic nerve endings, but a major part of the beta 2-adrenoceptors probably is subendothelial (most likely on smooth muscle cells). Angiotensin II, synthesized in response to beta 2-adrenoceptor activation, probably stimulates angiotensin receptors on the noradrenergic nerves, leading to an increase in noradrenaline release.

Effects of calcium channel antagonists on action potential conduction and transmitter release in the guinea-pig vas deferens.

The effects of the Ca2+ channel antagonists amlodipine, cobalt, diltiazem, nifedipine and verapamil and the local anaesthetic lignocaine were investigated on action potential conduction in and on evoked transmitter release from sympathetic nerves in the guinea-pig isolated vas deferens. Transmitter release was investigated by measurement of evoked (trains of pulses at 1 and 2 Hz, 0.1-0.5 ms supramaximal voltage) excitatory junction potentials (e.j.ps) using microelectrodes; tension was recorded simultaneously; tritium [3H] overflow from vasa preincubated (37 degrees C, 30 min) in Krebs solution containing either [3H]-noradrenaline (NA, 25 microCi ml-1, 2 X 10(-6) M NA) or [3H]-adenosine (50 microCi ml-1, 1 X 10(-6) M adenosine). Amlodipine (0.5-2 X 10(-4) M), verapamil (0.5-2 X 10(-4) M), diltiazem (1-8 X 10(-4) M), lignocaine (0.1-2 X 10(-3) M) and cobalt (2-6 X 10(-2) M) in descending order of potency, but not nifedipine (1-5 X 10(-3) M), increased the latency and inhibited, then abolished, the amplitude and number of action potentials in a concentration-dependent manner. Amlodipine (0.5-1 X 10(-4) M), verapamil (1-2 X 10(-4) M), diltiazem (1-5 X 10(-4) M) and cobalt (1 X 10(-3) M), in descending order of potency, but not nifedipine (5 X 10(-4) M), inhibited then abolished evoked e.j.ps in a concentration-dependent manner. Cobalt inhibited e.j.ps at a lower concentration than that (2-6 X 10(-2) M) required to block action potential conduction. In unstimulated tissues, the resting [3H] overflow following preincubation with [3H]-NA consisted largely of 4-hydroxy 3-methoxymandelic acid (VMA), 4-hydroxy 3-methoxy phenylglycol (MOPEG), 3,4 dihydroxyphenylglycol (DOPEG) and NA; stimulated tissues (300 pulses at 20 Hz, 0.5 ms supramaximal voltage) released mainly NA. Verapamil (0.1-1 X 10(-4) M), amlodipine (0.05-1 X 10(-4) M) and nifedipine (1-5 X 10(-4) M), but not cobalt (2 X 10(-3) M), increased, significantly, the resting overflow of 3H comprising mainly DOPEG. Cobalt (2 X 10(-3) M) inhibited, significantly, the stimulation-evoked overflow of 3H. Verapamil (1 X 10(-4) M) had little effect on the resting overflow of 3H following preincubation with [3H]-adenosine. Diltiazem (5 X 10(-4) M) and cobalt (2 X 10(-3) M) both inhibited evoked 3H overflow. Nifedipine (5 X 10(-4) M) was ineffective. 6 The effectiveness of Ca2+ channel antagonists at pre- and postjunctional sites differ; the results are discussed in terms of the selectivity of these drugs for each site and their differential effects on transmitter release.

Effects of iskedyl and its two constituents raubasine and dihydroergocristine on the release of [ 3H]noradrenaline and [ 3H]serotonin in canine basilar arteries

In strips of isolated canine basilar arteries, previously labeled with 3 × 10 −7 M of either [ 3H]noradrenaline or [ 3H]serotonin, three consecutive periods of electrical stimulation (2 Hz) evoked a reproducible overflow of the respective [ 3H]amine. Increasing concentrations of raubasine (7.5 × 10 −7−7.5 × 10 −6 M) did not influence the spontaneous 3H efflux but increased the stimulation-induced 3H overflow in a concentration-dependent way. The highest concentration of raubasine used (2.5 × 10 −5 M) caused an increased spontaneous 3H efflux but no longer augmented the stimulation-induced 3H overflow. Dihydroergocristine (5.4 × 10 −8−1.8 × 10 −6 M) did not affect the spontaneous 3H efflux; the compound slightly but significantly reduced the stimulation-evoked 3H overflow concentration dependently. High concentrations of Iskedyl (mixtures of raubasine and dihydroergocristine in a 14:1 molar ratio) augmented the spontaneous 3H efflux and moderately decreased the stimulation-induced 3H overflow. Although some quantitative differences were noted, the compounds exerted similar effects on arteries labeled with either [ 3H]noradrenaline or [ 3H]serotonin. The most important difference detected was that DHEC decreased the stimulation-induced release of [ 3H]serotonin more than that of [ 3H]noradrenaline. Our results allow a comparison of [ 3H]noradrenaline and [ 3H]serotonin release in the dog basilar artery: the basal fractional release of [ 3H]serotonin was higher than that of [ 3H]noradrenaline while the stimulation-induced overflow was equal in both groups of tissues. The constituents of Iskedyl can profoundly affect the release of the neurotransmitters. Raubasine, a presynaptic α-receptor antagonist, increases the stimulation-induced release of the neurotransmitters and both DHEC, a presynaptic receptor agonist, and the combination of the compounds, Iskedyl, decrease the release of the neurotransmitters.

Inhibitory presynaptic 5-hydroxytryptamine (5-HT) receptors on the sympathetic nerves of the human saphenous vein.

Superfused strips of the human saphenous vein preincubated with 3H-noradrenaline were used to investigate the influences of serotonin (5-HT) receptor agonists and antagonists on the electrically evoked tritium overflow. 5-HT and the preferential 5-HT1A receptor agonist 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin] concentration-dependently inhibited the evoked 3H overflow. The evoked 3H overflow was not affected by 0.1 or 1 mumol/l TVX Q 7821 (2-(4-[4-(2-pyrimidinyl)-1-piperazinyl]-butyl)-1,2-benzoisothiazol -3(2H)one-1,1-dioxide), which selectively binds to 5-HT1A sites; TVX Q 7821 10 mumol/l produced an increase in overflow. The inhibitory effect of 5-HT on the impulse-evoked 3H overflow was abolished by the nonselective 5-HT receptor antagonist metitepin, but was not attenuated by propranolol. Metitepin also abolished the inhibitory effect of 8-OH-DPAT on evoked 3H overflow, whereas the 5-HT2 receptor antagonist ketanserin was inactive in this respect. There was also no antagonism of the effect of 8-OH-DPAT by the alpha 2-adrenoceptor antagonist rauwolscine or the dopamine receptor antagonist flupenthixol. These results suggest that both 5-HT and 8-OH-DPAT inhibit noradrenaline release by activating inhibitory 5-HT receptors on the sympathetic nerves of the human saphenous vein. These receptors possess similarities to 5-HT1 recognition sites, but a further subclassification is not yet possible on the basis of the available data.

Evaluation of the direct actions of drugs with a serotonergic link in spinal analgesia on the release of [ 3H]serotonin from spinal cord synaptosomes

Morphine, ketamine, ethylketocyclazocine and quipazine, drugs with an apparent local spinal serotonergic action, which contributes to their analgesic effects, were tested for their ability to alter the release of [ 3H]serotonin ([ 3H]5-HT) from a synaptosomal preparation from the spinal cord of the rat. Related compounds including [ d-Ala 2, d-Leu 5]enkephalin (DADLE), n-allylnormetazocine and phencyclidine were also examined. None of the drugs was found to be capable of inducing a direct release of [ 3H]5-HT or of facilitating potassium-induced release of 5-HT. However, quipazine inhibited the depressant action of exogenous 5-HT on overflow of 3H (mediated through the 5-HT autoreceptor), an action that should facilitate serotonergic neurotransmission. In contrast to the other drugs, DADLE was found to depress K + stimulated release of 5-HT. The results suggest that the serotonergic mechanism involved in the antinociceptive action of some of these drugs (i.e. ketamine, morphine and ethylketocyclazocine) is not related to direct presynaptic interactions to promote release of 5-HT. On the other hand, a small population of serotonergic nerves critical for analgesia may be involved and are not detected using tissue from the whole spinal cord. However, it seems equally plausible that these drugs may produce their antinociceptive action through interactions with other neurotransmitter systems that in turn interface with the serotonergic nerves, perhaps through interneurons or collateral connections.

Receptor-mediated effects of serotonin and 5-methoxytryptamine on noradrenaline release in the rat vena cava and in the heart of the pithed rat.

In segments of the rat inferior vena cava preincubated with 3H-noradrenaline, it was examined whether presynaptic serotonin (5-HT) receptors exist on the postganglionic sympathetic nerves of the circulatory system; for this purpose the effects of 5-HT receptor agonists and antagonists on the electrically evoked 3H overflow were studied. Furthermore, vagotomized pithed rats (treated with atropine and captopril) were used to investigate the effects of these drugs on heart rate and on the tachycardia induced by electrical stimulation of the preganglionic sympathetic nerves (C7--T1) via the pithing rod; these experiments were carried out to provide evidence that the presynaptic 5-HT receptors are operative in vivo. 5-HT and 5-methoxytryptamine (5-OCH3-T) concentration-dependently inhibited the electrically evoked 3H overflow from the vena cava. The inhibitory effect was more pronounced at 0.66 Hz than at 2 Hz. 8-Hydroxy-2-(di-n-propylamino)tetralin did not alter the evoked overflow. The inhibitory effect of 5-HT or 5-OCH3-T was antagonized by metitepin but not affected by ketanserin or rauwolscine. In pithed rats 5-HT and 5-OCH3-T by themselves dose-dependently increased heart rate. The positive chronotropic effect of 5-HT 10 mumol/kg, which was not affected by ketanserin, was considerably decreased by desipramine, indicating that 5-HT at least at this high dose acts predominantly by a tyramine-like indirect sympathomimetic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Prejunctional and postjunctional actions of prostaglandins F 2α and I 2 and carbocyclic thromboxane A 2 in isolated dog mesenteric arteries

Prostaglandin (PG) F 2α in concentrations insufficient to alter the basal tone potentiated contractile responses of helical strips of dog mesenteric arteries to transmural electrical stimulation but did not alter the responses to norepinephrine. Carbocyclic thromboxane A 2 (cTxA 2) potentiated the response to transmural stimulation, norepinephrine, serotonin and angiotensin II. PGI 2 (up to 10 −7 M) attenuated the contraction induced by transmural stimulation, norepinephrine and serotonin. The potentiating effect of PGF 2α was not antagonized by diphloretin phosphate, a PG antagonist, whereas the effects of cTxA 2 and PGI 2 were prevented. 3H Overflow evoked by transmural stimulation in superfused arterial strips previously soaked in media containing [ 3H]norepinephrine was increased by PGF 2α but was not altered by cTxA 2 and PGI 2. It may be concluded that PGF 2α potentiates the contractile response to adrenergic nerve stimulation by increasing the release of norepinephrine, and that cTxA 2 potentiates the response by increasing arterial muscle contractility, whereas PGI 2 attenuates contractility. Prejunctional effects of PGs appear to be mediated by receptive sites different from those located postjunctionally.

Identity of inhibitory presynaptic 5-hydroxytryptamine (5-HT) autoreceptors in the rat brain cortex with 5-HT1B binding sites.

In rat brain cortex slices preincubated with [3H]5-HT, the potencies of 17 5-HT receptor agonists to inhibit the electrically evoked 3H overflow and the affinities of 13 antagonists (including several beta-adrenoceptor blocking agents) to antagonize competitively the inhibitory effect of unlabelled 5-HT on evoked 3H overflow were determined. The affinities of the compounds for 5-HT1B and 5-HT2 binding sites in rat brain cortex membranes (labelled by [125I]cyanopindolol = [125I]-CYP in the presence of 30 mumol/l isoprenaline and [3H]ketanserin, respectively), for 5-HT1A binding sites in pig and rat brain cortex membranes (labelled by [3H]8-hydroxy-2-(di-n-propylamino)tetralin = [3H]8-OH-DPAT) and for 5-HT1C binding sites in pig choroid plexus membranes (labelled by [3H]mesulergine) were also determined. The affinities of the drugs for the various 5-HT recognition sites ranged over 4-5 log units (the functional experiments revealed the same range of differences between the drugs). There were no significant correlations between the affinities of the drugs at 5-HT1C and 5-HT2 binding sites and their potencies or affinities, determined for the 5-HT autoreceptors. In contrast, significant correlations were found between the potencies or affinities of the drugs for the autoreceptors and their affinities at 5-HT1A or 5-HT1B binding sites; the best correlations were obtained with the 5-HT1B binding site. Some of the drugs investigated were not included in the correlation since their agonistic or antagonistic effects on the autoreceptors were weak and pEC30 or apparent pA2 values could not be determined (less than 5.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Serotonin release in human cerebral cortex and its modulation via serotonin receptors

Human cerebral cortex slices were prepared from brain tissue which had to be removed in order to gain access to deep-seated tumours. Subsequent to incubation with [ 3H]serotonin, the slices were superfused with physiological salt solution containing paroxetine, and 3H overflow was evoked by electrical field stimulation. The evoked tritium overflow (86% of which was accounted for by unmetabolized [ 3H]serotonin) was abolished by tetrodotoxin or omission of calcium from the superfusion fluid. Unlabelled serotonin decreased, and the serotonin receptor antagonist metitepin increased, the evoked overflow. The inhibition produced by serotonin was antagonized by metitepin. It is concluded that serotonin release in human cerebral cortex is modulated by inhibitory serotonin receptors, which may be localized presynaptically on the serotoninergic nerve fibers themselves. There are marked similarities between human and rat brain cortex with respect to action potential-induced, Ca 2+-dependent serotonin release and its modulation via serotonin receptors.

Inhibition by diltiazem of norepinephrine release from sympathetic nerves in the rabbit pulmonary artery.

In order to determine if the calcium blocker diltiazem could alter excitation-secretion coupling in vascular sympathetic nerves, superfused rabbit pulmonary arterial strips were preincubated with 3H-norepinephrine and stimulated electrically (2-8 Hz) and by KCl (60 mM). Diltiazem significantly inhibited tension development with 4 Hz (1.5 X 10(-5) M) and 8 Hz (1.5 X 10(-6), 1.5 X 10(-5) M) stimuli, but only at 1.5 X 10(-5) M did diltiazem inhibit the 3H overflow evoked by an 8-Hz stimulus. No inhibition of 3H overflow was noted with the 2 and 4 Hz stimuli. With an 8-Hz stimulus the inhibition of tension development (45.4%) by diltiazem (1.5 X 10(-5) M) was significantly greater than the inhibition of 3H overflow (33.8%). A similar relationship was noted with 60 mM KCl stimulation. These data suggest that excitation-secretion coupling in vascular sympathetic nerves can be inhibited by diltiazem.

Effects of ethylketocyclazocine on adrenergic transmission in the isolated perfused cat spleen.

The pre- and postsynaptic effects of ethylketocyclazocine (EKC), a putative kappa opiate receptor agonist, on sympathetic adrenergic neurotransmission were investigated using the isolated perfused cat spleen. Perfusion of spleens with EKC (10(-7) and 10(-6)M) produced a modest dose-dependent inhibition of nerve-stimulation-mediated overflow of norepinephrine (NE) and total 3H. In contrast, EKC (10(-4)M) produced an increase in the release of NE, and total 3H overflow. Perfusion with EKC (10(-5) and 10(-4)M) resulted in a dose-dependent inhibition of the postsynaptic response to stimulation-mediated release of NE. Likewise, EKC inhibited splenic contraction due to exogenously administered NE which was not antagonized by naloxone. These results suggest that EKC exerts a direct effect on peripheral adrenergic neurotransmission not mediated via classical kappa opiate receptors.

Cyanopindolol is a highly potent and selective antagonist at the presynaptic serotonin autoreceptor in the rat brain cortex.

Rat brain cortex slices preincubated with 3H-serotonin were superfused with physiological salt solution containing the serotonin uptake blocker DU 24565 (6-nitroquipazine). The effects of (+/-)-cyanopindolol and its enantiomers, of ICI 118,551 (erythro-dl-1-(7-methylindan-4-yloxy)-3-isopropylaminobut an-2-ol) and of isoprenaline on the electrically (3 Hz) evoked 3H overflow were studied. (+/-)-Cyanopindolol increased the evoked 3H overflow; this effect was prevented by preexposure to the previously characterized serotonin receptor antagonist metitepin. The concentration-response curve of unlabelled serotonin for its inhibitory effect on the electrically evoked 3H overflow was shifted to the right by (+/-)-cyanopindolol (apparent pA2 value: 8.29), whereas that of noradrenaline (determined in the absence of DU 24565) was not affected (apparent pA2 value: less than 6.0). The concentration-response curve of serotonin was also shifted to the right by (-)-cyanopindolol (apparent pA2 value: 8.30) and (+)-cyanopindolol (6.83) but not by ICI 118,551 (less than 5.5). Isoprenaline (up to 10 mumol/l; examined in the absence of DU 24565) did not influence the electrically evoked 3H overflow. The present results show that the presynaptic serotonin autoreceptor is blocked by cyanopindolol in a stereoselective way. This drug is 20 times more potent than metitepin as an antagonist at the presynaptic serotonin autoreceptor, and, in contrast to the latter, it does not act as an antagonist at the presynaptic alpha 2-adrenoceptor on the serotoninergic neurone.

Relationship between the overflow of endogenous and radiolabelled noradrenaline from canine blood perfused gracilis muscle.

The effects of sympathetic nerve stimulation (SNS) on the overflow of endogenous noradrenaline (NA) and on vasoconstrictor responses were studied in blood perfused canine gracilis muscle in situ. A conventional tracer technique with 3H-labelled NA (3H-NA) was used in parallel. At rest there was a net extraction of endogenous NA and adrenaline across the tissue. The SNS evoked overflow of endogenous NA was frequency-dependent and logarithmically correlated to the vasoconstrictor responses. The neuronal uptake inhibitor desipramine doubled the SNS induced overflow of endogenous NA without enhancing the vasoconstrictor responses. A further fourfold increase in NA overflow was caused by a dose of the alpha-blocker phenoxybenzamine which reduced the vasoconstrictor responses by 50-75%. Less than 10% of the spontaneous 3H efflux was recovered as unmetabolized 3H-NA, whereas virtually all 3H overflow evoked by SNS was 3H-NA. The fractional release of NA or 3H-NA per nerve impulse increased with increasing frequencies of SNS under all conditions studied. Although there was a preferential release of the newly stored radiolabelled transmitter, results concerning endogenous NA and 3H-NA overflow were qualitatively similar, also under conditions with marked changes in transmitter overflow. Endogenous NA gave a more reproducible index of transmitter overflow than did 3H-NA and, in particular, total 3H. The overflow of endogenous NA closely reflects SNS evoked neuronal release of NA in blood perfused skeletal muscle and seems more suitable than conventional radiotracer techniques for studies of NA release under in vivo conditions.

Role of cAMP for regulation of impulse-evoked noradrenaline release from the rabbit pulmonary artery and its possible relationship to presynaptic ACTH receptors.

Strips of the rabbit pulmonary artery preincubated with 3H-noradrenaline were superfused with physiological salt solution containing cocaine, corticosterone and propranolol. Basal tritium efflux and electrically evoked tritium overflow were determined. The basal efflux of tritium was not affected by forskolin 0.01-10 mumol/l, 8-Br-cAMP and dibutyryl-cAMP 10-330 mumol/l, or the phosphodiesterase inhibitors rolipram 1-10 mumol/l and AH 21-132 l mumol/l; it was increased by AH 21-132 10-100 mumol/l. Forskolin concentration-dependently increased the evoked 3H overflow, and this effect was not attenuated by omission of cocaine. The facilitatory effect of forskolin was more pronounced at 0.66 Hz than at 2 Hz. Rolipram, AH 21-132, 8-Br-cAMP or dibutyryl-cAMP also produced a concentration-dependent increase in evoked 3H overflow (8-Br-cAMP was more effective than dibutyryl-cAMP in this respect). Except for the highest concentration investigated, AH 21-132 was more effective in facilitating evoked overflow than in increasing basal efflux. Forskolin, AH 21-132 or 8-Br-cAMP did not alter the percentages of 3H-noradrenaline and 3H-metabolites contained in basal tritium efflux or in stimulation-evoked tritium overflow. When a combination of AH 21-132 plus 8-Br-cAMP or AH 21-132 plus forskolin was administered, the facilitatory effect on evoked tritium overflow was more pronounced than with the single compounds alone. ACTH1-24 also facilitated the evoked tritium overflow. Combined exposure to ACTH1-24 plus forskolin, ACTH1-24 plus AH 21-132 or ACTH1-24 plus forskolin plus AH 21-132 resulted in a clearly more pronounced increase in evoked tritium overflow than exposure to the single compounds alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Excitatory and inhibitory effects of 5-hydroxytryptamine in mesenteric arteries of spontaneously hypertensive rats

Some of the presynaptic and postsynaptic excitatory and inhibitory actions of 5-hydroxytryptamine (5-HT) in the rat mesentric arteries were reexamined with particular reference to the genetic hypertensive rat model. Mesentric arteries were perfused and the perfusion pressure monitored in the presence or absence of 5-HT, norepinephrine or periarterial sympathetic nerve stimulation. The vasoconstrictor response to 5-HT was resistant to prazosin but effectively inhibited by cyproheptadine and ketanserin. The vasoconstrictor responses to norepinephrine and nerve stimulation were markedly potentiated by 5-HT, and this potentiation was blocked by ketanserin at concentrations which inhibited the 5-HT-induced vasoconstriction, while much higher concentrations were required for cyprohheptadine. No significant difference was found in these regards between mesenteric arteries from the spontaneously hypertensive rats (SHR) and those from the normotensive Kyoto Wistar rats (WKY). 5-HT significantly increased the nerve stimulation-evoked 3H overflow in [3H]norepinephrine-treated mesenteric arteries of SHR, but reduced the 3H overflow in the WKY preparations. These results suggest that ketanserin-sensitive 5-HT2 receptors are involved in the potentiating effect of 5-HT in the rat mesenteric arteries, and that an increase in transmitter release by 5-HT may contribute to its potentiation of nerve stimulation-induced vasoconstriction in SHR.

Increased Affinity and Preference of Halogenated Derivatives of BE 2254 for α1-Adrenoceptors Demonstrated by Functional and Binding Experiments

Summary: The effects of congeners of BE 2254 (2-[β-(4′-hydroxyphenyl)-ethyl-aminomethyl]-tetralone), an α1-adrenoceptor antagonist, were compared in functional and binding experiments. In detail, we studied the effects of the compounds on the electrically evoked 3H overflow (α2-adrenoceptor-mediated) and on the evoked contractions (α1-adrenoceptor-mediated) of strips from rabbit pulmonary artery preincubated with [3H]noradrenaline as well as their effects on [3H]yohimbine binding to human platelet membranes (α2-adrenoceptors) and [3H]prazosin binding to rat liver plasma membranes (α1-adrenoceptors). The potencies of the drugs at the presynaptic α2-adrenoceptors of the rabbit pulmonary artery and their affinities for [3H]yohimbine binding sites of human platelets were closely correlated. The same held true for their potencies at the postsynaptic α1-adrenoceptors of the rabbit pulmonary artery and their affinities for [3H]prazosin binding sites of rat hepatic membranes. Compared with the parent compound, the monohalogenated derivatives of BE 2254 (i.e., the 3′-I, 3′-Br, and 3′-Cl analogues) exhibited an even higher affinity (equal to that of prazosin) and a higher selectivity for α1-adrenoceptors (inferior to that of prazosin, but similar to that of corynanthine).

Increased Affinity and Preference of Halogenated Derivatives of BE 2254 for α1-Adrenoceptors Demonstrated by Functional and Binding Experiments

The effects of congeners of BE 2254 (2-[beta-(4'-hydroxyphenyl)-ethyl-aminomethyl]-tetralone), an alpha 1-adrenoceptor antagonist, were compared in functional and binding experiments. In detail, we studied the effects of the compounds on the electrically evoked 3H overflow (alpha 2-adrenoceptor-mediated) and on the evoked contractions (alpha 1-adrenoceptor-mediated) of strips from rabbit pulmonary artery preincubated with [3H]noradrenaline as well as their effects on [3H]yohimbine binding to human platelet membranes (alpha 2-adrenoceptors) and [3H]prazosin binding to rat liver plasma membranes (alpha 1-adrenoceptors). The potencies of the drugs at the presynaptic alpha 2-adrenoceptors of the rabbit pulmonary artery and their affinities for [3H]yohimbine binding sites of human platelets were closely correlated. The same held true for their potencies at the postsynaptic alpha 1-adrenoceptors of the rabbit pulmonary artery and their affinities for [3H]prazosin binding sites of rat hepatic membranes. Compared with the parent compound, the monohalogenated derivatives of BE 2254 (i.e., the 3'-I, 3'-Br, and 3'-Cl analogues) exhibited an even higher affinity (equal to that of prazosin) and a higher selectivity for alpha 1-adrenoceptors (inferior to that of prazosin, but similar to that of corynanthine).