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PubMed1994

Direct demonstration of NO formation in vivo from organic nitrites and nitrates, and correlation to effects on blood pressure and to in vitro effects.

Previous studies, utilizing nitric oxide synthase inhibitors and nitric oxide application, indicate that nitric oxide has the capacity to modulate contractile responses in pulmonary vessels. In the present study, in vitro effects of organic nitrates/nitrites were compared with their in vivo ability to generate nitric oxide and their effects on blood pressure. Glyceryl trinitrate, ethyl nitrite, isobutyl nitrate, isobutyl nitrite, isoamyl nitrite and butyl nitrite inhibited contractions in response to nerve stimulation in guinea pig pulmonary artery and vas deferens. Glyceryl trinitrate (also known as nitroglycerin) was the most potent and isobutyl nitrate the least potent substance with this action (IC50 4.5 +/- 0.2 x 10(-10) and 1.1 +/- 0.1 x 10(-5) M, respectively). Contractile responses to noradrenaline were inhibited, whereas noradrenaline release was unaffected by organonitrates/nitrites, indicating a post-junctional inhibitory effect. When infused intravenously to anaesthetized rabbits glyceryl trinitrate, ethyl nitrite and isobutyl nitrate generated dose-dependent increments of nitric oxide in exhaled air and dose-dependent decrements in systemic blood pressure. Significant correlations were obtained between in vivo NO generation and effects on blood pressure, as well as between NO generation in vivo and the in vitro activity of the organic nitrites and organic nitrates. In conclusion, organic nitrites and organic nitrates can modulate adrenergic neuroeffector transmission in guinea pig pulmonary artery and vas deferens, and produce detectable concentrations of nitric oxide in exhaled air in vivo, in the rabbit. The observations give direct in vivo evidence that organic nitrites and nitrates generate NO, and strongly support them exerting their action via NO formation.

Animals↗
PubMed1986

Neuroeffector transmission in the guinea-pig internal anal sphincter: an electrical and mechanical study.

ATP (10(-7)-10(-4) M), ADP (10(-7)-10(-4) M), AMP (10(-7)-10(-4) M) and adenosine (10(-6)-10(-4) M) each hyperpolarized the membrane, inhibited spontaneous spike discharge and relaxed the guinea-pig internal anal sphincter. All experiments were carried out using intracellular microelectrode and simultaneous tension recording techniques in the presence of phentolamine (10(-6) M) and atropine (10(-6) M). ATP was the most effective and produced a concentration-dependent membrane potential change comparable in amplitude to that produced by field stimulation of non-adrenergic non-cholinergic (NANC) nerves. Inhibitory junction potentials, the accompanying relaxations and the responses to ATP (5 X 10(-6)-5 X 10(-5) M) were additive and were increased in K+-deficient and decreased in K+-rich solutions and inhibited by apamin (10(-7) M). A proteolytic enzyme, alpha-chymotrypsin (0.5 U/ml) preferentially antagonized the ability of vasoactive intestinal polypeptide (10(-7) M) to hyperpolarize the membrane and relax the sphincter. The electrical and mechanical responses to ATP (10(-5) M) and inhibitory nerve stimulation were only slightly reduced. The results are consistent with the view that ATP or a related adenine nucleotide may have a transmitter role in the guinea-pig internal anal sphincter.

Adenine Nucleotides↗
PubMed1985

Relative pre- and postjunctional roles of noradrenaline and adenosine 5'-triphosphate as neurotransmitters of the sympathetic nerves of guinea-pig and mouse vas deferens.

Experiments were designed to examine the relative roles of noradrenaline and adenosine 5'-triphosphate (ATP) as mediators of the contractile responses of the guinea-pig and the mouse vas deferens to electrical nerve stimulation. To study possible prejunctional actions of the agents used, in some experiments their effects on the secretion of [3H]noradrenaline were determined. The contractile responses were recorded with force displacement transducers. Pharmacological techniques were employed to examine the pre- and/or postjunctional effects mediated by noradrenaline and ATP, respectively. Noradrenaline-mediated components were "removed" by depleting the neuronal stores of noradrenaline (by pretreatment with reserpine), or by addition of adrenoceptor-blocking agents. ATP-mediated components were "removed" by desensitizing ATP receptors (with the stable analogue alpha, beta-methylene ATP). The results permit three major conclusions: (1) In both species noradrenaline and ATP "auto-inhibit" mechanisms responsible for transmitter secretion; the prejunctional effects of ATP are less marked in the mouse vas deferens, and in both species much weaker than those mediated by noradrenaline, acting via alpha 2-adrenoceptors. (2) In these species, both noradrenaline and ATP participate in the generation of both phases of the contractile responses to nerve stimulation. The relative roles of each vary with the frequency and train length of stimulation, and also with the species. The main transmitter of "phase I" contractions in guinea-pig vas deferens is ATP, and in the mouse vas deferens, noradrenaline. "Phase II" contractions are triggered mainly by noradrenaline, in both species. Sympathetic neuroeffector transmission in these tissues can be accounted for almost entirely in terms of dynamic interplay between pre- and postjunctional actions of noradrenaline and ATP. (3) The results are compatible with the hypothesis that ATP is a co-transmitter with noradrenaline in these sympathetic nerves.

Adenosine Triphosphate↗
PubMed1985

Neurogenic control of cerebral circulation.

The cerebral vascular neuromuscular apparatus consists of a varicose perivascular nerve plexus at the adventitial-medial border and smooth muscle cells in the medial coat that are functionally connected. In addition to noradrenaline and acetylcholine, a number of putative non-adrenergic, non-cholinergic neurotransmitters have been identified in cerebral perivascular nerves, including serotonin, substance P, vasoactive intestinal polypeptide, gastrin-releasing peptide, cholecystokinin, somatostatin, neurotensin, calcitonin gene-related peptide and neuropeptide Y. The role of adenosine-5'-triphosphate as a cotransmitter with noradrenaline in some perivascular sympathetic nerves, and of endothelial cells in mediating the vasodilatation produced by some neurohumoral agents is discussed. Speculations are made about the relation between vascular neuroeffector mechanisms and migraine, including the possibility of local vasospasm by serotoninergic nerves, reactive hyperaemia involving purine nucleotides and nucleosides, release of substance P from sensory nerve collaterals during antidromic ('axon reflex') impulses and secondary release of local agents such as prostanoids, histamine and bradykinin.

Acetylcholine↗
PubMed1991

Effects of cromakalim on neurally-mediated responses of guinea-pig tracheal smooth muscle.

1. The ability of cromakalim to modulate several different types of neuroeffector transmission has been assessed in guinea-pig isolated trachea. 2. In trachea treated with propranolol (10(-6) M) and indomethacin (2.8 x 10(-6) M), stimulation of the extrinsic vagal nerves evoked contractions which were blocked by hexamethonium (5 x 10(-4) M) or by tetrodotoxin (TTX; 10(-6) M). Cromakalim (10(-5) M) caused a two fold rightward shift of the frequency-response curve. 3. In carinal trachea treated with propranolol and indomethacin, transmural stimulation evoked an initial, rapid contraction followed by a more sustained secondary contraction. The initial, rapid contractile response was virtually ablated by atropine (10(-6) M) or by TTX but was resistant to hexamethonium. Cromakalim (10(-8)-10(-5) M) caused a concentration-dependent rightward shift of the frequency-response curve for the initial contraction. 4. In carinal trachea treated with atropine, propranolol and indomethacin, transmural stimulation evoked only the secondary (non-adrenergic, non-cholinergic (NANC] contractile responses. These were markedly reduced by TTX but were resistant to hexamethonium. Cromakalim (10(-8)-10(-5) M) suppressed the NANC contractile responses in a concentration-dependent manner. This action could be offset by glibenclamide (10(-6) M). 5. In trachea treated with atropine, histamine (10(-4) M), propranolol and indomethacin, transmural stimulation evoked NANC relaxant responses. Cromakalim (up to 10(-5) M) was without effect on the frequency-response curve for the stimulation of NANC inhibitory nerves. 6. Tested on trachea bathed by drug-free Krebs solution, cromakalim (10(-7)-10(-5) M) caused concentration-dependent suppression of tracheal tone. In trachea treated with propranolol and indomethacin, cromakalim (10- 7-1O- 5 M) caused concentration-dependent antagonism of acetylcholine (ACh). In trachea treated with atropine, propranolol and indomethacin, cromakalim (up to 10- 5M) failed to antagonize effects of either histamine or substance P.7. It is concluded that cromakalim can inhibit cholinergic (excitatory) neuroeffector transmission in the trachea but only at a concentration having demonstrable inhibitory activity against the action of exogenous ACh and the spontaneous tone of the airways smooth muscle. In contrast, cromakalim may depress NANC excitatory (putative peptidergic) neuroeffector transmission at a concentration below that exerting inhibitory activity on airways smooth muscle. Cromakalim does not concurrently depress NANC inhibitory neuroeffector transmission. Depression of NANC excitatory neuroeffector transmission could explain the ability of cromakalim to suppress airway hyperreactivity or bronchial asthma at doses lacking direct relaxant effect on airways smooth muscle.

Animals↗
PubMed1983

Membrane properties and innervation of smooth muscle cells in Hirschsprung's disease.

Mechanical and membrane properties of smooth muscle cells and/or neuroeffector transmission in the aganglionic segment of the large intestine (Hirschsprung's disease) were compared with findings in the ganglionic segment. Tension-recording, microelectrode, and double sucrose gap methods were used. There was no difference in resting membrane potential of the longitudinal or circular muscle cell in these two segments, which were obtained at biopsy in Japanese children. In the ganglionic preparations, generations of regular prepotentials, with or without the spike, correlated well to the rhythmic contractions. However, in the aganglionic segment, irregular spike and contraction only were observed. In the circular or longitudinal muscle of the ganglionic segments, field stimulations evoked inhibitory junction potentials, excitatory junction potentials, or both and triggered initial relaxation and then a contraction of the tissue. In the aganglionic segment, however, field stimulation evoked only excitatory junction potentials followed by contraction. These results indicate that, in cases of Hirschsprung's disease, there may be a deficiency in the nonadrenergic inhibitory pathways. This is the first evidence for a lack of spasticity in muscle from the aganglionic segment of the large intestine obtained from children with Hirschsprung's disease.

Cell Membrane↗
PubMed2003

The sources and sequestration of Ca(2+) contributing to neuroeffector Ca(2+) transients in the mouse vas deferens.

The detection of focal Ca(2+) transients (called neuroeffector Ca(2+) transients, or NCTs) in smooth muscle of the mouse isolated vas deferens has been used to detect the packeted release of ATP from nerve terminal varicosities acting at postjunctional P2X receptors. The present study investigates the sources and sequestration of Ca(2+) in NCTs. Smooth muscle cells in whole mouse deferens were loaded with the Ca(2+) indicator Oregon Green 488 BAPTA-1 AM and viewed with a confocal microscope. Ryanodine (10 microM) decreased the amplitude of NCTs by 45 +/- 6 %. Cyclopiazonic acid slowed the recovery of NCTs (from a time course of 200 +/- 10 ms to 800 +/- 100 ms). Caffeine (3 mM) induced spontaneous focal smooth muscle Ca(2+) transients (sparks). Neither of the T-type Ca(2+) channel blockers NiCl2 (50 microM) or mibefradil dihydrochloride (10 microM) affected the amplitude of excitatory junction potentials (2 +/- 5 % and -3 +/- 10 %) or NCTs (-20 +/- 36 % and 3 +/- 13 %). In about 20 % of cells, NCTs were associated with a local, subcellular twitch that remained in the presence of the alpha1-adrenoceptor antagonist prazosin (100 nM), showing that NCTs can initiate local contractions. Slow (5.8 +/- 0.4 microm s(-1)), spontaneous smooth muscle Ca(2+) waves were occasionally observed. Thus, Ca(2+) stores initially amplify and then sequester the Ca(2+) that enters through P2X receptors and there is no amplification by local voltage-gated Ca(2+) channels.

Adenosine Triphosphate↗
PubMed1990

Modulation of cholinergic neurotransmission by the peptide VIP, VIP antiserum and VIP antagonists in dog and cat trachea.

1. Comparative studies on the effects of vasoactive intestinal polypeptide (VIP), commercially available VIP antiserum or VIP antagonists [Ac-Tyr1, D-Phe2]-GRF(1-29)-NH2 and [4-Cl-D-Phe6, Leu17]-VIP on excitatory neuroeffector transmission in the dog and cat trachea were performed with microelectrode, double sucrose-gap, and tension recording methods. 2. VIP (10(-11)-10(-9) M) had no effect on the resting membrane potential or on the input resistance of the smooth muscle cells of dog and cat trachea. However, with increased concentrations (greater than 10(-8) M) VIP hyperpolarized the membrane and decreased the input resistance of the membrane in both tissues. 3. VIP (10(-10)-10(-7) M) dose-dependently reduced the amplitude of the contractions evoked through the nervous structure excited by field stimulation in the combined presence of indomethacin (10(-5) M) and guanethidine (10(-6) M) in the dog, and in the presence of guanethidine (10(-6) M) in cat trachea. In parallel with actions on twitch contractions, VIP (10(-11)-10(-7) M) reduced the amplitude of the excitatory junction potentials (EJPs) evoked through the nervous structure excited by single pulse field stimulation in both tissues. 4. VIP (10(-9) M) had no effect on the post-junctional response of smooth muscle cells to exogenous acetylcholine (ACh) (10(-9)-10(-5) M). 5. During repetitive field stimulation at the stimulus frequency of 0.033-0.1 Hz, the amplitude of the EJPs was gradually reduced, and VIP (10(-9) M) enhanced this depression phenomenon in the dog and cat trachea. 6. EJPs also showed summation when repetitive field stimulation was applied at high frequency (20 Hz) in the dog trachea. The slope of the relationship between the relative amplitude of the EJP and number of stimuli at 20 Hz was 2.2 +/- 0.4 mV/stimulation (n = 4) in the dog trachea. However, in the cat trachea, summation of EJPs was not prominent, giving a mean slope of 0.6 +/- 0.2 mV/stimulation (n = 6) measured by the microelectrode method. VIP (10(-9) M) shifted downward the relationship between the relative amplitude of the EJP and the number of stimuli at 20 Hz in both tissues. 7. Overnight incubation with VIP antiserum (10(-6) g/ml) had little effect on the depression of the EJP in the dog and cat trachea, or the summation of the EJP observed in the dog trachea.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcholine↗
PubMed1987

Electrophysiological evidence for an alpha 2-adrenergic inhibitory control of transmitter release in the rabbit mesenteric artery.

Excitatory junction potentials (e.j.p.s) evoked by nerve stimulation with 15 pulses at 1 Hz were recorded from muscle cells of the rabbit isolated mesenteric artery. Clonidine and B-HT 933 depressed all e.j.p.s in the train. The percentage inhibition was inversely related to the number of pulses. Yohimbine, rauwolscine and tolazoline reduced the early e.j.p. amplitudes but enhanced the later ones. The percentage facilitation of e.j.p.s increased with the number of pulses until a maximum was reached. Prazosin and corynanthine did not influence the first few e.j.p.s but potentiated the subsequent ones; their effects were less pronounced than those of yohimbine and rauwolscine. All the drugs antagonized the inhibition by clonidine but the effects of yohimbine and rauwolscine were more marked than those of prazosin and corynanthine. Phenylephrine, St 587 and noradrenaline depressed the e.j.p.s. Yohimbine diminished the effects of these substances and was a stronger antagonist of phenylephrine than prazosin. We suggest that, in the rabbit mesenteric artery, noradrenaline and the neuroeffector transmitter (probably ATP) are co-released from the terminals of postganglionic sympathetic nerves. Noradrenaline activates presynaptic alpha 2-adrenoceptors and thereby depresses transmitter release. The degree of presynaptic inhibition depends on the number of pulses applied, i.e. on the biophase concentration of noradrenaline.

Adrenergic alpha-Agonists↗
PubMed1992

Effects of BRL 38227 on neurally-mediated responses in the guinea-pig isolated bronchus.

1. In guinea-pig isolated bronchus treated with indomethacin (2.8 microM), electrical field stimulation (EFS; 10 Hz, 0.5 ms, 60-70 V, for 10 s) evoked a tetrodotoxin (3 microM)-sensitive, biphasic contraction comprising a rapid, atropine (1 microM)-sensitive cholinergic response succeeded by a slowly developing, capsaicin (10 microM)-sensitive, non-adrenergic, non-cholinergic excitatory (NANCe) response. 2. BRL 38227 (0.3-3 microM), salmeterol (0.003-3 microM) and ketotifen (1.0-300 microM) each produced concentration-dependent inhibition of both NANCe and cholinergic responses to EFS in guinea-pig isolated bronchus. 3. Substance P (SP; 1 microM) and neurokinin A (NKA; 0.07 microM) produced contractions equivalent in magnitude to the NANCe response to EFS, which were inhibited by salmeterol (1 microM), but not by BRL 38227 (3 microM) or ketotifen (100 microM). 4. Acetylcholine (ACh; 6 microM) was equi-effective with the electrical activation of cholinergic neurones. BRL 38227 (3 microM) slightly inhibited responses to ACh (6 microM). Salmeterol (1 microM) and ketotifen (100 microM) markedly inhibited responses to ACh (6 microM). 5. In bronchial rings pre-contracted with ACh (100 microM), BRL 38227 (0.1-30 microM), salmeterol (0.001-3 microM) and ketotifen (0.1-100 microM) each produced concentration-dependent relaxation. Unlike ketotifen, BRL 38227 and salmeterol only partially (18.8 +/- 2.1% and 51.8 +/- 3.9% respectively) reversed the ACh-induced contraction. 6. The (+)-analogue of BRL 38227, BRL 38226 (0.3-100 microM), was without effect on responses to EFS and had no effect on the inhibition caused by BRL 38227. The K+-channel activators pinacidil (3.0-30 microM) and RP 52891 (3.0-30 microM) exerted similar inhibitory actions on responses to EFS as BRL 38227, but were less potent. Glibenclamide (0.1-1.O microM) and phentolamine (3 microM) antagonized the inhibitory effects of BRL 38227 on responses to EFS.7. It is concluded that BRL 38227 and ketotifen can inhibit NANCe neuroeffector transmission at concentrations exerting little or no inhibitory effects on responses to exogenously applied tachykinins.By contrast, in addition to suppressing NANCe responses to EFS, salmeterol also markedly inhibits responses to SP and NKA. At concentrations markedly suppressing cholinergic neuroeffector transmission, BRL 38227 has only minor effects on responses to exogenously-applied ACh. Salmeterol and ketotifen both depress responses to ACh within the concentration-range over which they inhibit cholinergic responses to EFS. The inhibitory effects of BRL 38227 on responses to EFS exhibit stereo-specificity and may involve the opening of a neuronal K+-channel. This K+-channel is glibenclamide-and phentolamine-sensitive and appears similar to the smooth muscle K+-channel which is modulated by BRL 38227.

Albuterol↗
PubMed1976

Neurogenic sympathetic vasoconstriction of the rabbit basilar artery.

When examined by fluorescence microscopy the rabbit basilar artery contains a rich adrenergic-like plexus at the adventitiomedial junction. The fluorescence disappears upon chronic reserpinization and bilateral superior cervical ganglionectomy. Transmural stimulation of intramural nerves a results in a response which is predominantly constrictor but also contains a small, inconstant dilator component. The constrictor response is abolished by chronic reserpinization, bilateral superior cervical ganglionectomy, and cold storage of the preparation. The constriction is prevented by the adrenergic neuron blocking agents guanethidine and bretylium but not by such alpha-adrenergic receptor blocking agents as phenoxybenzamine (PBZ), phentolamine, and tolazoline. Our results show that doses of the three latter agents sufficient to abolish contractions to norepinephrine (NE) in concentrations of up to 10(-2) M only potentiate and prolong the contractile response to nerve stimulation. The beta-adrenergic receptor blocking agent, propranolol, and inhibitors of NE neuronal uptake, such as desipramine (desmethylimipramine, DMI) and cocaine, do not influence the size of the neurogenic response. These results suggest that the vasoconstrictor component of the rabbit basilar artery response to transmural nerve stimulation (TNS) is mediated via sympathetic adrenergic-like neurons, but at the same time also raise the question whether the transmission process is typical of classic adrenergic neuroeffector mechanisms.

Animals↗
PubMed1993

Effect of arachidonic acid on twitch tension of the rat phrenic nerve-diaphragm.

Recent studies have demonstrated that unsaturated fatty acids are involved in the regulation of neuroeffector function. I have extended these studies by examining the effect of arachidonic acid on neuromuscular function in vitro using the rat phrenic nerve-diaphragm preparation. Arachidonic acid caused a time-and dose-dependent reduction in indirectly stimulated twitch tension, but had no effect on directly stimulated twitch tension. Linoleic acid and linolenic acid also reduced indirectly stimulated twitch tension, whereas stearic acid, oleic acid and arachidic acid had no effect. None of three blockers of arachidonic acid metabolism, the cyclooxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguaiaretic acid or the cytochrome P-450 inhibitor ketoconazole, altered the effect of arachidonic acid on twitch tension. The free radical scavenger superoxide dismutase eliminated the inhibitory effect of arachidonic acid on twitch tension, suggesting that superoxide anion played a role in arachidonic acid's action.

Animals↗
PubMed1985

The effect of hypoxia on neuroeffector transmission in the bovine retractor penis and rat anococcygeus muscles.

The effects of reducing the PO2 of the bathing fluid were studied on non-adrenergic non-cholinergic (NANC) transmission in isolated preparations of the bovine retractor penis muscle, the rat anococcygeus muscle, the guinea-pig taenia caeci and the guinea-pig urinary bladder. Hypoxia rapidly and reversibly impaired NANC transmission in the bovine retractor penis and rat anococcygeus muscles but did not affect transmission in the guinea-pig taenia caeci or bladder, suggesting that different NANC mechanisms are involved. Although neurally-evoked relaxation of the bovine retractor penis was impaired by hypoxia, relaxations produced by vasoactive intestinal peptide, prostaglandin E1, sodium nitroprusside or an inhibitory factor isolated from the bovine retractor penis were unaffected. Since the inhibitory factor is similar to, and may actually be the NANC transmitter, the results suggest that the site of action of hypoxia in impairing transmission is prejunctional at the inhibitory nerve endings.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed1985

Pre- and postjunctional modulation of cholinergic neuroeffector transmission by adenine nucleotides. Experiments with agonist and antagonist.

Adenosine, 2-chloroadenosine, AMP, AMPNH2, ADP, ATP, AMPPNP and beta, gamma meATP dose-dependently and reversibly inhibited contractile responses to nerve stimulation in longitudinal plexus-containing muscle preparations of guinea pig ileum. All the purines, except for 2-chloroadenosine, were virtually equipotent and elicited maximal inhibition within 2 min after application. Adenosine deaminase abolished inhibition by adenosine but did not block the effect of 2-chloroadenosine or the adenine nucleotides. During transmural nerve stimulation, the nucleotidase-resistant analogues alpha, beta meADP and AMPPNP significantly depressed acetylcholine release measured by gas chromatography-mass spectrometry. The inhibitory effect of all the purines was competitively, reversibly and at comparable pA2 values antagonized by 8-p-sulphophenyltheophylline. The results indicate that nucleotides per se can inhibit neurotransmission via a prejunctional receptor common to nucleosides and nucleotides. An excitatory effect by all the di- and triphosphate nucleotides was also observed. The excitation was unaltered by atropine, tetrodotoxin and 8-p-sulphophenyltheophylline, thus suggesting an action at postjunctional ADP- and ATP-like receptive sites.

Adenine Nucleotides↗
PubMed1985

Antibiotic depression of evoked and spontaneous responses of opossum distal colonic muscularis mucosae in vitro: a factor in antibiotic-associated colitis?

Certain antibiotics depress both skeletal neuromuscular transmission and intestinal neuroeffector transmission. Impaired intestinal motility may facilitate the proliferation of the bacterium Clostridium difficle and thus lead to the development of antibiotic-associated pseudomembranous colitis. Many antibiotics accumulate in the colonic lumen at concentrations several times their associated blood levels. This study examined whether certain of these could interfere with colonic muscularis mucosal movement in vitro, using tissue from opossum distal colon as a model. At concentrations approximating those in the colonic lumen, ampicillin, clindamycin, erythromycin, and lincomycin depressed tone and spontaneous contractions of the muscularis mucosae. Clindamycin, gentamicin, kanamycin, and lincomycin abolished electrically evoked contractions but only gentamicin and kanamycin could abolish the ensuing relaxation. Vancomycin potentiated the response of the muscularis mucosae to acetylcholine; erythromycin and clindamycin depressed it. Antibiotic-induced depression of colonic muscularis mucosal movement may contribute to the development of antibiotic-associated pseudomembranous colitis.

Animals↗
PubMed1985

Neurohumoral control of blood vessels: some future directions.

The recent discoveries of vascular neuroeffector control mechanisms, involving a wide variety of neurohumoral agents, pre- and postjunctional neuromodulation, and cotransmission, leave the field poised for growth in new directions. Some of these are outlined in this article, including: the development of methods for quantitation of the pattern and density of different types of perivascular nerves; exploration of the potent actions of purine nucleotides and nucleosides on vascular smooth muscle and/or endothelial cells, particularly in relation to the development of drugs of therapeutic potential; expansion of studies of the regulatory implications of cotransmitter release of ATP together with noradrenaline from some sympathetic perivascular nerves and of VIP together with acetylcholine from some parasympathetic nerves; autoradiographic localization of receptors for monoamines, peptides of and purines in blood vessels; wider studies of "axon reflex" control of the circulation and of the roles of substance P; investigation of development, aging, and regeneration of different perivascular nerve types, and the long-term "trophic" actions of some neurohumoral agents. Lastly, the time is ripe to study abnormalities in neurohumoral control of vessels in disease and after chronic exposure to drugs.

Animals↗
PubMed1989

Presynaptic dopamine DA2-receptors in rabbit jejunal arteries. An electrophysiological study.

Excitatory junction potentials (e.j.ps) evoked by nerve stimulation with 15 pulses at 1 Hz were recorded from muscle cells of rabbit isolated jejunal arteries. LY 171555 1 mumol/l, SKF 38393 10 mumol/l, dopamine 10 mumol/l and clonidine 0.1 mumol/l depressed all e.j.ps in the train. The percentage inhibition was inversely related to the number of pulses. S- and R-sulpiride, 10 mumol/l, domperidone 1 mumol/l, SCH 23390 1 mumol/l and rauwolscine 1 mumol/l did not change, or even depressed the first e.j.ps. Of these compounds only S- and R-sulpiride, 10 mumol/l and rauwolscine 1 mumol/l facilitated the late e.j.ps. The percentage facilitation increased with the number of pulses until a maximum was reached; rauwolscine 1 mumol/l had the largest effect. S- and R-sulpiride, 10 mumol/l, as well as domperidone 1 mumol/l antagonized the action of LY 171555 1 mumol/l. S-Sulpiride was more potent than its R-isomer. SCH 23390 1 mumol/l and rauwolscine 1 mumol/l blunted the effect of SKF 38393 10 mumol/l. Rauwolscine 1 mumol/l slightly reduced the inhibition by dopamine 10 mumol/l; S-sulpiride 10 mumol/l was antagonistic only in the presence of rauwolscine 1 mumol/l. When rauwolscine 1 mumol/l, prazosin 0.1 mumol/l, propranolol 1 mumol/l and cocaine 10 mumol/l was added to the medium, dopamine 10 mumol/l continued to produce the same depression of e.j.ps, as in the absence of these compounds. Under such conditions S-sulpiride 10 mumol/l also counteracted dopamine 10 mumol/l. Rauwolscine 1 mumol/l prevented the effect of clonidine 0.1 mumol/l. The antagonists were not absolutely selective against only one type of agonist. We suggest that both presynaptic DA2- and postsynaptic DA1-receptors are present in rabbit jejunal arteries. The activation of either receptor-type may depress the e.j.ps. Dopamine interferes with neuroeffector transmission due to alpha 2-adrenoceptor agonist properties; its DA2-effect is unmasked only after alpha 2-adrenoceptor blockade. There was no evidence for a co-transmitter function of dopamine.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1994

Localization of nitric oxide synthase activity in the human lower urinary tract and its correlation with neuroeffector responses.

OBJECTIVES: The present study was designed to correlate the localization of nitric oxide synthase (NOS) activity to nerve-induced smooth muscle responses in the human lower urinary tract. METHODS: Nerve-induced smooth muscle activity was studied in the human lower urogenital tract. NOS activity was studied by measurement of citrulline formation and guanylate cyclase activity. RESULTS: Nerve-induced contractions in the human detrusor muscle, bladder neck, and prostatic urethra were not significantly enhanced by the NOS inhibitor N omega-nitro-L-arginine methyl ester (L-NAME). In the prostatic urethra, relaxations to transmural nerve stimulation were obtained after increase in tension. The relaxations were abolished by L-NAME and restored by L-arginine. Nerve-induced relaxations were occasionally obtained in the bladder neck, whereas nerve-induced relaxations were never obtained in the detrusor muscle. Citrulline formation was highest in the prostatic urethra, it was intermediate in the bladder neck, and it was less pronounced in the detrusor muscle. Guanylate cyclase activity was also highest in the prostatic urethra, whereas there was no significant difference in guanylate cyclase activity in the bladder neck and detrusor muscle. CONCLUSIONS: The nerve-induced smooth muscle responses and the localization of NOS activity were in good agreement. Thus, in areas where marked relaxations to nerve stimulation were obtained, there was also a high NOS activity. The data suggest that nitric oxide is a mediator for the neurogenic dilation of the bladder neck and urethra during the micturition reflex.

Amino Acid Oxidoreductases↗