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PubMed2001

Dopamine induces ERK activation in renal epithelial cells through H2O2 produced by monoamine oxidase.

BACKGROUND: The rat renal proximal tubule cells contain a large amount of monoamine oxidase, which catalyzes the oxidative deamination of catecholamines such as dopamine (DA). The aim of this study is to investigate the potential role of hydrogen peroxide (H2O2) produced by monoamine oxidase (MAO) isoform on regulation of cell signaling and function. METHODS: Primary rat proximal tubular cells, which contain almost exclusively MAO-A, and human embryonic kidney 293 (HEK 293) cells stably transfected with human MAO-B cDNA were treated with DA or tyramine in the presence or the absence of some inhibitors. Then, Shc protein tyrosine phosphorylation and extracellular-regulated kinase (ERK) activation were evaluated by immunoprecipitation/immunoblot analysis and cell proliferation by [3H]thymidine incorporation or cell counting. RESULTS: In rat proximal tubule cells, DA induced tyrosine phosphorylation of Shc, ERK activation, and a significant increase in DNA synthesis. The involvement of MAO-dependent H2O2 generation induced by DA (5 micromol/L) was supported by the demonstration that the DA effects were (1) fully prevented by cell pretreatment with the MAO inhibitor pargyline, the antioxydant N-acetylcysteine (NAC), and the DA uptake inhibitor GBR 12909; (2) not abrogated by the D1 and D2 receptor antagonists; (3) observed in HEK 293 MAO-B cells but not in HEK 293 wild-type cells, which do not express MAO; and (4) similar to those induced by another MAO substrate, tyramine. CONCLUSIONS: Taken together, these results show that in addition to the effects related to receptor stimulation, DA, and probably the other catecholamines, may induce some of its effects through the MAO-dependent H2O2 production.

Adaptor Proteins, Signal Transducing↗
PubMed1975

[Clinical experimental studies in patients with asympathicotonic hypotension].

Three patients with postural hypotension (two of the idiopathic type, one possibly due to familial dysautonomia) were found to have not only the pathognomonic postural hypotension, without rise in heart rate, cardiac output and peripheral vascular resistance, but also a similarly abnormal regulatory mechanism on ergometric stress when recumbent. There was a delayed-response to the bloodpressure fall on Valsalva a manoeuvre, and the blood volume was reduced. A combined effect of these factors explains that these patients have a more marked impairment of physical capcity than might be expected merely from the orthostatic hypotension. The actions of noradrenaline, adrenaline, phenylephrine, isoproterenol, angiotensin and tyramine on blood pressure and heart rate were different from normal. Plasma-renin activity was reduced in all three patients and could not be raised. Urinary excretion of adrenaline and noradrenaline was markedly diminished. Reactions to noradrenaline and tyramine, as well as the excretion pattern of the catecholamine metabolites suggest a disorder of active adrenaline liberation. Furthermore, different disorders of catecholamine metabolism underlie idiopathic orthostatic hypotension and familial autonomia. Therapeutic trials with fludrocortisone, beta-receptor blockers and levodopa brought improvement, but long-term results are not yet available.

Achievement↗
PubMed1986

Monoamine oxidase in bovine thyroid tissue.

Two functional forms of monoamine oxidase (MAO) defined as MAO A and MAO B have been described in several tissues. In this study the characteristics of MAO present in a particulate subcellular fraction of bovine thyroid tissue were investigated. The selective inhibitors of MAO, clorgyline (A form) and deprenyl (B form) were used. The monoamines 5-hydroxytryptamine (5-HT) (preferred of the A form), tyramine (both forms) and beta-phenylethylamine (PEA) (B Form) were used as substrates. MAO activity towards 5-HT was markedly inhibited by clorgyline. Tyramine oxidation was very sensitive to clorgyline and the curve obtained was in accordance with the presence of a high proportion of the A form. MAO activity towards PEA was also markedly inhibited by clorgyline. Deprenyl was not able to induce modifications in the MAO activity except when it was used at very high concentrations. According to these results the bovine thyroid tissue contains predominantly the A form of MAO. In this tissue PEA was deaminated by the A form of the enzyme.

Animals↗
PubMed1997

Synthesis and biological effects of N-alkylamine-labeled low-molecular-mass dermatan sulfate.

Dermatan sulfate (DS) is a component of connective tissue and catalyzes the heparin cofactor II-mediated inhibition of thrombin. Low-molecular-mass dermatan sulfates (LMMDS) are produced to prolong the antithrombotic activity of this substance. Cleavage of DS by nitrous acid leads to an LMMDS with a terminal 2,5-anhydrotalose (At) group at the reducing end which can react with primary amines. Tyramine (Tyr) was bound to the terminal At of LMMDS using reductive amination. LMMDS-tyr is produced using DS. LMMDS desacetglated were produced using totally deaminated DS. These compounds were employed as a model for the characterization of DS using NMR spectroscopy. The purity of the compounds was checked using capillary electrophoresis. The structure of the products was proven by 1H- and 13C-NMR spectroscopy. LMMDS-Tyr was radiolabeled with 125I for use in a radioimmunoassay. The anti-Xa activity and antithrombin activity of the tyramine-labeled DS are very low. The clotting assays Heptest, aPTT, thrombin time, and ecarin time indicate a highly anticoagulant-active substance. The heparin cofactor II-mediated inhibition of thrombin is similar to the parent compound. LMMDS were labeled "endpoint-attached." They are a new tool to understand the actions of DS in biologic systems.

Animals↗
PubMed2000

The neuropathic postural tachycardia syndrome.

BACKGROUND: The postural tachycardia syndrome is a common disorder that is characterized by chronic orthostatic symptoms and a dramatic increase in heart rate on standing, but that does not involve orthostatic hypotension. Several lines of evidence indicate that this disorder may result from sympathetic denervation of the legs. METHODS: We measured norepinephrine spillover (the rate of entry of norepinephrine into the venous circulation) in the arms and legs both before and in response to exposure to three stimuli (the cold pressor test, sodium nitroprusside infusion, and tyramine infusion) in 10 patients with the postural tachycardia syndrome and in 8 age- and sex-matched normal subjects. RESULTS: At base line, the mean (+/-SD) plasma norepinephrine concentration in the femoral vein was lower in the patients with the postural tachycardia syndrome than in the normal subjects (135+/-30 vs. 215+/-55 pg per milliliter [0.80+/-0.18 vs. 1.27+/-0.32 nmol per liter], P=0.001). Norepinephrine spillover in the arms increased to a similar extent in the two groups in response to each of the three stimuli, but the increases in the legs were smaller in the patients with the postural tachycardia syndrome than in the normal subjects (0.001+/-0.09 vs. 0.12+/-0.12 ng per minute per deciliter of tissue [0.006+/-0.53 vs. 0.71+/-0.71 nmol per minute per deciliter] with the cold pressor test, P=0.02; 0.02+/-0.07 vs. 0.23+/-0.17 ng per minute per deciliter [0.12+/-0.41 vs. 1.36+/-1.00 nmol per minute per deciliter] with nitroprusside infusion, P=0.01; and 0.008+/-0.09 vs. 0.19+/-0.25 ng per minute per deciliter [0.05+/-0.53 vs. 1.12+/-1.47 nmol per minute per deciliter] with tyramine infusion, P=0.04). CONCLUSIONS: The neuropathic postural tachycardia syndrome results from partial sympathetic denervation, especially in the legs.

Adult↗
PubMed1993

Supersensitivity to the stimulant action of noradrenaline on human myometrium near term.

Noradrenaline (10-50 nM) and tyramine (0.05-1 mM) enhanced contractile force elicited by field stimulation of strips of myometrium from non-pregnant and pregnant women. In higher concentrations, noradrenaline produced sustained contractions. The EC50 values for noradrenaline were 0.4 microM in tissues from pregnant women and 3.1 microM in tissues from non-pregnant women; maximum responses were greater in the former tissues. In addition, the effects of noradrenaline on myometrium from pregnant women were more marked on the inner layer than on the outer layer, antagonized by the alpha 1-adrenoceptor antagonist prazosin (0.1 and 1.0 microM), and unaffected by the inhibitor of neuronal uptake, nisoxetine (0.1 microM). Taken together, these observations confirm that supersensitivity to noradrenaline develops during pregnancy and is present near term. The supersensitivity to noradrenaline at term can be attributed only in part to a decrease in its removal by the sympathetic innervation, which declines towards term, because responses to tyramine were also enhanced in tissues from pregnant women. It is possible that gap junction formation may also contribute to this supersensitivity.

Adult↗
PubMed1988

Does anisocoria by clonidine reflect a central sympathetic dysfunction in cluster headache?

Local pharmacological manipulations of both pupils in persons with cluster headache (CH) have shown a reduced pain-side sympathetic activity. It is difficult to determine if this sympathetic defect is localized in the nuclei of the CNS and/or in peripheral neurons that innervate the pupil. This study demonstrates that in a CH group 2% tyramine (an intraneuronal norepinephrine releaser) instillation into both eyes induces an asymmetric and bilateral mydriasis with the onset of anisocoria characterized by a pupillary diameter being less on the pain-side eye. In addition, intravenous administration of 0.10 mg clonidine, an inhibitor of central sympathetic activity, causes a bilateral miotic response, which is more marked on the pain-side eye. In a healthy control group, clonidine induces a symmetric and bilateral miosis but less intense than that observed in both eyes of CH sufferers. In CH patients, pretreatment with clonidine augments the degree of anisocoria induced by tyramine instillation, increasing the mydriatic response only in the pain-free-side pupil. The hypothesis of a permanent sympathetic defect of the pain-side pupil expressing itself as a reduced sympathetic tone of CNS nuclei and peripheral neurons that innervate the pupil is proposed.

Adult↗
PubMed1997

Does the neuropeptide Y Y1 receptor contribute to blood pressure control in the spontaneously hypertensive rat?

OBJECTIVE: To study the effects of the selective neuropeptide Y (NPY) Y1 receptor antagonist BIBP 3226 in spontaneously hypertensive rats (SHR) in order to elucidate whether NPY function may be altered in the SHR and whether the NPY Y1 receptor plays a specific role in the maintenance of high blood pressure in this genetic form of hypertension. METHODS: Pithed and conscious SHR were studied after intravenous administration of 0.125-1 mg/kg BIBP 3226. The cardiovascular effects were evaluated under baseline conditions, under acute stress and after exogenous administration of 20 microg/kg NPY. The potentiating effects of NPY on pressor responses to phenylephrine and tyramine were studied in the SHR. RESULTS: Intravenous administration of 0.125-1 mg/kg BIBP 3226 dose-dependently inhibited the pressor response to exogenous NPY in pithed SHR. At higher doses BIBP 3226 had an effect duration of 20-40 min. In the pithed SHR, a 0.5 mg/kg bolus injection of BIBP 3226 shifted the pressor response curve for exogenous NPY significantly to the right It also inhibited significantly the potentiating effects of NPY on pressor responses to phenylephrine and tyramine. In conscious SHR, 0.125-1 mg/kg BIBP 3226 did not reduce the basal blood pressure. In combination with a hypotensive dose of prazosin, administration of 0.5 mg/kg BIBP 3226 had no added effects lowering the basal blood pressure. A stressful stimulus, namely an air jet, caused a brief increase in blood pressure and heart rate in the conscious SHR. In this model, 0.5 mg/kg BIBP inhibited the heart rate response slightly but had no effect on the blood pressure response. CONCLUSIONS: Our results demonstrate that, although the selective NPY Y1 receptor antagonist BIBP 3226 may shift the pressor response to exogenous NPY potently, it does not influence basal blood pressure significantly in the SHR.

Animals↗
PubMedDate not supplied

Pre- and postsynaptic effects of SKF64139, a phenylethanolamine N-methyltransferase inhibitor, in conscious normotensive rats.

We investigated in conscious normotensive rats the effect of SKF64139 (2 mg i.v.), a potent phenylethanolamine N-methyltransferase (PNMT) inhibitor, on blood pressure responses to norepinephrine (40, 80, and 160 ng i.v.); methoxamine (2.5, 5 and 10 micrograms i.v.), a directly active sympathomimetic agent that is not taken up by adrenergic nerves; and tyramine (20, 40, and 80 micrograms i.v.), an indirectly acting sympathomimetic amine. The pressor effect of norepinephrine was not changed by 2 mg of SKF64139, while those of methoxamine and tyramine were significantly reduced. The dose-response curve to exogenous norepinephrine was also evaluated following blockade of norepinephrine uptake in the nerve endings using 0.25 mg desipramine i.v. This dose of desipramine had no effect on blood pressure increase induced by methoxamine. In rats pretreated with the neuronal uptake inhibitor desipramine in a dose that did not affect alpha-adrenoceptors, SKF64139 significantly decreased the pressor responses to norepinephrine. Increasing the dose of SKF64139 to 8 mg i.v. resulted in a significant fall in base-line blood pressure and in a blunted blood pressure response to norepinephrine. These data demonstrate that in vivo the PNMT inhibitor SKF64139 blocks alpha-adrenoceptors and inhibits neuronal uptake. The alpha-adrenoceptor blocking properties of SKF65139 are masked by simultaneous blockade of norepinephrine uptake when agonists with affinity for the uptake system are used. These findings need to be taken into account when interpreting cardiovascular effects of the PNMT inhibitor SKF64139.

Animals↗
PubMedDate not supplied

Defibrotide, an antithrombotic substance that preserves postsynaptic alpha- and beta-adrenergic function in post acute infarcted rabbit hearts.

Defibrotide, a simple strand polydeoxyribonucleotide of mammalian origin with a molecular weight of 20,000 daltons, given intravenously to the rabbit before and after production of left ventricular infarction, prevents the alteration of the contractile response to postsynaptic adrenergic stimulation tested in isolated perfused heart preparations 3 days after coronary artery occlusion. According to the dose-response curves for isoproterenol and tyramine, left ventricular dP/dtmax was significantly depressed in infarcted hearts, whereas the dose-response curve for the inotropic effect of phenylephrine was markedly enhanced. These alterations were prevented by pretreatment of the rabbits with defibrotide (32 mg/kg/h i.v. for 6 h). In fact the potency ratios, calculated from the dose-response curves related to dP/dtmax of isoproterenol, tyramine, and phenylephrine in infarcted and control hearts excised from defibrotide treated and shamoperated rabbits, are nearly 1. The observed alterations in myocardial contractility in infarcted hearts seem to be specific for postsynaptic alpha and beta-adrenoceptors since the dose-response curve of left ventricular dP/dtmax for histamine is not different from control. The results obtained with defibrotide reflect the ability of this substance to protect the myocardial tissue from ischemic damage: this is also supported by the capacity of defibrotide (8 mg/kg/h i.v. for 6.5 h) to prevent the reduction of CPK-activity in the infarcted ventricle. Finally, we suggest that the observed beneficial effect of defibrotide in rabbit heart may also be explained by the antithrombotic effect of this substance, which is based on its profibrinolytic activity and PGI2-release.

Animals↗
PubMed1997

Nonexocytotic noradrenaline release from rat cardiac synaptosomal-mitochondrial fractions.

Nonexocytotic noradrenaline (NA) release was examined in rat cardiac synaptosomal-mitochondrial fractions prelabeled with [3H]NA (300 nM; 1 h at 37 degrees C). Ischemic conditions (1 mM iodoacetate + 2 mM NaCN; 15 min at 37 degrees C) evoked a Ca(2+)-independent release of [3H]NA from isolated synaptosomes, which represented 33.4% of total content, whereas the release evoked by 56 mM K+ was Ca2+ dependent and represented 5.8% of total content. Tyramine, phencyclidine (PCP), and rimcazole also caused important Ca(2+)-independent releases of [3H]NA (from 12 to 45% of total content) with median effective concentrations (EC50s) of 6.8, 182, and 41.8 microM, respectively. The release responses evoked by ischemic conditions, tyramine, PCP, and rimcazole were mimicked by the delta-receptor ligand, 1,3-ditolyl guanidine (DTG), and blocked by the uptake 1 inhibitor, desipramine (100 microM). The delta 1-receptors ligands, (+)-3-hydroxyphenyl-N-(1-propyl)piperidine ((+)-3-PPP) and (+)N-allylnormetazocine [(+)SKF-10047], were potent blockers of the release of [3H]NA evoked by ischemic conditions but not by PCP or rimcazole. These data indicate that ischemic conditions and PCP/delta 2-receptor ligands induce carrier-mediated NA efflux from cardiac sympathetic nerve terminals, whereas delta 1-receptor ligands produce marked inhibition of the ischemic response.

Animals↗
PubMed1996

Adrenergic activation confers cardioprotection mediated by adenosine, but is not required for ischemic preconditioning.

BACKGROUND: The aim of this study was to determine whether (1) adrenergic activation is cardioprotective, (2) adrenergic cardioprotection occurs via adenosine receptor activation, and (3) ischemic preconditioning requires alpha-adrenergic activation. METHODS: Anesthetised open chest rabbits underwent 30 min coronary occlusion and 3 h reperfusion. Ischemic preconditioning was elicited with 5 min coronary occlusion and 10 min reperfusion. Activation of adrenergic receptors with endogenous norepinephrine was achieved with tyramine (0.28 mg/kg/min intravenously for 5 min). Adenosine receptors were blocked with 8-p-sulfophenyl theophylline (10 mg/kg intravenously), alpha 1-adrenergic receptors were selectively blocked with prazosin (0.1 mg/kg intravenously), and alpha-adrenergic receptors were blocked with phentolamine (4 mg/kg intravenously). RESULTS: Ischemic preconditioning reduced risk-adjusted infarct volume by 79% (P < 0.0005). This protection was attenuated by adenosine receptor blockade. Tyramine infusion resulted in a 1305% change from baseline plasma norepinephrine concentration (P < or = 0.01), and reduced infarct volume by 55% (P = 0.01). Adenosine receptor blockade abolished this protection. Blockade of alpha 1-adrenergic receptors with prazosin failed to abolish ischemic preconditioning (79 versus 89% reduction in infarct volume, without and with prazosin, respectively). Similarly, non-selective blockade of alpha-adrenergic receptors also failed to abolish ischemic preconditioning (79 versus 57% reduction without and with phentolamine, respectively). CONCLUSIONS: We conclude that the cardioprotection of ischemic preconditioning and alpha-adrenergic activation both involve adenosine, but ischemic preconditioning does not require alpha-adrenergic activation.

Adenosine↗
PubMed2004

Production of coumaroylserotonin and feruloylserotonin in transgenic rice expressing pepper hydroxycinnamoyl-coenzyme A:serotonin N-(hydroxycinnamoyl)transferase.

Transgenic rice (Oryza sativa) plants were engineered to express a N-(hydroxycinnamoyl)transferase from pepper (Capsicum annuum), which has been shown to have hydroxycinnamoyl-CoA:tyramine N-(hydroxycinnamoyl)transferase activity, a key enzyme in the synthesis of hydroxycinnamic acid amides, under the control of constitutive maize (Zea mays) ubiquitin promoter. The transgenic rice plants require foliar application of amines to support synthesis of hydroxycinnamic acid amides, suggestive of limiting amine substrates in rice shoots. In addition, when T2 homozygous transgenic rice plants were grown in the presence of amines or phenolic acids, two novel compounds were exclusively identified in the leaves of the transgenic plants. These compounds eluted earlier than p-coumaroyltyramine and feruloyltyramine during HPLC chromatography and were identified as p-coumaroylserotonin and feruloylserotonin by liquid chromatography/mass spectrometry and other methods. To test whether the unpredicted production of serotonin derivatives is associated with the pepper N-(hydroxycinnamoyl)transferase, the substrate specificity of the pepper enzyme was analyzed again. Purified recombinant pepper N-(hydroxycinnamoyl)transferase exhibited a serotonin N-hydroxycinnamoyltransferase (SHT) activity, synthesized p-coumaroylserotonin and feruloylserotonin in vitro, and demonstrated a low K(m) for serotonin. SHT activity was inhibited by 10 to 50 mm tyramine. In addition, SHT activity was predominantly found in the root tissues of wild-type rice in parallel with the synthesis of serotonin derivatives, suggesting that serotonin derivatives are synthesized in the root of rice. This is the first report of SHT activity and the first demonstration, to our knowledge, that serotonin derivatives can be overproduced in vivo in transgenic rice plants that express serotonin N-(hydroxycinnamoyl)transferase.

Acyltransferases↗
PubMed1991

A specific, high-affinity binding site for the hepta-beta-glucoside elicitor exists in soybean membranes.

The presence of a specific binding site for a hepta-beta-glucoside elicitor of phytoalexin accumulation has been demonstrated in soybean microsomal membranes. A tyramine conjugate of the elicitor-active hepta-beta-glucoside was prepared and radiolabeled with 125I. The labeled hepta-beta-glucoside-tyramine conjugate was used as a ligand in binding assays with a total membrane fraction prepared from soybean roots. Binding of the radiolabeled hepta-beta-glucoside elicitor was saturable, reversible, and with an affinity (apparent Kd = 7.5 x 10(-10) M) comparable with the concentration of hepta-beta-glucoside required for biological activity. A single class of hepta-beta-glucoside binding sites was found. The binding site was inactivated by proteolysis and by heat treatment, suggesting that the binding site is a protein or glycoprotein. Competitive inhibition of binding of the radiolabeled hepta-beta-glucoside elicitor by a number of structurally related oligoglucosides demonstrated a direct correlation between the binding affinities and the elicitor activities of these oligoglucosides. Thus, the hepta-beta-glucoside-binding protein fulfills criteria expected of a bona fide receptor for the elicitor-active oligosaccharin.

Binding Sites↗
PubMed1976

The effect of nisoxetine (Lilly compound 94939), a potential antidepressant, on biogenic amine uptake in man.

Preclinical studies with nisoxetine (Compound 94939) (3-[o-Methoxyphenoxy]-N-methyl-3-phenylpropylamine HCl) had shown it to have antidepressant properties and to be almost devoid of anticholinergic activity and depressant effects on cardiac conduction (in contrast to the commonly used tricyclic antidepressants from which nisoxetine significantly differs in structure). Placebo and nisoxetine (10-20 mg b.d. for 7 days) were administered to normal volunteers in a single-bind crossover study. Adverse side effects were minimal. There were no significant changes in heart rate or blood pressure seen when no other drugs were given. The effect of nisoxetine on uptake of biogenic amines was utilized to study its mechanism of action. The transient rise in blood pressure seen after an intravenous bolus of tyramine decreased by one-half to two-thirds while the rise in blood pressure upon continuous noradrenaline infusion was enhanced some two-to eight-fold. Both effects occurred after on dose and were greater with larger doses and chronic administration. In vitro, nisoxetine inhibits 5-HT uptake into platelets. However, platelets harvested from subjects receiving chronic nisoxetine administration did accumulate 5-HT. Plasma concentration of nisoxetine in these individuals was shown to be lower than that needed to block 5-HT uptake. We concluded that nisoxetine, in safe doses, specifically increased the sensitivity of noradrenaline and decreased tyramine responsiveness, presumably by blocking uptake at the axonal membrane. In contrast, in these clinical doses it had virtually no effect on 5-HT uptake into platelets.

Adult↗
PubMed1981

Autonomic responsiveness in stress-sensitive and stress-resistant pigs.

The responsiveness of the autonomic nervous system was studied in twenty-six 140 day old thiopentone anaesthetized lean stress-sensitive Pietrain (P) and fatter stress-resistant Gloucester (G) pigs, using the Valsalva like manoeuvre (VLM), and the i.v. tyramine, noradrenaline (NA) and phenylephrine tests. The heart rate responses to the VLM and tyramine tests were greater in P. The pressor response to NA was lower in P, and the change in heart rate per unit change in blood pressure-during phenylephrine infusion was the same in the two breeds. The sympathetic nervous system in P was, therefore, more responsive than that in G, and this was attributable to a higher pre-adrenoreceptor responsiveness in P. The potentially greater sympathetic responsiveness in stress-sensitive pigs could account for their greater leanness, their stress-induced metabolic acidosis, and for their susceptibility to myocardial failure.

Animals↗
PubMed1988

Involvement of alpha 1-adrenoceptors in chronotropic responses to endogenously released amines in the pithed rat.

1. In pithed rats, yohimbine (1 mg/kg i.v.) enhanced the positive chronotropic responses to spinal stimulation of cardiac sympathetic nerves with eight pulses delivered at 2 or 4 Hz, indicating that auto-inhibition was operating, but did not increase responses to shorter lengths of trains of 8 pulses at 8, 16 or 32 Hz which did not allow sufficient time for auto-inhibition to come into effect. 2. The positive chronotropic response to cardiac sympathetic nerve stimulation with eight pulses at 8 Hz of about 60 beats/min was not affected by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg), but was reduced to about 20% of the control value by propranolol (1 mg/kg). 3. In the presence of propranolol, the residual positive chronotropic responses to cardiac sympathetic nerve stimulation were virtually abolished by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg). 4. The positive chronotropic response to tyramine (0.1 mg/kg i.v.) was reduced from 100 to 12 beats/min by propranolol (1 mg/kg), and the residual response was abolished by prazosin. 5. The findings indicate that noradrenaline released from cardiac sympathetic terminals by nerve stimulation or by tyramine acts on alpha 1-adrenoceptors to produce a positive chronotropic response that is revealed when beta-adrenoceptors are blocked.

Animals↗
PubMed1992

Inhibition of nitric oxide synthase specifically enhances adrenergic vasoconstriction in rabbits.

1. The effect of inhibition of nitric oxide biosynthesis using N-nitro-L-arginine (NOLA) was examined in conscious rabbits and rabbit isolated aortae. 2. In autonomically blocked conscious rabbits intravenous infusion of NOLA (15 mg/kg) significantly increased arterial pressure and hindlimb vascular resistance but did not affect heart rate. Depressor and hindlimb vasodilator responses to acetylcholine (3-12 micrograms/kg per min) were significantly attenuated in the presence of NOLA. In contrast, NOLA significantly enhanced responses to intravenous infusion of glyceryl trinitrate (10-40 micrograms/kg per min) in vivo. 3. Infusion of noradrenaline (1-4 micrograms/kg per min) or the release of neuronal noradrenaline in response to the infusion of tyramine (80-320 micrograms/kg per min) increased arterial pressure and hindlimb vascular resistance in autonomically blocked conscious rabbits. After the administration of NOLA, the vasoconstrictor responses to both noradrenaline and tyramine were significantly enhanced. 4. In isolated rabbit aortae, NOLA (10 mumol/L) significantly impaired relaxant responses to acetylcholine but did not affect responses to glyceryl trinitrate. NOLA enhanced contractile responses to the adrenoceptor agonists noradrenaline and phenylephrine but did not affect the contractile responses to the thromboxane-mimetic U46619. 5. These data indicate that in autonomically blocked conscious rabbits, NOLA causes systemic vasoconstriction, impairs dilator responses to acetylcholine and enhances dilator responses to glyceryl trinitrate. In addition, NOLA enhances constrictor responses to both exogenous and neuronally-released noradrenaline. These results suggest that nitric oxide is important in the regulation of normal vascular tone and in the modulation of vascular responses to vasodilator and vasoconstrictor agents.

Acetylcholine↗