Effects of thromboxane agonists on cardiac adrenergic neurotransmission.

The effects of thromboxane B2 (TxB2) and of two thromboxane mimetics, dl-(9,11), (11,12)-dimethano-TxA2 (ONO 11006) and 9,11-dideoxy-11,9-epoxymethano prostaglandin F2 alpha (U46619) on the cardiac response to adrenergic nerve stimulation in isolated guinea-pig atria were evaluated. All the agonists dose dependently reduced the positive inotropic effect induced by field stimulation, U46619 being the most active. The inhibitory effect of U46619 was reduced by the thromboxane receptor antagonists, sulotroban and AH 23848B. U46619 did not significantly reduce the positive inotropic effect induced by exogenous noradrenaline. However U46619 was unable to modify the tritium overflow induced by field stimulation in preparations preloaded with [3H]noradrenaline. In addition to this influence on adrenergic neurotransmission, U46619 also had a direct positive inotropic effect on cardiac contractility, which was antagonized by AH 23848B. These results indicate that U46619 reduces the cardiac response to sympathetic nerve stimulation and that is also has a direct stimulatory effect on cardiac muscle.     

Effects of S9977 on adrenergic neurotransmission

1. Experiments were designed to determine whether or not the putative promnesic drug S9977 (1,3,7-trimethyl 8-[3-(4-diethylaminocarbonyl-1-piperazinyl) 1-propyl]-3,7-dihydro (1H)2,6-purinedione hydrochloride) affects peripheral adrenergic neurotransmission.2. Rings of canine saphenous veins (without endothelium) were suspended for isometric tension recording in conventional organ chambers filled with modified Krebs-Ringer bicarbonate solution. The adrenergic nerve endings were activated with electrical impulses (9 V, 2 msec, 0.25–8 Hz).3. At 10⁻⁵ M, S9977 significantly reduced the contraction to 0.25, 0.5 and 1 Hz. The compound did not affect the response to higher stimulation frequencies or to exogenous noradrenaline. The inhibitory effect of S9977 was prevented by methiothepin, and not affected by atropine or 8-phenyltheophylline.4. Helical strips of canine saphenous veins were incubated with [³H]noradrenaline and suspended for superfusion and isometric tension recording. Under basal conditions, S9977 (10⁻⁴ M) augmented, the total ³H-overflow which was due mainly to an augmented overflow of [³H]deoxyphenylglycol (DOPEG); the extraneuronal metabolites 3,4-dihydromandelic acid (DOMA) and 3-methoxy-4-hydroxymandelic acid (VMA) were reduced.5. During electrical stimulation of the adrenergic nerves, S9977 (10⁻⁴ M) augmented the total ³H-overflow but reduced the contractile response; the evoked overflow of [³H]noradrenaline was not significantly affected.6. These experiments suggest that S9977 the displacement of noradrenaline from the adrenergic varicosities; most of the displaced transmitter is metabolized by intraneuronal monoamine oxidase before reaching the junctional cleft. In addition, S9977 exerts an inhibitory effect on the extraneuronal metabolism of catecholamines. S9977 does not inhibit the exocytotic release of the adrenergic neurotransmitter.     

Effects of glycerol acetonide on adrenergic neurotransmission in isolated rabbit heart.

In the present investigation, the solvent glycerol acetonide (GA, CAS 100-79-8) was added (110 mg/min) to the Tyrode buffer perfusing an isolated rabbit heart preloaded with 14C-noradrenaline (NA). GA inhibits the neuronal uptake of NA but stimulates its spontaneous release. The latter effect was not ascribed to the stimulation of NA biosynthesis or to an inhibition of its catabolism. Moreover GA inhibits the evoked-release of the transmitter by tyramine and dimethyl phenyl piperazinium (DMPP). By stimulating the spontaneous release of NA, GA may induce both a depletion of myocardial stores and an important increase of the transmitter, inhibiting thereby the evoked-release by a negative feed-back mechanism on presynaptic alpha 2 adrenoceptors. Hence, the impact of GA on some steps of the cardiac adrenergic transmission may provide an adequate explanation for its observed hypotensive effect.     

Effects of omega-conotoxin on adrenergic, cholinergic and NANC neurotransmission in the rabbit urethra and detrusor.

1. The effects of omega-conotoxin GVIA (an inhibitor of N-type voltage-operated calcium channels; VOCCs) were compared on adrenergic, cholinergic and non-adrenergic, non-cholinergic (NANC) responses induced by electrical field stimulation (EFS) in the rabbit urethra and detrusor. 2. EFS induced a relaxation in urethral smooth muscle and lamina propria precontracted by arginine vasopressin (AVP). The relaxation was abolished by tetrodotoxin (TTX) or the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginine. omega-Conotoxin inhibited the relaxation induced by EFS, but not that elicited by the NO donor 3-morpholino-sydnonimin. The inhibition, however, decreased with increasing frequencies of stimulation. Nimodipine, tetramethrin and nickel did not affect the omega-contoxin-resistant relaxation in lamina propria, suggesting that neuronal L or T VOCCs were not involved in the response. 3. EFS contracted urethral smooth muscle at resting tension. The contractions were virtually abolished by TTX or prazosin. omega-Conotoxin effectively inhibited the contractile responses to EFS, but not those to exogenous noradrenaline. An omega-conotoxin-resistant contraction was, however, observed at high frequencies of stimulation. 4. The detrusor responded with frequency-dependent contractions upon EFS. A TTX-resistant contraction less than 10% of controls remained at 30 Hz stimulation. At a stimulation frequency of 10 Hz, scopolamine reduced the EFS-induced contraction by 71%. omega-Conotoxin inhibited the responses in both the absence and presence of scopolamine. The inhibition decreased with increasing frequencies of stimulation (examined in the absence of scopolamine). omega-Conotoxin did not affect the contractile responses to carbachol or adenosine 5'-triphosphate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibitory effects of piribedil on adrenergic neurotransmission

The effects of piribedil on responses to sympathetic stimulation were investigated in anaesthetized dogs. Piribedil (1 mg/kg i.v.) impaired the vasoconstrictor responses to lumbar sympathetic chain stimulation of the perfused hindlimb without changing the effects of noradrenaline. Piribedil (2 mg/kg i.v.) depressed the chronotropic responses to stimulation of the right anterior ansa and the inotropic response to stimulation of the left anterior ansa. Stimulation of the splanchnic nerve induced frequency dependent increases in systemic blood pressure. Piribedil antagonized this effect. Piribedil (1 mg/kg i.v.) attenuated the constrictor responses of the perfused mesenteric artery to postganglionic sympathetic stimulation and reduced the decreases in renal blood flow caused by stimulation of sympathetic renal nerves. The inhibitory effects of piribedil were preferential on responses induced by low frequency stimulation of nerves. The hypertensive, vasoconstrictor and tachycardic effects of noradrenaline and tyramine were not affected. The effects of piribedil were reversed by haloperidol (0.5 mg/kg i.v.) or pimozide (0.2 mg/kg i.v.).     

Altered cardiac adrenergic neurotransmission in streptozotocin-induced diabetic rats.

1. Functional alterations of the sympathetic neuroeffector junction of the left atria were studied in rats with streptozotocin-induced diabetes. 2. Eight to 12 weeks of diabetes resulted in a marked decrease in the positive inotropic response of left atria to electrical field stimulation (EFS). 3. The overflow of [3H]-noradrenaline from diabetic left atria caused by EFS was much less than that from control preparations. 4. The concentration-response curves showed no change in sensitivities of the left atria to exogenous noradrenaline and tyramine in diabetic rats. The maximum positive inotropic response to these agents were similar in diabetic and control animals. 5. The left atrial content of noradrenaline was not significantly changed in diabetic rats. The cocaine-sensitive uptake of [3H]-noradrenaline was also unaltered. 6. Atropine enhanced the positive inotropic response and [3H]-noradrenaline overflow induced by EFS in control left atria. Similarly, yohimbine caused an enhancement of EFS-evoked inotropic response in control atria. However, these effects of the antagonists were not observed in diabetic left atria. 7. It is concluded that the decrease in the positive inotropic response of the left atria to EFS in diabetic rats is caused by an impairment of noradrenaline release from the sympathetic nerve terminals through a calcium-dependent exocytotic mechanism. The present results also indicate that presynaptic alpha 2-adrenoceptors and muscarinic receptors that are linked to inhibition of the noradrenaline release during nerve stimulation may be functionally impaired in diabetic animals.     

Effects of adenosine on adrenergic neurotransmission; Prejunctional inhibition and postjunctional enhancement

Summary The action of adenosine on adrenergic neuroeffector transmission was studied in the rabbit kidney in vitro and in situ, in the canine subcutaneous adipose tissue in situ and in the guinea-pig vas deferens in vitro. In the kidney, adenosine (0.1–10 M) caused a concentration-dependent increase in vascular resistance and in vasoconstrictor responses to nerve stimulation and administered noradrenaline. In the adipose tissue, adenosine also increased the vasoconstrictor responses but it decreased vascular resistance.In all three tissues studied adenosine significantly and reversibly depressed noradrenaline release evoked by nerve stimulation in a concentration-dependent manner. This effect of adenosine was not altered by phenoxybenzamine which blocked all vasoconstrictor responses and diminished the rise in vascular resistance by adenosine in the kidney. It is concluded that adenosine affects adrenergic neuroeffector transmission by two discrete mechanisms, prejunctional inhibition and postjunctional enhancement.     

Effects of vasoactive intestinal polypeptide antagonists on cholinergic neurotransmission in dog and cat trachea.

1. The effects of vasoactive intestinal polypeptide (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 investigated by use of microelectrode, double sucrose-gap and tension recording methods. 2. In the dog trachea, repetitive stimuli at high frequency (20 Hz) markedly enhanced the amplitude of contraction, the amplitude of contractions evoked by 50 stimuli at 20 Hz relative to that evoked by 5 stimuli being 14.2 +/- 3.8 times (n = 7, +/- s.d.). In the cat, the summation was much less marked, the amplitude of contractions evoked by 50 stimuli relative to that evoked by 5 stimuli being only 2.1 +/- 0.6 times (n = 5, +/- s.d.). Neither VIP antagonist had any effect on the relationship between the number of stimuli at 20 Hz and the relative amplitude of contraction in the dog trachea, but did enhance the amplitude of contractions to 1.1-1.5 times control in the cat trachea. 3. VIP antagonists dose-dependently enhanced the amplitude of excitatory junction potentials (e.j.ps) evoked by a single stimulus in the cat trachea, without changing the resting membrane potential or input membrane resistance of the smooth muscle cells. However, neither antagonist had any effect on the amplitude of the e.j.p. in the dog trachea. 4. Neither VIP antagonist had any effect on the post-junctional response of smooth muscle cells to exogenously applied acetylcholine (ACh; 10(-9)-10(-5) M) in the dog or cat trachea.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different effects of prostaglandins on adrenergic neurotransmission in atrial and ventricular preparations.

1. The effects of prostaglandin E2 (PGE2) and iloprost on the cardiac response to adrenergic nerve stimulation in guinea-pig atrial and ventricular preparations have been studied. 2. In guinea-pig isolated atria both PGE2 (0.1-10 nM) and iloprost (0.1-3 microM) concentration-dependently reduced the cardiac response to adrenergic nerve stimulation. 3. The inhibition of cyclo-oxygenase by indomethacin and acetylsalicylic acid potentiated the response to nerve stimulation in the atrial preparations. 4. Arachidonic acid (1-10 microM) reduced the response to nerve stimulation in atria. This effect was prevented by indomethacin and acetylsalicylic acid. 5. In guinea-pig ventricles PGE2 and iloprost were found to be effective at higher concentrations than in atrial preparations: arachidonic acid, indomethacin or acetylsalicylic acid did not modify the cardiac response to adrenergic nerve stimulation. 6. These results suggest a different modulator role for endogenous prostaglandins in atrial and ventricular tissue.     

Effects of three beta adrenergic receptor blockers on myocardial oxygen consumption in the dog

The effects of cardiac sympathetic nerve stimulation on heart rate, cardiac contractile force, cardiac output, arterial and left atrial blood pressure, coronary blood flow and myocardial oxygen consumption were studied before and after intravenous administration of alprenolol (0.3 mg/kg), propranolol (0.3 mg/kg) or practolol (1.2 mg/kg). The three β-blockers were equally effective inhibitors of cardiac stimulation, coronary vasodilatation and increase of myocardial oxygen consumption elicited by sympathetic nerve stimulation. A transient coronary vasoconstriction seen immediately after the start of sympathetic nerve stimulation tended to be slightly potentiated by all three blockers.     

Adenosine modulation of adrenergic neurotransmission in the human fallopian tube

The effects of adenosine and adenosine analogues on nerve-induced contractile responses and [3H]noradrenaline ([3H]NA) release, were studied in the isthmic part of human oviducts. Adenosine and L-N6-phenylisopropyladenosine (L-PIA) could enhance neurogenic contractile responses in preparations obtained mainly in the proliferative phase. At higher concentrations, adenosine derivatives inhibited contractile responses to nerve stimulation in both proliferative and secretory phase, with the potency order: 5'-N-ethylcarboxamideadenosine (NECA) greater than or equal to L-PIA much greater than D-PIA. This indicated actions at both stimulatory A1- and inhibitory A2-receptors. Adenosine, L-PIA and NECA but not D-PIA inhibited [3H]NA release during nerve stimulation. The relative potency order for the prejunctional inhibition was compatible with an action at A1-receptors. Furthermore, adenosine was found to modulate nerve-induced contractions via postjunctional stimulatory A1- and inhibitory A2-like receptors. The postjunctional effects may be influenced by cyclic hormonal changes. The adenosine antagonist 8-p-sulfophenyltheophylline (PS?T) reversibly antagonized the stimulatory and inhibitory effects by adenosine and analogues.     

Effects of potassium channel inhibitors on nitrergic and adrenergic neurotransmission in lamina propria of the female rabbit urethra

Electrical field stimulation of strip preparations of the female rabbit urethral lamina propria induces a frequency-dependent adrenergic contraction or a non-adrenergic, non-cholinergic (NANC) relaxation, mediated by nitric oxide, depending on the prevailing tension. To study the role of potassium channels in these responses, the effects of inhibitors of voltage-dependent (dendrotoxin I, 4-aminopyridine), low (apamin) and high (iberiotoxin, charybdotoxin) conductance calcium-activated and ATP-sensitive (glibenclamide) potassium channels on the frequency-response relationship were examined. 4-Aminopyridine (1 mM), but none of the other inhibitors, augmented the NANC relaxation. The maximal response was, however, unaffected by 4-aminopyridine. The adrenergic contraction was enhanced by 4-aminopyridine (1 mM), dendrotoxin I(0.1 M), iberiotoxin (0.1 M) and charybdotoxin (0.1 M), but not by apamin (0.1 M) and glibenclamide (10 M). Besides reducing the frequency eliciting half maximal contraction, dendrotoxin and charybdotoxin also enhanced the maximal response. None of the inhibitors affected the relaxation induced by the nitric oxide donor 3-morpholinosydnonimine or the contraction elicited by noradrenaline. The results suggest that dendrotoxin-sensitive voltage-dependent and high conductance calcium-activated neuronal potassium channels participate in adrenergic, but not in nitrergic, neurotransmission in the lamina propria of the female rabbit urethra. This offers a possibility to selectively interfere with the adrenergic neuroeffector system with drugs acting on these K-channels.     

Angiotensin effects on vas deferens adrenergic and purinergic neurotransmission

Angiotensin effects on purinergic and adrenergic neurotransmission in the rabbit vas deferens were examined. Both angiotensins inhibited the non-adrenergic, and potentiated the adrenergic, neurogenic contraction. Angiotensin III inhibited the non-adrenergic neurogenic contraction to a greater extent than angiotensin II at all concentrations tested (maximal inhibition being 42 +/- 4 vs. 17 +/- 3% for angiotensin II). Angiotensin II was more potent than angiotensin III at potentiating adrenergic neurotransmission. Neither peptide altered the postjunctional action of either putative neurotransmitter, ATP or norepinephrine. These results are inconsistent with the hypothesis that ATP and norepinephrine are released in constant ratios. Furthermore, the different pattern of angiotensin responses is consistent with the existence of at least two separate angiotensin receptors with markedly different affinities for angiotensin II and angiotensin III.     

Thromboxane mimetics enhance adrenergic neurotransmission in the rabbit-isolated portal vein

The thromboxane/prostaglandin H mimetics, U46619 and carbocyclic thromboxane A2 (cTA2) were examined for influences on adrenergic neural responses. Force generation in response to low-frequency electrical stimulation was enhanced 21 +/- 5% by U46619 and 20 +/- 4% by cTA2. These effects were antagonized by the thromboxane/prostaglandin H receptor antagonist, SQ29548. Norepinephrine-induced contractions were not significantly potentiated by the presence of U46619 or cTA2. Norepinephrine release from electrically stimulated portal veins was augmented by U46619 as compared to control preparations (p less than 0.05). These results are consistent with the hypothesis that thromboxane/prostaglandin H receptors mediate a potentiation of adrenergic neural responses by augmenting the release of neurotransmitters from adrenergic nerves and are inconsistent with a postjunctional potentiative site of action. The constrictor effect of U46619 on portal vein smooth muscle was less potent than the potentiative effect on neural responses suggesting that the latter would be a more likely physiological action of thromboxanes or prostaglandin endoperoxides in this vascular bed.     

Effect of etorphine on adrenergic neurotransmission in the rat and guinea pig heart

The effect of etorphine (ET) on nerve stimulation-mediated release of norepinephrine (NE) was investigated in isolated rat and guinea pig hearts. Hearts were perfused with Krebs bicarbonate solution via the aorta and the overflow of NE was measured after stimulation of the heart. ET (0.001-0.1 mumol/l) caused a dose-dependent inhibition of NE release in both preparations. Inhibition of NE release from guinea pig hearts ranged from 13% at 0.001 mumol/l to 24% at 0.1 mumol/l. The same concentrations of ET decreased NE release by 10 and 36% in the rat heart. The inhibitory effect of ET was blocked by naloxone. It is concluded that presynaptic opioid receptors located on the adrenergic neuronal terminals may be involved in the regulation of adrenergic neurotransmission in the rat and guinea pig heart.     

Characterization of endothelin receptors mediating the effects of the endothelin/sarafotoxin peptides on autonomic neurotransmission in the rat vas deferens and guinea-pig ileum.

1. To characterize the receptors mediating the effects of the endothelin/sarafotoxin family of peptides on the responses to electrical stimulation of the rat vas deferens (RVD) and guinea-pig ileum (GPI) we have used endothelin-1 (ET-1), ET-3, sarafotoxin 6b (SX6b) and SX6c as agonists and the endothelin-receptor antagonists BQ-123 (ETA receptor selective) and PD 142893 (non-selective). 2. In the RVD, ET-1 and SX6b increased the twitches induced by field stimulation starting at a threshold concentration of 10(-10) M while the threshold concentration for ET-3 was 3 x 10(-9) M. SX6c (up to 3 x 10(-8) M) did not potentiate the twitches. SX6b produced significantly (P < 0.05) greater potentiations than ET-1 at concentrations of 3 x 10(-9) M and higher, and 10(-7) M ET-3 also produced a significantly greater effect than ET-1 at the same concentration. Thus, at threshold the rank order of peptides was ET-1 = SX6b > ET-3 >>> SX6c, and at concentrations of 3 x 10(-8) M and higher, SX6b > ET-3 > ET-1 >>> SX6c. 3. In the presence of BQ-123 or PD 142893 (10(-5) M) the threshold concentrations for ET-1 to augment the twitches were increased 30 fold. In the same conditions neither SX6b nor ET-3 potentiated the responses. The relative activities of the endothelin/sarafotoxin peptides and the effectiveness of the endothelin receptor antagonists are consistent with postjunctional ETA receptors mediating these effects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Resistance of adrenergic neurotransmission in the toad heart to adrenoceptor blockade

Summary Stimulation of sympathetic nerves to the toad heart produced increases in both the rate and force of cardiac beat. Although these responses were abolished by treatment with bretylium (10^–6 mol ·l^–1) or 6-hydroxydopamine (100 mg·kg^–1), and surgical sympathetic denervation, they were not abolished by treatment with propranolol (10^–6 mol·l^–1) and phentolamine (3×10^–6 mol·l^–1), either alone or in combination. The responses remaining after adrenoceptor blockade could not be ascribed to the effects of neurally released dopamine, ATP, adenosine, histamine or a variety of neuropeptides, although the participation of an as yet unidentified co-transmitter cannot be ruled out. Quantitative analysis of the interactions between propranolol and adrenaline on cardiac adrenoceptors, after blockade of -receptors and amine uptake mechanisms, revealed that these interactions do not comply with the conditions for simple competitivity. Therefore, in addition to its action on -receptors, adrenaline seems to be producing excitation of the toad heart by acting on adrenoceptors which cannot be classified as either -or -receptors. These results, together with the existence of close neuromuscular gaps (<50nm) in the toad heart, are consistent with the hypothesis that sympathetic excitation of the toad heart is mediated by both extra-junctionl -adrenoceptors, and junctional adrenoceptors which are neither -nor -receptors.     

Effects of adrenergic agents on secretion of salivary kallikrein in the submandibular gland of the dog]

The effects of sympathetic nerve stimulation and administrations of sympathomimetics on the secretion of salivary kallikrein induced by stimulation of Chorda tympani were examined quantitatively and qualitatively in the dog submandibular gland. Both sympathetic stimulation and administrations of sympathomimetics such as norepinephrine, epinephrine, and isoproterenol caused increased secretion of salivary kallikrein. Among these effects, those of the sympathetic stimulation, norepinephrine, and epinephrine were not completely abolished by pretreatment with phenoxybenzamine or propranolol, but the effect of isoproterenol was abolished by pretreatment with propranolol, and was hardly influenced by pretreatment with phenoxybenzamine. From these results, it would appear that secretion of salivary kallikrein may be mediated through adrenergic alpha- and beta-receptors. On the other hand, in contrast with the activities of the salivary kallikrein secreted by Chorda tympani stimulation or administration of isoproterenol which were not inhibited by SBTI, the activities of the salivary kallikrein secreted by sympathetic stimulation as well as administration of norepinephrine or epinephrine were markedly inhibited by SBTI. From these results, it is concluded that secretion of glandular kallikrein is due either to Chorda tympani stimulation or is mediated through adrenergic beta-receptor, while secretion of plasma kallikrein is mediated through adrenergic alpha-receptor.