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PubMed1998

Activation of alpha- and beta-adrenoceptors by sympathetic nerve stimulation in the large intestine of the rat.

1. The effects of sympathetic nerve stimulation on the motility of the circular and longitudinal muscle of the large intestine were investigated in vitro, and the involvement of various adrenoceptor subtypes determined. A comparison between the sympathetic supply arising from the prevertebral and pelvic ganglia was also made. 2. In the longitudinal muscle of the distal colon, sympathetic nerve stimulation caused responses which were contractile (0.1-2 Hz), biphasic (5-10 Hz) or purely inhibitory (20-30 Hz). All contractile responses were removed with phentolamine (3 microM), whereas the inhibitory responses were significantly diminished by propranolol (0.1 microM) and completely abolished by alprenolol (3 microM) or nadolol (300 microM). 3. In the longitudinal muscle of the proximal colon, the effects of sympathetic nerve stimulation were predominantly inhibitory. Some of this inhibition was removed by propranolol (0.1 microM), but was largely unaffected by alprenolol (3 microM). The remainder of the inhibitory response was probably non-noradrenergic as it was not removed by a combination of phentolamine (3 microM) and alprenolol (3 microM). 4. In the circular muscle of both the proximal and distal colon, sympathetic stimulation caused a strong contractile response which was completely removed by phentolamine (3 microM) to reveal an inhibitory response. This inhibitory response was unchanged by propranolol (0.1 microM) but was removed by alprenolol (3 microM), following which a weak non-noradrenergic contractile response was unmasked. 5. Stimulation of the hypogastric nerve to activate pelvic sympathetic pathways had no effect on the motility of the longitudinal muscle, but caused a contractile response in the circular muscle which was completely removed by phentolamine (3 microM). 6. We conclude that sympathetic nerves innervate adrenoceptors of different types in the various muscle layers and regions of the colon. They innervate a mixture of alpha-, and beta(3)-adrenoceptors in the longitudinal muscle of the proximal colon, alpha-, classical beta- and beta(3)-adrenoceptors in the distal colon, and primarily alpha-adrenoceptors with a few beta(3)-adrenoceptors in the circular muscle. In addition, the pelvic sympathetic innervation of the rectum differs from the prevertebral supply by innervating only excitatory alpha-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1987

Differential antagonism of the initial fast and secondary slow contractile responses of the rat isolated aorta to 5-hydroxytryptamine by mianserin and ketanserin.

1 The rat isolated aorta is contracted by 5-hydroxytryptamine (5-HT) with an initial fast and secondary slow response. The secondary slow responses were greater than the initial fast. The effects of antagonists (prazosin, idazoxan, phentolamine, dihydroergotamine, methysergide, cyproheptadine, mianserin and ketanserin) on these initial fast and secondary slow contractile responses to 5-HT were studied. 2 Prazosin and idazoxan at 10(-7)M had no effect on responses to 5-HT. Thus all concentrations of 5-HT contract the aorta by stimulating receptors distinct from alpha-adrenoreceptors. 3 Phentolamine, dihydroergotamine, methysergide and cyproheptadine had similar inhibitory effects on the initial fast and secondary slow responses to 5-HT. Phentolamine at 10(-6)M caused parallel, whereas dihydroergotamine (10(-9)-10(-8)M), methysergide (10(-9)-10(-8)M) and cyproheptadine (3 X 10(-11)-10(-8)M) caused non-parallel rightward shifts of the concentration-response curves. 4 Mianserin and ketanserin had greater inhibitory effects on the initial fast than secondary slow responses. Mianserin (10(-9)-10(-7)M) caused a non-parallel and parallel rightward shift of the concentration-response curves to the initial fast and secondary slow responses to 5-HT, respectively. Ketanserin (10(-8)-10(-7)M) produced non-parallel rightward shifts of the concentration-response curves. 5 One possible explanation of these results is that the rat aorta has no spare 5-HT2 receptors and that in inhibiting responses to 5-HT: (a) phentolamine is a competitive antagonist, (b) mianserin and ketanserin are slowly dissociating antagonists, and (c) dihydroergotamine, methysergide and cyproheptadine are irreversible antagonists. Furthermore, the competitive and irreversible antagonists have similar effects on initial fast and secondary slow responses to 5-HT, whereas the slow dissociating antagonists (mianserin and ketanserin) have a greater inhibitory effect on the initial fast than secondary slow response.

Animals↗
PubMed1980

An electrophysiological analysis of the effects of noradrenaline and alpha-receptor antagonists on neuromuscular transmission in mammalian muscular arteries.

1 The effects of exogenously applied noradrenaline (NA) and alpha-adrenoceptor antagonists on the mechanical and intracellularly recorded responses to perivascular nerve stimulation were examined in the rabbit ear artery, rabbit saphenous artery and rat tail artery. 2 Excitatory junction potentials (e.j.ps) and action potentials recorded from these smooth muscles were not blocked or depressed by phentolamine, phenoxybenzamine, prazosin, or labetolol in concentrations as high as 10 microgram/ml. Phentolamine (1 to 10 microgram/ml) depressed neurally-evoked contractions of the ear and saphenous, but not the tail artery, and also depressed the contractions produced by direct muscle stimulation in the ear and saphenous arteries. Prazosin and labetolol (0.1 to 10 microgram/ml) had no effect on the neurally evoked contractile response in any of the arteries examined. 3 The amplitude of the steady-state e.j.p. during repetitive stimulation at 0.45 to 2 Hz was increased by phentolamine or phenoxybenzamine but not by prazosin or labetolol. Phentolamine and phenoxybenzamine also increased the amplitude of the e.j.p. evoked by a single stimulus in the majority of the preparations. 4 Concentrations of NA greater than or equal to 1 microgram/ml depolarized the smooth muscle while concentrations greater than or equal to 0.5 microgram/ml depressed the amplitude of the e.j.ps recorded from these arteries. alpha-Antagonists did not suppress either the NA-induced membrane depolarization or depression of e.j.ps. 5 These observations call into question the physiological relevance of both pre- and postsynaptic alpha-receptors in regard to adrenergic neuromuscular transmission in muscular arteries.

Action Potentials↗
PubMed1982

A pharmacological analysis of the hyperactivity syndrome induced by beta-phenylethylamine in the mouse.

1 The effects of the putative 5-hydroxytryptamine (5-HT) receptor antagonists, methysergide, mianserin and methergoline, the dopamine receptor antagonists, haloperidol, thioridazine and clozapine, and the noradrenaline (NA) receptor antagonists, phentolamine, phenoxybenzamine and propranolol on the behavioural responses of mice to beta-phenylethylamine (PEA, 75 mg/kg) have been examined.2 PEA produced a syndrome consisting of three distinct phases. The brief initial phase (0-5 min after injection) which consisted of forward walking, sniffing and headweaving, was succeeded by a locomotor depressant phase (5-20 min after injection) which consisted of abortive grooming, headweaving, splayed hindlimbs, forepaw padding, sniffing and hyperreactivity, and a late locomotor stimulant phase (20-35 min after injection), which was characterized by forward walking, sniffing, hyperreactivity, rearing and licking.3 Methysergide, mianserin, methergoline, clozapine and propranolol inhibited headweaving and splayed hindlimbs, whereas haloperidol, thioridazine, phentolamine and phenoxybenzamine had no effect on these responses. Forepaw padding was strongly inhibited by methergoline and a high dose of mianserin, and weakly antagonized by methysergide, clozapine, haloperidol and thioridazine. In contrast, padding was mildly potentiated by phenoxybenzamine and phentolamine but strongly potentiated by propranolol. It is proposed that headweaving and splayed hindlimbs are 5-HT-mediated responses whereas forepaw padding also involves 5-HT mechanisms but may be partially due to release of tryptamine.4 Rearing and licking were inhibited by haloperidol (most strongly), thioridazine and clozapine but potentiated by mianserin, methysergide, propranolol, phenoxybenzamine or phentolamine. Methergoline inhibited licking without affecting rearing. It is suggested that PEA-induced rearing and licking are produced by activation of dopaminergic neurones and inhibited by 5-HT or NA stimulation.5 Phenoxybenzamine inhibited sniffing and produced backward walking when administered prior to PEA, suggesting mediation by NA of sniffing and an inhibitory influence of NA on backward walking.6 Clozapine and thioridazine were the most effective antagonists of hyperreactivity and it is proposed that this response is dopamine-mediated. Forward walking was inhibited by high doses of haloperidol or clozapine and potentiated by methergoline, mianserin or methysergide, suggesting that hyperactivity may also be mediated by dopamine but subject to 5-HT inhibition.7 Abortive grooming was the dominant behavioural component observed after PEA administration and was prevented by all of the antagonists tested which suggests that catecholamine and 5-HT mechanisms may be involved in the expression of this response.8 Since PEA is an endogenous compound in animals and man, and has been claimed to be present in abnormal amounts in some schizophrenics, PEA-induced behavioural stimulation in mice (which includes the postulated hallucinogenic responses of abortive grooming and backward walking) may be a useful animal model of psychosis.

5-Hydroxytryptophan↗
PubMed1984

A pharmacological study of oesophageal muscularis mucosae from the cat, dog and American opossum (Didelphis virginiana).

Strips of muscularis mucosae from the oesophagi of cat, dog and opossum have been studied to determine their responses to drugs to electrical field stimulation. All tissues were contracted by acetylcholine, histamine and, with the exception of strips of muscularis mucosae from the opossum proximal oesophagus, noradrenaline. The effects of acetylcholine and histamine were competitively antagonized by atropine (50 nM) and mepyramine (50 nM) and were abolished by atropine (1 microM) and mepyramine (1 microM) respectively. Contractile responses to noradrenaline were competitively antagonized by phentolamine (50 nM) but were converted to propranolol (50 nM)-sensitive relaxations by phentolamine (1 microM). Relaxations were abolished by propranolol (1 microM). Cholecystokinin octapeptide, gastrin 1 and vasoactive intestinal polypeptide were ineffective on any of the tissues examined. Substance P caused contractions in tissue from all three species. These effects were atropine and tetrodotoxin insensitive. All tissues gave atropine (50 nM)- and tetrodotoxin (100 nM)-sensitive contractions in response to electrical field stimulation. Contractions were not followed by relaxations and spontaneous mechanical activity was not suppressed between periods of stimulation. No evidence was obtained for the presence of non-adrenergic, non-cholinergic inhibitory innervation of the oesophageal muscularis mucosae in any species. During electrical field stimulation noradrenaline always reduced the amplitude of evoked contractions and, with the exception of tissue from proximal opossum oesophagus, increased resting tension. In opossum distal oesophageal muscularis mucosae, the effects of noradrenaline during electrical field stimulation were abolished by a 30 min pretreatment of the tissue with phentolamine (1 microM) and propranolol (1 microM). To Achieve this in all other tissues, it was also necessary to use yohimbine (1 microM). 7 In all tissues where noradrenaline caused a phentolamine (1 microM)-and propranolol (1 microM)- resistant depression of electrically evoked responses, clonidine produced a yohimbine (1 microM)- sensitive depression. 8 Evidence was obtained for the presence of excitatory alpha 1-and inhibitory alpha 2- and beta-adrenoceptors. Inter-species differences in their distribution are discussed.

Acetylcholine↗
PubMed1988

Pressor responses induced by Bay K 8644 involve both release of adrenal catecholamines and calcium channel activation.

1. The dihydropyridine calcium channel activator, Bay K 8644, is believed to increase mean arterial blood pressure in several animal models, as a result of direct activation of vascular smooth muscle cells by increasing calcium influx through the voltage-dependent calcium channels. The purpose of the current study was to elucidate further the mechanism of action of Bay K 8644, by examining the possibility that the pressor response to Bay K 8644 may also be the result of indirect activation of the vascular smooth muscle cells by release of adrenal catecholamines. 2. Intravenous administration of Bay K 8644 increased mean arterial pressure in a dose-dependent manner in conscious, normotensive rats. This pressor response was blocked by calcium channel blockers (nifedipine, verapamil, and diltiazem) at doses lower than were necessary to decrease resting mean arterial pressure. 3. alpha-Adrenoceptor antagonists (phentolamine, yohimbine, and prazosin) completely blocked the Bay K 8644-induced pressor responses and converted them to depressor responses. Adrenalectomy did not alter the inhibitory effect of phentolamine on the pressor response to Bay K 8644. However, adrenalectomy or adrenal demedullectomy prevented the phentolamine-induced reversal of the Bay K 8644 pressor response to a depressor response. In addition, adrenalectomy did not affect the ability of phentolamine to reverse the pressor response to exogenous adrenaline administration to a depressor response. 4. These data suggest that the pressor response to Bay K 8644 may involve both direct activation of vascular smooth muscle cells and indirect activation of the muscle cells by release of adrenal catecholamines.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

The modulatory role of vascular endothelium in the interaction of agonists and antagonists with alpha-adrenoceptors in the rat aorta.

1. We have examined the effect of endothelium on the antagonistic action of prazosin, doxazosin, yohimbine and phentolamine against phenylephrine, clonidine and noradrenaline. 2. The action of prazosin against phenylephrine was similar to that earlier reported against noradrenaline, acting as a non-competitive antagonist in the presence of endothelium and as a competitive antagonist in the absence of endothelium. Prazosin also acted as a non-competitive antagonist against clonidine in the absence of endothelium. 3. Doxazosin behaved in a similar way to prazosin against noradrenaline, phenylephrine and clonidine acting as a non-competitive antagonist in the presence of endothelium and as competitive antagonist after removal of endothelium. In contrast, yohimbine and phentolamine acted as competitive antagonists both in the presence and in the absence of endothelium. 4. Analysis of the concentration-response curves for noradrenaline, phenylephrine and clonidine in the presence and in the absence of endothelium showed that the affinity for all three agonists was the same but not the efficacy and the receptor reserve, both of which were lower in the presence than in the absence of endothelium. 5. The rank order of agonist potency in the absence of endothelium was noradrenaline greater than phenylephrine greater than clonidine. The rank order of antagonist potency was prazosin greater than or equal to doxazosin greater than phentolamine greater than yohimbine. 6. The results show that vascular endothelium modulates the contractile response to alpha-adrenoceptor agonists and also modifies the action of the antagonists prazosin and doxazosin but not that of yohimbine and phentolamine. This effect of endothelium was related to a change in agonist efficacy and receptor reserve. These results also suggest that the alpha-adrenoceptors of the isolated aorta of the rat are predominantly, if not exclusively of the alpha 1-subtype.

Adrenergic alpha-Agonists↗
PubMed1991

Possible dependence of pressor and heart rate effects of NG-nitro-L-arginine on autonomic nerve activity.

1. The effects of NG-nitro-L-arginine (L-NNA) on mean arterial pressure (MAP) and heart rate (HR) were investigated in conscious rats. 2. Intravenous bolus cumulative doses of L-NNA (1-32 mg kg-1) dose-dependently increased MAP. Both mecamylamine and phentolamine increased MAP responses to L-NNA, angiotensin II and methoxamine. Propranolol, reserpine, atropine and captopril did not affect MAP response to L-NNA. 3. A significant negative correlation of HR and MAP responses to L-NNA was obtained in control rats but not in rats pretreated with reserpine or mecamylamine. Significant negative correlations also occurred in the presence of atropine, propranolol, phentolamine or captopril. 4. A single i.v. bolus dose of L-NNA (32 mg kg-1) raised MAP to a peak value of 53 +/- 3 mmHg and the effect lasted more than 2 h; the rise and recovery of MAP were accompanied by significant decrease and increase in HR, respectively. While both phentolamine and mecamylamine increased peak MAP response to L-NNA, mecamylamine abolished the biphasic HR response and phentolamine potentiated the bradycardiac component of HR. 5. Blockade of the autonomic nervous and renin-angiotensin systems did not attenuate the pressor effects of L-NNA. However, the biphasic HR response to L-NNA is mediated via modulation of autonomic nerve activities.

Animals↗
PubMed1980

Electrophysiologic properties of hydralazine in man.

There is considerable interest in selecting the proper drug to preserve the ischemic myocardium, or twilight zone, in a patient with a recent myocardial infarction. Vasodilator therapy with an infusion of nitroprusside or phentolamine has been shown to improve left ventricular function by reducing both preload and afterload. Sublingual nitroglycerin as well as an infusion of nitroglycerin can also alleviate left ventricular failure in patients with an acute myocardial infarction. Similarly, chronic congestive heart failure patients, irrespective of the etiology, improve hemodynamically after an infusion of phentolamine, nitroprusside or hydralazine. Oral nitrates, phentolamine, and hydralazine have also been demonstrated to produce improvement in chronic heart failure patients. Recently data has become available on the effects of phentolamine, nitroglycerin and nitroprusside on cardiac conduction in man. However there is no information on the electrophysiological properties of hydralazine in man. The present study involving 12 human subjects was undertaken to determine what effect intravenously administered hydralazine has on the human conduction system.

Aged↗
PubMed1985

Neuropeptide Y (NPY) and sympathetic control of blood flow in oral mucosa and dental pulp in the cat.

Neuropeptide Y (NPY) immunoreactivity (-IR) was found to be present in perivascular nerves in the cat dental pulp and oral mucosa. Many ganglion cells in the superior cervical ganglion also contained NPY-IR. Ligation of the inferior alveolar or lingual nerves produced an accumulation of NPY-IR in axons proximal to the site of ligation, suggesting an anterograde axonal transport of the peptide. After unilateral sympathectomy the NPY-IR disappeared in the dental pulp and oral mucosa on the ipsilateral side. Reversed phase high performance liquid chromatography showed that the main peak of NPY-like immunoreactivity found in the superior cervical ganglion co-chromatographed with synthetic porcine NPY. Changes in blood flow in dental pulp or oral mucosa were measured indirectly by recording local clearance of 125I during electrical stimulation of the sympathetic nerve or during close intra-arterial infusion of noradrenaline or NPY. All three procedures resulted in a pronounced decrease in local blood flow of a similar magnitude in both tissues. After alpha-adrenoceptor blockade with phentolamine, the vasoconstrictor effect of noradrenaline was abolished. However, the effect of sympathetic stimulation after phentolamine was only partially reduced (23-54%) and the response to NPY was almost unaffected by the alpha-receptor blockade. The remaining effect of sympathetic stimulation after phentolamine was abolished by guanethidine. However, the response to NPY was not changed by the latter drug. In conclusion, the vasoconstrictor response in the dental pulp and oral mucosa caused by activation of sympathetic nerves is more resistant to phentolamine than the response induced by infusion of exogenous noradrenaline. Since NPY is probably co-localized with noradrenaline in the sympathetic perivascular nerves and NPY reduces local blood flow, it is proposed that this peptide is involved in sympathetic vascular control in oral tissues.

Adrenergic alpha-Agonists↗
PubMed1984

Antagonism of the antidiarrhoeal effect of clonidine and the lethal effect of noradrenaline in rats: a reliable procedure to evaluate the in-vivo alpha 1- and alpha 2-blocking activity of drugs?

Eight compounds with alpha-adrenergic blocking activity were tested for their ability to antagonize the antidiarrhoeal effect of clonidine (clonidine test) and the lethal effect of noradrenaline (noradrenaline test). Six of the compounds studied are alpha-adrenergic blocking agents with known alpha 2/alpha 1 selectivity. Two compounds, ketanserin (R 41 468) and butanserin (R 53 393), are 5-hydroxytryptamine S2-antagonists. The ED50-values (mg kg-1) obtained in the clonidine test were: phentolamine (0.34), RX781094 (0.34), yohimbine (0.51), piperoxan (9.36), butanserin (greater than 5.0), prazosin (greater than 10.0), phenoxybenzamine (greater than 40.0), and ketanserin (greater than 80.0). In the noradrenaline test the ED50's (mg kg-1) were: butanserin (0.014), prazosin (0.032), phentolamine (0.59), phenoxybenzamine (1.02), ketanserin (4.69), RX781094 (12.4), piperoxan (21.5), and yohimbine (25.0). The selectivity alpha 2/alpha 1-ratios (ED50 clonidine/ED50 noradrenaline were: yohimbine (0.020), RX781094 (0.027), piperoxan (0.44), phentolamine (0.58), ketanserin (greater than 39), prazosin (greater than 312), and butanserin (greater than 357). These results show that yohimbine and RX781094 are equipotent and relatively selective alpha 2-antagonists; piperoxan and phentolamine block both alpha 1- and alpha 2-receptors at closely related doses; ketanserin, prazosin and butanserin are selective blockers of alpha 1-receptors, ketanserin being very weak, prazosin and butanserin being very potent compounds in this respect. The potent and selective alpha 1-blocking activity of butanserin, combined to its 5-HT S2-antagonism makes butanserin a very interesting experimental drug in view of earlier reported data concerning the amplifying effects between 5-hydroxytryptaminergic and noradrenergic vascular mechanisms.

Adrenergic alpha-Antagonists↗
PubMed1992

Effects of anaesthetic agents on pressor response to beta-blockers in the rat.

It has been shown that paradoxical pressor response to a beta-adrenoceptor antagonist occurs in conscious rats pretreated with an alpha-adrenoceptor antagonist. This study examines the influence of anaesthetic agents on mean arterial pressure (MAP) response to a beta-blocker. Cumulative dose-response curves of propranolol (non-selective), ICI 118,551 (beta 2-selective) and atenolol (beta 1-selective) were constructed in phentolamine-treated rats anaesthetized with urethane, pentobarbitone or halothane. I.v. injections of all three beta-blockers caused dose-dependent increases in MAP in urethane-anaesthetized rats. In halothane-anaesthetized rats, propranolol and atenolol did not alter MAP while ICI 118,551 caused a small dose-dependent increase in MAP. In the presence of pentobarbitone, none of the beta-blockers raised MAP. In the second series of experiments, a single i.v. bolus dose of propranolol was given in phentolamine-treated rats anaesthetized with pentobarbitone, amobarbitone, ketamine or chloralose. Propranolol did not affect MAP in rats anaesthetized with pentobarbitone, amobarbitone and chloralose but it partially reversed the hypotensive effect of phentolamine in ketamine-anaesthetized rats. In the third series, propranolol or atenolol was i.v. injected in pentobarbitone-anaesthetized rats treated with both phentolamine and adrenaline. Both propranolol and atenolol raised MAP. Our results show that anaesthetic agents differentially affect the MAP response to a beta-blocker.

Adrenergic beta-Antagonists↗
PubMed1983

Modulation of noradrenergic transmission in the guinea-pig mesenteric artery: an electrophysiological study.

We carried out electrophysiological experiments on guinea-pig mesenteric arteries in an attempt to clarify the modification of noradrenaline (NA) release from noradrenergic nerve terminals by the action of prejunctional adrenoceptors. NA (10(-7)-10(-5) M) suppressed the amplitude of the first excitatory junction potential (e.j.p.(f], the facilitation process, and the e.j.p. after facilitation was completed (e.j.p.(s]with no change in the post-junctional membrane properties of smooth muscles. These actions of NA on e.j.p.s were antagonized by high concentrations of extracellular Ca, [Ca]o, but not in a simple competitive manner. NA (10(-7) M) suppressed the appearance but not the amplitude of the miniature e.j.p.s. These effects of NA on transmission indicate that NA acts on prejunctional nerve terminals and suppresses the release of NA from nerve terminals rather than producing a desensitization of post-junctional adrenoceptors. Prazosin and phentolamine (10(-6) M) did suppress the NA-induced contraction (greater than 10(-6) M) but did not suppress the contraction evoked by perivascular nerve stimulation, below a frequency of 1.0 Hz. At a dose of 10(-7) M, yohimbine, clonidine, prazosin and phentolamine had no effect on the muscle membrane potential and resistance. Yet on the e.j.p.(f), yohimbine and clonidine caused suppression, phentolamine enhancement and prazosin had no effect. On the e.j.p.(s), yohimbine and phentolamine caused enhancement, clonidine suppression and prazosin had no effect. These results indicate that at least three different adrenoceptors are distributed on the neuromuscular junction in this tissue, i.e. alpha 1-extrajunctional, alpha 2-prejunctional, and an unknown subtype of intrajunctional adrenoceptors. Furthermore, the feedback mechanism on NA release is mediated by suppression of the influx of Ca. Nonselective and non-specific actions of alpha-adrenoceptor agonists and antagonists were also elucidated.

Adrenergic alpha-Antagonists↗
PubMed1985

Noradrenaline and adenosine triphosphate as co-transmitters of neurogenic vasoconstriction in rabbit mesenteric artery.

The largest rami caecales of the ileocolic artery, which is a branch of the mesenteric artery, were perfused at a constant rate of flow. Either vasoconstriction (as an increase in perfusion pressure) or the release of previously incorporated [3H]-noradrenaline was measured. Noradrenaline and ATP, but not carbachol, serotonin, adenosine, Arg-vasopressin and neuropeptide Y, caused marked vasoconstriction. When the sympathetic vasoconstrictor axons in the arterial wall were stimulated by electrical field pulses (either 5 pulses at 10 Hz or 100 pulses at 5 Hz; 0.3 ms pulse width, 200 mA current strength), the ensuing vasoconstriction was at best slightly reduced by phentolamine, prazosin and phenoxybenzamine. The response to 100 pulses, 5 Hz was even enhanced by phentolamine and yohimbine. All antagonists except yohimbine blocked the effect of exogenous noradrenaline. Prazosin did not change the effect of exogenous ATP. alpha,beta-Methylene-ATP (3-15 mumol/l) elicited transient vasoconstriction. Subsequently, responses to ATP as well as to electrical stimulation were reduced and recovered slowly. The response to noradrenaline was not changed. That part of the electrically induced vasoconstriction that remained after alpha,beta-methylene-ATP was almost abolished by phentolamine or prazosin. Pre-treatment of the animals with reserpine decreased but did not prevent the electrically evoked contraction of their arteries. The reserpine-resistant response was not changed by prazosin but was abolished by alpha,beta-methylene-ATP. The vasoconstriction elicited by electrical pulses was not affected by atropine or methysergide but was entirely blocked by tetrodotoxin, guanethidine or exposure to 6-hydroxydopamine. In arteries pre-incubated with [3H]-noradrenaline, electrical stimulation (100 pulses at 5 Hz) increased the outflow of tritium. The evoked overflow was blocked by tetrodotoxin, not changed by alpha,beta-methylene-ATP (9 mumol/l) or prazosin, and enhanced by phentolamine, phenoxybenzamine and yohimbine. We conclude that, in the branch of the mesenteric artery examined, both noradrenaline and ATP or a closely related compound transmit information from sympathetic neurones to smooth muscle. An alpha-adrenoceptor antagonist can reduce neurogenic vasoconstriction by blockade of post-junctional alpha-(probably alpha 1) receptors, reserpine by selective depletion of noradrenaline, and alpha,beta-methylene-ATP by desensitization of the post-junctional ATP (probably P2) receptor mechanism. Noradrenaline and ATP appear to be released from the same neurone. In addition, prejunctional alpha 2-adrenergic autoinhibition of transmitter release operates in the artery. alp

Adenosine Triphosphate↗
PubMed1988

Adrenergic modulation of pancreatic glucagon and insulin secretion in sheep.

The effect of intravenous infusion of epinephrine, either alone or together with various doses of phentolamine or propranolol, on the secretion of both glucagon and insulin was determined in six sheep. Intravenous infusion of epinephrine alone caused increases in plasma glucagon and glucose concentrations and produced a slight but significant decrease in plasma insulin concentration. The concomitant infusion of propranolol and epinephrine augmented glucagon release and inhibited insulin secretion. Combined propranolol plus epinephrine infusion also caused a marked hyperglycemia. The concomitant infusion of phentolamine and epinephrine produced slight inhibition of glucagon secretion and markedly promoted insulin secretion. Epinephrine-induced hyperglycemia was eliminated by phentolamine infusion. The effects of isoproterenol infusion on plasma glucagon, insulin, and glucose concentrations were similar to that caused by the concomitant infusion of phentolamine and epinephrine. The effects of isoproterenol were abolished by the infusion of propranolol. It is concluded that an alpha-receptor mechanism is the most important component of adrenergic modulation of pancreatic glucagon secretion, whereas beta-receptor activation stimulates and alpha-receptor activation inhibits insulin secretion in sheep.

Adrenergic alpha-Antagonists↗
PubMed2004

Enhanced arteriolar alpha-adrenergic constriction impairs dilator responses and skeletal muscle perfusion in obese Zucker rats.

The present study tested the hypothesis that enhanced vascular alpha-adrenergic constriction in obese Zucker rats (OZR) impairs arteriolar dilation and perfusion of skeletal muscle at rest and with increased metabolic demand. In lean Zucker rats (LZR) and OZR, isolated gracilis arterioles were viewed via television microscopy, and the contralateral cremaster muscle or gastrocnemius muscle was prepared for study in situ. Gracilis and cremasteric arterioles were challenged with dilator stimuli under control conditions and after blockade of alpha-adrenoreceptors with prazosin, phentolamine, or yohimbine. Gastrocnemius muscles performed isometric twitch contractions of increasing frequency, and perfusion was continuously monitored. In OZR, dilator responses of arterioles to hypoxia (gracilis), wall shear rate (cremaster), acetylcholine, and iloprost (both) were impaired vs. LZR. Treatment with prazosin and phentolamine (and in cremasteric arterioles only, yohimbine) improved arteriolar reactivity to these stimuli in OZR, although responses remained impaired vs. LZR. Gastrocnemius muscle blood flow was reduced at rest in OZR; this was corrected with intravenous infusion of phentolamine or prazosin. At all contraction frequencies, blood flow was reduced in OZR vs. LZR; this was improved by infusion of phentolamine or prazosin at low-moderate metabolic demand only (1 and 3 Hz). At 5 Hz, adrenoreceptor blockade did not alter blood flow in OZR from levels in untreated rats. These results suggest that enhanced alpha-adrenergic constriction of arterioles of OZR contributes to impaired dilator responses and reduced muscle blood flow at rest and with mild-moderate (although not with large) elevations in metabolic demand.

Adrenergic alpha-Agonists↗
PubMed1989

Effect of noradrenaline on rubidium (86Rb) efflux in the rat isolated seminal vesicle.

The effect of noradrenaline (NA) on the efflux of rubidium (86Rb) from the rat isolated seminal vesicle was studied in the absence and presence of phentolamine and papaverine. Strips of spirally cut seminal vesicles were incubated in radioactive 86Rb (10 microCi.ml-1) for 2 h. Radioactivity was measured using an autogamma spectrometer, and the flux data were expressed in terms of rate constants per minute, of the reactive isotope efflux. A concentration-effect curve for the effect of NA on rat seminal vesicles was constructed, alone and in the presence of phentolamine (1 mumol/l) or papaverine (5 mumol/l). The results showed that NA (10-1,000 mumol/l) produced concentration-dependent contractions in the rat seminal vesicle. These responses were greatly reduced by phentolamine but markedly enhanced by papaverine. NA significantly increased 86Rb efflux from rat seminal vesicles (control rate constant 0.0042 +/- 0.001; test 0.0064 +/- 0.002, means +/- SE; n = 8 rats; p less than 0.001). This increase (52%) occurred within an exposure of 7 +/- 1 min to NA. Phentolamine decreased the NA-induced increase in 86Rb efflux, by 75 +/- 2%, whereas papaverine enhanced it by 86 +/- 5% of the control value. The mechanism of NA-induced increase in 86Rb efflux was not further investigated but was interpreted in terms of an increase in intracellular K+ (here represented by 86Rb), which will leave the cell (efflux) after initial membrane depolarization.

Animals↗
PubMed1988

Erythrocyte water, Na+-K+ cotransport, and forearm vascular function in humans.

We examined the relationships between erythrocyte (RBC) composition (Na+, K+, and water content) and ouabain-insensitive transports (Na+-K+ cotransport, Li+-Na+ countertransport) and forearm vascular hemodynamics under standardized basal conditions and during vasoconstriction (intra-arterial infusion of graded doses of norepinephrine and angiotensin II) and vasodilation (intra-arterial phentolamine and postischemic exercise). RBC water content correlated positively and significantly (r = 0.53, p = 0.001) with minimum forearm vascular resistance, a measure of vascular structural change, and negatively with maximal forearm blood flow (r = -0.55, p less than 0.001). Similar correlations with forearm vascular resistance and blood flow were observed under all experimental conditions. RBC Na+-K+ cotransport correlated positively and significantly (r = 0.43, p = 0.01) with the change in forearm blood flow produced by phentolamine, a functional measure of alpha-adrenergic tone, and was as strong an independent predictor of phentolamine-induced blood flow change as was arterial norepinephrine concentration. RBC Na+-K+ cotransport was also significantly positively correlated with residual forearm blood flow and resistance after phentolamine administration, where nonadrenergic influences predominate. RBC water correlated negatively with Li+-Na+ countertransport (r = -0.33, p less than 0.05) and Na+-K+ cotransport (r = -0.44, p less than 0.01). We propose that RBC water is a marker for a vascular structural property that contributes to vascular reactivity. RBC Na+-K+ cotransport seems to relate most strongly to the sympathetically mediated control of forearm blood flow and may also be linked to the intrinsic myogenic tone of the forearm vasculature.(ABSTRACT TRUNCATED AT 250 WORDS)

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