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PubMed1986

Smoking-induced coronary vasoconstriction in patients with atherosclerotic coronary artery disease: evidence for adrenergically mediated alterations in coronary artery tone.

In patients with atherosclerotic coronary artery disease, cigarette smoking increases myocardial oxygen demand but may cause an inappropriate decrease in coronary blood flow and myocardial oxygen supply. This study was performed to explore the mechanism of smoking-induced coronary vasoconstriction and, specifically, to determine if smoking causes an alpha-adrenergically mediated increase in coronary artery tone. In 36 chronic smokers with coronary artery disease (27 men and nine women, 50 +/- 9 [mean +/- SD] years old), heart rate-systolic arterial pressure double product and coronary sinus blood flow (by thermodilution) were measured before and during smoking both before and after (1) normal saline (n = 5, control subjects), (2) an alpha-adrenergic-blocking agent, phentolamine, 5 mg (n = 15), (3) a beta-adrenergic-blocking agent, propranolol, 0.1 mg/kg (n = 12), or (4) sodium nitroprusside, 0.4 to 0.8 micrograms/kg/min, given in a dose sufficient to diminish systolic arterial pressure by 15% (n = 4). During the initial smoking period, rate-pressure product increased and coronary sinus blood flow was unchanged by smoking in all groups. After 30 to 75 min, saline, phentolamine, propranolol, or sodium nitroprusside was given, and measurements were repeated. In the control subjects, rate-pressure product and coronary sinus blood flow responded in a similar manner to that observed previously. In those receiving phentolamine, rate-pressure product was unchanged, but coronary sinus blood flow rose substantially with smoking (percent change +2 +/- 15% during the first smoking period [before phentolamine] and +32 +/- 17% during the second smoking period [after phentolamine]; p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Pharmacological studies on ginger. III. Effect of the spinal destruction on (6)-shogaol-induced pressor response in rats.

(6)-Shogaol-induced pressor responses in blood pressure of rats were studied. Intraventricular injection of (6)-shogaol (0.1 to 0.5 microgram) caused a pressor response in a dose-dependent manner. (6)-Shogaol (0.5 mg/kg, i.v.)-induced pressor response was markedly reduced by a spinal destruction to the sacral cord level. However, norepinephrine (10 micrograms/kg, i.v.)-induced pressor response was not affected by the spinal destruction. In rats in which the spinal cord was destroyed to the thoracic cord level, (6)-shogaol-induced pressor response was reduced by hexamethonium (10 mg/kg, i.v.) and phentolamine (10 mg/kg, i.v.), etc. When the spinal cord was destroyed to the sacral cord level, the pressor response was not affected by these blockades. In the hindquarters of rats which were perfused with rats' blood, (6)-shogaol caused two pressor responses on the perfusion pressure. The first pressor response, which was accompanied by a rise in systemic blood pressure, was reduced by hexamethonium but was not entirely eliminated by phentolamine. However, the pressor response disappeared with spinal destruction to the sacral cord level. The second pressor response, which occurred about when the systemic blood pressure regained its original pressure, was not affected by hexamethonium, phentolamine or spinal destruction. Pressor response induced by the injection of (6)-shogaol (10 micrograms) into the perfusion circuit was not affected by phentolamine and spinal destruction. Furthermore, (6)-shogaol-induced peripheral pressor response disappeared with the combined treatment of [D-Arg1, D-Pro2, D-Trp7.9, Leu11]-substance P (0.5 mg/kg, i.v.), phentolamine and the section of the sciatic nerves.

Animals↗
PubMed2004

Glucose dependence of imidazoline-induced insulin secretion: different characteristics of two ATP-Sensitive K+ channel-blocking compounds.

The glucose dependence of the insulinotropic action of KATP channel-blocking imidazoline compounds was investigated. Administration of 100 micromol/l phentolamine, but not 100 micromol/l efaroxan, markedly increased insulin secretion of freshly isolated mouse islets when the perifusion medium contained 5 mmol/l glucose. When the glucose concentration was raised to 10 mmol/l in the continued presence of either imidazoline, a clear potentiation of secretion occurred as compared with 10 mmol/l glucose alone. In the presence of efaroxan, a brisk first-phase-like increase was followed by a sustained phase, whereas a more gradual increase resulted in the presence of phentolamine. Administration of 100 micromol/l phentolamine was somewhat more effective than 100 micromol/l efaroxan to inhibit KATP channel activity in intact cultured beta-cells (reduction by 96 vs. 83%). Both compounds were similarly effective to depolarize the beta-cells. When measured by the perforated patch-technique, the depolarization by efaroxan was often oscillatory, whereas that by phentolamine was sustained. In perifused cultured islets, both compounds increased the cytosolic calcium concentration ([Ca2+]c) in the presence of 5 and 10 mmol/l glucose. Efaroxan induced large amplitude oscillations of [Ca2+]c, whereas phentolamine induced a sustained increase. It appears that a KATP channel block by imidazolines is not incompatible with a glucose-selective enhancement of insulin secretion. The glucose selectivity of efaroxan may involve an inhibitory effect distal to [Ca2+]c increase and/or the generation of [Ca2+]c oscillations.

Animals↗
PubMed1992

The sympathetic nervous system facilitates endothelin-1 effects on venous tone.

The effects of endothelin-1 (ET-1) or normal saline (0.9% NaCl) on mean arterial pressure (MAP), heart rate (HR) and mean circulatory filling pressure (MCFP), an index of body venous tone, were studied in 10 groups (n = 6 each) of conscious, unrestrained rats continuously i.v. infused with vehicle, verapamil, both hexamethonium and verapamil, phentolamine or, both phentolamine and verapamil. Infusion (i.v.) of normal saline into the five control groups did not significantly alter MAP, HR or MCFP. Cumulative i.v. bolus of ET-1 (0.8, 1.6, 3.2, 6.4, 12.8 and 19.4 x 10(-10) mol/kg) reduced HR in all five treatment groups and dose-dependently increased MAP in the presence of either vehicle or phentolamine, but did not affect MAP in the groups treated with verapamil. The ability of ET-1 to reduce HR in verapamil-treated rats, despite the absence of a pressor response, suggests that ET-1 is negatively chronotropic. ET-1 alone slightly increased MCFP and it did not alter MCFP in the presence of phentolamine. In the presence of verapamil, ET-1 markedly raised MCFP, and this was abolished by concurrent treatment with either hexamethonium or phentolamine. Therefore, ET-1 markedly elevates venous tone in the presence of verapamil via reflex-mediated increase in sympathetic nerve activity and the activation of alpha adrenoceptors.

Animals↗
PubMed1994

Adenosine formation during hypoxia in isolated hearts: effect of adrenergic blockade.

Adrenergic receptor blockade has been reported to decrease cardiac adenosine formation and release during hypoxia. We wished to determine whether this occurs by an improvement in the energy supply/demand ratio. Isolated guinea pig hearts were perfused at a constant pressure of 50 mm Hg. Hypoxia (30% O2) was maintained for 20 min while adenosine release and venous PO2 were measured in the coronary venous effluent. beta-adrenergic blockade with 5 microM atenolol did not change hypoxic adenosine release (Control: 15.6 +/- 2.7, Atenolol: 23.6 +/- 5.7 nmol/g/20 min). Addition of 6 microM phentolamine with atenolol significantly reduced hypoxic adenosine release (4.4 +/- 1.4 nmol/g/20 min, P < 0.05). Atenolol was without hemodynamic effects, but addition of phentolamine reduced left ventricular pressure development, heart rate, and oxygen consumption prior to hypoxia. Atenolol plus phentolamine did not change venous PO2 during hypoxia. Treatment with phenoxybenzamine (1 microM) plus atenolol also reduced adenosine release (7.4 +/- 0.8 nmol/g/20 min). Control experiments and atenolol plus phentolamine experiments were repeated using 31P-NMR to measure high energy phosphates. Adrenergic blockade had no effect on phosphate concentrations during normoxia, but resulted in higher [PCr], lower [P(i)] and higher phosphorylation potentials during hypoxia. Adrenergic blockade also prevented the hypoxia-induced rise in intracellular [H+], [AMP] and [ADP] seen in control hearts. The changes in phosphorylation potential are correlated with similar changes in adenosine release in adrenergically intact hearts. We conclude that the primary effect of adrenergic blockade during hypoxia is a reduction in ATP use due to alpha-receptor blockade. This leads to improved high energy phosphate concentrations during hypoxia and a reduction in adenosine formation.

Adenosine↗
PubMed1987

Studies on alpha adrenoceptors in guinea-pig peripheral lung strips.

Contractile responses of guinea-pig peripheral lung strips to noradrenaline were determined in the presence of propranolol (2.5 X 10(-6) mol/l). All strips (n = 44) contracted to noradrenaline and a geometric mean EC50 of 1.4 X 10(-6) mol/l (1.1 X 10(-6) mol/l, 1.8 X 10(-6) mol/l 95% confidence limits) was obtained. Contractions were antagonised by phentolamine (5 X 10(-7)-10(-5) mol/l) and by prazosin (10(-8)-10(-7) mol/l). Dose-ratios (DR) were calculated and log (DR-1) was plotted against log concentration of antagonist to yield slopes (+/- SE) of 0.84 +/- 0.14 and 0.73 +/- 0.22 respectively which were not significantly different from unity. A pA2 value (+/- SE) of 6.7 +/- 0.2 was obtained for phentolamine and 7.5 +/- 0.1 for prazosin. Yohimbine (10(-7)-10(-5) mol/l) did not significantly affect the maximal tension generated or the EC50 values for noradrenaline. These results suggest that alpha 1 adrenoceptors are mediating the contractile responses to noradrenaline. In the presence of cocaine (10(-5) mol/l, n = 18), normetanephrine (2 X 10(-5) mol/l, n = 15), hydrocortisone (2.5 X 10(-5) mol/l, n = 15) and normetanephrine (2 X 10(-5) mol/l) plus cocaine (10(-5) mol/l, n = 15) pA2 values for phentolamine of 6.9, 6.7, 6.6, and 6.3 respectively were obtained. Since these pA2 values are not significantly different from 6.7, it is unlikely that this original pA2 value, which is lower than values obtained with phentolamine at alpha-adrenoceptors in other tissues, may be explained by neuronal or extraneuronal uptake of noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1975

Frequency-dependence of the positive inotropic effect of methoxamine and naphazoline mediated by alpha-Adrenoceptors in the isolated rabbit papillary muscle.

Under the conditions of different stimulation frequencies the inotropic effects of the alpha-adrenoceptor stimulationg agents, methoxamine, naphazoling and oxymetazoline were studied on the isolated rabbit papillary muscle. 1. On the papillary muscle stimulated at 0.5 Hz methoxamine in concentrations from 10(-5)M caused a significant and dose-dependent positive inotropic effect. At 10(-3)M methoxamine decreased the developed tension. With increasing frequency of stimulation (0.5--1--1.5Hz), the positive inotropic effect became smaller, while the negative inotropic one was more pronounced. The time course of the disappearance of the negative inotropic effect of methoxamine by washout differed from that of the positive inotropic effect: the negative component disappeared within 30 min, whereas the positive one lasted for about 100 min. The positive inotropic effect of noradrenaline (10(-6)M), in contrast ot that of methoxamine, was not influenced by the frequency under the same conditions of stimulation. Also naphazoline (10(-5)M) caused a significant positive inotropic effect on the papillary muscle stimulated at 0.5 Hz, while oxymetazoline induced exclusively a negative inotropic effect. 2. The positive inotropic effect of metoxamine (10(-4)M) as well as of naphazoline (10(-5)M) evoked at a frequency of 0.5 Hz was abolished by phentolamine (10(-6)M). Methoxamine (10(-4)M) induced a significant negative inotropic effect in the presence of phentolamine. Phentolamine antagonized the positive inotropic effect of methoxamine in a non-competitive manner: the pD2-value was 7.76. 3. In the presence of methoxamine (10(-4)M) the developed tension in the lower range (0.05--1 Hz) of the frequency-force relationship was enhanced, while that in the higher range (greater that 1.5 Hz) was decreased. The enhancement was abolished by phentolamine (10(-6)M). 4. Papaverine (2x10(-5)M) did not affect the positive inotropic effect of methoxamine. 5. The present results show that methoxamine and naphazoline induced a positive inotropic effect via alpha-adrenoceptor in the ventricular myocardium of the rabbit. These effects were caused only at low, but not at high frequencies of stimulation.

Animals↗
PubMed1977

Possible feed-back inhibition of noradrenaline release by purine compounds.

The contractile responses to transmural stimulation of, and the overflow of tritium from the rat portal vein prelabelled with 3H-noradrenaline were studied. The contractile responses of the rat portal vein were sustained throughout the period of stimulation. The tension developed did not decline when two consecutive periods of stimulation were compared. In contrast, the tritium overflow decreased during the second period of stimulation. Preincubation with 3 micronM phenoxybenzamine during 30 min increased 3-fold the tritium overflow during stimulation. Phentolamine and phenoxybenzamine were nearly equipotent in reducing the vascular response to stimulation. In contrast, phentolamine was less potent than phenoxybenzamine in increasing the 3H-noradrenaline overflow elicited by stimulation. The results obtained with phentolamine are interpreted in terms of a different potency of phentolamine to produce blockade of prejunctional and postjunctional alpha-adrenoceptors in the rat portal vein. ATP inhibited by 70% the tritium overflow induced by stimulation. The potency of ATP in inhibiting the overflow increased when the prejunction alpha-adrenoceptors were blocked. The purine compounds ATP, ADP, AMP and adenosine were roughly equipotent in inhibiting stimulation-induced tritium overflow. The tritium released by stimulation decreased when uptake and metabolism of adenosine were inhibited. Under physiological conditions, a prejunctional purinergic inhibition of noradrenaline release might be involved in an endogenously mediated negative feed-back regulatory mechanism. It is possible that the purinergic inhibition of the noradrenaline liberation elicited by stimulation plays a physiological role in tissues with both purinergic and adrenergic innervation.

Adenine Nucleotides↗
PubMed1985

A kinetic study of the release of noradrenaline by electrical stimulation: influence of presynaptic alpha-adrenoceptors.

Dog saphenous vein strips were incubated with 1.4 mumol/l 3H-(--)-noradrenaline for 60 min, after inhibition of the noradrenaline-metabolizing enzymes and of extra-neuronal uptake. At the end of the incubation period the strips were perifused for 150 min; cocaine (10 mumol/l) was added to the perifusion fluid from t = 75 min onwards. In some experiments either phentolamine (10 mumol/l) or clonidine (0.1 mumol/l) was also added at this time. Some strips were subjected to electrical stimulation from t = 100 to 150 min of perifusion (t = 0 being the start of perifusion), with frequencies ranging from 0.5 to 13.5 Hz. A compartmental analysis of spontaneous or electrically-induced efflux of 3H-noradrenaline was made. The spontaneous efflux had a long half time (t/2 = 124 min) and most of the 3H-noradrenaline which had accumulated in the strips did not participate in the efflux ("bound fraction", representing 90% of tissue activity at t = 100 min of perifusion). Neither phentolamine nor clonidine modified the half time or the "bound fraction" observed for spontaneous efflux. Electrical stimulation (greater than 0.5 Hz) mobilized only one compartment of noradrenaline, which represented about 50% of the noradrenaline accumulated in the strips. The half time of 3H-efflux induced by electrical stimulation decreased when the frequency increased from 0.5 Hz up to 13.5 Hz. Phentolamine increased the rate of efflux for all frequencies of stimulation and decreased the half time of efflux. However, the releasable pool of noradrenaline was only increased by phentolamine at 0.5 Hz, but not at higher frequencies.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Lack of a direct effect of the autonomic nervous system on glucose-stimulated gastric inhibitory polypeptide (GIP) secretion in man.

To determine whether the autonomic nervous system has a direct effect on GIP secretion, six normal subjects received a 4-hr intraduodenal perfusion of glucose (225 mg/min) and polyethylene glycol on four successive days. During the latter 2 hr, either normal saline, propranolol, phentolamine, or atropine were infused intravenously. Glucose absorption was calculated by measuring glucose and polyethylene glycol following luminal aspiration distal to the perfusion site. Basal and peak or nadir values in the saline study of plasma glucose, insulin, glucagon, and GIP were similar to the other three studies prior to autonomic blockade. During the latter 2 hr of the glucose perfusion, the plasma glucose and glucagon responses to saline did not differ from responses to the three blocking agents. Phentolamine but not atropine or propranolol resulted in a greater insulin response compared to saline (3247 +/- 762 vs 1348 +/- 388 microU/ml/120 min, P less than 0.01). GIP was not significantly affected by phentolamine (18,146 +/- 4574), propranolol (7585 +/- 5854), or atropine (15,797 +/- 6297) compared to saline (11,717 +/- 5204 pg/ml/120 min). Glucose absorption was unaffected by infusions of saline, phentolamine, and propranolol, but was increased following atropine infusion (5841 +/- 1120 vs 1044 +/- 808 mg/120 min, P less than 0.02). There appears to be no direct effect of the autonomic nervous system on glucose-induced secretion of GIP.

Adult↗
PubMed1998

Assessing microcirculation in familial dysautonomia by laser Doppler flowmeter.

Microcirculatory vasomotor responses to an alpha-adrenergic agonist and an antagonist were assessed in 11 familial dysautonomia and nine control subjects by laser Doppler flowmetry. Using two iontophoresis machines, blood flow in the midclavicular areas was continuously monitored by two channel laser Doppler flowmeter. Simultaneously, the alpha-antagonist (0.5 mM phentolamine hydrochloride) and a control solution (0.9% saline) were iontophoresed at 200 microA for 15 min. The alpha-agonist (0.5 mM norepinephrine bitartrate) was then iontophoresed (20 microA) to both pretreated areas for progressively longer pulses separated by 3-min observation intervals (15, 30, 60, 90, 120 s). The familial dysautonomia subject group had higher mean baseline perfusion with widely fluctuating baselines, especially on the phentolamine pretreated side (P = 0.03). Saline iontophoresis significantly increased perfusion in the control group, but not in the familial dysautonomia group (ANOVA: P = 0.02 and 0.15, respectively). There was > 100% increase in flow by the end of the saline observation period in seven of nine controls, but in only three of 11 familial dysautonomia subjects. Phentolamine iontophoresis differentiated familial dysautonomia subjects into responders and nonresponders by 7-8 min when all nine control subjects, but only five of 11 familial dysautonomia subjects, had > 200% increase in blood flow. Irrespective of pretreatment type, norepinephrine decreased blood flow in both familial dysautonomia and control groups (ANOVA: P < 0.0001), but the final mean change after saline was greater in the control group, P = 0.02. The final mean changes of flow after phentolamine pretreatment were not different between the two groups and were comparable to the familial dysautonomia group's smaller response after saline pretreatment. Higher baseline perfusion suggests dilation may be intrinsic to familial dysautonomia vasculature. Two populations of familial dysautonomia subjects are noted; those who like controls increase blood flow with iontophoresis of the alpha-antagonist and those who are refractory. In addition, in familial dysautonomia subjects, the microcirculatory constrictive response to alpha-agonist iontophoresis is less than that observed for controls. These data suggest that some familial dysautonomia subjects may have decreased or dysfunctional adrenoceptors as well as decreased innervation.

Adolescent↗
PubMed1997

Does sympathetic activation blunt nitric oxide-mediated hyperemia in the human forearm?

To determine if the vasodilating substance nitric oxide (NO) interferes with the ability of sympathetic nerves to regulate blood flow in humans, forearm blood flow (FBF) was measured during brachial artery infusions of acetylcholine (ACh) to evoke endothelial NO release, and during infusions of the NO donor nitroprusside (NTP) in five healthy volunteers. Sympathetic activity was increased by application of lower body suction and antagonized by brachial artery infusions of phentolamine. In the control condition, FBF was 2.4 +/- 0.4 ml/100 ml per min and rose by 16.9 +/- 3.6 ml/100 ml per min during ACh at 16 micrograms/min and by 17.0 +/- 4.3 ml/100 ml per min at 64 micrograms/min. With suction, FBF was 1.7 +/- 0.6 ml/100 ml per min (p < 0.05 versus control) and rose by 11.4 +/- 3.2 ml/100 ml per min during ACh at 16 micrograms/min (p < 0.05 versus control). After phentolamine, FBF was 3.8 +/- 0.5 ml/100 ml per min at baseline (p < 0.05 versus control) and the increases in flow with ACh at either 16 or 64 micrograms/min were identical to control. During the control NTP trial, FBF rose by 6.3 +/- 1.1 ml/100 ml per min with NTP at 2.5 micrograms/min and by 12.1 +/- 1.4 ml/100 ml per min at 10 micrograms/min. Suction blunted and phentolamine augmented the increases in flow with NTP by approximately 50% (p < 0.05). Due to the unexpected results with ACh, the effects of suction and pharmacological sympathectomy with both phentolamine and bretylium on ACh-mediated dilation were evaluated with lower doses of ACh (8 and 32 micrograms/min) in six additional studies. Again, altered sympathetic activity had inconsistent effects on the rise in FBF with ACh administration. The effects of altered sympathetic activity on the blood flow responses to NTP indicate that sympathetic activity can modulate NO-mediated vasodilation, suggesting that NO does not have a major sympatholytic effect in the human forearm. That sympathetic activity did not consistently alter ACh-mediated vasodilation suggests that vasodilating mechanisms, in addition to NO release, can be activated by arterial administration of ACh in the human forearm.

Acetylcholine↗
PubMed1997

Subtype determination of soma-dendritic alpha2-autoreceptors in slices of rat locus coeruleus.

The aim of the study was to subclassify the soma-dendritic alpha2-autoreceptors in the locus coeruleus (LC) of the rat by means of antagonists. To this end, the frequency of spontaneous action potentials was recorded extracellularly from single LC neurones in brain slices. The neurones fired spontaneously at an average rate of 1 Hz. The selective alpha2-adrenoceptor agonist 5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline (UK 14,304) and noradrenaline decreased the action potential discharge with IC50 values of 5 and 510 nM, respectively. The concentration-inhibition curves of UK 14,304 and noradrenaline were shifted to the right by phentolamine (0.15 microM) and rauwolscine (0.15 microM) but not by prazosin (1 microM). Apparent Kd values of phentolamine were 17 nM (against UK 14,304) and 20 nM (against noradrenaline). Apparent Kd values of rauwolscine were 47 nM (against UK 14,304) and 70 nM (against noradrenaline). (+)-Oxaprotiline (1 microM) suppressed the firing of the neurones within 10 to 33 min. In the continued presence of oxaprotiline, phentolamine and rauwolscine restored firing with EC50 values of 120 and 250 nM, respectively. Prazosin (1 microM) again was ineffective. All three antagonist affinity estimates - against UK 14,304, exogenous noradrenaline and endogenous noradrenaline (that accumulates in the extracellular space in the presence of oxaprotiline) - yield an affinity order phentolamine > rauwolscine >> prazosin, prazosin being ineffective even at a concentration of 1 microM. These findings identify the soma-dendritic alpha2-autoreceptors of the LC as the rat variant of the alpha2A/D-adrenoceptor, i.e. alpha2D. Not only presynaptic but also soma-dendritic alpha2-autoreceptors may at least predominantly be alpha2A/D throughout the nervous system.

Action Potentials↗
PubMed1989

High affinity binding of 3H rauwolscine and 3H RX781094 to alpha 2 adrenergic receptors and non-stereoselective sites in human and rabbit brain cortex membranes.

The radiolabeled antagonists 3H RX 781094 and 3H rauwolscine bind with high affinity to alpha 2 adrenergic receptors as well as to non-receptor sites in human and rabbit brain cortex membranes. These non-receptor sites form an important contaminant of the specific binding when non-specific binding is determined in the presence of 10 microM phentolamine or more. While phentolamine is no suitable ligand to discriminate both sites, (-)-epinephrine displays a sufficient affinity ratio to separate radioligand binding to these sites. When 1 microM (-)-epinephrine is used for the determination of the non-specific binding, both radioligands bind specifically to alpha 2 receptors. Under these conditions, 3H rauwolscine and 3H RX 781094 bind to the same amount of non-cooperative sites; binding isotherms for human brain are Bmax = 113 +/- 15 fmol/mg protein and Kd = 22.8 +/- 4.2 nM for 3H RX781094 and Bmax = 110 +/- 17 fmol/mg protein and Kd = 4.7 +/- 2.5 nM for 3H rauwolscine. Competition binding experiments show, for both radioligands and in both species, the typical pharmacological potency order of alpha 2 adrenergic receptors, i.e. phentolamine greater than yohimbine greater than prazosin for the antagonists and UK 14304 greater than p-aminoclonidine greater than or equal to (-)-epinephrine greater than (+)-epinephrine greater than isoproterenol for the agonists. Whereas the alpha 2 receptor sites display high affinity and stereoselectivity towards (-)-epinephrine and (+)-epinephrine, the non-receptor sites bind both epinephrine isomers with equal low affinity. Specific binding of both radioligands to these sites can be determined when total binding is performed in the presence of 1 microM (-)-epinephrine and non-specific binding the presence of 1 mM phentolamine. 3H rauwolscine binding to the non-stereoselective sites can be displaced with high affinity by 5-HT, suggesting binding to a 5-HT1-receptor. The 3H RX 781094 binding displays low affinity for most alpha adrenergic ligands and do not correspond to beta adrenergic, dopaminergic or serotonergic receptors.

Adrenergic alpha-Antagonists↗
PubMed1993

Effects of adrenergic agonists and antagonists on the metabolism of [1-14C]oleic acid by rat hepatocytes.

The possibility that the antihypertensive adrenoceptor antagonists (propranolol, phentolamine and metoprolol) may alter hepatic lipid metabolism was examined in freshly dispersed rat hepatocytes with [1-14C]oleate. Propranolol (1.8 x 10(-4) M) and phentolamine (1.4 x 10(-4) M) increased incorporation of [1-14C]oleate into cholesteryl esters by 51 and 92%, respectively, and decreased ketogenesis by 46 and 62%, respectively. While neither drug affected incorporation into total phospholipid, propranolol decreased triglyceride synthesis by 37%. These effects of propranolol and phentolamine may not occur through beta- or alpha-receptor inhibition since neither epinephrine nor norepinephrine reversed the effects of the adrenoceptor antagonists. Although epinephrine and norepinephrine per se did not alter the incorporation of [1-14C]oleate into triglyceride, phospholipid, cholesteryl esters or ketone bodies, they stimulated the production of 14CO2 (control 5.6 +/- 1.3; epinephrine 7.6 +/- 1.1; norepinephrine 9.1 +/- 0.2 nmol oleate incorporated/mg protein), and these effects were reversed by phentolamine and propranolol. The data suggest that adrenoceptor antagonists exert direct effects on hepatic metabolism of oleate.

Animals↗
PubMed1985

Evidence for the involvement of descending noradrenergic pathways in the antinociceptive effect of baclofen.

The role of descending monoaminergic pathways in the antinociceptive effect of baclofen following intraperitoneal (i.p.) administration was investigated by determining the effect of intrathecal (i.t.) administration of neurotoxins [6-hydroxydopamine (6-OHDA) and 5,6-dihydroxytryptamine (5,6-DHT)] and receptor antagonists (phentolamine and methysergide) on baclofen in the tail-flick and hot-plate tests. Pretreatment with 6-OHDA (20 and 50 micrograms) inhibited baclofen antinociception in both tests 4-13 days after treatment. but pretreatment with 5,6-DHT (20 and 100 micrograms) produced a slight increase in the tail-flick test. The higher doses of both neurotoxins produced hyperalgesia in the tail-flick test. In other experiments, baclofen was injected intraperitoneally followed by i.t. amine antagonists when a plateau level of antinociception was attained. Phentolamine (30-100 micrograms) reversed baclofen antinociception in both the tail-flick and hot-plate tests. Methysergide (30-100 micrograms) only reversed the effect of baclofen in doses greater than or equal to 50 micrograms in the tail-flick test. Phentolamine (15 and 30 micrograms) and methysergide (50 micrograms) antagonized the antinociceptive effect of i.t. noradrenaline. Both phentolamine and methysergide produced hyperalgesia in the tail-flick test. However, hyperalgesia per se does not appear to be the only factor responsible for the reversal of baclofen antinociception because dose and agent dissociations between these effects were observed. These results suggest that a major mechanism of action of baclofen in producing antinociception is the activation of noradrenergic pathways descending to the spinal cord.

5,6-Dihydroxytryptamine↗
PubMed1985

Spinal mechanisms of the analgesic action of electroconvulsive shock.

The present study investigated the spinal systems involved in the analgesic action of electroconvulsive shock (ECS). To identify such systems complete spinal transections and discrete lesions within the dorsal half of the spinal cord were performed. Complete spinal transection eliminated ECS analgesia totally, demonstrating that the observed analgesic effect is attributable to neural conduction. Lesions within the region of the dorsolateral funiculus (DLF) caused a pronounced, but incomplete, attenuation of ECS analgesia. Larger lesions of the dorsal aspects of the spinal cord including both the DLF and the dorsal column area did not result in further attenuation of analgesia. Thus, it appears that within the dorsal cord the area of the DLF contains the fibers mediating the antinociceptive action of ECS. Additional experiments were conducted to determine the neuromediators involved in ECS analgesia. Of a wide range of antagonists injected intraperitoneally (methysergide, phentolamine, haloperidol, diphenhydramine, naloxone, picrotoxin, theophylline and scopolamine), only methysergide produced a significant attenuation of ECS analgesia. In contrast, following intrathecal injections of antagonists a dose-related decrease of analgesia could be seen after the injections of methysergide, phentolamine and naloxone implicating spinal serotonin, noradrenaline and the enkephalins in the analgesic action of ECS. To assess further the interaction between the action of these neurotransmitter systems, we evaluated the effect of drug pair combinations on ECS analgesia. Intrathecal phentolamine + naloxone, methysergide + naloxone and methysergide + phentolamine were injected at doses that caused maximal attenuation of analgesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Analgesia↗
PubMed1990

Action site of adrenergic blockers to suppress the development of tolerance to morphine analgesia.

The effect of locally applied adrenergic blockers in the restricted area of the central nervous system on morphine analgesia and the development of tolerance to the analgesic effect was examined in the mouse. Intrathecal (i.t.) injection of phentolamine decreased the analgesic effect of morphine administered either subcutaneous (s.c.), intracerebroventricular (i.c.v.) or i.t., while i.t. propranolol was less potent in suppressing morphine analgesia and, in particular, did not affect the analgesic effect of i.t. morphine. I.c.v. phentolamine enhanced i.t. injected morphine analgesia; on the other hand, i.c.v. propranolol tended to reduce the analgesic effect of s.c. morphine. Compared with the effect on the analgesia, i.t. administration of both phentolamine and propranolol did not affect the development of tolerance to morphine and i.p. or i.c.v. blockers suppressed the development of tolerance to s.c. or i.t. morphine analgesia. Moreover, morphine tolerance induced by i.c.v. administration was blocked by i.c.v. phentolamine. These results not only provide further evidence for the importance of the spinal and supraspinal adrenergic systems in the analgesic effects of morphine and the development of tolerance to the effect, respectively, and also suggest the difference in both the site and mechanisms involved in the production of morphine analgesia and the development of tolerance to morphine.

Adrenergic alpha-Antagonists↗