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PubMed1990

Reversal of alpha-adrenoceptor blockade by propranolol in isolated rat pulmonary artery.

Pulmonary artery rings were prepared from rats (group I to VI, n = 5-7 per group) in order to investigate if a beta-adrenoceptor antagonist interferes with the effect of alpha-adrenoceptor blockade. In I, four cumulative noradrenaline (NA) dose-response curves (10(-9) to 10(-3) M) were constructed. In II, NA curves were constructed first, without blockers, then in the presence of phentolamine (10(-6) M), then propranolol (10(-8) M), then phentolamine plus propranolol (10(-8) M). III, IV and V were treated similar to II, except that atenolol (10(-8) M), ICI 118,551 (10(-8) M) and propranolol (10(-6) M), respectively, were added instead of propranolol (10(-8) M). In VI, NA (10(-6) M) was added followed by phentolamine and then propranolol (10(-9) to 10(-6) M). Phentolamine shifted the NA curve to the right with an increase in the EC50 value. Propranolol but not atenolol or ICI 118,551, reduced the elevated EC50 values caused by phentolamine. In group VI, the increase in force by NA was reduced by phentolamine; the effect of phentolamine was completely abolished by propranolol. Thus, propranolol interferes with the effect of phentolamine in the rat pulmonary artery.

Adrenergic alpha-Antagonists↗

PubMed1990

Alpha-adrenergic coronary constriction in effort angina.

In order to assess the role of alpha-adrenergic coronary tone in exercise-induced ischemia, 23 patients with chronic stable angina underwent, after coronary angiography, a symptom-limited supine exercise test on a cyclo-ergometer. After recovery, either phentolamine (for the first nine patients) or indoramin (for the following nine patients) was directly injected into the most diseased vessel at identical doses (2 mg over 5 min). In the remaining 5 patients, a placebo was injected. Immediately thereafter the same exercise (identical workloads and exercise duration) was repeated. During exercise 1, heart rate (HR), mean blood pressure, and cardiac index increased by 51%, 23% and 33% in the phentolamine group, and by 45%, 15%, and 33% in the indoramin group. After intracoronary injection of phentolamine or indoramin, control values (including pulmonary artery wedge pressure (PA wedge] at rest did not change significantly. During exercise 2, HR, mean blood pressure, and cardiac index increased in a similar way; however, the increase in PA wedge was less pronounced (p less than 0.01 in the phentolamine group and p less than 0.05 in the indoramin group). ST-segment depression at the end of exercise 2 was significantly smaller for identical workloads and double products in the phentolamine group: 1.5 +/- 0.3 mm vs 2.5 +/- 0.3 mm (p less than 0.01). However, these changes did not reach a statistical significance in the indoramin group: 1.7 +/- 0.2 mm vs 2.0 +/- 0.1 mm (NS). ST/HR slope in exercise 2 decreased by 51% (p less than 0.01) in the phentolamine group and by 34% (p less than 0.05) in the indoramin group. In the placebo group, exercise 2 was identical to exercise 1 and the ST/HR slopes were quite reproducible. These results show a less severe ischemic response after intracoronary alpha-blockade. Therefore, our results argue for a role of alpha-adrenergic coronary tone in exertional angina. The relatively higher efficiency of phentolamine vs indoramin suggests that alpha 2-adrenergic mechanisms contribute to the inappropriate coronary vasoconstriction during exercise in these patients.

Adult↗

PubMed1986

A comparison of the effects of combined or separate alpha- and beta-blockade in the treatment of hypertension in the acute stage of myocardial infarction.

We have assessed the benefit of separate or combined alpha- and beta-receptor blockade in the treatment of 33 patients suffering from acute (less than 48 hr) myocardial infarction complicated by sustained (greater than 6 hr) systolic hypertension (systolic blood pressure greater than 150 mm Hg). Eight patients have been treated with metoprolol, 7 with phentolamine and 18 with labetalol. We evaluated the effects of these drugs on hemodynamics and arterial and mixed venous blood gases. The patients were divided into two groups on the basis of the pulmonary wedge pressure. The first group had a pressure greater than 15 mm Hg. It included 9 patients treated with labetalol (1.8 mg/min for 1 hr) and 7 others with phentolamine (0.6 mg/min for 1 hr). The wedge pressure in the second group was less than 13 mm Hg. Nine patients in this group had been treated with labetalol (2.1 mg/min for 1 hr) and 8 others with metoprolol (0.2 mg/kg in 15 min). Labetalol normalized the blood pressure in both groups within 1 hr as did phentolamine. Metoprolol did not significantly reduce either the systolic or the diastolic pressures. The high wedge pressures in the first group were reduced by both labetalol and phentolamine. The cardiac index was increased following phentolamine administration while it was reduced by labetalol. In the group with low wedge pressure, labetalol and metoprolol induced a slight but significant reduction in cardiac index but the pulmonary wedge pressures were significantly increased for metoprolol only. The rate-pressure product was very significantly decreased by labetalol and metoprolol but not by phentolamine. The emergency treatment of systemic hypertension occurring in the setting of acute myocardial infarction would thus appear to be best achieved by combined alpha- and beta-blockade rather than with either pure alpha- or pure beta-blockade. Phentolamine, however, would be a good drug in the presence of a reduced cardiac index.

Adult↗

PubMed1989

Evidence for involvement of prostaglandins in central alpha adrenergic activity and LH release in sheep.

Circhoral pulsatile release of immunoreactive luteinising hormone (LH) and prostaglandin F2 alpha (PGF2 alpha) occur synchronously into the jugular vein in ovariectomised sheep. Following a 4-hour control period, intra-carotid injections of phentolamine or intramuscular injections of phenoxybenzamine were given to ovariectomised sheep and the pulsatile release of LH and PGF2 alpha was monitored for a further 6 to 8 hours. Phenoxybenzamine caused a fall in LH and PGF2 alpha in jugular venous plasma. Phentolamine also reduced LH significantly but in this case a marked rise in PGF2 alpha as measured by radioimmunoassay (RIA) occurred after very high doses of phentolamine. Interpretation of the latter results was complicated by the fact that phentolamine at high dose levels interfered with the RIA of PGF2 alpha in plasma. Experiments were repeated in ovariectomised sheep with cannulae placed in the lateral ventricles of the brain for sampling cerebrospinal fluid (CSF). In contrast to the previously observed rise in jugular venous PGF2 alpha following high doses of phentolamine, a fall in CSF levels of immunoreactive PGF2 alpha occurred following intracarotid phentolamine or phenoxybenzamine in 3 out of 7 experiments, while no change was observed in the remaining 4 animals. Phentolamine did not reduce LH significantly in animals with intraventricular cannulae. The work provides support for the view that circhoral pulses of immunoreactive PGF2 alpha in sheep are neural in origin and may be related to sympathetic neurotransmission.

Animals↗

PubMed1984

Effect of alpha-adrenergic blockade on arrhythmias induced by acute myocardial ischemia and reperfusion in the dog.

Studies in cats suggest alpha-adrenergic contributions to arrhythmias during myocardial ischemia and reperfusion. The validity of this concept in other species, however, remains uncertain. Thus, 106 chloralose-anesthetized open-chest dogs undergoing a 25 min coronary artery occlusion followed by reperfusion received saline (n = 52), prazosin (1 mg/kg, n = 26), phentolamine (5 mg/kg, n = 18), or phentolamine (same dose) + propranolol (1 mg/kg, n = 10). Alpha-blockade was confirmed by alpha-agonist dose-response studies. In phentolamine-treated dogs, arterial pressure and heart rate were kept constant to prevent exacerbation of ischemia. Control and treated groups were comparable with respect to variables known to affect arrhythmias, such as size of occluded and reperfused vascular beds, coronary collateral flow, severity of ischemia estimated from intramyocardial CO2 tension, and peak reactive hyperemia. During coronary occlusion, the number of single premature ventricular complexes was reduced by phentolamine (P less than 0.01), but not by prazosin or phentolamine + propranolol; no treatment affected the total number of couplets, ventricular tachycardia episodes and ventricular ectopic complexes, or the incidence of ventricular tachycardia and ventricular fibrillation. During coronary reperfusion, arrhythmias did not differ in control and treated groups. Thus, selective alpha 1-(prazosin), nonselective alpha 1- and alpha 2-(phentolamine), and combined alpha- and beta-blockade (phentolamine + propranolol) failed to attenuate complex arrhythmias induced by acute myocardial ischemia and reperfusion. Alpha-adrenergic mechanisms appear unimportant in the genesis of these arrhythmias in the canine model.

Adrenergic alpha-Antagonists↗

PubMed1982

Effects of 3,4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-benzopyran (K-351) on smooth muscle cells and neuromuscular transmission in the canine mesenteric artery.

1 The effects of K-351 on the electrical and mechanical responses were investigated in the canine mesenteric artery by isometric tension recording and the use of intracellular microelectrodes. The results were compared to the responses observed with other alpha-adrenoceptor blocking agents. 2 K-351 (greater than 3 X 10(-7)M) consistently inhibited the contraction evoked by perivascular nerve stimulation; however, K-351 had no effect on the contraction evoked by direct muscle stimulation, after pretreatment with 3 X 10(-7)M tetrodotoxin. 3 Phentolamine enhanced and prazosin had no effect on the amplitude of contraction evoked by perivascular nerve stimulation at a high frequency (over 1.0 Hz). Pretreatment with phentolamine inhibited the contraction evoked by lower frequencies of perivascular nerve stimulation (below 0.5 Hz). 4 The potency for the inhibition of the response to perivascular nerve stimulation was in the order of K-351 greater than phentolamine greater than prazosin, while the contractions induced by exogenously applied noradrenaline (5 X 10(-7)M) were inhibited in the order: prazosin greater than phentolamine greater than K-351. 5 K-351 (less than 3 X 10(-5)M) did not modify the resting membrane potential or the membrane resistance, as estimated from the change in the amplitude of electrotonic potentials in the smooth muscle cell membranes. 6 K-351 (greater than 3 X 10(-7)M) inhibited the amplitude of the first e.j.p. and e.j.ps after completion of the facilitation process following stimulation at frequencies over 0.25 Hz. 7 K-351 (less than 3 X 10(-5)M) did not modify the compound action potentials recorded from peripheral nerve bundles distributed on the mesenteric artery. 8 Phentolamine (greater than 1 X 10(-8)M) inhibited the first e.j.p. but this agent either inhibited or enhanced the amplitude of e.j.p. after completion of the facilitation process produced by repetitive stimulation below or over 1.0 Hz stimulus frequencies, respectively. Prazosin (1 X 10(-6)M) had no effect on e.j.ps evoked by perivascular nerve stimulation, at any stimulus frequency applied. 9 These results indicate that K-351 inhibits the extra-junctional adrenoceptor with a slightly weaker potency than prazosin or phentolamine, but that this agent has a potent action as an intra-junctional adrenoceptor blocking agent. Phentolamine acts mainly on the extra-junctional adrenoceptors and also has weak actions on intra-junctional adrenoceptors, as a blocking agent. This agent also inhibits the presynaptic alpha 2-adrenoceptor. Prazosin inhibits only the extra-junctional alpha 1-adrenoceptor.

Adrenergic alpha-Antagonists↗

PubMed1994

Blood pressure reflexes following activation of capsaicin-sensitive afferent neurones in the biliopancreatic duct of rats.

1. Inflammatory diseases of the pancreas or diseases which cause obstruction within the biliary or within the biliary or pancreatic duct system are associated with severe pain. Although neuropeptides such as substance P are present in the biliary tree, only few capsaicin-sensitive, substance P-positive nerve fibres have been found in the ducts. In order to obtain functional evidence whether capsaicin-sensitive afferent neurones transmit nociceptive information arising from the biliopancreatic duct, blood pressure reflexes following electrical stimulation of the duct or increases in intraductal pressure were determined in barbiturate-anaesthetized rats. 2. Electrical stimulation of neurones in the biliopancreatic duct was carried out at 30 V, 3 ms, 50 Hz for 20s. In untreated animals the electrical stimulation resulted in rises in blood pressure by up to 25 mmHg, but in about a quarter of all animals tested this response was absent. Following the administration of phentolamine (7 mumol kg-1, i.p.) the blood pressure responses were changed to pronounced and reproducible depressor reflexes of -5 to -30 mmHg. Retrograde injections into the biliopancreatic duct of 300 microliters of a 154 mM sodium chloride solution produced increases in intraductal pressure of approximately 10 mmHg. This elicited shortlasting falls in blood pressure of 3-15 mmHg. Phentolamine significantly augmented the fall in blood pressure to 8-30 mmHg. 3. The depressor reflexes observed in both models after the administration of phentolamine were abolished by morphine (1 mumol kg-1, i.v.). The inhibition by morphine was reversed by naloxone (3 mumol kg-1, i.v.). Naloxone given before morphine did not affect the depressor reflex but prevented the inhibitory action of subsequently injected morphine.4. Acute s.c. injection of capsaicin (30 mg kg-1) abolished the depressor reflexes in response to both types of nociceptive stimulation in phentolamine-treated rats. The initial pressor effects of electrical stimulation were only partly inhibited by capsaicin whereas the basal depressor reflexes in response to elevation of intraductal pressure were abolished. In rats which had received capsaicin on the day before the experiment or had been treated with capsaicin as neonates, only minor rises in blood pressure were induced by electrical stimulation at the beginning of the experiment and no changes in blood pressure occurred after the administration of phentolamine. After adult or neonatal pretreatment with capsaicin the depressor reflexes in response to increased intraductal pressure were only small and were unchanged by phentolamine.5. The depressor reflexes following either electrical stimulation or increases in intraductal pressure were abolished by the unselective Beta-blocker, (-)-propranolol (3 micromol kg-1, i.p.), and greatly reduced by the Beta 1-blocker, metoprolol (6 micromol kg- 1, i.p.). The Beta2-preferring adrenoceptor antagonist, butoxamine(3 micromol kg-1, i.p.), had no effect on the depressor responses. The reflex falls in blood pressure were also abolished by hexamethonium (10 micromol kg-1, i.p.) but not by atropine (3 micromol kg-1, i.p.).6. Both models of stimulation of nociceptive afferents caused identical patterns of blood pressure responses following adrenalectomy or chemical sympathectomy. In adrenalectomized rats, the initial responses consisted of depressor reflexes which were not augmented but significantly reduced by phentolamine and further inhibited by metoprolol. In rats that had been pretreated with 6-hydroxydopamine(total dose 0.6 mmol kg-1) to accomplish chemical sympathectomy, nociceptive stimulation caused rises in blood pressure. Phentolamine treatment abolished these pressor effects but revealed only minor, if any, depressor responses that were unaffected by metoprolol.7. In summary, the hypotensive effects in both models constitute nociceptive reflexes since they are abolished by morphine and restored by naloxone. The afferent part of the reflex is mediated by nerve fibres sensitive to capsaicin. Both experimental procedures seem to elicit two, presumably separate, reflex mechanisms. Firstly, catecholamines released from the adrenal medulla elevate blood pressure or limit hypotensive responses via activation of vascular alpha receptors. Secondly, the reflex inhibition of the sympathetic nerve activity in the heart and the vasculature causes the nociceptive depressor reflexes.

Adrenalectomy↗

PubMed1990

Hemodynamic changes that accompany the pressor response to propranolol in urethane anesthetized rats subjected to alpha-blockade.

It has been shown that a paradoxical pressor response to a beta-blocker occurs in rats given an alpha-blocker. The dual-isotope microsphere technique was used to investigate the hemodynamic changes that accompany the pressor response to propranolol in phentolamine-treated, urethane-anesthetized rats. Rats were divided into four groups (n = 8 per group): group I received 10 min of saline infusion; group II received intravenous infusion of phentolamine (300 micrograms/kg/min) for 10 min; group III received intravenous injection of propranolol (100 micrograms/kg) after 20 min of phentolamine infusion, and group IV received intravenous injection of saline after 20 min of phentolamine infusion. In groups I and IV, saline did not cause any significant hemodynamic changes. In group II, phentolamine decreased the mean arterial pressure (MAP) and total peripheral resistance (TPR) by 34 +/- 3 mm Hg and 0.28 +/- 0.07 mm Hg/min/ml, respectively. Arterial conductances in the skeletal muscle and skin were increased to 157 and 165% of control values, respectively. Cardiac output and conductances in other tissues and organs were not significantly affected. In rats given phentolamine (group III), propranolol raised MAP (+40 +/- 2 mm Hg) by increasing TPR (+0.41 +/- 0.03 mm Hg/min/ml). Vascular conductances in the skeletal muscle, skin and kidneys were decreased to 38, 57 and 69% of control values, respectively. Conductances in other tissues and organs were not significantly affected. Our results show that propranolol raised MAP by increasing flow resistance, primarily via the reversal of the vasodilator effects of phentolamine in the muscle and skin.

Adrenergic alpha-Antagonists↗

PubMed1983

Comparison between an alpha-adrenergic antagonist and a beta 2-adrenergic agonist in bronchial asthma.

Fifteen patients suffering from asthma received inhalations of phentolamine, albuterol (salbutamol), a combination of phentolamine and albuterol, and placebo, in a single-blind fashion; the changes in the pulmonary function tests were recorded over a three-hour period. Three patients responded to phentolamine with marked bronchodilatation, whereas severe bronchoconstriction was induced by the drug in two patients. Five patients improved more with phentolamine than with placebo, while all patients improved more markedly with albuterol and still more following inhalation of the combination of both drugs. As a group, there were no statistically significant differences between the responses to phentolamine compared with placebo, or between albuterol alone compared with the combination of both drugs. We concluded that both alpha-antagonist and beta 2-agonist agents act in the same direction in most patients, the beta 2-agonist being the dominant. These results do not offer convincing proof that enhanced alpha-adrenergic activity is the main bronchoconstrictor mechanism even in those few with good response to phentolamine, who also showed very good responsiveness to albuterol. The mechanism of phentolamine-induced bronchoconstriction was discussed, but in the light of presently accepted theories, we were unable to evolve a reasonable explanation.

Adult↗

PubMed1986

Calcium levels in rat submandibular gland and saliva after sympathetic nerve stimulation in the presence of alpha, beta 1 and beta 2-adrenergic antagonists.

Calcium concentration was reduced by 51 per cent compared with unstimulated contralateral glands after 60-min of electrical stimulation to the sympathetic nerve. When the alpha-adrenergic antagonists, phentolamine or phenoxybenzamine, were given 20 min before stimulation, the decrease in glandular calcium concentration (45-47 per cent) was similar to that after nerve stimulation alone; with the selective beta 2-adrenergic antagonist added to the phentolamine, the percentage decrease was similar to that found after phentolamine and sympathetic nerve stimulation only. When atenolol, a beta 1-adrenergic antagonist, was given with phentolamine, there was no secretion after subsequent nerve stimulation, nor was calcium concentration different from that of unstimulated glands. When propranolol (3 mg/kg, body wt), or atenolol + butoxamine (3 mg/kg, body wt), was given prior to stimulation there was a decrease of 21-22 per cent in gland-calcium concentration. Calcium concentration of nerve-stimulated saliva was nearly 6 m-equiv./l, and twice as high with phentolamine prior to stimulation; for butoxamine together with phentolamine the change was similar to that with phentolamine alone. When beta-adrenergic antagonists were given prior to nerve stimulation, concentration of the saliva was either unchanged (propranolol) from that with nerve stimulation alone or somewhat decreased (atenolol + butoxamine). Thus sympathetic stimulation results in activation of alpha and beta 1-adrenoceptors; calcium secretion is principally regulated by the beta-adrenoceptors, and beta 1-receptors have the principal role.

Adrenergic alpha-Antagonists↗

PubMed1990

Evidence for the existence of 'atypical' beta-adrenoceptors (beta 3-adrenoceptors) mediating relaxation in the rat distal colon in vitro.

1. Experiments were carried out to characterize the adrenoceptors mediating relaxant responses in the rat distal colon. Three agonists were used: noradrenaline, isoprenaline and the beta 3-adrenoceptor agonist BRL 37344. Phentolamine, propranolol and (+/- )-cyanopindolol were tested as antagonists. Tone in the rat distal colon was induced with KCl (30-40 mM) as a spasmogen, and relaxations of this KCl-induced tone produced by the agonists were measured. 2. Relaxant responses to noradrenaline that were obtained in the presence of propranolol (1 microM) were not antagonized by phentolamine (0.01 to 1 microM). Relaxant responses to isoprenaline that were obtained in the presence of phentolamine (1 microM) were antagonized in a concentration-dependent manner by propranolol (0.01 to 3 microM), although this antagonism was weak and non-competitive. Relaxant responses to BRL 37344 that were obtained in the presence of phentolamine (1 microM) were only weakly antagonized by high (1 microM) concentrations of propranolol. 3. Tachyphylaxis to BRL 37344 was observed, a second concentration-response curve being shifted to the right by 15 fold. Exposure of the tissues to BRL 37344 (1 microM) between concentration-response curves also caused rightward shifts in the responses to noradrenaline (18 fold) and isoprenaline (19 fold) but not to papaverine. 4. In the presence of phentolamine (1 microM) and propranolol (1 microM), the rank order of potency of the agonists was: (-)-isoprenaline (1.0) greater than or equal to BRL 37344 (0.93) greater than (-)-noradrenaline (0.3). 5. Responses to BRL 37344 in the presence of phentolamine (1 microM) and propranolol (1 microM) were antagonized by (+/-)-cyanopindolol (I microM), with an apparent pA2 value of 6.67. Responses to isoprenaline, under the same conditions, were antagonized in a competitive manner by (+/-)-cyanopindolol (0.1 to 10 microM), with the slope of the Schild plot close to unity and a pA2 value of 7.12. 6. The resistance of the relaxant responses to antagonism by phentolamine and propranolol, along with the relatively high potency of the beta 3-adrenoceptor agonist BRL 37344 and the antagonism of 'resistant' responses by (+/-)-cyanopindolol would suggest that 'atypical' beta 6-adrenoceptors, similar to the beta 3-adrenoceptors of rat adipocytes and other tissues, exist in the rat distal colon.

Adrenergic alpha-Antagonists↗

PubMed1993

Afferent and efferent components of the cardiovascular reflex responses to acute hypoxia in term fetal sheep.

1. We studied the effects of acute isocapnic hypoxia on arterial and central venous pressures, carotid and femoral blood flows and heart rate in intact and carotid denervated fetal sheep between 118 and 125 days gestation, after pre-treatment with either saline, atropine or phentolamine. Electrocortical activity (ECoG) and the incidence of fetal breathing movements (FBM) were also compared between intact and carotid denervated fetuses. 2. There were no significant differences between intact and denervated fetuses in any variable measured during normoxia. Soon after the onset of hypoxia a marked bradycardia occurred in intact, but not in denervated fetuses. Femoral blood flow and femoral vascular resistance (perfusion pressure/femoral blood flow) increased in intact, but not in denervated fetuses. Carotid blood flow increased in both groups of fetuses during hypoxia, but carotid vascular resistance did not change. During hypoxia, the incidence of FBM and low-voltage ECoG was similarly reduced in both groups of fetuses. 3. Atropine produced a rise in fetal heart rate during the control period in intact but not in denervated fetuses. At the onset of hypoxia atropine prevented the initial bradycardia seen in intact fetuses. In denervated fetuses a further increase in heart rate occurred throughout the hypoxia. 4. All denervated fetuses treated with phentolamine died during the hypoxic challenge, but nine out of fourteen intact fetuses treated with phentolamine survived. 5. In intact fetuses which survived hypoxia after treatment with phentolamine, the increase in arterial blood pressure was smaller and the increase in femoral resistance did not occur. In these fetuses a rise in heart rate occurred in hypoxia. Carotid vascular resistance decreased during hypoxia after administration of phentolamine. 6. Our results indicate that the initial cardiovascular responses of the late gestation sheep fetus to hypoxia are reflex, and that the carotid chemoreceptors provide the afferent limb of this reflex. The bradycardia is mediated through a muscarinic pathway, as it is blocked by atropine. The femoral vasoconstriction is mediated through an alpha-adrenergic mechanism, mediated both neurally by a carotid chemoreflex and via catecholamines released directly from the adrenal medulla. Both these components are blocked by phentolamine. 7. The differences in survival between intact and denervated fetuses during hypoxia after phentolamine suggest that the carotid chemoreflex response to hypoxia involves mechanisms in addition to vagal efferents to the heart and alpha-adrenergic actions at peripheral blood vessels.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗

PubMed1992

An analysis of the inhibitory effects of prazosin on the phenylephrine response curves of the rat aorta.

On the endothelium-intact rat aorta some studies have shown prazosin to cause nonparallel rightward shifts of alpha 1-adrenoceptor agonist response curves. The aim of the present study was to analyze the inhibitory effect of prazosin on the phenylephrine responses of the endothelium-intact and endothelium-denuded rat aorta. Firstly I used phenoxybenzamine treatment to characterize the phenylephrine responses. The KA values for phenylephrine were 0.13-0.18 microM and 0.07-0.16 microM in the endothelium-intact and endothelium-denuded rat aorta, respectively. In order to produce maximal responses of the endothelium-intact or--denuded preparation, phenylephrine had to occupy 95-99% of the alpha 1-adrenoceptors. Secondly I compared the inhibitory effects of phentolamine and prazosin on the endothelium-intact rat aorta. Phentolamine at 0.1 and 1 microM caused parallel rightward shifts of phenylephrine response curves with no effect on phenylephrine maximal responses (phentolamine pA2 = 7.9). The inhibitory effects of phentolamine were readily reversible. Prazosin at 0.1-10 nM caused nonparallel rightward shifts of the phenylephrine response curves with a depression of the maximal response. These inhibitory effects of prazosin were either irreversible or only very slowly reversible in drug-free solution and slowly reversible in the presence of phentolamine. Ninety min was required for the inhibitory effect of prazosin to reach equilibrium whereas phentolamine was at equilibrium after 45 min. Finally I have characterized the inhibitory actions of prazosin on the endothelium-denuded rat aorta. Prazosin caused parallel rightward shifts of phenylephrine response curves with no effect on phenylephrine maximal responses. The inhibitory effects of prazosin were at equilibrium after 45 min and were readily reversible.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1984

Effects of alpha-adrenoceptor antagonists on electrical and mechanical responses of the isolated dog mesenteric vein to perivascular nerve stimulation and exogenous noradrenaline.

The effects of four different alpha-adrenoceptor antagonists (prazosin, phentolamine, yohimbine, and nipradilol) on the electrical and mechanical responses of smooth muscle cells of the dog isolated mesenteric vein to perivascular nerve stimulation and exogenous noradrenaline were investigated. Perivascular nerve stimulation generated an excitatory junction potential (e.j.p.), a spike potential and a slow depolarization. The latter component was blocked by yohimbine or phentolamine at doses over 10(-7) M, while the former two components were suppressed by 10(-6)-10(-5) M yohimbine, but not by prazosin, nipradilol or phentolamine (up to 10(-5) M). Nerve-mediated muscle contractions were suppressed by these alpha-adrenoceptor antagonists in a concentration-dependent manner, at doses over 10(-7) M. The order of potency was yohimbine greater than nipradilol = phentolamine greater than prazosin. Exogenously applied noradrenaline (10(-6) M) depolarized the smooth muscle membrane and generated slow waves. The slow waves were blocked by all of these alpha-adrenoceptor antagonists (10(-5) M), while the depolarizations were inhibited by yohimbine (greater than 10(-7) M) or phentolamine (10(-5) M), but not by nipradilol or prazosin (up to 10(-5) M). Contractions produced by exogenously applied noradrenaline (10(-6) M) were inhibited by the alpha-adrenoceptor antagonists; yohimbine or phentolamine (10(-6)-10(-5) M) showed complete inhibition and prazosin or nipradilol (up to 10(-5) M) partial inhibition. Contractions produced by high-potassium or current-stimulation were suppressed by high-concentrations (10(-6)-10(-5) M) of these alpha-adrenoceptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1999

Heterogeneous characteristics of imidazoline-induced insulin secretion.

Imidazolines are regarded as a pharmacological group of insulin secretagogues with one uniform mechanism of action, namely closure of ATP-dependent K+ channels (K(ATP) channels) and, in consequence, depolarization of the plasma membrane, Ca2+ influx and stimulation of secretion. This assumption was investigated by measuring insulin secretion from perifused pancreatic islets in response to three imidazoline compounds and comparing the characteristics of secretion with changes in membrane potential and cytosolic Ca2+ concentration [Ca2+]i of single beta-cells. Phentolamine (32 microM) stimulated insulin secretion from perifused mouse islets in the presence of stimulatory (10 mM and 30 mM) and substimulatory (5 mM) glucose concentrations and even in the absence of glucose. Idazoxan in concentrations up to 500 microM was virtually ineffective in the presence of 5 mM glucose. At 10 mM glucose, there was a moderate but significant increase of secretion by idazoxan, 20 microM being nearly as effective as 100 microM. The effect of phentolamine was of slow onset and irreversible in the time frame of the experiments, while the effect of idazoxan was of fast onset and reversible. Alinidine also stimulated secretion in the presence of 10 mM glucose with fast and reversible kinetics, but in contrast to idazoxan, 100 microM was clearly more effective than 20 microM. These heterogeneous characteristics of secretion were reflected by changes of [Ca2+]i: the increase of [Ca2+]i by phentolamine was slow and only partially reversible, whereas idazoxan led to a smaller, but faster and reversible response. The increase of [Ca2+]i by phentolamine and idazoxan was abolished by the Ca2+ channel blocker D 600. Surprisingly, all three compounds depolarized the beta-cell plasma membrane from a resting potential of -71 mV to about -36 mV. Again, the effect of phentolamine was slow and that of idazoxan and alinidine fast. Thus, the characteristics of phentolamine-induced secretion appear to be attributable to the consequences of K(ATP) channel closure. It is unclear, however, why all three test compounds achieved the same degree of depolarization in spite of their known different efficiency to close K(ATP) channels. Apparently, there are additional mechanisms involved in the action of idazoxan and alinidine, which may contribute to the obvious differences in the characteristics of secretion.

Adrenergic alpha-Antagonists↗

PubMed1979

The effects of levodopa on plasma glucose in two strains of rat.

The effects of levodopa on plasma glucose were examined in two strains of rats. In fasted Wistar rats levodopa produced a dose-dependent hyperglycaemic response which was augmented by pretreatment with nialamide. This response in nialamide-treated rats was prevented by pretreatment with phentolamine and converted to a hypoglycaemic response. Phentolamine increased the plasma concentration of immunoreactive insulin (IRI). In phentolamine-pretreated rats levodopa produced a further marked increase in the plasma IRI concentration. It is suggested that the prevention of levodopa hyperglycaemia by phentolamine is due to the marked increase in the plasma IRI concentration produced by pretreatment with phentolamine. Moreover the fall in the plasma glucose concentration produced by levodopa in phentolamine-pretreated rats is likely to be due, at least in part, to the additional increase in the plasma IRI concentration produced by levodopa under these conditions. In contrast, in fasted Sprague-Dawley rats pretreated with nialamide, levodopa produced either no effect on plasma glucose, or in larger doses, a marked hypoglycaemic effect followed by death. This hypoglycaemic effect was accompanied by a decrease in the plasma IRI concentration.

Animals↗

PubMed1995

Effects of imidazoline antagonists of alpha 2-adrenoceptors on endogenous adrenaline-induced inhibition of insulin release.

We studied the effects of adrenoceptor antagonists and imidazoline derivatives on endogenous adrenaline-induced inhibition of insulin release in anesthetized rats. The intracerebroventricular injection of neostigmine increased plasma levels of catecholamines and glucose but not insulin. Pretreatment with an i.p. injection with phentolamine caused a dose-dependent increase in insulin secretion. When atropine was coadministered with phentolamine, the phentolamine-induced increase in insulin secretion was inhibited. Neither phentolamine nor atropine affected plasma levels of catecholamine. Yohimbine and idazoxan, which are alpha 2-adrenoceptor antagonists, and tolazoline, a non-selective alpha-adrenoceptor antagonist, also reversed adrenaline-induced inhibition of insulin secretion. Phenoxybenzamine, prazosin, propranolol, and antazoline, an imidazoline without alpha 2-adrenoceptor activity, did not affect insulin levels. When agents were preinjected i.p. in rats that were given saline into the third cerebral ventricle, phentolamine and antazoline, but not yohimbine and idazoxan, increased plasma levels of insulin. The results suggest that the inhibition of insulin release induced by adrenaline was reversed by antagonism of alpha 2-adrenoceptors. Phentolamine and antazoline, both of which are imidazoline derivatives, induced insulin secretion independently of the adrenoceptors only under the resting conditions.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1992

Influence of sympatho-adrenal system on insulin sensitivity using the euglycemic clamp technique.

The aim of the present study was to further investigate the role of the adrenergic system on insulin action using the euglycemic clamp technique. Whole-body glucose metabolism (GM) was calculated as the glucose infusion rate for maintaining euglycemia under insulin infusion and used as an indicator of insulin sensitivity. Euglycemic clamps were performed in adrenodemedullated, epinephrine-treated, phentolamine-treated (alpha-blockade), propranolol-treated (beta-blockade), and epinephrine plus phentolamine and/or propranolol-treated rats. The following results were obtained at an insulin level of approximately 80 mU/l. GM in adrenodemedullated rats (13.97 +/- 0.98 mg/kg/min) was significantly higher than that of the control rats (10.26 +/- 0.50 mg/kg/min, P less than 0.01). GM in epinephrine-treated rats (1.7 mg/kg body weight/h) was 2.12 +/- 0.49 mg/kg/min (P less than 0.001 vs. control). Dose-response curves for phentolamine and propranolol established maximally effective doses (3.0 mg and 12 mg/kg body weight/h, respectively). Using these doses, GM in epinephrine plus phentolamine-treated rats (4.90 +/- 0.39 mg/kg/min) was significantly higher than that of epinephrine alone and GM in epinephrine and propranolol-treated rats (4.49 +/- 0.47 mg/kg/min) was also significantly higher than that of the epinephrine alone. GM in the epinephrine plus both propranolol and phentolamine (5.94 +/- 0.45 mg/kg/min) was significantly higher than that of the epinephrine alone, but not different from either treatment alone and was not additive. Neither phentolamine alone (9.48 +/- 1.45 mg/kg/min), propranolol alone (10.36 +/- 0.55 mg/kg/min) or the combination of blockades (11.14 +/- 0.65 mg/kg/min) had any effect on GM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Medulla↗