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PubMed1991

Adrenergic vasoconstriction limits coronary blood flow during exercise in hypertrophied left ventricle.

This study was carried out to test the hypothesis that alpha-adrenergic vasoconstriction limits coronary blood flow (CBF) during exercise in the chronically pressure overloaded, hypertrophied left ventricle. Studies were performed in dogs in which left ventricular hypertrophy had been produced by banding the ascending aorta at 9 wk of age. Left circumflex coronary artery blood flow and myocardial O2 consumption (MVO2) were examined at rest and during treadmill exercise during control conditions, after selective alpha 1-adrenergic blockade with prazosin, and after nonselective alpha-adrenergic blockade with phentolamine. All studies were performed after beta-adrenergic blockade with propranolol. During control conditions CBF and MVO2 increased progressively during exercise, while coronary sinus O2 tension decreased. Neither prazosin nor phentolamine altered CBF at rest but, in comparison with control measurements, both agents significantly increased CBF during exercise and abolished the decrease in coronary sinus O2 tension that normally occurred during exercise. Both prazosin and phentolamine caused similar significant increases of MVO2 relative to the heart rate times systolic left ventricular pressure during exercise, indicating that the increased CBF produced by these agents enhanced MVO2. Similar findings after prazosin and phentolamine indicate that adrenergic restraint of CBF during exercise resulted principally from alpha 1-adrenergic vasoconstrictions with little additional contribution from postjunctional alpha 2-adrenergic mechanisms.

Animals↗
PubMed1999

Activation of antilipolytic alpha(2)-adrenergic receptors by epinephrine during exercise in human adipose tissue.

The involvement of the antilipolytic alpha(2)-adrenergic pathway and the specific role of epinephrine in the control of lipolysis during exercise in adipose tissue (AT) were investigated in healthy male subjects (age: 24.1 +/- 2.2 yr; body mass index: 23.0 +/- 1.6). An in vitro study carried out on isolated adipocytes showed that the weak lipolytic effect of epinephrine was potentiated after blockade of alpha(2)-adrenergic receptor (AR) by an alpha(2)-AR antagonist and reached that of isoproterenol, a beta-AR agonist. The effect of the nonselective alpha(2)-AR antagonist phentolamine on the response of the extracellular glycerol concentration (EGC) in AT during two successive bouts of aerobic exercise (50% maximum O(2) uptake, 60 min duration) was evaluated using the microdialysis method. The metabolic responses measured in perfused probes with Ringer solution were compared with those obtained in perfused probes with Ringer plus 0.1 mmol/l phentolamine. Plasma norepinephrine level was not different during the two exercise bouts, whereas that of epinephrine was 2.5-fold higher during the second exercise. EGC in AT was twofold higher in the second compared with the first exercise, and the same response pattern was found for plasma glycerol. The exercise-induced increase in EGC was higher in the probe perfused with phentolamine compared with the control probe in both bouts of exercise. However, the potentiating effect of phentolamine on EGC was significant during the second exercise bout but did not reach a significant level during the first. These results suggest that epinephrine is involved in the control of lipid mobilization through activation of antilipolytic alpha(2)-AR in human subcutaneous AT during exercise.

Adipocytes↗
PubMed1982

Glucose, glucagon, and insulin during adrenergic blockade in exercising sheep.

The interrelationships of glucagon and insulin with the sympathetic system on glucose turnover during exercise were examined in sheep. Six sheep were run for 45 min on a treadmill with and without alpha- and/or beta-adrenergic blockade. The exercise-induced increase in glucose appearance, as assessed by infusion of [2-3H]glucose, was reduced during the first 25 min of exercise by phentolamine administration. The metabolic clearance rate of glucose also was greater during exercise with phentolamine treatment than without. Phentolamine was associated with a rise in insulin concentrations and appeared to delay the exercise-induced rise in glucagon. Propranolol administration had no effect on glucose turnover and plasma glucagon and insulin. Nor did it have any effect on the changes in glucose, insulin, or glucagon induced by phentolamine administration. These observations are consistent with the alpha-adrenergic mediation of the sympathetic influences on insulin and glucagon secretion, which may account in part for the glucose adaptations to exercise in sheep. However, direct affects of circulating catecholamines on and increased stimulation of sympathetic innervation to the liver cannot be ruled out.

Animals↗
PubMed1984

Role of prejunctional alpha 2-adrenergic receptors in the regulation of myocardial performance during exercise in conscious dogs.

We examined, in conscious dogs, the potential role of prejunctional alpha 2-adrenergic receptors for the regulation of heart rate and contractility response to exercise through modulation of the neurotransmitter release. Changes in heart rate and left ventricular pressure with time during comparable exercise levels, together with changes in norepinephrine concentration in the coronary sinus, were compared before and after the intravenous administration of: prazosin (0.5 mg/kg), a preferential postjunctional alpha 1-adrenergic receptor blocking agent; phentolamine (1 mg/kg), a nonselective alpha-adrenergic blocking agent; and yohimbine (0.3 mg/kg), a preferential prejunctional alpha 2-adrenergic receptor blocking agent. During exercise after phentolamine or yohimbine, changes in heart rate and left ventricular dP/dt were markedly potentiated compared to the control exercise, as well as to exercise after prazosin, whereas the norepinephrine concentration in the coronary sinus was substantially elevated. After intracoronary administration of phentolamine (0.1 mg/kg) or yohimbine (0.03 mg/kg), heart rate and contractility response to exercise were also potentiated, compared to the control exercise. These observations indicate that, in the intact conscious animal, prejunctional alpha 2-adrenoreceptors are stimulated during exercise, thereby modulating the norepinephrine release through a negative feedback inhibitory mechanism. Blocking these receptors by phentolamine or yohimbine results in an uncontrolled norepinephrine release during exercise associated with an augmented beta-adrenergic receptor-mediated end organ response, i.e., a potentiation in heart rate and contractility response.

Adrenergic alpha-Antagonists↗
PubMedDate not supplied

Post-ischemic hypermetabolism in cat brain.

Delayed postischemic brain hypoperfusion and hypermetabolism are likely detrimental factors to neurologic recovery after transient global brain ischemia and may be mediated by catecholamines acting via adrenergic receptors. We evaluated the effects of alpha and beta receptor blockade on cerebral blood flow (CBF) and metabolism after 16 min transient global brain ischemia. Ischemia was induced by arterial hypotension and a high pressure neck tourniquet in 13 anesthetized cats. Six cats were untreated, 4 received propranolol 1 mg/kg, IV and 3 a combination of propranolol and phentolamine, one mg/kg injected one min before recirculation. Total CBF was measured by continuous monitoring of cerebral venous 133Xe clearance after bolus intra-arterial injection. Arterial and cerebral venous oxygen, glucose and lactate were measured. Cerebral cortex glucose and lactate were measured 3 hours post-ischemia after in situ freezing with liquid N2. The cerebral cortex of 3 cats anesthetized, but not subjected to ischemia, was similarly frozen and analyzed for glucose and lactate. Total CBF was relatively constant for up to 3 h post-ischemia in all groups, but significant changes in fast and slow-flow rates and compartment sizes were observed. In untreated cats, the normal 60/40 percent relative weight of the fast and slow-flow compartments was reversed to 30/70 percent by 1 hr post-ischemia. Propranolol attenuated the size of the fast-flow compartment in the first 30 min post-ischemia which was partially restored by phentolamine. Brain oxygen consumption increased 2 to 3-fold by 1 h post-ischemia in all groups. Propranolol compromised CBF and impaired glucose and lactate oxidation which was partly reversed by phentolamine. We concluded that within the first 30 min post-ischemia, beta, and to a lesser extent, alpha receptors predominate in the modulation of cerebrovascular tone. By 1 h post-ischemia, however, adrenergic modulation of cerebrovascular tone is lost. Delayed post-ischemic hypermetabolism unlike stress-induced, but like hypoxia-induced hypermetabolism is only partially affected by beta blockade. Propranolol apparently compromises brain oxygen consumption secondary to a reduction in brain O2 supply while phentolamine improves perfusion and oxygen consumption.

Animals↗
PubMed1967

A receptor mechanism for the inhibition of insulin release by epinephrine in man.

Normal adult men and women have been infused with epinephrine, 6 mug per minute, during lipolytic blockade with nicotinic acid, beta-adrenergic blockade with propranolol and Butoxamine, and alpha-adrenergic blockade with phentolamine. Epinephrine infusion was associated with low serum levels of immunoreactive insulin (IRI) except when phentolamine was given simultaneously. These findings are compatible with an alpha receptor mechanism for the epinephrine inhibition of insulin release. Phentolamine had no blocking effects on the tachycardia and widened pulse pressure or lipolytic stimulation by epinephrine, whereas both propranolol and Butoxamine blocked lipolysis, tachycardia, and widened pulse pressure. These findings are consistent with an alpha receptor blocking action for phentolamine and beta receptor blocking action for propranolol and Butoxamine. Inhibition of lipolysis by nicotinic acid did not alter IRI or glucose responses to epinephrine. It is concluded that the lipolytic effect of epinephrine is unrelated to its effects on IRI release. Lipolytic blockade by nicotinic acid also did not change IRI or glucose in fasting subjects or their responses to a glucose infusion, 300 mg per minute. These observations appear to conflict with the Randle hypothesis (the glucose-fatty acid cycle) and raise some doubt as to whether plasma FFA concentrations are direct determinants of glucose or IRI concentrations in normal man.

Blood Glucose↗
PubMed1974

Adrenergic modulation of pancreatic glucagon secretion in man.

In order to characterize the influence of the adrenergic system on pancreatic glucagon secretion in man, changes in basal glucagon secretion during infusions of pure alpha and beta adrenergic agonists and their specific antagonists were studied. During infusion of isoproterenol (3 mug/min), a beta adrenergic agonist, plasma glucagon rose from a mean (+/-SE) basal level of 104+/-10 to 171+/-15 pg/ml, P < 0.0002. Concomitant infusion of propranolol (80 mug/min), a beta adrenergic antagonist, prevented the effects of isoproterenol, although propranolol itself had no effect on basal glucagon secretion. During infusion of methoxamine (0.5 mg/min), an alpha adrenergic agonist, plasma glucagon declined from a mean basal level of 122+/-15 to 75+/-17 pg/ml, P < 0.001. Infusion of phentolamine (0.5 mg/min), an alpha adrenergic antagonist, caused a rise in plasma glucagon from a mean basal level of 118+/-16 to 175+/-21 pg/ml, P < 0.0001. Concomitant infusion of methoxamine with phentolamine caused a reversal of the effects of phentolamine. The present studies thus confirm that catecholamines affect glucagon secretion in man and demonstrate that the pancreatic alpha cell possesses both alpha and beta adrenergic receptors. Beta adrenergic stimulation augments basal glucagon secretion, while alpha adrenergic stimulation diminishes basal glucagon secretion. Furthermore, since infusion of phentolamine, an alpha adrenergic antagonist, resulted in an elevation of basal plasma glucagon levels, there appears to be an inhibitory alpha adrenergic tone governing basal glucagon secretion. The above findings suggest that catecholamines may influence glucose homeostasis in man through their effects on both pancreatic alpha and beta cell function.

Adult↗
PubMed1979

Role of glucagon, catecholamines, and growth hormone in human glucose counterregulation. Effects of somatostatin and combined alpha- and beta-adrenergic blockade on plasma glucose recovery and glucose flux rates after insulin-induced hypoglycemia.

To further characterize mechanisms of glucose counterregulation in man, the effects of pharmacologically inducd deficiencies of glucagon, growth hormone, and catecholamines (alone and in combination) on recovery of plasma glucose from insulin-induced hypoglycemia and attendant changes in isotopically ([3-(3)H]glucose) determined glucose fluxes were studied in 13 normal subjects. In control studies, recovery of plasma glucose from hypoglycemia was primarily due to a compensatory increase in glucose production; the temporal relationship of glucagon, epinephrine, cortisol, and growth hormone responses with the compensatory increase in glucose appearance was compatible with potential participation of all these hormones in acute glucose counterregulation. Infusion of somatostatin (combined deficiency of glucagon and growth hormone) accentuated insulin-induced hypoglycemia (plasma glucose nadir: 36+/-2 ng/dl during infusion of somatostatin vs. 47+/-2 mg/dl in control studies, P < 0.01) and impaired restoration of normoglycemia (plasma glucose at min 90: 73+/-3 mg/dl at end of somatostatin infusion vs. 92+/-3 mg/dl in control studies, P<0.01). This impaired recovery of plasma glucose was due to blunting of the compensatory increase in glucose appearance since glucose disappearance was not augmented, and was attributable to suppression of glucagon secretion rather than growth hormone secretion since these effects of somatostatin were not observed during simultaneous infusion of somatostatin and glucagon whereas infusion of growth hormone along with somatostatin did not prevent the effect of somatostatin. The attenuated recovery of plasma glucose from hypoglycemia observed during somatostatin-induced glucagon deficiency was associated with plasma epinephrine levels twice those observed in control studies. Infusion of phentolamine plus propranolol (combined alpha-and beta-adrenergic blockade) had no effect on plasma glucose or glucose fluxes after insulin administration. However, infusion of somatostatin along with both phentolamine and propranolol further impaired recovery of plasma glucose from hypoglycemia compared to that observed with somatostatin alone (plasma glucose at end of infusions: 52+/-6 mg/dl for somatostatin-phentolamine-propranolol vs. 72+/-5 mg/dl for somatostatin alone, P < 0.01); this was due to further suppression of the compensatory increase in glucose appearance (maximal values: 1.93+/-0.41 mg/kg per min for somatostatin-phentolamine-propranolol vs. 2.86+/-0.32 mg/kg per min for somatostatin alone, P < 0.05). These results indicate that in man (a) restoration of normoglycemia after insulin-induced hypoglycemia is primarily due to a compensatory increase in glucose production; (b) intact glucagon secretion, but not growth hormone secretion, is necessary for normal glucose counterregulation, and (c) adrenergic mechanisms do not normally play an essential role in this process but become critical to recovery from hypoglycemia when glucagon secretion is impaired.

Adrenergic alpha-Antagonists↗
PubMed1982

Brain stem infusion of the gamma-aminobutyric acid antagonist bicuculline increases plasma insulin levels in the rat.

Previous neuroanatomical and physiological studies have indicated that nucleus ambiguus (Amb) is one source of vagal motoneurons in the brain stem that innervates the pancreas and which, when stimulated, increases insulin release. To investigate one of the neurotransmitter inputs to Amb neurons and its relation to insulin secretion, bicuculline, a specific gamma-aminobutyric acid (GABA) antagonist, was infused bilaterally into the Amb region as well as into a neighboring area, the rostral level of the lateral nucleus tractus solitarius (nts) of anesthetized male rats. Experiments were carried out in the presence or absence of the alpha-adrenergic blocker phentolamine. In the absence of phentolamine, no increases in plasma insulin levels were seen after bicuculline or vehicle infusion into the Amb region or after bicuculline infusion into the nts, while plasma glucose levels were significantly increased. In the presence of phentolamine, bicuculline infusion into the Amb region led to a prompt and significant increase in plasma insulin levels that could not be accounted for by changes in glycemia. The infusion of vehicle into Amb or of bicuculline into nts produced small or insignificant increases in plasma insulin levels. These results suggest that Amb neurons capable of modulating plasma insulin levels are under tonic GABA inhibition, an effect that appears to be specific for Amb neurons, since bicuculline infusion into another brain stem nucleus (nts) had no effect on insulin release. The fact that phentolamine pretreatment was necessary to reveal the bicuculline-induced effects corroborates previous studies showing that in addition to a central nervous system inhibition of vagal motoneurons by GABA, there is a tonic sympathetic inhibitory input to the endocrine pancreas capable of masking any disinhibition of vagal motoneurons. The physiological role of GABA inhibition of Amb neurons that innervate the pancreatic beta-cells remains to be determined.

Animals↗
PubMed1986

[Alpha-adrenoceptor blocking action of terazosin].

alpha-Adrenoceptor blocking activities and vascular relaxation activities of terazosin, a new antihypertensive agent, were studied. Terazosin had no effect on Ba2+, serotonin, angiotensin II and Ca2+ induced contractions in the isolated rat aorta. Terazosin competitively inhibited norepinephrine (NE) and phenylephrine (PE) induced contractions of the isolated rat aorta, and their pA2 values were 9.28 and 8.74, respectively. The potency of terazosin in the NE induced contraction was about 0.11, 8 and 176 times more than prazosin, phentolamine and yohimbine, respectively. The potency of terazosin in the PE induced contraction was about 0.09, 6 and 60 times more than prazosin, phentolamine and yohimbine. Terazosin (i.v.) competitively inhibited the PE induced pressor response. The "pA2" values of postsynaptic alpha-adrenoceptor blocking activity was 5.22, and its potency was about 0.05, 5 and 62.5 times more than prazosin, phentolamine and yohimbine, respectively. Terazosin (0.3 mg/kg, i.v. or less) did not show any significant effect on clonidine induced bradycardia during electrical stimulation of cardiac sympathetic nerve, whereas prazosin (0.3 mg/kg), phentolamine (0.1 mg/kg) and yohimbine (0.1 mg/kg) antagonized the effect of clonidine by 37%, 80.6% and 63.3%, respectively. Terazosin, 0.3 and 1 mg/kg, p.o., antagonized the PE (3 micrograms/kg, i.v.) induced pressor response in conscious unrestrained rats. This effect lasted for 8 hr in the case of 0.3 mg/kg and lasted for 12 hr in the case of 1 mg/kg. Thus, it is strong suggested that the antihypertensive effect of terazosin is based on the postsynaptic alpha-adrenoceptor blocking action.

Adrenergic alpha-Antagonists↗
PubMed1980

alpha-Adrenoceptor blocking properties of a new antihypertensive agent, 2-[4-(n-butyryl)-homopiperazine-1-yl]-4-amino-6,7-dimethoxyquinazoline (E-643).

Postsynaptic alpha-receptor blocking properties of E-643 were studied in vivo and in vitro and compared with these same properties of phentolamine and phenoxybenzamine. In anesthetized rats, E-643 (i.v.) attenuated pressor response to adrenaline dose-dependently and an adrenaline-reversal was seen with large doses. The in vivo alpha-adrenoreceptor blocking effect of E-643 was 3.4 times more potent than that of phentolamine. On the other hand, hypotensive action of E-643 was 9.4 times more potent than that of phentolamine. In the isolated rabbit aorta, E-643 blocked noradrenaline-induced contraction of the aorta with a parallel shift of the dose-response curve to the right. The pA2 values for E-643 and phentolamine were 8.60 and 7.65, respectively. The alpha-blocking effect of E-643 was reversible. E-643 protected alpha-receptors against irreversible inhibition by phenoxybenzamine. E-643 neither exhibited significant blocking effects on K+-, Ba2+- and angiotensin-induced contractions of the aorta nor caused relaxation of the aorta contracted by Ca2+. These data suggest that E-643 is a specific and competitive inhibitor of noradrenaline at the alpha-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1981

Chronotropic and inotropic effects of 3 kinds of alpha-adrenergic blockers on the isolated dog atria.

Using the isolated and blood-perfused dog atrial preparation, chronotropic and inotropic responses to 3 kinds of alpha-adrenergic blockers, phentolamine, phenoxybenzamine, and E-643, were compared. When phenoxybenzamine was administered into the cannulated sinus node artery, positive chronotropic and inotropic responses were induced in doses of 10-300 microgram. Phentolamine also produced positive responses, but at larger doses such as 100 and 300 microgram, accompanying initial negative responses. E-643 usually produced only negative chronotropic and inotropic effects. Positive responses to phenoxybenzamine and phentolamine were significantly suppressed by propranolol, and negative responses to E-643 and phentolamine were not modified by atropine treatment. From these results and previous reports, it is assumed that sinus tachycardia induced by alpha-blockers in situ may be due to 3 different mechanisms, i.e., 1) reflex tachycardia induced by the hypotension, 2) augmented catecholamine release mediated by the block of the presynaptic alpha-adrenoceptors, and 3) direct catecholamine release from locally innervated sympathetic nerve terminals.

Adrenergic alpha-Antagonists↗
PubMed2000

Adrenergic influences on coeliac ganglion affect the release of progesterone from cycling ovaries: characterisation of an in vitro system.

The superior ovarian nerve (SON) arrives at the ovary through the suspensory ligament and innervates mainly the ovarian stroma. Most neurones from which the SON fibres originate are located in the complex coeliac and mesenteric ganglia. Taking into account that other ganglia have been shown to have alpha- and beta-adrenergic receptors, and that the coeliac ganglion receives adrenergic fibres from other sympathetic paravertebral and preaortic ganglia, we utilised adrenergic agonists and antagonists specific to the ganglion, to analyse the role of the alpha and beta receptors in ovarian physiology. To that end, it was necessary to develop and standardise an in vitro coeliac ganglion-SON-ovary (coeliac ganglion-SON-O) experimental system that would enable study of the release of steroids in the ovary in the absence of humoral factors. We investigated the effect of adrenergic agents on the liberation of progesterone in the different stages of the oestrous cycle. To this end we placed the coeliac ganglion and the ovary in different compartments, connected through the SON, to produce a system being studied as a whole. Combined neural and hormonal (luteinising hormone (LH)) effects were also examined. Non-specific stimulation with KCl in the ganglion compartment evoked different responses in terms of release of progesterone, depending on the physiological conditions of the cycle; this demonstrated the sensitivity and viability of the system. During pro-oestrus, stimulation of the ganglion compartment with adrenergic agents such as the agonist noradrenaline or the beta-adrenergic antagonist propranolol, did not modify the release of progesterone. In contrast, the alpha-adrenergic antagonist, phentolamine, induced a strong inhibitory response. During the oestrous stage, noradrenaline was inactive, but phentolamine and propranolol exerted a strong stimulus throughout the experiment. On dioestrus day 1 (D1), both noradrenaline and propranolol increased the release of ovarian progesterone, whereas phentolamine had the opposite effect. Finally, on dioestrus day 2 (D2), what was noteworthy was the pronounced inhibitory effect of noradrenaline, whereas phentolamine was inactive and propranolol showed its greatest stimulatory effect. In order to compare the combined neural and endocrine effects on the ovarian release of progesterone, the experiment was carried out during stages D1 and D2, when the corpora lutea are at their peak of activity. Adrenergic agents were added to the ganglion and LH in a final concentration of 50 ng/ml was added to the ovarian comparment. Different effects were observed indicating a differential response to these agents in stimulated and basal conditions. We conclude that the in vitro coeliac ganglion-SON-ovary system is a functional entity because it possesses its own autonomic tone. This is verified because different basal values of progesterone appear in the different stages of the oestrous cycle. In similar fashion, variations of progesterone induced via the neural pathway were observed under different experimental conditions. In contrast, on D2, noradrenaline added to the ganglion compartment had an inhibitory effect on the liberation of ovarian progesterone. This would indicate that, during this phase, noradrenaline may not be the neurotransmitter released in the ovarian compartment, but that other inhibitory molecules might participate in the observed effects. Finally, during D2, the neural input would condition the ovarian response to LH, facilitating the decrease in progesterone necessary to start a new cycle. The experimental scheme is, in our opinion, a valuable tool for the study of peripheral neural participation in ovarian physiology.

Adrenergic Agents↗
PubMed2004

Vasomotor responses to hypoxia in type 2 diabetes.

Type 2 diabetes is associated with vascular dysfunction, accelerated atherosclerotic morbidity, and mortality. Abnormal vasomotor responses to chemoreflex activation may contribute to the acceleration of atherosclerotic diabetes complications, but these responses have not previously been investigated. We measured forearm mean blood flow (MBF) and mean vascular conductance (MVC) responses to isocapnic hypoxia in seven healthy and eight type 2 diabetic subjects during local intra-arterial saline infusion and alpha-adrenergic blockade (phentolamine). The effects of hypoxia on saline and phentolamine responses significantly differed between groups; relative to normoxia, the %DeltaMVC with hypoxia during saline was -3.3 +/- 11.2% in control and 24.8 +/- 13.3% in diabetic subjects, whereas phentolamine increased hypoxic %DeltaMVC to similar levels (39.4 +/- 9.7% in control subjects and 48.0 +/- 11.8% in diabetic subjects, P < 0.05, two-way ANOVA). Absolute normoxic MBF responses during saline infusion were 91.9 +/- 21.1 and 77.9 +/- 15.3 in control and diabetic subjects, respectively, and phentolamine increased normoxic MBF to similar levels (165.2 +/- 40.1 ml/min in control subjects and 175.9 +/- 32.0 ml/min in diabetic subjects; both P < 0.05). These data indicate that diabetic and control subjects exhibit similar responses to hypoxia in the presence of alpha-adrenergic blockade despite evidence of exaggerated alpha-mediated vasoconstriction at rest.

Adrenergic alpha-Antagonists↗
PubMed1983

The effect of alpha- and beta-adrenergic agonists and blockers on postprandial pancreatic polypeptide release in dogs.

The influence of adrenergic agonists--phenylephrine (alpha), isoproterenol (beta), and salbutamol (beta 2)--and of adrenergic blockers--phentolamine (alpha), pranolol (beta), and practolol (beta 1)--on the postprandial pancreatic polypeptide (PP) release has been assessed in five Labrador retrievers. Infusions of phenylephrine, 0.12 mg kg-1h-1; isoproterenol, 3 micrograms kg-1h-1; salbutamol, 12 micrograms kg-1h-1, did not significantly affect PP release. Propranolol, 0.5 mg kg-1, and propranolol, 0.5 mg kg-1, + phentolamine, 1 mg kg-1, combined, given as intravenous boluses before the meal significantly reduce PP release (44% and 58% of controls, p less than 0.05), whereas phentolamine, 1 mg kg-1, and practolol, 1 mg kg-1, had no effect. Phenylephrine combined with phentolamine and isoproterenol combined with propranolol and practolol did not influence PP secretion. It is concluded that the postprandial PP release is stimulated by beta 2-adrenergic mechanisms.

Adrenergic alpha-Agonists↗
PubMed1998

Effect of alpha-adrenergic blockade on the cerebrovascular response to increased intracranial pressure after hemorrhage.

OBJECT: In this study the authors tested the hypothesis that hemorrhagic hypotension and high intracranial pressure induce an increase in cerebrovascular resistance that is caused by sympathetic compensatory mechanisms and can be modified by alpha-adrenergic blockade. METHODS: Continuous measurements of cerebral blood flow were obtained using laser Doppler microprobes placed in the cerebral cortex in anesthetized pigs during induced hemorrhagic hypotension and high cerebrospinal fluid pressure. Eight pigs received 2 mg/kg phentolamine in 10 ml saline, and 13 pigs served as control animals. During high intracranial pressure occurring after blood loss, cerebral perfusion pressure (CPP) (p < 0.01) and cerebral blood flow (p < 0.01) decreased in both groups. Cerebrovascular resistance increased (p < 0.05) in the control group and decreased (p < 0.005) in the phentolamine-treated group. The cerebrovascular resistance was significantly lower in the phentolamine-treated group (p < 0.05) than in the control group. Cerebrovascular resistance increased at lower CPPs in the control group (linear correlation, r = 0.39, p < 0.01) and decreased with decreasing CPP in the phentolamine-treated group (linear correlation, r = 0.76, p < 0.001). CONCLUSIONS: This study shows that the deleterious effects on cerebral hemodynamics induced by blood loss in combination with high intracranial pressure are inhibited by alpha-adrenergic blockade. This suggests that these responses are caused by alpha-adrenergically mediated cerebral vasoconstriction.

Adrenergic alpha-Antagonists↗
PubMed2000

Supplemental oxygen does not modulate responses to acetylcholine or ascorbic acid in the forearm of patients with congestive heart failure.

Despite providing symptomatic relief in patients with congestive heart failure (CHF), supplemental oxygen (O(2)) has been demonstrated to increase total peripheral resistance. The present study investigated the possibility that O(2) inhalation reduces nitric oxide (NO) bioavailability, using endothelium-dependent (acetylcholine) and -independent (phentolamine) vasodilators, and the antioxidant ascorbic acid. Ten patients (nine male and one female) with primary left ventricular failure participated in the study. Forearm venous occlusion plethysmography was used to study blood flow responses to acetylcholine and the alpha-adrenergic antagonist phentolamine during inhalation of either room air or 100% O(2), with and without the simultaneous infusion of ascorbic acid. Neither O(2) inhalation (3.9+/-0.4 compared with 3.8+/-0.3 ml.min(-1).100 ml(-1)) nor ascorbic acid infusion (5.2+/-0.4 compared with 5.5+/-0.4 ml.min(-1).100 ml(-1)) affected resting forearm blood flow. The percentage increase from basal blood flow after acetylcholine infusion was not altered by either O(2) inhalation or ascorbic acid infusion (room air, 140+/-55%; O(2), 118+/-46%; ascorbic acid, 147+/-39%; ascorbic acid+O(2), 109+/-31%). O(2) inhalation did, however, reduce the dilation induced by phentolamine (room air, 131+/-24%; O(2), 80+/-14%; P<0.05). These data indicate that oxygen inhalation does not increase forearm vascular resistance. Secondly, preservation of reactivity to acetylcholine during O(2) inhalation suggests that degradation of NO by O(2)-derived free radicals is not enhanced. Attenuation of phentolamine-induced vasodilation during O(2) inhalation, however, implies increased adrenergic activity, which may possibly exacerbate the detrimental effects of elevated sympathetic activity in CHF.

Acetylcholine↗
PubMed1976

A review of the animal pharmacology of labetalol, a combined alpha- and beta-adrenoceptor-blocking drug.

1 The animal pharmacology of labetalol, a drug that blocks both alpha- and beta-adrenoreceptors, is reviewed. 2 In isolated tissues the blockade by labetalol of both alpha- and beta-adrenoreceptors satisfied accepted critera for competitive antagonism. In contrast phentolamine was a competitive antagonist at alpha-adrenoreceptors only, and propranolol a competitive antagonist at beta-adrenoreceptors only. Labetalol was 6-10 times less potent than phentolamine in blocking alpha-adrenoreceptors and 1.5-3 times less potent than propranolol in blocking beta-adrenoreceptors. Labetalol itself was 4-8 times more potent at beta- than at alpha-adrenoreceptors. 3 In anaesthetized dogs labetalol given intravenously blocked vasopressor responses to phenylephrine positive chronotropic, vasodepressor and bronchodilator response to isoprenaline. Phentolamine blocked the effect of phenylephrine only, and propranolol the effects of isoprenaline only. Labetalol was about 7 times less potent than phentolamine in blocking alpha-adrenoreceptors, about 4 times less potent than propranolol in blocking cardiac beta1-adrenoreceptors, and 11-17 times less potent than propranolol in blocking vascular and bronchial beta2-adrenoceptors. This difference in the relative potency of labetalol arises because propranolol is a slightly more potent antagonist at beta2- than at beta1-adrenoreceptors. Labetaol itself was about 16 times more potent at cardiac beta1- than at vascular alpha-adrenoreceptors. In conscious dogs labetaol given orally blocked vasopressor responses to phenylephrine and positive chonotropic responses to isoprenaline. 4 In anesthetized dogs and pithed rats labetaol blocked alpha- or beta-adrenoreceptor-mediated responses to sympathetic nerve stimulation and intravenously administered phenylephrine or isoprenaline to approximately the same extent. 5 Labetalol does not possess partial agonist (intrinsic sympathomimetic) activity at cardiac beta1-adrenoreceptors. 6 The blocking action of labetalol both in vivo was shown to be specific for alpha- and beta-adrenoreceptors. 7 The haemodynamic effects of labetalol are attributable to its adrenoreceptor-blocking actions. The observed responses vary from one experiment situation to another depending on the balance of autonomic influences. For example, in barbitone-anaesthetized dogs, in which sympathetic tone predominates, both labetalol and propranolol reduced heart rate, contractility, output and work--effects which are attributable to beta-adrenoreceptor blockade. Labetalol differed from propranolol in decreasing rather than increasing total peripheral resistance and in causing larger falls in blood pressure at equipotent beta-adrenoreceptor-blocking doses. These differences are probably attributable to peripheral vasodilatation resulting from the vascular alpha-adrenoreceptor-blocking action of labetalol...

Adrenergic alpha-Antagonists↗