Effects Of Alpha-adrenergic Blockade Research Articles

Alpha2-adrenergic blockade emulates the enhancing effect of chronic stress on breast cancer progression

Experimental studies in preclinical mouse models of breast cancer have shown that chronic restraint stress can enhance disease progression by increasing catecholamine levels and subsequent signaling of beta-adrenergic receptors. Catecholamines also signal alpha-adrenergic receptors, and greater alpha-adrenergic signaling has been shown to promote breast cancer in vitro and in vivo. However, antagonism of alpha-adrenergic receptors can result in elevated catecholamine levels, which may increase alpha-adrenergic signaling, because pre-synaptic alpha2-adrenergic receptors mediate an autoinhibition of sympathetic transmission. Given these findings, we examined the effect of alpha-adrenergic blockade on breast cancer progression under non-stress and stress conditions (chronic restraint) in an orthotopic mouse model with MDA-MB-231HM cells. Chronic restraint increased primary tumor growth and metastasis to distant tissues as expected, and non-selective alpha-adrenergic blockade by phentolamine significantly inhibited those effects. However, under non-stress conditions, phentolamine increased primary tumor size and distant metastasis. Sympatho-neural gene expression for catecholamine biosynthesis enzymes was elevated by phentolamine under non-stress conditions, and the non-selective beta-blocker propranolol inhibited the effect of phentolamine on breast cancer progression. Selective alpha2-adrenergic blockade by efaroxan also increased primary tumor size and distant metastasis under non-stress conditions, but selective alpha1-adrenergic blockade by prazosin did not. These results are consistent with the hypothesis that alpha2-adrenergic signaling can act through an autoreceptor mechanism to inhibit sympathetic catecholamine release and, thus, modulate established effects of beta-adrenergic signaling on tumor progression-relevant biology.

Combination Drug Therapy Improves Compliance of the Neurogenic Bladder

Typical management of increased bladder storage pressures and decreased compliance related to neurogenic bladder dysfunction consists of antimuscarinic therapy with or without clean intermittent catheterization. However, these measures are often unsuccessful. In this patient group we commonly use combination therapy consisting of antimuscarinics combined with imipramine and/or an alpha-blocker. A retrospective chart review was performed identifying all patients with neurogenic bladder dysfunction who were initially on no drug therapy or antimuscarinic therapy alone and were later switched to 2 or 3 drug therapy. In the group initially on no therapy and subsequently on 2 drugs (22) mean bladder pressure at capacity decreased 52% and mean compliance increased 5.0-fold. Similarly in the group starting without therapy but ending up on 3 drugs (28) bladder pressure decreased 67% and compliance increased 9.7-fold. In the group initially on an antimuscarinic agent alone (27) triple drug therapy decreased bladder pressure 60% and compliance increased 3.0-fold (all p <0.01). There were also improvements in incontinence, vesicoureteral reflux, detrusor overactivity and detrusor sphincter dyssynergia. In this highly selected group of patients with neurogenic bladder dysfunction and poor bladder compliance combination medical therapy with 2 or 3 drugs improved compliance, decreased bladder pressures at capacity and improved clinical outcomes. Combination therapy requires further study of the side effect profile but these results suggest that it should be considered for patients in whom antimuscarinic agents alone fail.

Secretory immunoglobulin A and cardiovascular reactions to mental arithmetic, cold pressor, and exercise: Effects of alpha-adrenergic blockade

The mechanism underlying acute changes in secretory immunoglobulin A (sIgA) remains to be determined. In this experiment, sIgA and cardiovascular activity were monitored at rest and while participants performed a mental arithmetic task, cold pressor, and submaximal cycle exercise following placebo or 1 mg of the alpha-adrenergic blocker, doxazosin. Under placebo, the tasks produced patterns of cardiovascular activity indicative of combined alpha- and beta-adrenergic, alpha-adrenergic, and beta-adrenergic activation, respectively. Doxazosin was associated with reduced blood pressure during cold pressor, but not during arithmetic or exercise. Mental arithmetic elicited increases in sIgA concentration and exercise produced increases in both sIgA concentration and secretion rate; these changes were unaffected by alpha blockade. In contrast, the cold pressor was associated with decreases in both sIgA concentration and secretion rate, which were blocked by doxazosin. These data suggest that acute decreases, but not increases, in sIgA are mediated by alpha-adrenergic mechanisms.

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

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. 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). 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.

Effect of alpha adrenergic blockade on thermoregulation in adrenal demedullated burned rats

This study in burned rats studied at two ambient temperatures (22° and 28° C) and housed at 28° C was designed to investigate the role of catecholamines in the maintenance of thermal homeostasis following burn injury. Two weeks prior to burn or sham burn, animals underwent adrenal medullectomy or sham adrenal medullectomy. Between postburn days 9 and 13, simultaneous direct and indirect calorimetry was performed following administration of 2mg/kg of phentolamine (alpha adrenergic blocking agent) via a carotid arterial line. Following administration of phentolamine, heat production and body temperature decreased and heat loss increased immediately. The cooling slopes for the burn groups were significantly sleeper than for the control groups, within ambient temperatures. Within ambient temperatures, the presence or absence of the adrenal medulla had no discernible effect on the cooling slope of the burns or the controls. The burned animals cooled 1.9 – 3.5 times faster at 22° than at 28° C, and controls cooled 2.0–3.9 times faster at 22° than at 28° C. Phentolamine produced a several-fold increase in serum concentrations of both norephinephrine (NE) and epinephrine (E), indicating a gross overlap in alpha and beta adrenergic receptor utilization for E and NE. The progressive cooling of the adrenal demedullated burn group at 22° C following phentolamine administration seems to indicate that norepinephrine is calorigenic for rats under these experimental circumstances. These experimental results indicate a relatively non-essential role for catecholamines in the maintenance of thermal homeostasis within the thermal neutral zone in the rat.

Effects of alpha and beta adrenergic blockade on coronary arterial microvessels in the beating canine heart.

The aim was to clarify the effects of alpha and beta adrenergic blockade on coronary arterial microvessels and to assess the role of alpha and beta adrenergic tone in normally beating hearts. 47 anaesthetised open chest dogs were studied. The diameters of epicardial arterial microvessels were measured in beating hearts using an incident light fluorescence microscope equipped with a floating objective. Drugs were infused into the left anterior descending coronary artery keeping the heart rate and aortic pressure at control levels. To examine the effect of alpha adrenergic blockade, phentolamine (100 micrograms.kg-1) was given in the absence or presence of beta adrenergic blockade (propranolol 50 micrograms.kg-1). To examine the effect of beta adrenergic blockade, propranolol (50 micrograms.kg-1) or three doses of ICI 118,551 (a selective beta 2 antagonist, 0.1, 0.5, and 1.0 microgram.kg-1.min-1) was given. Coronary arterial microvessels were divided into three groups according to the control diameters (D) of small (D less than 100 microns), medium (100 less than or equal to D less than 200 microns) and large (D greater than or equal to 200 microns) groups. In the absence of beta adrenergic blockade, phentolamine significantly dilated all vessel groups: small +19.6 (SEM 5.6)%, medium +5.8(2.3)%, large +5.3(0.9)%. In the presence of beta adrenergic blockade, the vasodilator effect of phentolamine was completely abolished. Propranolol constricted all vessel groups: small -3.6(1.1)%, medium -4.8(1.0)%, large -3.5(1.0)%. ICI 118,551 significantly constricted the large vessel group [-2.5(0.6)%] at the mid dose, and the medium and large vessel groups [medium -3.1(0.8)%, large -3.5(1.3)%] at the highest dose. These data indicate that (1) the vasodilator effect of phentolamine is induced by beta adrenergic stimulation; (2) resting alpha adrenergic tone of coronary arterial microvessels is minimal in normally beating hearts, and (3) resting beta adrenergic tone may play a physiological role in coronary arterial microvessels, and beta 2 adrenergic tone predominates in arterial microvessels greater than 100 microns in diameter.

Effect of alpha-adrenergic blockade with prazosin on large coronary diameter during exercise.

Exercise-induced dilation of coronary resistance vessels is limited by alpha-adrenergic mechanisms. However, the effect of alpha-adrenergic mechanisms on large coronary arteries during exercise is not known. In the present study, sonomicrometry was used to measure circumflex coronary arterial diameter during treadmill exercise before and after alpha 1-adrenergic blockade with prazosin in eight instrumented dogs. Before infusion of prazosin, exercise caused a fall in coronary vascular resistance (2.1 +/- 0.4 to 1.6 +/- 0.2 units, p less than 0.05) and dilation of the circumflex coronary artery (4.66 +/- 0.37 to 4.79 +/- 0.34 mm, p less than 0.05). Intracoronary infusion of prazosin during exercise caused a further decrease in coronary vascular resistance (1.6 +/- 0.2 to 1.4 +/- 0.2 units, p less than 0.05) and a further increase in circumflex coronary arterial diameter (4.79 +/- 0.34 to 4.83 +/- 0.34 mm, p less than 0.05). Intracoronary infusion of vehicle without prazosin during exercise did not cause a further decrease in coronary vascular resistance or increase in coronary diameter. Prazosin caused no significant increase in heart rate, aortic pressure, or coronary blood flow. Therefore, both small coronary resistance vessels and large epicardial coronary arteries dilated during exercise and dilated further after alpha-adrenergic blockade. This finding indicates that alpha 1-adrenergic activity during exercise limits dilation of both large and small coronary arteries.

Acute effect of passive Heymann nephritis on renal blood flow and glomerular filtration rate in the rat: role of the anaphylatoxin C5a and the alpha-adrenergic nervous system.

In earlier studies, we have shown that induction of passive Heymann nephritis (PHN) by intrarenal infusion of anti-Fx1A antibodies provokes an immediate fall in renal blood flow (RBF) and glomerular filtration rate (GFR). This was probably mediated via the complement system, as infusion of the F(ab')2 fraction of anti-Fx1A did not reduce RBF and GFR. In the present study, the effects of alpha-adrenergic blockade upon the acute hemodynamic changes during induction of PHN and of C5a infusion were studied. Group 1 was infused with anti-Fx1A antibodies during blockade of the sympathetic nervous system with the alpha-blocker phentolamine; control animals were treated similarly, but infused with normal rat IgG. Group 2 was infused with the anaphylatoxin C5a, normally produced during complement activation, and compared with control animals infused with saline. In group 1, RBF did not differ from control animals after the infusion of anti-Fx1A antibodies (6.6 +/- 0.5 compared to 7.3 +/- 1.0 ml/min/g in the controls). GFR in the left, antibody-infused kidney fell compared to controls, and was 0.25 +/- 0.08 ml/min/g at the end of the experiment compared to 0.60 +/- 0.13 ml/min/g (p less than 0.05 with Student's t test, p = 0.07 with two-way analysis of variance (ANOVA). GFR in the right kidney remained unchanged compared to controls. In group 2, C5a induced a significant fall in RBF (from 7.9 +/- 0.9 to 3.1 +/- 0.4 ml/min/g kidney weight), significantly different from control animals where it fell from 8.1 +/- 0.5 to 6.8 +/- 0.7 ml/min/g (p less than 0.0001 with two-way ANOVA, p less than 0.001 with t test).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of alpha adrenergic blockade during stellate ganglion stimulation on arrhythmias induced by acute myocardial ischemia in pigs

The effects of alpha-adrenergic receptor blockade during stellate ganglion stimulation on arrhythmias induced by repeated coronary artery occlusion in pigs under spontaneous breathing were studied. Prazosin, alpha 1-receptor blocker, did not have any effect on the early ischemic dysrhythmia. Yohimbine, which selectively blocks alpha 2-receptor, significantly increased the number of premature ventricular complexes (19 +/- 3----32 +/- 2 PVC; P less than 0.01), but produced no effects on the percentage of appearance of ventricular fibrillation (VF) and ventricular tachycardia (VT). However, nonselective alpha-receptor blocker phentolamine significantly reduced the number of premature ventricular complexes (30.5 +/- 4.5----11 +/- 3 PVC; P less than 0.05), but did not affect the frequency of occurrence of VF and VT. The above results show that alpha-adrenergic mechanisms do not play any important role in the genesis of arrhythmias during ischemia in the pig model.

The effects of alpha adrenergic blockade on central haemodynamics and regional blood flows during positive pressure ventilation. An experimental study in the pig.

The effects of alpha receptor blockade on cardiac output distribution in pigs were studied. Recordings were made during spontaneous breathing (SB), during ventilator treatment with 8 Pa positive end-expiratory pressure (8 PEEP), after alpha blockade during SB (SB-alpha) and at 8 PEEP (8 PEEP-alpha). The microsphere method was used for blood flow determinations. The animals received either 5 ml.kg-1.h-1 (Group A) or 10 ml.kg-1.h-1 (Group B) of fluids. In Group A on SB-alpha, CO was maintained due to tachycardia but mean arterial pressure (MAP) decreased, renal blood flow and urine production decreased. At 8 PEEP-alpha, CO decreased despite increased heart rate (HR), MAP decreased alarmingly, renal blood flow decreased, urine production ceased and cerebral blood flow decreased, reflecting failing autoregulation. In Group B, CO increased during SB-alpha, SVR decreased, myocardial blood flow increased and organ blood flows were otherwise unchanged. At 8 PEEP-alpha, MAP, SVR, renal, pancreatic and splenic blood flows decreased in Group B. Gastric, intestinal and muscular blood flows were unchanged at 8 PEEP-alpha in Group B which is interpreted as an effect of the alpha blockade. In both groups peripheral arterio-venous shunting increased after alpha blockade.

Effects of alpha-adrenergic blockade on coronary autoregulation in dogs.

In alpha-chloralose-anesthetized, open-chest dogs, left coronary blood flow and oxygen extraction were measured at perfusion pressures from 25 to 175 mmHg. Pressure-flow relationships were obtained before and after alpha-blockade with prazosin or alpha 2-blockade with yohimbine in the presence of beta-blockade with propranolol. The efficiency of flow autoregulation with increments in pressure was calculated as the closed-loop gain and as the slope of flow to pressure. In all animals the highest gain and the lowest slope were seen when pressure increased from 75 to 125 mmHg. In the prazosin group before alpha-blockade the gain with this pressure increase was 0.76 +/- 0.05, whereas in the yohimbine group before alpha-blockade this gain was 0.75 +/- 0.03. Prazosin reduced the gain within the pressure range of 75-125 mmHg by 41%, and this reduction was statistically significant (P less than 0.05). Prazosin also significantly increased the flow to pressure slope within this range. In addition, at all pressures greater than or equal to 50 mmHg, the level of coronary flow was significantly increased by prazosin. The increase in flow and the reduction in autoregulatory efficiency with prazosin were not attributable to an increase in myocardial oxygen consumption. Yohimbine had no effects on the level of coronary flow or on the autoregulatory efficiency. These data indicate that an alpha 1-adrenoceptor mediated coronary constriction modulates coronary autoregulation.

Acute Urinary Retention Secondary to Benign Prostatic Hyperplasia. Effect of Alpha-Adrenergic Blockade

Acute Urinary Retention Secondary to Benign Prostatic Hyperplasia. Effect of Alpha-Adrenergic Blockade

Effects of alpha-adrenergic blockade on cardiovascular responses to static exercise in cats.

Static exercise performed by conscious cats elicits increases in heart rate (HR), left ventricular systolic pressure (LVSP), and the maximal rate of left ventricular pressure development [LV(dP/dt)max]. The increased HR is mediated primarily by withdrawal of parasympathetic tone, whereas a beta-adrenergic mechanism is responsible for the LV(dP/dt)max increase. In the present study the cardiovascular responses to static exercise in awake cats was recorded before and after alpha-adrenergic blockade. Pressure transducers were implanted into the left ventricle of cats who had been trained operantly to perform static exercise. Significant increases in LVSP, LV(dP/dt)max and HR occurred in all cats during static exercise before blockade. In contrast, alpha-adrenergic blockade (phentolamine, 2.5 mg/kg iv) abolished the exercise-induced increase in LVSP but did not prevent increases in HR and LV(dP/dt)max. The cats performed fewer exercise bouts per day during alpha-blockade than when unblocked. We conclude that an alpha-adrenergic mechanism mediates the increase in LVSP in response to static exercise in conscious cats.

Effect of alpha‐adrenergic blockade and anticholinergic agents on the decentralized primate bladder

AbstractThe effect of anticholinergic and alpha‐adrenergic blocking agents on the primate bladder decentralized at the sacral level was studied. Both agents diminish the intravesical pressure response to filling and slightly increase capacity. Each appears to exert an independent effect.

The Effect of Alpha-Adrenergic Blockade on Cardiac Performance and Tissue Oxygen Delivery During Excision on Pheochromocytoma

The Effect of Alpha-Adrenergic Blockade on Cardiac Performance and Tissue Oxygen Delivery During Excision on Pheochromocytoma

The effect of alpha-adrenergic blockade on cardiac performance and tissue oxygen delivery during excision of pheochromocytoma.

To establish criteria for administration of the optimal dose of alpha-adrenergic receptor blocking drugs, we studied cardiac performance and tissue oxygen tension in three patients who underwent excision of pheochromocytoma. Subcutaneous oxygen tension was measured by the method of Niinikoski and Hunt. Cardiac function was assessed by thermodilution cardiac output, systemic and pulmonary arterial blood pressures, and continuous two-dimensional transesophageal echocardiography of a cross section of the left ventricle at the level of the papillary muscles. Despite large changes in cardiac output and systemic, pulmonary, and wedge pressures, intraoperative tissue oxygen tensions and ejection fractions remained normal (even at times of peak catecholamine excretion and very abnormal wedge pressures). Studies of healthy animals that received no alpha-adrenergic receptor blocking drugs showed major decrements of tissue oxygen in response to modest doses of epinephrine. We conclude that progressive administration of alpha-adrenergic receptor blocking drugs does not absolutely protect the patient from major changes in blood pressure during operation for pheochromocytoma, but that cardiac performance and oxygen supply to the tissues are unimpaired.

The role of alpha-adrenergic receptors in the pathogenesis of coronary spasm.

The role of alpha-adrenergic receptors in the pathogenesis of coronary spasm.

The effect of alpha-adrenergic blockade on the pulmonary vascular response to dopamine in neonatal lambs.

The effect of alpha-adrenergic blockade by phentolamine on the pulmonary vascular response to dopamine was studied in chronically prepared newborn lambs. Dopamine was administered at doses of 2.7 micrograms . kg-1 . min-1, 27 micrograms . kg-1 . min-1 and 270 micrograms . kg-1 . min-1 with and without alpha-adrenergic blockade. Dopamine infusion at 270 micrograms . kg-1 . min-1 caused a rise in the mean pulmonary artery pressure from 22 +/- 3.2 mmHg (mean +/- S.E.) at baseline to 36 +/- 4.1 mmHg (P less than 0.001). This rise was unaffected by alpha-adrenergic blockade. Dopamine infusion alone did not change pulmonary blood flow, but, in the presence of alpha-adrenergic blockade, pulmonary blood flow rose from 190 +/- 12 ml . min-1 . kg-1 at baseline to 280 +/- 13 ml . min-1 . kg-1 at the maximum dopamine infusion rate (P less than 0.001). Pulmonary vascular resistance was the same before and after alpha-adrenergic blockade and did not change from the baseline value during dopamine infusion.

253 The effect of alpha adrenergic blockade on histamine and exercise-induced asthma

253 The effect of alpha adrenergic blockade on histamine and exercise-induced asthma

Alpha-adrenergic blocking agents and the cardiovascular response to pharmacological doses of vasopressin.

The effects of alpha-adrenergic blockade with phentolamine or dibenamine on the cardiovascular response to pharmacological doses of vasopressin were studied in anesthetized dogs. Some observations were also made on the combined effects of vasopressin and norepinephrine. Changes in mean systemic arterial pressure, portal pressure, and resistance in the prehepatic splanchnic vasculature during vasopressin infusion were noted. A total of 97 dogs were used. alpha-Blockade appeared to enhance the response of arterial pressure to vasopressin, possibly because of loss of baroreceptor-mediated buffering action which normally attenuates its pressor action. Effects of vasopressin on mesenteric vascular resistance and portal pressure were unchanged or somewhat less after alpha-blockade, hence no evidence that its therapeutic effect would be improved by this combination. Vasopressin and norepinephrine when given together result in an additive pressor response with little or no evidence of potentiation.