Nonselective Alpha-adrenergic Antagonist Research Articles

Alpha-adrenergic receptor activation after fetal hypoxia-ischaemia suppresses transient epileptiform activity and limits loss of oligodendrocytes and hippocampal neurons

Exposure to hypoxic-ischaemia (HI) is consistently followed by a delayed fall in cerebral perfusion. In preterm fetal sheep this is associated with impaired cerebral oxygenation, consistent with mismatch between perfusion and metabolism. In the present study we tested the hypothesis that alpha-adrenergic inhibition after HI would improve cerebral perfusion, and so attenuate mismatch and reduce neural injury. Chronically instrumented preterm (0.7 gestation) fetal sheep received sham-HI (n = 10) or HI induced by complete umbilical cord occlusion for 25 minutes. From 15 minutes to 8 hours after HI, fetuses received either an intravenous infusion of a non-selective alpha-adrenergic antagonist, phentolamine (10 mg bolus, 10 mg/h infusion, n = 10), or saline (n = 10). Fetal brains were processed for histology 72 hours post-HI. Phentolamine infusion was associated with increased epileptiform transient activity and a greater fall in cerebral oxygenation in the early post-HI recovery phase. Histologically, phentolamine was associated with greater loss of oligodendrocytes and hippocampal neurons. In summary, contrary to our hypothesis, alpha-adrenergic inhibition increased epileptiform transient activity with an exaggerated fall in cerebral oxygenation, and increased neural injury, suggesting that alpha-adrenergic receptor activation after HI is an important endogenous neuroprotective mechanism.

PSUN11 Outcomes of Nonselective or Selective Alpha-Adrenergic Antagonist for Preoperative Management of Intra-adrenal Pheochromocytoma

Abstract Background Pheochromocytoma is a rare neoplasm of the adrenal medulla that leads to catecholamine excess. Adrenalectomy is the standard management for operative candidates. Preoperative alpha-adrenergic antagonism has been traditionally performed with the non-selective irreversible agent phenoxybenzamine. Recently, use of this agent has been limited due to availability and cost. We sought to determine whether type of preoperative antihypertensive management with nonselective alpha-adrenergic antagonist or selective alpha-1 antagonist was associated with differences in patient outcomes for those undergoing adrenalectomy. Methods We performed a retrospective review of adult patients at a single institution undergoing index adrenalectomy for initial diagnosis of intra-adrenal pheochromocytoma from 2012 through 2021. Exclusion criteria were prior adrenalectomy and extra-adrenal pheochromocytoma or paraganglioma. Clinical and demographic factors were assessed. Our primary outcome was intraoperative hemodynamic stability, secondary outcomes were postoperative hemodynamic instability, and surgical complications. Data were analyzed using Chi-squared, Fisher's exact and Mann Whitney U tests. Results During the study period, 38 patients underwent index adrenalectomy for initial diagnosis of intra-adrenal pheochromocytoma. Patient age was a mean of 57.8 years (SD 13.6) with 14 male (37%) and 34 (90%) white. On preoperative cross-sectional imaging, the mean tumor size was 3.9cm (IQR 2.5–5.2) with 15 (40%) left sided, 21 (58%) right sided and 1 (3%) bilateral with 32 (87%) undergoing minimally invasive laparoscopic or robotic assisted adrenalectomy. The mean pre-contrast density on computed tomography imaging was 35.4 Hounsfield units (SD 15). Preoperative plasma metanephrines were mean 0.65 (SD 6.7), plasma normetanephrines 11.1 (SD 14.3). For preoperative pharmacologic therapy, 16 (42%) were on phenoxybenzamine, 21 (55%) selective alpha-1 antagonist, and 1 (3%) patient on both who was excluded from comparative analysis. Nine patients overall (24%) had preoperative hypertensive crisis with no difference between the groups. There was no difference between the groups for intraoperative hemodynamic instability with 6 (38%) in the phenoxybenzamine group and 10 (48%) in the selective alpha blockade group (p = 0.74) or postoperative hemodynamic instability with 5 (31%) compared with 9 (45%) respectively (p = 0.50). Groups were also similar with regard to age, sex, body mass index, comorbidities, preoperative catecholamine levels, American Society of Anesthesiologists Physical Status classification, minimally invasive or open surgery, tumor size, estimated surgical blood loss, and postoperative complications. Follow up duration was longer for the phenoxybenzamine group at 55 months (SD 35) compared with 21 months (SD 25) for the selective alpha blockade group (p = 0.003). Conclusions Use of preoperative alpha adrenergic antagonism selective alpha-1 antagonists showed similar outcomes intraoperative and postoperatively compared with irreversible nonselective alpha-adrenergic antagonists in this cohort. Use of selective alpha-1 antagonists should be considered when nonselective agents are not accessible. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Sex Differences in the Sympathetic Restraint of Skeletal Muscle Blood Flow in the Human Leg Vasculature

BackgroundThe sympathetic nervous system plays an important role in regulating skeletal muscle blood flow at rest and during exercise. Previous studies have identified sex differences in resting muscle sympathetic nerve activity1 and forearm alpha‐adrenergic receptor sensitivity.2 However, whether sympathetic restraint of limb blood flow differs between sexes, and the degree to which this restraint persists during dynamic exercise, is not well understood.MethodsIn four young men (28±2 yrs; 26±2 kg/m2) and six young women (24±2 yrs; 23±1 kg/m2), we evaluated changes in leg blood flow (LBF, Doppler ultrasound), mean arterial blood pressure (MAP, indwelling femoral artery catheter), and leg vascular conductance (LVC) before and after intra‐arterial infusion of phentolamine (PHEN, non‐selective alpha‐adrenergic antagonist, 5 μg/dL/min) at rest and during small muscle mass knee‐extensor (KE) exercise (15W). Influences from beta‐adrenergic receptors were blocked by intravenous administration of propranolol (0.07 mg/kg bolus).ResultsNo sex differences in LBF, MAP, or LVC were observed at rest. Following PHEN administration, sex differences were evident for both the drug‐induced increase in resting LBF (+337±79 vs. +172±43 mL/min, p<0.05, men vs. women) and LVC (+3.69±1.04 vs. +1.97±0.45 mL/min/mmHg, men vs. women, p=0.06). During KE exercise, no sex differences were evident for LBF, MAP, or LVC prior to PHEN infusion, and drug administration provoked similar increases in LBF (+630±128 vs. +560±85 mL/min, men vs. women) and LVC (+7.2±1.5 vs. +6.9±1.6 mL/min/mmHg, men vs. women) between groups.ConclusionAt rest, men demonstrate a larger increase in LBF and LVC in response to local alpha adrenergic receptor blockade via PHEN infusion, suggesting a greater degree of basal sympathetic vasoconstriction than their female counterparts. However, during exercise, similar increases in leg hemodynamics were observed between men and women following PHEN administration. Together, these data support the presence of a sex difference in the sympathetic restraint of resting limb blood flow that does not persist during moderate intensity exercise.Support or Funding InformationThis project is funded in part by the National Institutes of Health (HL118313) and the U.S. Department of Veterans Affairs (RX001697, RX001418, E6910R).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Efecto hiperalgésico de la fentolamina por vía subaracnoidea en ratones

Background and objectivesPainful phenomenon is one of the most important and complex experiences. Phentolamine is a non-selective alpha-adrenergic antagonist. The objective of this study was to compare the effect of increasing doses of phentolamine into subarachnoid space in rats in the modulation of painful phenomenon. MethodsEighty four male Wistar rats were divided into formalin and plantar incision groups, subdivided into six subgroups (n=7). Control group (CG) received only saline (10μL); active subgroups received phentolamine 10μg (GF10), 20μg (GF20), 30μg (GF30), 40μg (GF40), and 50μg (GF50). In formalin group, pain was induced by injection of 50μL of 2% formalin in dorsal region of right posterior paw. In plantar incision group, pain was induced by plantar incision and evaluated using Von Frey filaments. Induction and maintenance of anesthesia were performed with 3% halothane for catheter placement into subarachnoid space and plantar incision. Statistical analysis was performed using the JMP® program from SAS with 5% significance level. ResultsPhentolamine at doses of 20 and 30μg increased the algesic response in the intermediate phase of the formalin test. In plantar incision test, it had hyperalgic effect on first, third, fifth, and seventh days at a dose of 10μg and on first, third, and fifth days at a dose of 20μg and on fifth day at a dose of 30μg. ConclusionSubarachnoid administration of phentolamine showed hyperalgesic effect, possibly due to the involvement of different subclasses of alpha-adrenergic receptors in modulating pain pathways.

Hyperalgesic effect of subarachnoid administration of phentolamine in mice

Background and objectivesPainful phenomenon is one of the most important and complex experiences. Phentolamine is a non-selective alpha-adrenergic antagonist. The objective of this study was to compare the effect of increasing doses of phentolamine into subarachnoid space in rats in the modulation of painful phenomenon. Methods84 male Wistar rats were divided into formalin and plantar incision groups, subdivided into six subgroups (n=7). Control group received only saline (10μL); active subgroups received phentolamine 10μmg (GF10), 20mg (GF20), 30mg (GF30), 40mg (GF40), and 50g (GF50). In formalin group, pain was induced by injection of 50μL of 2% formalin in dorsal region of right posterior paw. In plantar incision group, pain was induced by plantar incision and evaluated using von Frey filaments. Induction and maintenance of anesthesia were performed with 3% halothane for catheter placement into subarachnoid space and plantar incision. Statistical analysis was performed using the JMP program from SAS with 5% significance level. ResultsPhentolamine at doses of 20 and 30g increased the algesic response in the intermediate phase of the formalin test. In plantar incision test, it had hyperalgic effect on first, third, fifth, and seventh days at a dose of 10g and on first, third, and fifth days at a dose of 20g and on fifth day at a dose of 30g. ConclusionSubarachnoid administration of phentolamine showed hyperalgesic effect, possibly due to the involvement of different subclasses of alpha-adrenergic receptors in modulating pain pathways.

Intrinsic vasomotricity and adrenergic effects in a model of isolated rabbit eye

We aimed to investigate the responsiveness of the ocular arteries to adrenergic drugs in a model of perfused isolated rabbit eye. Rabbit external ophthalmic arteries (n = 15) in a head-mounted preparation were cannulated and the retinal and uveal vasculature perfused at a constant flow with warmed tyrode. The three-way polypropylene catheter was further connected to a pressure transducer and intraluminal pressure was taken as a measure of vascular resistance. Effects of intra-arterial injections of phenylephrine (group A, n = 5), prazosin (group B, n = 5) and phentolamine (group C, n = 5) on the recorded pressure were obtained. Student's paired-t test and one-way analysis of variance were used for statistical analysis (p < 0.05). Intrinsic vasomotricity was observed in all preparations prior to any drug administration. Phenylephrine produced an increase in total vascular resistance. Intrinsic vasomotricity became more evident, showing a lower frequency but higher amplitude of oscillations. Evoked vasomotor responses with phenylephrine (250 microg/ml) were inhibited by intra-arterial administration of the selective alpha(1)-adrenergic antagonist, prazosin (0.5 mg/ml), as well as the non-selective alpha-adrenergic antagonist phentolamine (6 mg/ml). Rabbit external ophthalmic arteries showed spontaneous contractions under constant perfusion. Phenylephrine elicited a vasoconstrictor response that was inhibited by adrenergic antagonists. In addition, the intrinsic vasomotricity was enhanced by phenylephrine and blocked by adrenergic antagonists. These results show that under in vitro perfusion the territory presents similar responses to adrenergic drugs to those observed in in vivo models and also provides evidence of myogenic autoregulatory properties in the rabbit ophthalmic artery and/or choroid.

Treatment of Complex Regional Pain Syndrome Type I With Oral Phenoxybenzamine: Rationale and Case Reports

The nonselective alpha-adrenergic antagonist, phenoxybenzamine, has been used in the treatment of neuropathic pain syndromes, specifically, complex regional pain syndrome (CRPS) types I and II. This agent has also previously been used in intravenous regional peripheral blocks for treatment of CRPS I; however, an intravenous preparation of phenoxybenzamine is not currently available in the U.S.A. In this case series, systemic administration was more appropriate for three of the four patients, as their syndromes had spread beyond the initial area of surgery or trauma. We report an apparent clinical benefit in three of the four patients following oral administration. We postulate that this may be due to the noncompetitive (irreversible) blockade of alpha(1)- and alpha(2)-adrenergic receptors. We further hypothesize that this blockade could reduce stimulation of an increased population of adrenergic receptors in hyperalgesic skin, blunt the stimulation by norepinephrine of alpha(2)-adrenergic receptors on macrophages, and ultimately reduce the release of proinflammatory cytokines from cellular elements.

Enaminones and norepinephrine employ convergent mechanisms to depress excitatory synaptic transmission in the rat nucleus accumbens in vitro

We recently reported that anticonvulsant anilino enaminones depress excitatory postsynaptic currents (EPSCs) in the nucleus accumbens (NAc) indirectly via gamma-aminobutyric acid (GABA) acting on GABA(B) receptors [S.B. Kombian et al. (2005)Br. J. Pharmacol., 145, 945-953]. Norepinephrine (NE) and dopamine (DA), both known to be involved in seizure disorders, also depress EPSCs in this nucleus. The current study explored a possible interaction between enaminones and adrenergic and/or dopaminergic mechanisms that may contribute to their synaptic depression and anticonvulsant effect. Using whole-cell recording in rat forebrain slices containing the NAc, we show that NE-induced, but not DA-induced, EPSC depression occludes E139-induced EPSC depressant effect. UK14,304, a selective alpha(2) receptor agonist, mimicked the synaptic effect of NE and also occluded E139 effects. Phentolamine, a non-selective alpha-adrenergic antagonist that blocked NE-induced EPSC depression, also blocked the E139-induced EPSC depression. Furthermore, yohimbine, an alpha(2)-adrenoceptor antagonist, also blocked the E139-induced EPSC depression, while prazosin, a selective alpha(1)-adrenergic antagonist, and propranolol, a non-selective beta-adrenoceptor antagonist, did not block the E139 effect. Similar to the E139-induced EPSC depression, the NE-induced EPSC depression was also blocked by the GABA(B) receptor antagonist, CGP55845. By contrast, however, neither SCH23390 nor sulpiride, D1-like and D2-like DA receptor antagonists, respectively, blocked the E139-induced synaptic depression. These results suggest that NE and E139, but not DA, employ a similar mechanism to depress EPSCs in the NAc, and support the hypothesis that E139, like NE, may act on alpha(2)-adrenoceptors to cause the release of GABA, which then mediates synaptic depression via GABA(B) receptors.

α1A-Adrenoceptors Mediate Sympathetically Evoked Pupillary Dilation in Rats

Evidence suggests that in some species (cats, rabbits, and possibly humans) alpha-adrenoceptors in the iris dilator muscle are "atypical" in that they cannot be readily classified by conventional criteria. This study was undertaken in an attempt to characterize the alpha-adrenoceptor subtype(s) mediating sympathetically elicited mydriasis in rats. Frequency-response pupillary dilator curves were generated by stimulation of the preganglionic cervical sympathetic nerve (1-32 Hz) in pentobarbital-anesthetized rats. Evoked responses were inhibited by systemic administration of nonselective alpha-adrenergic antagonists, phentolamine (0.3-10 mg/kg) and phenoxybenzamine (0.03-1 mg/kg). The selective alpha(1)-adrenergic antagonist, prazosin (0.01-1 mg/kg), also was effective, although alpha(2)-adrenergic antagonism with rauwolscine (0.1-1 mg/kg) was not. alpha(1A)-Adrenoceptor-selective antagonists, 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB-4101; 0.1-1 mg/kg) and 5-methylurapidil (0.1-1 mg/kg), as well as the alpha(1D)-adrenoceptor-selective antagonist 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY-7378; 1-3 mg/kg), were used to determine the subtype(s) involved. Evoked mydriasis was significantly antagonized by both WB-4101 and 5-methylurapidil but not by BMY-7378. These results suggest that, unlike some other species, adrenoceptors in the rat iris dilator mediating neurogenic mydriasis are "typical" and, in addition, can be characterized as being primarily of the alpha(1A)-adrenoceptor subtype.

Noradrenaline inhibits glutamate release in the rat bed nucleus of the stria terminalis: in vivo microdialysis studies.

The microdialysis technique was used to simultaneously study the in vivo extracellular levels of noradrenaline, glutamate, and gamma aminobutyric acid (GABA) in the bed nucleus of the stria terminalis in order to assess the regulation that noradrenaline may exert upon the release of amino acid neurotransmitters. Perfusion through the probe with UK14304, a selective alpha2-adrenergic agonist, produced a significant decrease of noradrenaline and glutamate extracellular levels. Perfusion through the probe with RX821002, a selective alpha2-adrenergic antagonist, produced a significant increase of noradrenaline and glutamate basal extracellular levels. Perfusion with prazosine, a selective alpha1-adrenergic antagonist, produced a significant decrease of noradrenaline basal extracellular levels without affecting glutamate levels. Under the same conditions, GABA basal extracellular levels were not changed in the presence of any of the alpha-adrenergic ligands studied. The perfusion of high potassium through the probe induced a significant Ca++dependent release of the three neurotransmitters; however, extracellular noradrenaline returned to normal levels even though potassium was still present. In addition, it was observed that alpha-adrenergic receptor ligands exerted differential effects upon K+-induced release of noradrenaline and glutamate. Perfusion with the nonselective alpha-adrenergic antagonist, phenoxybenzamine, presented a biphasic effect upon K+-induced release of noradrenaline; a significant decrease during the first 5 min of stimulation followed by a significant increase in the next 5 min of stimulation. Perfusion with RX821002 produced a significant increase in K+-induced release of noradrenaline that returned to normal basal values before the end of the stimulation period. In contrast, local perfusion with prazosine caused a significant decrease of K+-induced noradrenaline release. In the case of glutamate, perfusion through the probe with phenoxybenzamine produced a significant increase in K+-induced release of glutamate. In addition, RX821002 and prazosine produced a significant increase in K+-induced release of glutamate. Perfusion through the probe with UK14304 produced a significant decrease of both noradrenaline and glutamate K+-induced release. The present results show that noradrenaline in the bed nucleus of stria terminalis exerts a significant inhibition over its own release through alpha2-adrenergic receptors and over glutamate release mainly through alpha2-adrenergic receptors. Thus, the results suggest that noradrenaline in the bed nucleus of the stria terminalis maintains an inhibitory tone over the information flow mediated by glutamate.

Beta-Adrenergic agonist-induced nitrite production in isolated pig ciliary processes.

We performed an experiment to assess whether in ciliary processes adrenergic-receptor agents can modulate the production of nitrite, an oxidized metabolite of nitric oxide (NO). The porcine ciliary processes and the iris were dissected and stored at -20 degrees C. Later, tissues were thawed, and nitrite measured by Griess reaction, before and 2 h after exposure to various drugs. In the ciliary processes, but not in the iris, the alpha-, beta-adrenergic receptor agonist, norepinephrine (0.01-10 microM), increased nitrite production (95 +/- 12%, P < 0.01). The norepinephrine-induced (0.1 microM) nitrite production was inhibited by the inhibitor of NO synthase, N omega-nitro-L-arginine methyl ester (0.5 mM; P < 0.05) and by the non-selective beta-adrenergic receptor antagonist, propranolol (10 microM; P < 0.01), but not by the non-selective alpha-adrenergic receptor antagonist, phentolamine (10 microM). In isolated porcine ciliary processes, beta-adrenergic receptor stimulation increases NO production.

Phase III Multicenter Placebo-Controlled Study of Tamsulosin in Benign Prostatic Hyperplasia

Objectives. To evaluate the efficacy and safety of two once-daily doses of tamsulosin, the first selective alpha 1A-antagonist studied in clinical trials. Methods. Patients with benign prostatic hyperplasia (BPH) were randomized to receive either tamsulosin (0.4 and 0.8 mg/day) or placebo (n = 756). Primary efficacy parameters were improvement in the total American Urological Association (AUA) symptom score and peak urinary flow (Qmax). Secondary efficacy parameters were improvement in measurements at individual double-blind visits corresponding to the primary efficacy parameters; percentage of patients with a 3-mL/s increase in Qmax; total AUA irritative, obstructive, and bother scores; individual AUA symptom scores; total, irritative, obstructive, and individual Boyarsky symptom scores; average urinary flow rate and other uroflowmetric parameters; and investigator’s global assessment. Results. Statistically significant improvements in all efficacy parameters were observed in tamsulosin-treated compared with placebo-treated patients. Additionally, the 0.4-mg/day dose demonstrated a rapid onset of action (4 to 8 hours) based on Qmax after the first dose of double-blind medication. A review of the safety parameters demonstrated excellent tolerance at 1 week after the initial 0.4-mg/day dose and continued tolerance during the additional 12 weeks of 0.4- and 0.8-mg/day dosing. The incidence of positive orthostatic test results in the tamsulosin groups was comparable to that observed in the placebo group. Adverse events were comparable in the 0.4-mg/day tamsulosin and placebo groups and were somewhat higher in the 0.8-mg/day tamsulosin group. Conclusions. Tamsulosin was effective, safe, and well tolerated in the target BPH population at both the 0.4- and 0.8-mg/day dose levels, without the blood pressure-lowering effects typical of nonselective alpha-adrenergic antagonists.

An α-Adrenergic Coronary Constriction During Esophageal Distention in the Dog

Previous work has shown an increase in sympathetic stimulation of the heart during chemical or mechanical irritation of visceral organs, but the involvement of the coronary circulation in such reflexes is not clear. In five preliminary experiments in anesthetized dogs, esophageal distention produced a sympathetic stimulation of the heart, as evidenced by an increase in heart rate, which was abolished by non-selective beta-adrenergic and muscarinic blockades. On the basis of these preliminary data, we further examined a sympathetic coronary constriction during acute esophageal distension in which any direct adrenergic coronary constriction was unmasked by muscarinic blockade with atropine (100 micrograms/kg, i.v.), and non-selective beta-adrenergic blockade with propranolol (1 mg/kg, i.v.). In seven dogs anesthetized with alpha-chloralose in an open-chest procedure, the esophagus was rapidly distended to a pressure of 36 +/- 2 mm Hg, which was not significantly different from the distending pressure used in the preliminary experiments. During esophageal distention, the mean circumflex blood flow decreased to 77 +/- 10% (SEM) of the predistention value. This decrease was statistically significant (p less than 0.05). There was no change in left ventricular pressure, mean arterial pressure dP/dtmax, or heart rate. Intracoronary administration of the nonselective alpha-adrenergic antagonist phentolamine completely abolished the reduction in mean circumflex coronary blood flow caused by esophageal distention in the presence of beta-adrenergic and muscarinic blockades. These results demonstrate a direct sympathetic coronary vasoconstriction elicited by esophageal distention. This vasoconstriction was due to activation of coronary alpha-adrenergic receptors.

α-Adrenergic Effects of Dopamine and Dobutamine on the Coronary Circulation

After beta-adrenergic blockade, dopamine causes coronary vasoconstriction that is blocked by non-selective alpha-adrenergic antagonists. This study was carried out to determine the relative importance of alpha 1- and alpha 2-adrenoceptors in mediating coronary vasoconstriction in response to dopamine. Because dobutamine has been reported to cause alpha-adrenergic stimulation, the response to dobutamine was also examined. The circumflex coronary artery was cannulated and perfused at a constant blood flow rate in 14 dogs; coronary vasomotor responses were assessed from changes in perfusion pressure. Central effects were eliminated by vagotomy and stellate ganglionectomy; propranolol (1 mg/kg i.v.) was administered to block beta-adrenergic effects. The coronary responses to intracoronary bolus doses of dopamine and dobutamine were determined; the effects of selective alpha 1-blockade with prazosin (600 micrograms/kg i.v.) and selective alpha 2-blockade with idazoxan or rauwolscine (1-5 micrograms/kg per min intracoronary for 10 min) were examined. Dopamine produced dose-related coronary vasoconstriction; this response was not significantly altered by alpha 1-blockade with prazosin, but was abolished by the addition of alpha 2-adrenergic blockade with idazoxan or rauwolscine. Dobutamine did not produce coronary vasoconstriction at any dose tested. These data demonstrate that coronary vasoconstriction produced by dopamine is mediated through postjunctional alpha 2-adrenergic receptors.

Effect of vasodilators on hepatic microcirculation: A study of the inhibition of norepinephrine-induced vasoconstriction in the isolated perfused rat liver

We studied the effects of a series of 16 vasodilators on the intrahepatic vasoconstriction induced by norepinephrine in the isolated perfused rat liver. The vasodilators were nonselective alpha-adrenergic antagonists (phentolamine, ifenprofil, isoxsuprine and buflomedil), a nonselective beta-adrenergic antagonist (propranolol) and an agonist (isoproterenol), an alpha 2-adrenergic agonist (clonidine), calcium channel blockers (verapamil and diltiazem), nitrovasodilators (nitroglycerin, sodium nitroprusside), papaverine and other unclassified vasodilators, some of them with rheological properties (diazoxide, vincamine, cinepazide, naftidofuryl and pentoxifylline). The most potent drugs were ifenprofil, phentolamine, isoxsuprine, clonidine, sodium nitroprusside and buflomedil. Diazoxide, papaverine, pentoxifylline and trinitrine were less powerful. Verapamil, diltiazem, propranolol, isoproterenol, vincamine, cinepazide and naftidofuryl were ineffective. We conclude that different classes of pharmacological agents have significant vasodilatory properties on the hepatic microvasculature. This offers interesting perspectives in the treatment of cirrhosis and stressful states where high levels of circulating norepinephrine may contribute to the altered liver perfusion.

Electrogenic and electroneutral components of the sympathetic effect on fluid absorption in the rat jejunum

The aim of the study was to test the hypothesis that the sympathetic nerves to the jejunum enhance net fluid absorption rate by inhibiting an electrogenic flux of anions into the lumen. The design of the experiments was based on the observation that the effect of catecholamines on electrogenic transport is abolished by yohimbine, an alpha 2 adrenergic antagonist. Net electrogenic transport in jejunal segments of anaesthetized rats was estimated by measurement of the transepithelial potential difference (PD) and short-circuit current (SCC). Net fluid absorption rate was quantified by a gravimetric technique. The sympathetic nerves to the segment were stimulated electrically, both in vitro and in vivo. The effect of sympathetic nerve stimulation on SCC and net fluid transport was determined in the absence and presence of the alpha-adrenergic antagonists phentolamine (a non-selective alpha-adrenergic antagonist), prazosin (a selective alpha 1-antagonist) and yohimbine (a selective alpha 2-antagonist). Sympathetic nerve stimulation decreased PD and SCC and increased net fluid absorption rate. Phentolamine abolished both the electrogenic response and the effect on net fluid absorption rate, without having any significant intrinsic effects on either parameter. Prazosin per se markedly increased net fluid absorption rate, but did not significantly influence the sympathetic effect on SCC or net fluid absorption rate. Yohimbine abolished the electrogenic effect of sympathetic stimulation, and per se increased net fluid absorption rate in innervated but not in denervated segments. In innervated segments, the absorption rate during sympathetic nerve stimulation was similar in controls and yohimbine-treated animals. In denervated segments, yohimbine significantly attenuated the sympathetic response. The results suggest that the sympathetic nerves enhance fluid absorption rate via effects on both electrogenic and electroneutral epithelial transport. These two components of the sympathetic response seem to be mediated by different alpha-receptor mechanisms.

Role of alpha 1- and alpha 2-adrenergic receptors in the growth hormone and prolactin response to insulin-induced hypoglycemia in man.

The effects of intravenous infusion of the nonselective alpha-adrenergic antagonist phentolamine or of the selective alpha 2-adrenergic antagonist yohimbine on growth hormone (GH), prolactin (PRL) and cortisol secretion during insulin-induced hypoglycemia were studied in 11 healthy young men. The GH response was blunted following each antagonist used, PRL secretion was higher after yohimbine and diminished after phentolamine when compared to controls. The plasma cortisol response was not influenced by either compound. In another series of experiments no effect of an oral administration of prazosin, a selective alpha 1-adrenergic antagonist, on the secretion of GH, PRL and cortisol was found in any of 7 subjects. Prazosin inhibited blood pressure increase during hypoglycemia and induced slight drowsiness and fatigue in the subjects. It is concluded that in man alpha-adrenergic stimulation of GH secretion during hypoglycemia is transmitted via alpha 2-receptors, PRL secretion is mediated via alpha 1-receptors, whereas inhibition of PRL release is mediated via alpha 2-receptors. In this experiment no effect of alpha 1- or alpha 2-blockade on cortisol response to hypoglycemia was seen.

Norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha 1 adrenergic response.

We have shown recently that norepinephrine stimulates muscle cell hypertrophy in primary cultures from the neonatal rat ventricle and that this stimulation is not blocked by the beta adrenergic antagonist propranolol. The present study was done to define the adrenergic specificity of the myocyte hypertrophic response to norepinephrine. 90% pure, single-cell cultures of nongrowing myocytes were maintained in serum-free medium 199 with transferin and insulin. Myocyte size was quantitated 48 h after addition of adrenergic agents, by measuring cell volume, cell surface area, and cell protein. L-norepinephrine increased myocyte size to a maximum 150% of control; half-maximum effect was obtained at a concentration of 0.2 microM. This increase in cell size was inhibited by the nonselective alpha adrenergic antagonist phentolamine and by the alpha 1 adrenergic antagonists prazosin and terazosin; it was not inhibited by propranolol or by the alpha 2 adrenergic antagonist yohimbine. The beta adrenergic agonist isoproterenol did not increase cell size. Thus, norepinephrine-stimulated hypertrophy of cultured rat myocardial cells is an alpha 1 adrenergic response.

Identification of alpha adrenoceptor subtypes in dog arteries by ( 3H) yohimbine and ( 3H) prazosin

Binding of the alpha adrenergic antagonists ( 3H) prazosin and ( 3H) yohimbine to membranes of dog arteries exhibit the characteristics expected of alpha adrenoceptors. Binding of both ligands is saturable with dissociation constants of 0.19nM and 1.15nM for ( 3H) prazosin and ( 3H) yohimbine respectively. A series of catecholamines inhibit binding of both ligands with a potency in the order epinephrine > norepinephrine a ̊ isoproterenol , corresponding with the activity of these agents at alpha adrenoceptors in blood vessels. Competition for binding in both instances is stereoselective. ℓ-Phenylephrine has similar potencies in inhibiting ( 3H) prazosin and ( 3H) yohimbine specific binding whilst the imidazoline related partial alpha adrenergic agonists clonidine and guanfacine are more potent in inhibiting ( 3H) yohimbine specific binding. The affinity of prazosin for the ( 3H) yohimbine binding site is approximately 2500 times less than for the ( 3H) prazosin site whilst yohimbine is approximately 150 times more potent in inhibiting ( 3H) yohimbine than ( 3H) prazosin specific binding. Non-selective alpha adrenergic antagonists have similar affinities for both binding sites. The concentrations of ( 3H) yohimbine binding sites in different arteries vary about two fold whilst for ( 3H) prazosin the variation was about three fold. These results indicate that there are two discrete noradrenergic binding sites in the major arteries of dog which have binding properties expected of alpha 1 and alpha 2 adrenoceptors.

Interaction of verapamil with human platelet alpha-adrenergic receptors.

Platelet aggregation induced by epinephrine is an alpha-adrenergic event and is inhibited in vitro by the calcium-channel blocker, verapamil. We wondered whether this inhibition might be mediated by an interaction of verapamil with platelet alpha-adrenergic receptors. Verapamil inhibited the specific binding of [3H]dihydroergocryptine ([3H]DHE), a nonselective alpha-adrenergic antagonist, to intact platelets in a concentration-dependent and competitive manner. At 10 microM verapamil caused a fivefold decrease in the affinity of binding of [3H]DHE to platelet alpha-adrenergic receptors (P less than 0.001) with no change in the number of receptors per platelet. The inhibition of binding was not reversed by excess calcium. Verapamil also inhibited the binding of a selective alpha 2-adrenergic antagonist, [3H]yohimbine, to intact platelets, and inhibited the binding of an alpha 2-partial agonist, [3H]clonidine, to platelet membranes. Moreover there was a strong correlation between verapamil's effect on [3H]DHE binding and its effect on epinephrine-induced aggregation (r = 0.98). Although verapamil is commonly used as an inhibitor of calcium flux across cell membranes, the present studies demonstrate that verapamil also inhibits epinephrine-induced aggregation at the level of the platelet alpha-adrenergic receptor.