Affinity Of Alpha 1-adrenergic Receptors Research Articles

Priapism secondary to antipsychotic treatments with favorable response to amisulpride

IntroductionPriapism is an abnormally prolonged erection, painful and irreducible, unrelated to sexual stimulation. Around 25-40% of cases are iatrogenic, especially associated with pharmacological treatments, of which antipsychotics (first and second generation) account for 50%.ObjectivesThe aim is to discuss a clinical case to provide further evidence.MethodsThe patient was a 37-year-old man with a diagnosis of schizophrenia who was admitted for clinical decompensation. He had stopped antipsychotic treatment three months earlier due to side effects. He reported previous episodes of priapism associated with Risperidone, Aripiprazole, Olanzapine, and Paliperidone. At admission, he was administered Asenapine 20mg with development of priapism. Treatment was stopped. The urologists performed a lavage of the corpora cavernosa and administered adrenaline. In the absence of effectiveness, surgical intervention was successfully performed. Given the psychopathological improvement, he was discharged without antipsychotic treatment and close follow-up.ResultsHe presented a new admission one month later. Amisulpride was prescribed up to 800mg/day with good evolution and no adverse effects.ConclusionsAntipsychotic-induced priapism appears to be related to the blockade of alpha-1 adrenergic receptors in the corpora cavernosa. There is a positive correlation between the affinity for the receptor and the propensity to cause priapism. The dose and duration of the medication do not appear to be correlated. Other risk factors are a history of previous episodes, restarting medication after noncompliance, use of concomitant substances or medications that cause priapism. Our choice of amisulpride was based on the fact that it has no affinity for alpha-1 adrenergic receptors.DisclosureNo significant relationships.

Isoproterenol-Induced Intramural Cytotoxicity Does Not Correlate with Echocardiographic Functional Abnormalities in Wistar Rat Hearts

Background: Isoproterenol (ISO) is a potent non-selective beta-adrenergic agonist with very low affinity for alpha-adrenergic receptors used for treatment of various cardiac problems including ventricular arrhythmias, asthma and shock. In addition, ISO is also used postoperatively after cardiac surgery. The aim of this study was to analyze the association between histopathological and functional effects of ISO in the rat myocardium. Methods: 24 Wistar rats (healthy, males) were used in these experiments. The animals were randomly divided two groups. Group I (n=12): all animals received ISO subcutaneous administration (0,3 mg/Kg/day for 8 days). Group II (n=12): all animals received Phosphate Buffered Saline (PBS) subcutaneous administration as a control. One day after drug administration has been completed; echocardiographic analysis of cardiac function was performed. Histopathological analysis of the specimens was made by using H&E, Gomori’s Trichrome and picrosirius red staining procedures. The results were analyzed using Student’s t-test (p 0.05), however the heart rate differed significantly between both groups (p=0.0053). Conclusion: Short-term ISO administration (8 days) caused notable intramural cytotoxicity of the heart. In contrast, echocardiographic findings did not show any functional abnormalities in accordance with this cytotoxicity.

The effect of combined treatment with imipramine and amantadine on the behavioral reactivity of central ??1-adrenergic system in rats

The problem of drug-resistant depression implies a strong need for alternative antidepressant therapies. Recently, it has been shown that joint administration of a tricyclic antidepressant, imipramine (IMI), with amantadine (AMA), a drug already approved for clinical use in the treatment of other diseases, induces a stronger 'antidepressant' effect in the forced swimming test in rats than treatment with either drug given separately. Combined treatment with IMI and AMA also induces up-regulation of dopamine D2 and D3 receptors in the rat brain, and appears to be effective in the treatment of patients with drug-resistant unipolar depression. In the present study, we examined the effect of IMI (5 or 10 mg/kg p.o.) and AMA (10 mg/kg p.o.) given separately or jointly, either as a single dose or repeatedly (twice daily for 14 days) on the development of adaptive changes in the behavioral reactivity of the central alpha1-adrenergic system. Following repeated administration of the higher dose of IMI together with AMA, we observed an increase in clonidine-induced aggression in mice, and significant enhancement of D-amphetamine-induced locomotor hyperactivity, as well as phenylephrine-induced exploratory behavior, in rats. In binding studies using [3H]prazosin, no changes in the density (Bmax) or affinity (Kd) of alpha1-adrenergic receptors were observed in rat brain cortex. However, competition analysis allowed us to observe an increase in the affinity of alpha1-adrenergic receptors (Ki) for an agonist (phenylephrine) upon repeated treatment with IMI, given alone or in combination with AMA. AMA appears to act through several pharmacological mechanisms, none of which has been identified as the chief mode of action. In the light of data obtained in the present study, one can supplement the postulated mechanisms of antidepressant action of AMA by adaptive changes in the reactivity of alpha1-adrenergic receptors, which develop upon repeated combined treatment with IMI.

Two week nicotine treatment selectively increases bone vascular constriction in response to norepinephrine

This study was designed to determine if nicotine treatment alters the constrictor and/or dilator function of the vessels which regulate blood flow to intact bone. Nicotine (1.7 mg/kg/day) or nicotine-free, phosphate-buffered saline was administered subcutaneously to mature male rats for 2 weeks via osmotic mini-pumps. On the 14th day, the rats were anesthetized and in vivo experiments were performed to quantitate the changes in arterial blood pressure and perfusion of the intact tibia (measured by laser Doppler flowmetry) in response to two constrictor agonists (norepinephrine, NE and arginine vasopressin, AVP) and two vasodilator agents (acetylcholine, ACh and sodium nitroprusside, SNP). Dose–response curves were generated by plotting the change in the bone vascular resistance index (mmHg/bone perfusion units) evoked by each dose of agonist. In addition, bone arteriolar expression of endothelial nitric oxide synthase protein was quantitated by Western blot analysis. Nicotine treatment significantly enhanced the constriction of the bone vasculature in response to NE, but not to AVP. Vascular dilation in response to ACh and SNP was not changed by nicotine. These results indicate that nicotine selectively accentuates the constrictor response of the bone vasculature to exogenous NE. This enhanced constriction to NE is not due to impaired endothelial cell release of nitric oxide or diminished smooth muscle response to nitric oxide. Since NE and AVP activate similar cell signaling mechanisms to induce constriction, the selective enhancement of NE-induced constriction suggests that nicotine alters a mechanism unique to NE signaling; possibly the number or binding affinity of alpha adrenergic receptors. Since endogenous NE regulates basal blood flow to bone, the effect of nicotine to augment NE-induced constriction could lead to a chronic reduction in blood flow to bone.

Increased food consumption by clozapine, but not by olanzapine, in satiated rats

Various drugs used to treat schizophrenia have been repeatedly shown to increase body weight in both animals and humans. There are different theories as to why this occurs, but the most recently studied theory is that these drugs which cause weight gain do so because of an antagonist effect at the 5HT2C receptor. In this work, we studied the effects of olanzapine, clozapine, and risperidone on feeding behavior. Over a 4-hour test period in satiated rats, clozapine, over a broad dose range, significantly increased food consumption. Similarly, risperidone increased food consumption relative to control. In contrast, olanzapine did not significantly increase food consumption in rats at any dose tested over the 4-hour test period. This suggests that olanzapine may be different from clozapine and risperidone with respect to potential weight gain in schizophrenic patients. Moreover, we believe that the effect produced by clozapine and risperidone is due to the alpha-adrenergic activity of these compounds, since olanzapine has a much lower affinity for alpha adrenergic receptors than does clozapine or risperidone, and not due to the 5HT2C activity, which all three compounds have in common. Drug Dev. Res. 41:48–50, 1997. © 1997 Wiley-Liss, Inc.

Increased food consumption by clozapine, but not by olanzapine, in satiated rats

Various drugs used to treat schizophrenia have been repeatedly shown to increase body weight in both animals and humans. There are different theories as to why this occurs, but the most recently studied theory is that these drugs which cause weight gain do so because of an antagonist effect at the 5HT2c receptor. In this work, we studied the effects of olanzapine, clozapine, and risperidone on feeding behavior. Over a 4-hour test period in satiated rats, clozapine, over a broad dose range, significantly increased food consumption. Similarly, risperidone increased food consumption relative to control. In contrast, olanzapine did not significantly increase food consumption in rats at any dose tested over the 4-hour test period. This suggests that olanzapine may be different from clozapine and risperidone with respect to potential weight gain in schizophrenic patients. Moreover, we believe that the effect produced by clozapine and risperidone is due to the alpha-adrenergic activity of these compounds, since olanzapine has a much lower affinity for alpha adrenergic receptors than does clozapine or risperidone, and not due to the 5HT2 C activity, which all three compounds have in common.

Effects of maturation on alpha-adrenergic receptor affinity and occupancy in small cerebral arteries

The present experiments examine the hypothesis that changes in receptor affinity and occupation mediate maturational changes in norepinephrine sensitivity in small cerebral arteries. In second-order (2B) and fourth-order (4B) branch middle cerebral artery segments from newborn and adult sheep, we first found that a stretch ratio based on artery diameter better estimated optimal prestretch than did passive tension. Next, we determined norepinephrine dose-response relations before and after prazosin, yohimbine, and benextramine. Prazosin competitively blocked contractions to norepinephrine, but yohimbine had no effect, indicating that alpha 1-adrenoceptors mediated contraction. Norepinephrine sensitivity [determined from the -log of the half-maximal effective dose (pD2)], maximal response, and binding affinity all decreased with age in 4B but not 2B segments. Receptor occupancy at the pD2 increased with age only in 2B segments. In conclusion, maturation of ovine middle cerebral arteries involves branch-specific changes in affinity and receptor occupation of the alpha 1-adrenoceptors that mediate contractile responses to norepinephrine. Age-related changes in receptor density and/or intrinsic efficacy probably are involved also.

Effects of Terbutaline on α‐Adrenergic Responses and Ca2+Influx in Isolated Rabbit Aorta

Effects of terbutaline applied in vivo or in vitro on alpha-adrenergic receptors in the rabbit aorta in normal and Ca(2+)-free solution, and on basal, high potassium-, and phenylephrine-stimulated Ca2+ uptake into aorta were investigated. Three day terbutaline administration (25 mg/kg, subcutaneously three times daily) to rabbits increased the pKB for phentolamine in aorta rings (control 7.3 +/- 0.2, n = 9; terbutaline 7.8 +/- 0.2, n = 15). It also depressed phenylephrine-stimulated contractions of aorta rings in Ca(2+)-free but not those in normal Krebs solution. It did not significantly depress the basal, or phenylephrine-evoked Ca2+ influx into aorta rings, but decreased high potassium-induced Ca(2+)-influx (control 0.58 +/- 0.05 mumoles/g aorta; n = 3, terbutaline 0.41 +/- 0.06 mumoles/g aorta, n = 3). In vitro application of 50 microM terbutaline did not significantly alter phenylephrine-stimulated contractions of aorta rings in Ca(2+)-free Krebs solution or significantly depress basal or phenylephrine-induced Ca2+ influx into aortas, but did decrease high potassium-stimulated Ca(2+)-influx. Thus, 3-day terbutaline administration increased the affinity of alpha-adrenergic receptors for phentolamine and had a tendency to increase contractions of aorta rings to phenylephrine. It also decreased high potassium-stimulated Ca2+ influx, and depressed phenylephrine-induced contractions in Ca(2+)-free Krebs solution, while in vitro terbutaline application also decreased potassium-induced Ca2+ influx.

Novel serotonergic mechanisms and clinical experience with nefazodone.

Chronic administration of antidepressant drugs enhances synaptic serotonergic transmission. Nefazodone, a member of a new class of antidepressants, has a pharmacologic profile that is distinct from the first-generation agents (e.g., tricyclics and monoamine oxidase inhibitors) as well as the more selectively acting second-generation agents (e.g., serotonin or norepinephrine uptake inhibitors, and serotonin type 1A partial agonists). Nefazodone acts both as a 5-HT2 receptor antagonist and as a serotonin (5-HT) reuptake inhibitor. Nefazodone's potent 5-HT2 antagonism in combination with 5-HT reuptake inhibition appears to enhance 5-HT1A-mediated neurotransmission. Nefazodone has very selective serotonergic effects, with negligible affinity for cholinergic and histamine receptors and low affinity for alpha 1-adrenergic receptors. It is also free of cardiotoxicity and is well tolerated even at high doses. The two primary effects on serotonergic neurotransmission, 5-HT2 antagonism and 5-HT reuptake inhibition, are thought to contribute importantly to nefazodone's therapeutic efficacy and clinical utility. It is postulated that 5-HT2 antagonism dampens the activating side effects experienced by some patients when treated with existing 5-HT reuptake inhibitors. Nefazodone's effectiveness as an antidepressant drug has been shown in a series of well-controlled, placebo-comparison studies of somewhat differing designs involving patients with major depression. In placebo-controlled studies comparing nefazodone and the tricyclic antidepressant imipramine, the drugs produced comparable and significant therapeutic benefit. Nefazodone is associated with fewer adverse events than imipramine. Nefazodone lacks the troublesome anticholinergic side effects of tricyclic antidepressants, as well as serotonergic/noradrenergic-mediated effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of adrenalectomy on Ca2+ signaling in rat hepatocytes.

To pursue our studies of the effects of adrenalectomy on the adrenergic regulation of phosphorylase a, cAMP, cell calcium, and Ca2+ signaling in rat hepatocytes (Studer, R.K., and Borle, A.B. (1984) Biochim. Biophys. Acta 804, 377-385; Freudenrich, C.C., and Borle, A.B. (1988) J. Biol. Chem. 263, 8604-8610), we have further examined the alpha 1-adrenergic pathway in adrenalectomized and sham-operated male rats. We measured the number and affinity of alpha 1-adrenergic receptors, the cytosolic free Ca2+ concentration [(Ca2+]i) of hepatocytes with aequorin, inositol triphosphate (IP3) accumulation, and Ca2+ influx and efflux across the plasma membrane. We also compared the effects of vasopressin with those obtained with epinephrine. We found that the number of alpha 1-adrenergic receptors was slightly depressed (-23%), but that their affinity was unchanged. However, IP3 accumulation evoked by epinephrine was decreased 50%. This is probably the main cause for the depressed peak rise in [Ca2+]i we previously observed and reported. We also found that the basal resting Ca2+ influx was increased after adrenalectomy. Experiments with the beta-blocker propranolol, which abolished the epinephrine-evoked increase in Ca2+ influx, suggest that this effect may be mediated by cAMP, at least in adrenalectomized animals. The effects of vasopressin on IP3 [Ca2+]i and Ca2+ influx and efflux were also significantly decreased after adrenalectomy, indicating that alpha 1-adrenergic-mediated and other IP3-dependent Ca2+ signaling pathways are depressed after adrenalectomy.

Alpha 1-adrenergic receptors in pulmonary and systemic vascular smooth muscle. Alterations with development and pregnancy.

alpha 1-Adrenergic receptors mediate vasoconstriction in the pulmonary and systemic vasculature. In sheep the in vivo vasoconstrictor response to alpha 1-adrenergic stimulation is less in the pulmonary circulation compared with the systemic circulation of the fetus, the response increases in both vascular beds with fetal and postnatal development, and it decreases in the systemic vasculature with pregnancy. In an effort to determine the mechanisms underlying these differences, alpha 1-adrenergic receptor binding characteristics were determined by using [3H]prazosin in intrapulmonary and systemic (thoracic aorta) vascular smooth muscle (VSM) from late-gestation fetal lambs and from pregnant and nonpregnant ewes. alpha 1-Adrenergic receptor density was less in fetal intrapulmonary VSM that in fetal aortic VSM (12.4 +/- 1.5 versus 29.4 +/- 3.2 fmol/mg protein, p less than 0.05), and it was less (p less than 0.05) in the fetus compared with the pregnant ewe in both intrapulmonary and aortic VSM (51.0 +/- 5.2 and 76.5 +/- 5.9 fmol/mg protein, respectively). alpha 1-Adrenergic receptor density in intrapulmonary VSM was similar in the pregnant and nonpregnant ewe (61.9 +/- 7.2 fmol/mg protein), whereas in aortic VSM it was less (p less than 0.05) in pregnant ewes compared with nonpregnant ewes (101.0 +/- 5.5 fmol/mg protein). alpha 1-Adrenergic receptor affinity was similar in all the VSM sources tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Diabetes on Hormone-Stimulated and Basal Hepatocyte Calcium Metabolism*

The effects of diabetes on basal calcium metabolism and the response to endocrine stimulation were studied in hepatocytes from acute and long term diabetic rats. Hepatocyte calcium sequestration and turnover were increased in both acute and chronic diabetes. Cytosolic free calcium (Cai2+) was significantly increased in the chronic diabetics, but the rise in Cai2+ evoked by epinephrine, angiotensin, vasopressin, and glucagon was depressed. The blunted stimulation of phosphorylase-alpha activity in the diabetics was influenced by a 50-60% decrease in total cell activity of glycogen phosphorylase and the decreased rise in cytosolic free calcium. Insulin replacement corrected both basal and stimulated changes in the acute diabetes model. Depressed [3H]inositol trisphosphate formation in response to epinephrine or vasopressin and increased intracellular organelle calcium buffering were observed in hepatocytes from diabetic animals; both may effect the diminished rise in Cai2+. Several possible causes for the depressed rise in Cai2+ after stimulation in chronic diabetic animals were eliminated: 1) the number and affinity of alpha 1-adrenergic receptors for epinephrine were normal; 2) the initial rise in calcium influx evoked by epinephrine or vasopressin was not depressed; and 3) the ability of inositol trisphosphate to release calcium from intracellular organelles was not changed. The results suggest that the diabetic changes in calcium-mediated endocrine regulation of hepatic carbohydrate metabolism contribute to the general pathology of the disease.

Characterization of intrarenal arterial adrenergic receptors in renovascular hypertension.

alpha-Adrenergic receptor subtypes were investigated using [3H]prazosin, an alpha 1 selective antagonist, and the alpha 2 selective antagonist [3H]rauwolscine in a smooth muscle plasma membrane enriched microsomal fraction prepared from rabbit intrarenal arterial vasculature. Both radioligands displayed single components on Scatchard analysis. The specific binding of [3H]prazosin was of high affinity (0.54 +/- 0.04 nM) with a maximum binding capacity (Bmax) of 212 +/- 15 fmol/mg protein. The maximum number of [3H]rauwolscine binding sites was 64 +/- 4 fmol/mg of protein with a dissociation constant (Kd) of 5.60 +2- 0.27 nM. Binding of both radioligands was rapid, saturable, and specific. alpha 1- and alpha 2-adrenergic receptors in the intrarenal arterial membrane preparation were also characterized at 2-, 4-6-, and 10-12-week intervals during the course of development and maintenance of chronic two-kidney, one clip (2K1C) Goldblatt hypertension and in age-matched sham-operated normotensive control rabbits. The alpha 1-adrenergic receptor affinity for [3H]prazosin binding in hypertensive rabbits was significantly increased in the stenotic, but not contralateral, kidney at 2 weeks; however, at 6 weeks the receptor affinity of both kidneys was significantly increased compared with those of the normotensive control group. No difference in alpha 1-adrenergic receptor affinity was seen at 12 weeks, and there were no changes in Bmax at any of the weekly intervals. Neither the Kd, nor Bmax, for [3H]rauwolscine in either kidney showed a significant difference between hypertensive rabbits and normotensive control rabbits. These studies demonstrate the existence in the rabbit intrarenal arterial vasculature of binding sites with alpha 1- and alpha 2-adrenergic receptor specificity.(ABSTRACT TRUNCATED AT 250 WORDS)

Region‐Specific loss of α1‐adrenergic receptors in rat brain with aging: A quantitative autoradiographic study

The effects of aging on the density and affinity of alpha 1-adrenergic receptors (alpha 1-ARs) were studied in several circumscribed areas of the Fischer 344 male rat brain. Computer-assisted quantitative autoradiography was used to analyze saturation binding isotherms of [125I]BE-2254, a selective alpha 1-AR antagonist. Significant decreases in receptor density of 15 and 29% were observed in the thalamus at 16-18 and 24-28 months of age, respectively, when compared to 3-4-month-old controls. Progressive declines in receptor density of 24 and 44% were also found in the olfactory tubercle. In the cerebral cortex, a significant 26% loss in receptors occurred only in the oldest age group. No changes were found in any of the other brain areas investigated, including the cerebellum, brainstem, caudate-putamen, and several subregional areas of the hippocampal formation. Kd values ranged from 12 +/- 1.8 pM in the brainstem to 23 +/- 1.6 pM in the thalamus and were not affected by aging in any area examined. It is concluded that the density of alpha 1-ARs in the Fischer 344 rat brain is diminished with aging in a region-specific manner and that loss of these receptors may account for age-related functional deficits only in a few brain areas.

Profile of in vitro binding affinities of neuroleptics at different rat brain receptors: cluster analysis comparison with pharmacological and clinical profiles.

A series of 21 neuroleptics with different chemical structures (phenothiazines, thioxanthenes, dibenzodiazepines, butyrophenones, benzamides, etc.) was examined for their in vitro interactions with 12 neurotransmitter binding sites in the rat brain (alpha- and beta-noradrenergic, dopaminergic, muscarinic, serotoninergic, histaminic, and opioid receptors, calcium channels, and serotonin uptake binding sites). The biochemical profile obtained from the binding data was compared with reported pharmacological and clinical profiles for this class of compounds by cluster analysis. Cluster analysis on binding data classified the compounds in three main subgroups: benzamides, compounds with an affinity mainly for DA2 and 5-HT2 receptors and inactive at muscarinic receptors, and compounds with a high affinity for alpha 1-adrenergic receptors and muscarinic receptors. The main subgroups resulting from cluster analysis of previously published pharmacological and clinical data for neuroleptics contain compounds common to the present study, with some correlations. The results extend previous observations that a complete binding profile corresponds to the pharmacological and clinical profile of this class of compounds.

Effects of Lidocaine and Procaine on Canine Nasal Blood Vessels

The effects of lidocaine and procaine on contractile responses of isolated canine nasal mucosal blood vessels to field stimulation and methoxamine were investigated. Analysis of cumulative dose-response curves showed that the two local anesthetics antagonized methoxamine and inhibited the field-stimulation response. The latter effect was interpreted as due to the blockade of Na+ channels. This would inhibit nerve conduction induced by field stimulation. The former effect on methoxamine is probably caused by the effect of these anesthetics on the mobilization of Ca++ needed for smooth muscle contraction. Preincubation of the nasal mucosa with low doses of procaine or lidocaine shifts the methoxamine dose-response curve to the right. With higher doses, the maximal response is also reduced. The shift of the dose-response curve showed that procaine or lidocaine can change the alpha-adrenergic receptor affinity. Commercial 1% lidocaine with 1:100,000 epinephrine also inhibits field stimulation and antagonizes methoxamine contractions. Lidocaine can increase the basal tone of nasal mucosa, while procaine cannot. From these results, we conclude that procaine and lidocaine have common mechanisms in blocking Na+ channels but differ in their ability to modify Ca++ stores or channels.

Increased alpha-adrenergic receptor affinity in resistance vessels from hypertensive rats.

alpha-Adrenergic receptor-related properties, specifically, norepinephrine affinity, occupancy and reserve during contraction, were determined in segments of rat resistance arteries. These were obtained from the superior mesenteric bed of spontaneously hypertensive rats and Wistar-Kyoto strain controls. Receptor affinity for norepinephrine in the spontaneously hypertensive rats was significantly greater than that for the Wistar-Kyoto controls. There were no differences in the estimates of receptor occupancy and reserve. This finding taken together with other studies is consistent with the conclusion that increased alpha-adrenergic receptor-mediated sensitivity of vascular smooth muscle of the spontaneously hypertensive rat reflects differences in the agonist site on the alpha-adrenergic receptor.

The aortic alpha 1-adrenergic receptor in familial amyloidotic polyneuropathy.

To assess the pathophysiology of the sympathetic nervous system in familial amyloidotic polyneuropathy (FAP), we used 3H-bunazosin to identify and characterize the alpha 1-adrenergic receptor in human aortic membranes. The binding of 3H-bunazosin was rapid, readily reversible, stereospecific, and saturable. The Scatchard analysis described a single class of binding sites with a dissociation constant (KD) of 0.370 +/- 0.035 nM and a maximal binding capacity (Bmax) of 11.8 +/- 1.30 fmol/mg protein in control patients. Competition analysis demonstrated the alpha 1-adrenergic specificity of the 3H-bunazosin binding sites in human aortic membranes. The KD and Bmax of 3H-bunazosin binding in four FAP patients was 0.274 +/- 0.052 nM and 7.79 +/- 0.15 fmol/mg protein, respectively; these values did not differ significantly from those in 14 control patients. An increase in Bmax or affinity of alpha 1-adrenergic receptors may not be the cause for denervation supersensitivity in FAP.

Effect of dietary salt and cholesterol loading on vascular adrenergic receptors.

To evaluate the effects of salt and cholesterol intake on vascular responses to catecholamines, alpha 1- and beta-adrenergic receptor densities were determined in control, cholesterol-loaded, salt-loaded with desoxycorticosterone acetate (DOCA) and furosemide-loaded male rabbits, using [3H]-prazosin and (-)-[125I]-cyanopindolol as ligands, respectively. In the aortic membrane, the density of alpha 1-adrenergic receptors (Bmax = 120 +/- 14 fmol/mg protein, Kd = 0.48 +/- 0.05 nM) was higher than that of beta-adrenergic receptors (Bmax = 10.5 +/- 1.7 fmol/mg protein, Kd = 47.1 +/- 8.6 pM). Salt loading and depletion did not alter the density or affinity of either the alpha 1- or beta-adrenergic receptors. By contrast, cholesterol loading significantly decreased alpha 1-adrenergic receptor affinity to a Kd value of 0.81 +/- 0.11 nM from the control level of 0.48 +/- 0.05 and increased the beta-adrenergic receptor density to a Bmax of 18.7 +/- 1.9 fmol/mg protein from the control level of 10.5 +/- 1.7. These results showed that the density of alpha 1-adrenergic receptors was higher than that of beta-adrenergic receptors in the rabbit aortic membrane preparation, and suggested that the sensitivity of aortic membrane to catecholamines was changed by cholesterol loading.

5-HT2-Receptor Antagonists

LY53857, spiperone, ketanserin, and setoperone were potent and competitive 5-HT2-receptor antagonists in the rat jugular vein with equivalent affinities at 5-HT2 receptors. In the rat jugular vein, ritanserin blocked 5-HT2-mediated contractile responses with a depression of the maximum response in concentrations greater than 3 X 10(-10) M. Ketanserin, spiperone, ritanserin, and setoperone were also alpha 1-adrenergic receptor antagonists, although affinity at alpha 1-adrenergic receptors was less for ritanserin and setoperone than for ketanserin or spiperone. Of the 5-HT2-receptor antagonists examined, LY53857 was the most selective with respect to alpha 1-adrenergic receptor affinity, showing 250,000-fold selectivity as an antagonist at 5-HT2 receptors. The possibility that the dual properties of 5-HT2- and alpha 1-receptor blockade confer greater antihypertensive efficacy than alpha 1-receptor blockade alone was also examined in vivo. However, acute administration of LY53857 at doses sufficient to abolish 5-HT2-receptor activation did not enhance blood pressure reduction produced by the alpha-adrenergic receptor antagonist phentolamine in normotensive or spontaneously hypertensive rats. These data argue against an important role for 5-HT2 receptors in blood pressure regulation even in combination with alpha-adrenergic receptor blockade.