Subclassification and nomenclature of alpha- and beta-adrenoceptors.

The subclassification of alpha- and beta-adrenoceptors has resulted in many opportunities for drug discovery. Important adrenoceptor targets include beta(2)-agonists as bronchodilators, beta(1) or beta(1)/beta(2) antagonists as antihypertensives, centrally acting alpha(2)-agonists for a variety of applications and alpha(1)-antagonists for hypertension and benign prostatic hyperplasia. The pharmacology and nomenclature of 9 adrenoceptors is now established, with alpha(1), alpha(2) and beta-adrenoceptors being divided into three subtypes each. It is unlikely that additional discrete adrenoceptor sequences will be identified; however the presence of "affinity states" can give rise to tissue specific differences in pharmacology for a specific subtype. Polymorphisms and splice variants of adrenoceptors continue to be identified; in some cases these modifications can affect pharmacological characteristics and could influence the efficacy of adrenoceptor-targeted therapy. Selective antagonists are now available of all 9 adrenoceptor subtypes. Although these will not all have therapeutic application, the availability of improved pharmacologic tools could lead to the identification of new adrenoceptor targets.

Vasorelaxant activity of phthalazinones and related compounds.

Several series of dihydrostilbenamide, imidazo[2,1-a]isoindole, pyrimido[2,1-a]isoindole and phthalazinone derivatives were obtained and their vasorelaxant activity was measured on isolated rat aorta rings pre-contracted with phenylephrine (10(-5)M). Some phthalazinones attained, practically, the total relaxation of the organ at micromolar concentrations. For the most potent compound 9h (EC(50)=0.43microM) the affinities for alpha(1A), alpha(1B) and alpha(1D) adrenergic sub-receptors were determined.

Neuron specific alpha-adrenergic receptor expression in human cerebellum: implications for emerging cerebellar roles in neurologic disease.

Recent data suggest novel functional roles for cerebellar involvement in a number of neurologic diseases. Function of cerebellar neurons is known to be modulated by norepinephrine and adrenergic receptors. The distribution of adrenergic receptor subtypes has been described in experimental animals, but corroboration of such studies in the human cerebellum, necessary for drug treatment, is still lacking. In the present work we studied cell-specific localizations of alpha1 adrenergic receptor subtype mRNA (alpha 1a, alpha 1b, alpha 1d), and alpha2 adrenergic receptor subtype mRNA (alpha 2a, alpha 2b, alpha 2c) by in situ hybridization on cryostat sections of human cerebellum (cortical layers and dentate nucleus). We observed unique neuron-specific alpha1 adrenergic receptor and alpha2 adrenergic receptor subtype distribution in human cerebellum. The cerebellar cortex expresses mRNA encoding all six alpha adrenergic receptor subtypes, whereas dentate nucleus neurons express all subtype mRNAs, except alpha 2a adrenergic receptor mRNA. All Purkinje cells label strongly for alpha 2a and alpha 2b adrenergic receptor mRNA. Additionally, Purkinje cells of the anterior lobe vermis (lobules I to V) and uvula/tonsil (lobules IX/HIX) express alpha 1a and alpha 2c subtypes, and Purkinje cells in the ansiform lobule (lobule HVII) and uvula/tonsil express alpha 1b and alpha 2c adrenergic receptor subtypes. Basket cells show a strong signal for alpha 1a, moderate signal for alpha 2a and light label for alpha 2b adrenergic receptor mRNA. In stellate cells, besides a strong label of alpha 2a adrenergic receptor mRNA in all and moderate label of alpha 2b message in select stellate cells, the inner stellate cells are also moderately positive for alpha 1b adrenergic receptor mRNA. Granule and Golgi cells express high levels of alpha 2a and alpha 2b adrenergic receptor mRNAs. These data contribute new information regarding specific location of adrenergic receptor subtypes in human cerebellar neurons. We discuss our observations in terms of possible modulatory roles of adrenergic receptor subtypes in cerebellar neurons responding to sensory and autonomic input signals, and review species differences in cerebellar adrenergic receptor expression.

Different modulation of inhibitory and stimulatory pathways mediated by adenosine after chronic in vivo agonist exposure.

After 6 days of in vivo treatment with two selective adenosine receptor agonists, 5'-N-ethylcarboxamido adenosine (NECA) and R-N6-phenylisopropiladenosine (R-PIA), we investigated their effects on adenosine receptors/adenylyl cyclase system in synaptic plasma membranes isolated from rat brain. NECA treatment caused a significant loss of NECA-stimulated adenylyl cyclase activity, suggesting a desensitization of the adenosine A2 receptors-mediated pathway. No significant differences in total adenosine A2 receptors were observed, but Gs protein levels were decreased, suggesting Gs down-regulation as a mechanism for desensitization. On the other hand, NECA treatment caused a significant decrease in high-affinity adenosine A1 receptors population; however, no changes in CHA-inhibited adenylyl cyclase activity or Gi protein level were observed. Finally, when we studied the effects of R-PIA, a selective adenosine A1 receptor agonist, on stimulatory pathway of adenosine, low-affinity adenosine A2 binding sites were decreased without affecting the functionality of the pathway. These results show that adenosine A1 and A2 receptors are modulated in a different way after chronic agonist exposure and suggest the existence of cross-talk mechanisms between both stimulatory an inhibitory pathways mediated by adenosine.

Investigations on the pharmacology of the cardioprotective guanidine ME10092.

The guanidine compound ME10092 (1-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine), which possesses a strong cardioprotective effect to ischemia-reperfusion, was assessed for different pharmacological actions that may underlie its cardioprotective effect. In the living rat ME10092 decreased the blood pressure and heart rate in a dose-dependent manner. We found ME10092 to bind to alpha 1- and alpha 2-adrenoreceptors with moderate affinity (Ki values 1-4 microM), and to block adrenaline-elicited contractile responses in isolated guinea pig aortas. Our results indicate that ME10092 possesses a certain anti-oxidant profile. Thus, in a competitive manner and with low affinity it inhibited the bovine milk xanthine oxidase enzyme, as well as NAD(P)H oxidase driven oxyradical formation in membrane fractions isolated from the rat brain. By using electron paramagnetic resonance we here show that, after its systemic administration, ME10092 modulates the nitric oxide (NO) content in several tissues of the rat in a time-dependent manner. However, in vitro ME10092 inhibited the activities of nitric oxide synthases nNOS and eNOS, but not that of iNOS. Our data give evidence that the cardioprotective effect of ME10092 could be mediated through pharmacological mechanisms that include some modulation of NO production, as well as possible inhibition of radical formation during ischemia-reperfusion.

Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality.

Although all currently used antipsychotic drugs act as dopamine (DA) D2 receptor antagonists, clozapine, the prototype for atypical antipsychotics, shows superior efficacy, especially regarding negative and cognitive symptoms, in spite of a significantly reduced central D2 receptor occupancy compared with typical (conventional) antipsychotic drugs. Clozapine, as well as several other atypicals, displays significant affinities also for several other neurotransmitter receptors, including other dopaminergic receptors, alpha-adrenergic receptors and different serotonergic and cholinergic receptors, which in several ways may contribute to the clinical effectiveness of the drugs. Preclinical and clinical results suggest a dysregulated mesocorticolimbic DA system in schizophrenia, with an impaired prefrontal DA projection, which may relate to negative and cognitive symptoms, concomitant with an overactive or overreactive striatal DA projection, with bearing on psychotic (positive) symptomatology. Available data suggest that blockage of alpha1-adrenoceptors by antipsychotics may contribute to suppress positive symptoms, especially in acute schizophrenia, whereas alpha2-adrenoceptor blockage, a prominent effect of clozapine and, to some extent, risperidone but not other antipsychotics, may rather be involved in relief of negative and cognitive symptoms. Whereas alpha1-adrenoceptor blockage may act by suppressing, at the presynaptic level, striatal hyperdopaminergia, alpha2-adrenoceptor blockage may act by augmenting and improving prefrontal dopaminergic functioning. Thus, the prominent alpha1- and alpha2-adrenoceptor blocking effects of clozapine may generally serve to stabilize dysregulated central dopaminergic systems in schizophrenia, allowing for improved efficacy in spite of a reduced central D2 receptor occupancy compared with typical antipsychotic drugs.

Distribución y función de los receptores alfaadrenérgicos del músculo liso vascular / Distribution and function of alpha adrenergic receptors in vascular smooth muscle

En la década de los setenta se estableció la existencia de dos tipos de receptores alfaadrenérgicos; los alfa1 y los alfa2. El receptor alfa1 usualmente media las respuestas en el órgano efector, y el receptor alfa2 se localiza presinápticamente y regula la liberación del neurotransmisor. Sin embargo, el receptor alfa2 también aparece a nivel postsináptico y coexiste en el músculo liso vascular con el receptor alfa1. Ambos receptores son importantes para el control del tono vascular, y de ellos nos ocuparemos en esta revisión. Hoy se sabe que los receptores alfa1 y los alfa2 no representan poblaciones homogéneas y se pueden subdividir unos y otros en distintos subtipos. Actualmente la clasificación de los receptores alfa1-adrenérgicos ha quedado establecida de la siguiente manera: subtipo alfa1A (clonado alfa1c y nombrado provisionalmente por algunos investigadores alfa1a/c), subtipo alfa1B (clonado alfa1b) y subtipo alfa1D (clonado alfa1d y nombrado provisionalmente por algunos investigadores alfa1a/d). Parece que el subtipo alfa1A estaría más implicado en el mantenimiento del tono basal y la tensión arterial en animales conscientes y, sin embargo, los subtipos alfa1B y alfa1D probablemente participan más en la respuesta de los agonistas. Se ha estudiado sobre todo la regulación de la expresión del subtipo alfa1B porque se sabe que la expresión de este receptor puede alterarse en situaciones patológicas. Actualmente la clasificación de los receptores alfa2-adrenérgicos ha quedado establecida de la siguiente manera: subtipo alfa2A/D (hoy se acepta que el subtipo alfa2A y el subtipo alfa2D son el mismo receptor identificado en diferentes especies: el alfa2A en el hombre y el alfa2D en la rata), subtipo alfa2B (clonado alfa2b) y subtipo alfa2C (clonado alfa2c). Hoy se sabe que el subtipo alfa2A/D y el alfa2B controlan la contracción arterial y que el subtipo alfa2C es sobre todo responsable de la vasoconstricción venosa. También se sabe que el subtipo alfa2A/D media fundamentalmente los efectos centrales de los agonistas alfa2 (AU)

Noradrenaline-induced contraction of human saphenous vein and human internal mammary artery: involvement of different alpha-adrenoceptor subtypes.

Although saphenous veins and internal mammary arteries are commonly used for coronary artery bypass grafting, only a very few comparative studies are available on alpha-adrenoceptor-mediated vasoconstriction in these vessels. Thus, we determined, in isolated rings from human saphenous vein and human internal mammary artery, contractile responses to noradrenaline (10(-8)-10(-4) M) in the absence and presence of the alpha-adrenoceptor antagonists yohimbine (alpha(2)-adrenoceptor antagonist, 10(-8)-10(-6) M), prazosin (alpha(1)-adrenoceptor antagonist, 10(-9)-10(-7) M), 5-methyl-urapidil (5-MU, alpha(1A)-adrenoceptor antagonist, 10(-8)-10(-6) M), BMY 7378 (alpha(1D)-adrenoceptor antagonist, 10(-7)-10(-6) M), and chloroethylclonidine (CEC, irreversible alpha(1B)-adrenoceptor antagonist, 3x10(-5) M for 30 min). All experiments were carried out in the presence of 10(-7) M propranolol and 10(-5) M cocaine. In both vessel types noradrenaline evoked concentration-dependent contractions. In saphenous veins yohimbine was a potent antagonist (pA(2)-value 8.32) while prazosin, 5-MU and BMY exhibited only marginal antagonistic effects. CEC, however, significantly decreased noradrenaline-induced contractions. In contrast, in internal mammary arteries prazosin (pA(2)-value 9.65) and 5-MU (pK(B)-values 7.2-7.5) were potent antagonists, while yohimbine and BMY exhibited only weak antagonistic effects. CEC, however, significantly decreased noradrenaline-induced contractions. We conclude that in saphenous vein the contractile response to noradrenaline is mediated predominantly by alpha(2)-adrenoceptors, while in internal mammary artery it is mediated (to a major part) by alpha(1B)- and (to a minor part) by alpha(1A)-adrenoceptors.

Are all alpha-blockers created equal? An update.

alpha-Receptor blockers, used to treat lower urinary tract symptoms, exert effects on areas of the body other than the prostate where alpha-receptors are located, including the blood vessels and the central nervous system. alpha-Receptors in the central and peripheral nervous system may be involved in bladder activation. alpha(1a)-Receptors are the appropriate target in men with obstructive symptoms, although alpha(1d)-receptors may also be important in patients with irritative symptoms. There is conflicting evidence about the selectivity of alpha-blockers. Clinical trials of these agents do not necessarily reflect results observed in animal and laboratory studies on uroselectivity. The few published comparator studies of alpha-blockers indicate similar efficacies, although side-effect profiles differ somewhat. Randomized, controlled studies of different alpha-blockers with sufficient power to detect differences in side effects between agents are needed.

Terazosin, doxazosin, and prazosin: current clinical experience.

Lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction are common in aging men. Nearly 25% of men >40 years of age have LUTS. Medical therapy with alpha-blockade is the most common method of medical therapy for benign prostatic obstruction. Multiple methods of minimally invasive surgical therapies have been introduced in the last decade. These methods include balloon dilatation, temporary and permanent urethral stents, various laser techniques, microwave thermotherapy, transurethral needle ablation, electrovaporization, and high-intensity focused ultrasound. alpha-Receptor blockers to reduce the sympathetic tone of the prostate are considered as first-line therapy to relieve the symptoms of benign prostatic hyperplasia. Selective alpha(1)-receptor blockers relax prostatic smooth muscle, relieve bladder outlet obstruction, and enhance urine flow with fewer side effects. In addition, it was determined that treating patients with alpha-blockers increases prostatic apoptosis. Pharmacokinetic activity, mode of action, clinical efficacy, and side effects of the selective alpha(1)-receptor blockers terazosin, doxazosin, and prazosin are reviewed.

Alpha-adrenoceptor subtypes.

Different studies have led to our present knowledge of the membrane receptors responsible for mediating the responses to the endogenous catecholamines. These receptors were initially differentiated into alpha - and beta-adrenoceptors. Alpha-adrenoceptors mediate most excitatory functions, and were in turn differentiated in the 1970s into alpha(1)- and alpha(2)-adrenoceptors. The alpha(1)-adrenoceptor type usually mediates responses in the effector organ. The alpha(2)-adrenoceptor type is located presynaptically and regulates the release of the neurotransmitter but it is also present in postsynaptical locations. Both alpha-adrenoceptors are important for the control of vascular tone, but we now know that neither alpha(1)- nor alpha(2)-adrenoceptors constitute homogeneous groups. Each alpha-adrenoceptor type can be subdivided into different subtypes and in this review we have turned our attention to these. The alpha(1)- and the alpha(2)-adrenoceptor subtypes were previously defined pharmacologically by functional and binding studies, and later they were also isolated and identified using cloning methods. In fact, the study of alpha-adrenoceptors was revolutionized by the techniques of molecular biology which permitted us to establish the present classification. The present classification of alpha(1)-adrenoceptors stands as follows: alpha(1A)-adrenoceptor subtype (cloned alpha(1c) and redesignated alpha(1a/c)), alpha(1B)-adrenoceptor subtype (cloned alpha(1b)) and alpha(1D)-adrenoceptor subtype (cloned alpha(1d) and redesignated alpha(1a/d)). It has not been easy to establish the distribution of these alpha(1)-adrenoceptor subtypes in the various organs and tissues, or to define the functional response mediated by each one in the different species studied. Nevertheless it seems that the alpha(1A)-adrenoceptor subtype is more implicated in the maintenance of vascular basal tone and of arterial blood pressure in conscious animals, and the alpha(1B)-adrenoceptor subtype participates more in responses to exogenous agonists. It has also been observed that the expression of the alpha(1B)-adrenoceptor subtype can be modified in pathological situations and particular attention has been paid to the regulation of expression of this receptor. The present classification of alpha(2)-adrenoceptors stands as follows: alpha(2A/D)-adrenoceptor subtype (today it is accepted that the alpha(2A)-adrenoceptor subtype and the alpha(2D)-adrenoceptor subtype are the same receptor but they were identified in different species: the alpha(2A) in human and the alpha(2D) in rat); alpha(2B)-adrenoceptor subtype (cloned alpha(2b)) and alpha(2C)-adrenoceptor subtype (cloned alpha(2c)). Today we know that the alpha(2A/D)- and alpha(2B)-adrenoceptor subtypes in particular control arterial contraction, and that the alpha(2C)-adrenoceptor subtype is responsible above all for venous vasoconstriction. We also know that the alpha(2 A/D)-adrenoceptor subtype fundamentally mediates the central effects of the alpha(2)-adrenoceptor agonists. Despite the validity of the above-mentioned classification of the alpha(1)- and alpha(2)-adrenoceptors, it seems clear that the contractions of a large number of tissues including smooth muscle are mediated by more than one alpha-adrenoceptor subtype. Moreover, few ligands recognise only one alpha-adrenoceptor subtype and the lack of specifity in the different drugs for each one limits their administration in vivo and their therapeutic use.

Characterization of alpha-adrenoceptor subtypes in smooth muscle of equine ileum.

OBJECTIVE: To determine the concentration and binding characteristics of alpha-adrenoceptor subtypes in smooth muscle cell membranes of equine ileum. SAMPLE POPULATION: Segments of longitudinal and circular smooth muscle from the ileum of 8 male and 8 female adult horses. PROCEDURE: Distribution of alpha-adrenoceptor subtypes was assessed by use of radioligand binding assays incorporating [3H]-prazosin and [3H]-rauwolscine, highly selective alpha1- and alpha2-adrenoceptor antagonists, respectively. Characterization of adrenoceptor subtypes was performed by use of binding inhibition assays. RESULTS: On the basis of binding affinity for specific radioligands, low- and high-affinity alpha1- and alpha2-adrenoceptors were detected. Concentration of low-affinity alpha2-adrenoceptors was significantly greater in male horses, compared with females. Competition studies confirmed the specificity of the radioligands used in the binding assays. Alpha1-adrenoceptors of both subtypes in male and female horses had a higher affinity for prazosin than phentolamine, whereas yohimbine did not compete with the radioligand for binding. For alpha2-adrenoceptors regardless of subtype, potency of inhibition elicited by each drug varied between sexes. In males, yohimbine was a more potent inhibitor than phentolamine, which was more potent than prazosin. In females, yohimbine was more potent than prazosin, which was more potent than phentolamine. CONCLUSIONS AND CLINICAL RELEVANCE: High- and low-affinity alpha1- and alpha2-adrenoceptors were detected in smooth muscle of equine ileum. Because alpha-adrenoceptor subtypes, particularly alpha2-adrenoceptors, are involved in the regulation of gastrointestinal tract function, characterization of these receptors may represent the basis for development of new therapeutic strategies for the control of gastrointestinal disturbances in horses.

Vascular adrenoceptors: an update.

The total and regional peripheral resistance and capacitance of the vascular system is regulated by the sympathetic nervous system, which influences the vasculature mainly through changes in the release of catecholamines from both the sympathetic nerve terminals and the adrenal medulla. The knowledge of the targets for noradrenaline and adrenaline, the main endogenous catecholamines mediating that influence, has recently been greatly expanded. From two types of adrenoceptors (alpha and beta), we have now nine subtypes (alpha1A, alpha1B, alpha1D, alpha2A/D, alpha2B, alpha2A/D, beta1, beta2, and beta3) and two other candidates (alpha1L and beta4), which may be conformational states of alpha1A and beta1-adrenoceptors, respectively. The vascular endothelium is now known to be more than a pure anatomical entity, which smoothly contacts the blood and forms a passive barrier against plasma lipids. Instead, the endothelium is an important organ possessing at least five different adrenoceptor subtypes (alpha2A/D, alpha2C, beta1, beta2, and beta3), which either directly or through the release of nitric oxide actively participate in the regulation of the vascular tone. The availability of transgenic models has resulted in a stepwise progression toward the identification of the role of each adrenoceptor subtype in the regulation of blood pressure and fine-tuning of blood supply to the different organs: alpha2A/D-adrenoceptors are involved in the central control of blood pressure; alpha1-(primarily) and alpha2B-adrenoceptors (secondarily) contribute to the peripheral regulation of vascular tone; and alpha2A/D- and alpha2C-adrenoceptors modulate transmitter release. The increased knowledge on the involvement of vascular adrenoceptors in many diseases like Raynaud's, scleroderma, several neurological degenerative diseases (familial amyloidotic polyneuropathy, Parkinson disease, multiple-system atrophy), some kinds of hypertension, etc., will contribute to new and better therapeutic approaches.

Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers.

Beta-adrenoceptors are highly expressed on SW 480 colon carcinoma cells as was assessed by flow cytometry. We investigated the influence of norepinephrine on the migration of these cells using time-lapse videomicroscopy. Norepinephrine-treatment increased the locomotor activity within the population from 25% spontaneously locomoting cells to 65% locomoting cells. The beta1/2-blocker propranolol but not the beta1-blocker atenolol inhibited this increase. The intracellular signaling solely of norepinephrine-induced locomotion involved protein tyrosine kinase activity, whereas both spontaneous and norepinephrine-induced migration were reduced by inhibiting phospholipase Cgamma and protein kinase Calpha activity. In summary, norepinephrine-induced locomotion of SW 480 cells is beta2-adrenoceptor mediated and distinct from spontaneous locomotion concerning the PTK involvement.

Peripheral adrenergic system and hypertension.

Hypertension is a condition where adrenergic responsiveness, sympathetic activity and adrenoceptors are somewhat altered. Many techniques are available to assess human sympathetic nervous system activity. They each present limitations and disadvantages. Characterization and subdivision of the alpha and beta-adrenoceptors, according to their localization and answer to different agonists, was facilitated in recent years by the extensive use of pharmacological and molecular biology techniques. Some adrenoceptor studies were conducted on animal models, human tissues and peripheral blood cells to assess their changes in various forms and stages of hypertension. Our group has pointed out that alpha1-adrenergic receptors expressed by human peripheral blood lymphocytes underwent changes of density in essential hypertensives, compared to normotensive control subjects. The importance of these findings could provide an assessment of alpha1-peripheral receptors with possible future clinical implications in the pathophysiology and treatment of hypertension.

Heterogeneity of vascular smooth muscle alpha-adrenoceptors in canine blood vessels.

1. For the past decade, using radioligand binding, contractility and immunohistochemical techniques, we have been characterizing vascular smooth muscle (VSM) adrenoceptors in four functionally different canine blood vessels, namely the dog aorta (DAO), dog mesenteric artery (DMA), dog mesenteric vein (DMV) and dog saphenous vein (DSV). 2. This communication briefly reviews our findings (with a special emphasis on alpha-adrenoceptor subtypes), which showed that none of the four canine vessels showed the same complement of alpha-adrenoceptor subtypes. 3. All four vessels elicited alpha 1-adrenoceptor contractile responses (antagonized by prazosin), but alpha 2-adrenoceptor responses (sensitive to rauwolscine), were found only in DMV and DSV. 4. Pharmacological characterization using alpha 1-adrenoceptor subtype-selective antagonists showed that DAO contains mainly alpha 1B-adrenoceptors (some alpha 1D-adrenoceptors) and DMA has primarily alpha 1A/1L-adrenoceptors, alpha 1-Adrenoceptors in DMV are primarily of the alpha 1D subtype, but either a new or unusual alpha 1-adrenoceptor subtype was revealed in the DSV.

Characterization of adrenergic receptors in the accessory lacrimal glands of the upper eyelid.

PURPOSE: To identify the histologic location as well as the exact subtype of adrenergic receptors in the accessory lacrimal glands of the upper eyelid. METHODS: Upper eyelid specimens were collected from 19 patients undergoing routine blepharoptosis correction via a posterior tarsoconjunctival mullerectomy. Immunohistochemical staining using polyclonal antibodies against human alpha 1, alpha 2, beta 1, and beta 2 receptors was performed on all specimens. RESULTS: beta 1 receptors were the predominant adrenergic receptor subtype in the glands of Wolfring. CONCLUSIONS: The presence of beta 1 receptors in the accessory lacrimal glands of the upper eyelid may suggest a possible role for selective beta 1 agonists in the treatment of keratitis sicca.

[Autonomic nervous system and prostatic physiology. Specific features of the alpha-adrenergic system]. / Système nerveux végétatif et physiologie prostatique. Particularités du système alpha adrénergique.

A better understanding of the rich autonomic innervation of the prostate allows more effective treatment of voiding disorders secondary to benign prostatic hyperplasia. The glandular contingent possesses mainly cholinergic innervation (M2 muscarinic receptors). Smooth muscle cells are richly supplied with alpha and beta catecholaminergic receptors, involved in muscle contraction and muscle relaxation, respectively, but they may also be involved in growth. These alpha receptors, divided into 2 families (alpha 1 and alpha 2), belong to the family of G protein-coupled seven membrane-spanning helix receptors. The genes, followed by the recombinant proteins of 3 subtypes of alpha 1 receptors have been described: alpha 1-a, -b, -d. In the prostate, these receptors are predominantly located in the stroma, mainly in the centroprostatic region. The mRNA present mainly code for the alpha 1a subtype. The use of specific agonists and antagonists shows that these receptors control smooth muscle contraction according to a mechanism initially considered to be of the alpha 1a type. However, their low affinity for prazosin and the development of new alpha 1 blocking agents is in favour of the involvement of a different functional subtype: alpha 1L. This difference could be explained by a different conformation of the receptor or by different coupling mechanisms. The subtype involved in prostatic smooth muscle contraction has yet to be characterized.

Smooth muscle layer-specific variations in the autonomic innervation of bovine myometrium.

1. To clarify the autonomic innervation regulating longitudinal muscle (LM) and circular muscle (CM) motility in the bovine uterus, functional (nerve stimulation, adrenergic drug responsiveness) and biochemical studies (catecholamine content, radioligand binding) were conducted on parous luteal-phase myometrium. 2. Electrical field stimulation (EFS; 60 V, 0.5-msec duration) caused tetrodotoxin (1 microM)-sensitive contractions in a frequency-dependent manner (0.5-20 Hz) in both LM and CM layers. 3. The EFS-induced LM contractions were potentiated by propranolol and conspicuously decreased by phentolamine, yohimbine, idazoxan or guanethidine, but were unaffected by prazosin or atropine. 4. On the other hand, CM contractions were only slightly decreased by phentolamine, idazoxan, yohimbine and guanethidine, but were insensitive to propranolol, prazosin or atropine. 5. The noradrenaline content in LM was about five times higher than that in CM. 6. Noradrenaline, adrenaline, clonidine, xylazine, UK14,304 and phenylephrine caused concentration-dependent contractions of both smooth muscle layers. 7. Clonidine, UK14,304 and xylazine were more potent contractile agents than noradrenaline and phenylephrine. 8. The contractile response to noradrenaline was competitively antagonized by yohimbine, but not by prazosin. 9. Binding studies using [3H]-prazosin and [3H]-rauwolscine revealed that the bovine myometrium contained both alpha1- and alpha2-adrenoceptors, but the alpha2-type receptor was dominant in both LM (94% of alpha-adrenoceptors) and CM (88%) layers. 10. The distribution of alpha-adrenoceptors was muscle layer-specific; that is, the concentration of alpha1-receptors in LM was the same as in CM, but the concentration of alpha2-receptors in LM was 2.6 times higher than that in CM. 11. The results of the present study indicate that there are layer-specific variations in the functional innervation of the parous bovine myometrium (exclusive adrenergic innervation in LM and adrenergic [minor] plus nonadrenergic, noncholinergic innervation [major] in CM), and that alpha2-adrenoceptors, which were responsive to the excitatory response of endogenous and exogenous noradrenaline, were dominant in both muscle layers of the bovine myometrium.