Adrenergic Receptors in the Urogenital Tract

The expression pattern of adrenergic receptors and their subtypes within the urogenital tract varies greatly among the individual tissues. The human kidney expresses few aradrenergic receptors (and these are primarily on renal arteries and of the a1A subtype; 29), but a large number of ^-adrenergic receptors, particularly the ^-subtype, are involved in the regulation of vascular resistance, inhibition of renin release, and modulation of tubular function (60). Hence, blood pressure lowering by ^-adrenergic agonists is accompanied by smaller alterations of renal perfusion than that by other classes of blood pressure-lowering drugs.

Healthy human bladder expresses few a1-adrenergic receptors; these are predominantly of the a1D-subtype, but their physiological role remains to be determined (61). Some data obtained with experimental animals raise the possibility that bladder dysfunction is accompanied by enhanced action of these receptors, and that such regulation may involve a subtype switch (62). Human bladder also expresses a large number of ^-adrenergic receptors, largely belonging to the ^-subtype, for which no physiological postjunctional function has as yet been identified (63). P-Adrenergic receptors are considered the main physiological mediator for relaxation of bladder smooth muscle, hence allowing accommodation of increasing volumes of urine at acceptable pressure during the filling phase of the micturition cycle (64). In humans, this appears to occur predominantly, if not exclusively, through a P3-subtype (65). The finding that few other human tissues are so enriched in p3-adrenergic receptors makes these receptors attractive as a target for drugs that treat bladder dysfunction (66). Accordingly, several P3-selective agonists are currently in clinical development for the treatment of the overactive bladder syndrome and urinary urge incontinence.

The bladder outflow tract, particularly the urethra, also expresses several types of adrenergic receptors. a1A-Adrenergic receptor-mediated urethral contraction may contribute to bladder outlet resistance and the maintenance of continence. a-Adrenergic agonists have been used "off label" to treat stress urinary incontinence (67), but the best-studied drug, phenylpropanolamine, was withdrawn from the market by the Food and Drug Administration because of concerns of increased risk for stroke during treatment. An a1A-selective partial agonist, Ro 115-1240, demonstrated efficacy without cardiovascular effects in a placebo-controlled study of women with stress incontinence (68), but its clinical development has been stopped.

Hyperplastic growth of the prostate, an important part of the male bladder outflow tract, occurs with increasing age; the resultant enlargement, benign prostatic hyperplasia (BPH), is frequently associated with bothersome symptoms (69). This hyperplasia represents growth of stromal and, to a lesser extent, glandular-epithelial elements and is accompanied by a dynamic component:

increased smooth muscle tone within the prostatic capsule and bladder outlet, largely as a consequence of adrenergic innervation (70). The human prostate contains a large number of ^-adrenergic receptors, mostly of the a2A-subtype, and all three P-adrenergic receptors, but their function remains unclear (63,71). The human prostate also expresses a1-adrenergic receptors, predominantly of the a1A-subtype, as detected both at the mRNA and protein levels and primarily located on smooth muscle cells; thus, a1A-adrenergic receptors are the main, if not exclusive, subtype that mediates prostatic contraction (70,72). As a consequence, a1-adrenergic antagonists have become a mainstay of medical treatment of BPH.

BPH, a histological diagnosis, affects the majority of elderly men by causing lower urinary tract symptoms (LUTS) that affect both the voiding and storage phase of the micturition cycle. In the past, BPH was treated surgically, but with the advent and success of a1-adrenergic antagonists, the majority of patients now primarily receive this form of medical treatment. The use of a1-adrenergic receptor antagonists to treat LUTS suggestive of BPH was originally based on the concept that a1-adrenergic receptors, particularly of the a1A-subtype, mediate contraction of the prostate, bladder neck, and urethra and hence contribute to the dynamic (phasic) component of increased bladder outlet resistance (70). However, a1-adrenergic antagonists have only moderate effects in the treatment of BPH-associated obstruction but are considerably more effective in alleviating irritative LUTS, implying that symptoms of BPH that occur during the storage phase of the micturition cycle are unlikely to result directly from obstruction. Therefore, it is currently thought that an additional component contributes to symptom relief in BPH patients, possibly blockade of a1D-adrenergic receptors located in the bladder or the spinal cord (72).

Inhibitors of the enzyme 5a-reductase (e.g., finasteride and dutasteride) are the other current main option for medical treatment of BPH. Four comparative studies with a duration of 6 mo to longer than 4 yr demonstrated that ^-adrenergic receptor antagonists are more effective than 5a-reductase inhibitors in relieving BPH symptoms (73-76). Although 5a-reductase inhibitors are inferior in relieving symptoms, they prevent prostatic growth and can reduce BPH complications, such as acute urinary retention, over periods of 4 yr and longer (76,77). Because of their different mechanisms of action, it is not surprising that the combined administration of an a1-adrenergic receptor antagonist and a 5a-reductase inhibitor has significantly greater long-term effects on BPH progression than either drug alone (76).

Prior to their use in BPH patients, a1-adrenergic receptor antagonists were used in the treatment of arterial hypertension. Therefore, a1-antagonists originally developed for the treatment of hypertension, such as doxazosin and terazosin, lower blood pressure when used to treat BPH patients; as a result, such patients can have blood pressure-related side effects, such as orthostasis, dizziness, and asthenia. Interestingly, alfuzosin, which is chemically similar to doxazosin and terazosin, largely lacks these side effects and has a tolerability similar to placebo despite exhibiting some blood pressure lowering (78). Tamsulosin is a chemically different ^-antagonist with selectivity for a1A- and a1D- relative to a1B-adrenergic receptors (79). In therapeutically equivalent doses, tamsulosin causes much less vasodilation than do other a1-adrenergic receptor antagonists (80) and even when given in combination with anti-hypertensive drugs causes little blood pressure lowering (81). Accordingly, its tolerability is close to placebo, including in patients with comorbidities or who are taking multiple medications (81,82). Whether this tolerability and relative lack of vascular effects of tamsulosin are explained by its subtype selectivity or its pharma-cokinetic properties remains unclear, but slow-release formulations of other a1-antagonists also show improved tolerability (83,84). Taken together, these data show that a1-adrenergic receptor antagonists are an effective form of medical treatment for LUTS resulting from BPH, and that subtype selectivity or pharmacokinetic factors can provide selectivity for the urogenital relative to the cardiovascular system.

The human penis expresses various subtypes of a-adrenergic receptors that are involved in smooth muscle contraction (85,86). Nevertheless, the a2-antago-nist yohimbine has only moderate efficacy in treating erectile dysfunction (87), and a1-adrenergic receptor antagonists have failed to demonstrate efficacy relative to placebo in clinical trials for this indication (9). P2 and P3-Adrenergic receptors have been shown to relax corpus cavernosum smooth muscle and thus are suggested as possible targets for treatment of erectile dysfunction (88).

The human uterus expresses a1-adrenergic receptors that mediate contraction, but specific roles of individual subtypes and the overall contribution to myome-trial tone are not well established (89). All three a2-adrenergic receptor subtypes are also expressed; their expression is highly regulated during pregnancy, with protein expression of the a2A-subtype predominating at term (90). The relaxant action of P-adrenergic receptors opposes the contractile responses of myometrial a-adrenergic receptors. Among the P-adrenergic receptors, expression of the P2-subtype dominates in the human myometrium, but the other two subtypes can also be detected (91). There is considerable intersubject variability in expression of P2-adrenergic receptors, with a decrease in expression at term that likely contributes to an enhancement in uterine tone at that time (92,93). P-Adrenergic agonists have been used for many years to treat preterm labor, but myometrial P2-adrenergic receptors undergo rapid desensitization and downregulation on agonist treatment (94). Accordingly, P2-adrenergic agonists have only moderate efficacy, particularly when used for more than a few days (10). It has been suggested that P3-adrenergic agonists might provide an alternative approach for such tocolytic therapy, but no clinical assessment of such agents has been undertaken (95).

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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