Introduction

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Lower urinary tract symptoms (LUTS) refer to a constellation of irritative (filling) and obstructive (voiding) symptoms such as frequency, urgency, and slow flow. LUTS is more frequent and severe in older age groups and has a strong negative impact on the quality of life of those affected (Garraway et al., 1991; Girman et al., 1994, 1995; Kirby, 2000). Although LUTS may have a number of underlying etiologies, it is often attributed in older men to benign prostatic enlargement resulting in bladder outlet obstruction. In this subset of cases, it is referred to as symptomatic or clinical benign prostatic hyperplasia (BPH). In the United States, an estimated 5.6 million men suffer, a number that is expected to double by the year 2025 due to increased life expectancy (Chapple, 1999).

₁-Adrenoceptor antagonists represent first-line pharmacotherapy for the treatment of LUTS suggestive of benign prostatic obstruction (BPO). Cloning and pharmacological studies suggest the presence of three distinct subtypes of ₁-adrenoceptors (_1A, _1B, and _1D) (Hancock, 1996; Zhong and Minneman, 1999). Several studies have shown that the _1A-subtype predominates in the human prostate and that it mediates the contractile effects of norepinephrine in this tissue (Lepor et al., 1993; Forray et al., 1994; Taniguchi et al., 1997). Despite the proven safety and utility of nonselective ₁-adrenoceptor antagonists such as terazosin and doxazosin in the treatment of clinical BPH, these compounds were initially developed as antihypertensives and can cause arterial pressure related effects that limit dosing. It was hypothesized that _1A-selective antagonists would be more "prostate-selective" thereby improving BPH symptoms with improved tolerability. Indeed, tamsulosin, a compound with enhanced selectivity for _1a- versus _1b-adrenoceptors, relative to terazosin in vitro (Hancock et al., 2002), is better tolerated clinically due to fewer cardiovascular-related adverse events. However, Ro-70-004, a newer antagonist with even greater subtype selectivity in vitro (50-fold for _1a- versus _1b- or _1d-adrenoceptors; Williams et al., 1999) failed to improve LUT symptoms in a clinical trial, although increases in flow rate were observed (Blue et al., 2000). These findings and the long-standing observation that ₁-adrenoceptor antagonists produce beneficial effects on filling symptoms, even in the absence of obstruction, have stimulated a reevaluation of the previous notion that the clinical efficacy of ₁-adrenoceptor antagonists is related primarily to relaxation of prostatic smooth muscle alone (Michel et al., 2000). There is an increased appreciation that both prostatic and extraprostatic ₁-adrenoceptors play a role in lower urinary tract function and may mediate the therapeutic efficacy of ₁-adrenoceptor antagonists in clinical BPH. Indeed, in addition to the well established role of _1A-adrenoceptors in mediating urethral resistance, _1D-adrenoceptors predominate in detrusor smooth muscle (Malloy et al., 1998) and _1D-adrenoceptor message in that tissue is increased in response to partial outlet obstruction in rats (Hampel et al., 2000). _1D-Adrenoceptors can also be found in areas of the lumbosacral spinal cord involved in mediating voiding reflexes (Smith et al., 1999). Hypotensive potency of ₁-adrenoceptor antagonists is highly correlated with _1b-affinity and but not to _1a- and to a lesser extent, _1d-affinity (Hancock et al., 2002). An emerging hypothesis is that improved clinical separation between LUT symptom improvement and undesired cardiovascular-related effects may not be related solely to pharmacological selectivity for a single subtype in vitro even though that subtype mediates the contractile effects of ₁-agonists in LUT smooth muscle. Instead, selectivity for those ₁-receptors involved in mediating symptoms versus those involved in tonic control of arterial pressure, regardless of subtype, may result in an improved clinical profile. Fiduxosin is a _1a- (K_i = 0.16 nM)/_1d (K_i = 0.92 nM)-adrenoceptor antagonist displaying 155-fold selectivity for _1a- versus _1b (K_i = 25 nM)-subtypes in radioligand binding studies (Hancock et al., 2000). Its pharmacological profile is suitable for testing the hypothesis that a mixed _1A- and _1D- over _1B-adrenoceptor antagonist would result in a superior therapeutic agent for the treatment of LUTS suggestive of BPO. In this study, we used a conscious dog model to evaluate the effects of fiduxosin on urethral and arterial pressure responses after oral dosing. Using this model, we determined the selectivity of fiduxosin to block prostatic and prostatic urethral ₁-adrenoceptors over those in the vasculature and compared the results with clinically used agents.¹

	Experimental Procedures

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Male beagle dogs (>2 years old, 12-15 kg; Marshall Farms, North Rose, NY) were chronically instrumented for the continuous measurement of arterial blood pressure by implanting a telemetry transducer/transmitter (TA11PA-C40; Data Sciences International, St. Paul, MN) into a carotid artery. On test day, dogs were placed in sling restraints and an Abbocath-T i.v. catheter (18-G; Abbott Laboratories, North Chicago, IL) was inserted into a cephalic vein for blood sampling and for the administration of agonist. Prostatic intraurethral pressure (IUP) was measured using a transurethral 7F Swan-Ganz balloon catheter (41224-01; Abbott Laboratories) as previously described (Brune et al., 1995). Dose responses of the intraurethral and arterial pressor effects of 8, 16, and 32 µg/kg i.v. phenylephrine (PE) were obtained before and at various time points after a single p.o. dose of an antagonist. Fiduxosin was dissolved in a vehicle of 20% ethanol, 30% propylene glycol, and 50% water. Terazosin and tamsulosin were dissolved in water. All antagonists were given by gavage in a volume of 1 ml/kg. PE was dissolved in saline and administered in a volume of 0.1 ml/kg. The increase in IUP or mean arterial pressure (MAP) caused by PE was allowed to return to baseline before the next dose was administered. Dogs were cared for according to National Institutes of Health guidelines on canine care and all experimental protocols described herein were reviewed and approved by the Institutional Animal Care and Use Committee of Abbott Laboratories.

Data Analysis. Data were expressed as percentage of blockade of the baseline pressure responses obtained in the absence of antagonist. Hypotensive effects were expressed as net change from predose MAP and represent the maximum change in MAP seen at any time after dosing. One-way analysis of variance was used to compare the extent of blockade of PE-induced IUP or MAP effects at each time point during the experiment. If statistical significance was indicated, comparisons between groups were performed using Dunnett's multiple range test. ED₅₀ values are an estimate of the dose required to cause a maximum inhibition of the IUP or MAP pressor response to PE of 50%. Hypotensive ED_{10 mm Hg} values are an estimate of the dose required to produce a maximum decrease in baseline MAP of 10 mm Hg. All ED values were determined by interpolation by using a standard linear regression analysis of doses producing a response just above or below the indicated index value. A paired t test was used to compare the maximum blockade values of IUP to MAP after a given antagonist dose. The same test was used to compare duration of effect values of IUP to MAP as well.

Materials. Fiduxosin (ABT-980), terazosin, and tamsulosin were synthesized as hydrochloride salts at Abbott Laboratories. Phenylephrine hydrochloride was purchased from Sigma Chemical (St. Louis, MO).

	Results

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Baseline control MAP values in all dogs tested ranged from 83 to 110 mm Hg and the overall mean (S.E.M.) was 97 (1.4) mm Hg. Average IUP pressor responses to 8, 16, and 32 µg/kg i.v. PE in the absence of antagonist were 16 (0.7), 24 (1.1), and 33 (1.3) mm Hg. Corresponding MAP pressor responses to these three PE doses were 27 (1.4), 43 (1.3), and 57 (1.6) mm Hg (n = 48). There were no statistical differences in baseline MAP or in the baseline IUP or MAP pressor responses to PE between groups (one-way analysis of variance; data not shown). When normalized to the corresponding control agonist response, any dose of an ₁-adrenoceptor antagonist produced similar attenuation of all three PE doses (data not shown). Therefore, although for clarity only data obtained after administration of the 32-µg/kg i.v. dose is presented herein, the results for all antagonists at this PE dose were representative of those obtained after the 8 and 16 µg/kg i.v. The relative potencies and selectivities of these antagonists were not dependent on the agonist dose (data not shown).

Some attenuation of the MAP and IUP pressor responses to PE was seen over time in the absence of antagonists in the vehicle only group (Figs. 1-3). The reasons for this are unclear but could be associated with handling conscious animals as previously discussed (Brune et al., 1996) or receptor desensitization with repeated agonist administration. Regardless, these effects were small relative to those evoked by the antagonists.

View larger version (32K): [in this window] [in a new window]   Fig. 1.   Time course effects of terazosin to block PE-induced increases in IUP (A) and block PE-induced increases in MAP (B) measured simultaneously in conscious dogs. Doses are mg/kg p.o. as indicated in the inset. Data represent mean ± S.E.M., n = 4 to 5/dose. *p  0.05 compared with vehicle.

View larger version (31K): [in this window] [in a new window]   Fig. 2.   Time course effects of tamsulosin to block PE-induced increases in IUP (A) and block PE-induced increases in MAP (B) measured simultaneously in conscious dogs. Doses are mg/kg p.o. as indicated in the inset. Data represent mean ± S.E.M., n = 4 to 5/dose. *p  0.05 compared with vehicle.

View larger version (33K): [in this window] [in a new window]   Fig. 3.   Time course effects of fiduxosin to block PE-induced increases in IUP (A) and block PE-induced increases in MAP (B) measured simultaneously in conscious dogs. Doses are mg/kg p.o. as indicated in the inset. Data represent mean ± S.E.M., n = 4 to 5/dose. *p  0.05 compared with vehicle.

Figures 1 to 3 illustrate the time course of antagonist inhibition of the IUP and MAP pressor effects of PE. As these figures indicate, all three antagonists dose dependently inhibited the IUP and MAP pressor responses to i.v. PE. There were differences between compounds in the magnitude of blockade of each simultaneously measured parameter. Terazosin, for example, always blocked the MAP pressor response to an equal or greater extent than IUP (Fig. 1, A and B). The maximum percentage of inhibition (E_max) of the MAP pressor response after terazosin at 0.1, 0.3, and 1.0 mg/kg p.o. was 60, 82, and 98, whereas the corresponding IUP E_max values were 23, 67, and 97. Selectivity at each dose as measured by IUP E_max  MAP E_max was 37, 15, and 1, indicating that terazosin is "MAP-selective" at submaximally effective doses (Fig. 4A). The time course effects of tamsulosin in the model are included in Fig. 2, A and B. The same selectivity analysis applied to the tamsulosin IUP inhibition E_max values (40, 82, and 100%) minus corresponding MAP E_max values (38, 66, and 90%) yielded differences of 2, 16, and 10% at 0.001, 0.01, and 0.1 mg/kg p.o., respectively (Fig. 4B). Although the absolute IUP selectivity of tamsulosin is modest, these data indicate some degree of IUP selectivity of tamsulosin relative to terazosin.

View larger version (25K): [in this window] [in a new window]   Fig. 4.   Maximal blockade of PE-induced increases in IUP () or MAP () seen after oral dosing with terazosin (A), tamsulosin (B), or fiduxosin (C). Data represent mean ± S.E.M. of four to five dogs per dose. Data analyzed using paired t test. +p  0.05 MAP blockade maximums exceeded IUP blockade maximums; *p  0.05 IUP blockade maximums exceeded MAP blockade maximums.

Fiduxosin (0.1, 0.3, 1.0, and 3.0 mg/kg p.o.) always blocked IUP responses to a greater extent than MAP responses (Fig. 3, A and B). IUP inhibition E_max values at each respective increasing dose (34, 60, 75, and 91) were greater than corresponding MAP E_max values (27, 35, 36, and 71) by 7, 24, 39, and 20% (Fig. 4C). These differences exceeded those obtained after either terazosin or tamsulosin as shown above.

In Fig. 6A, the same maximum inhibition data set was used to estimate a dose of terazosin or tamsulosin that produces IUP blockade equal to that seen with fiduxosin at 1.0 mg/kg p.o. (75%). Then the degree of MAP blockade at these equieffective IUP doses was estimated. The doses of terazosin and tamsulosin estimated to block IUP responses by 75% were 0.46 and 0.0085 mg/kg p.o. Corresponding MAP blockade values were much less for fiduxosin (38%) than either terazosin (86%) or tamsulosin (61%). These data indicate a uroselectivity rank order of fiduxosin > tamsulosin > terazosin.

View larger version (18K): [in this window] [in a new window]   Fig. 5.   Duration of antagonist-induced IUP () or MAP () pressor response blockade exceeding 50% of the predose baseline. Data represent mean ± S.E.M. of four to five dogs per dose. Data analyzed using paired t test. +p  0.05 MAP blockade duration exceeded IUP blockade duration; *p  0.05 IUP blockade duration exceeded MAP blockade duration.

We also examined the duration of blockade of each parameter as an indication of selectivity. Figure 5, A to C, illustrate the length of time after each compound where the duration of IUP or MAP blockade exceeded 50%. As indicated in Fig. 6A, terazosin blocked MAP responses several hours longer than IUP responses at all doses. Only after the 0.01-mg/kg dose of tamsulosin, where IUP selectivity was greatest by the comparison of peak responses described above, did IUP blockade duration significantly exceed that of MAP (Fig. 5B). That modest dose and time-specific selectivity is also illustrated by examining the dose-response data in Fig. 2, A and B. At 6 h after 0.01 mg/kg tamsulosin, the MAP response had returned to baseline but the IUP response was still significantly blocked (62%). In contrast, fiduxosin blocked IUP responses significantly longer than MAP responses at all doses. Consistent with the analysis of maximal blockade above, the duration difference was greatest after 1 mg/kg (Fig. 5C).

View larger version (28K): [in this window] [in a new window]   Fig. 6.   A, estimates of the maximal blockade of PE-induced MAP pressor effects at doses of each antagonist that produce an equivalent IUP blockade maximal effect of 75%. "Uroselectivity" is, therefore, inversely proportional to the extent of MAP blockade at these IUP equieffective doses. B, doses of each antagonist were estimated that produce an equivalent duration of IUP effect where pressor effects were blocked >50% of baseline. Because IUP effect durations are equivalent, uroselectivity is inversely proportional to MAP effect duration. As indicated in Fig. 3, MAP blockade after fiduxosin was always less than 50% at 1 mg/kg p.o., therefore, the MAP duration bar heights are zero. These analyses suggest the same antagonist rank order of uroselectivity: fiduxosin > tamsulosin > terazosin.

A similar analysis to that described above for E_max data was used to estimate the dose of terazosin or tamsulosin that would cause an IUP blockade greater than 50% for a duration equal to that achieved by fiduxosin at 1.0 mg/kg p.o. (9 h). MAP blockade duration of an effect greater than 50% at these equieffective IUP doses was then estimated. Doses of terazosin and tamsulosin estimated to block IUP responses greater than 50% for 9 h were 0.7 and 0.022 mg/kg p.o., respectively. Corresponding MAP blockade duration values were less for fiduxosin (0 h) than either terazosin (21 h) or tamsulosin (5 h; Fig. 6B). These data also indicate a uroselectivity rank order of fiduxosin > tamsulosin > terazosin.

View larger version (19K): [in this window] [in a new window]   Fig. 7.   Dose-response effects of terazosin, tamsulosin, and fiduxosin to decrease resting MAP in conscious dogs. A net change greater than 5 mm Hg was considered to be above the noise level associated with this assay. Terazosin and tamsulosin caused dose-dependent hypotension. Fiduxosin did not cause hypotension at any dose tested.

Hypotensive effects of these antagonists were also monitored in these dogs and the dose-response data are summarized in Fig. 7. Maximum changes after the two vehicles used in this study (ethanol, propylene glycol, water and water alone) were +4 and 2.5%, respectively (data not shown). Also, our practical experience suggests changes in MAP of ±5 mm Hg were within the noise range of this assay, and therefore were not considered biologically significant. As Fig. 7 indicates, terazosin and tamsulosin caused dose-dependent hypotension, whereas fiduxosin did not affect baseline arterial pressure at any dose tested.

To summarize the results, the doses of each antagonist required to produce the following effects were calculated: 1) maximum 50% inhibition of IUP pressor effect, 2) maximum 50% inhibition of MAP pressor effect, and 3) 10 mm Hg decrease in baseline MAP. These potency indices and resulting selectivity ratios are summarized in Table 1.

	Discussion

Top Abstract Introduction Experimental Procedures Results Discussion References

The results of the present study illustrate clear differences in the ₁-adrenoceptor antagonist potency and pharmacological selectivity of these compounds in vivo. Tamsulosin was the most potent compound and was somewhat IUP-selective relative to terazosin, a compound that was consistently MAP-selective in the assay. Fiduxosin was clearly the most IUP-selective compound by using either a comparison with MAP E_max values or blockade effect duration. The selectivity comparison in Fig. 5 where MAP blockade was less at equieffective doses of the antagonists that produce 75% inhibition may be particularly relevant. In a previous report modeling the relationship between the plasma levels of terazosin and pharmacodynamic effects in this model (Witte et al., 1997), the estimated plasma concentration of terazosin to produce 75% blockade was 100 ng/ml, which is equal to peak plasma levels achieved clinically with 5 mg of terazosin (Taguchi et al., 1998).

Fiduxosin also demonstrated superior IUP selectivity over hypotensive effects, which is of potential clinical importance. Unfortunately, the true selectivity of fiduxosin in this regard may be underestimated due to a lack of hypotensive effects in these normotensive animals. Indeed, the hypotensive effects of ₁-adrenoceptor antagonists used clinically to treat LUTS suggestive of BPO are minimal at effective doses in normotensives but these agents do lower arterial pressure in hypertensives. The lack of hypotensive potency of fiduxosin relative to terazosin and tamsulosin seen herein was confirmed in conscious SHR, a model highly sensitive to the depressor effects of ₁-antagonists (Hancock et al., 2002). These data indicating a similar rank order of antagonist potency to produce hypotension in both normotensive dogs and hypertensive rats are consistent with the notion that similar subtype populations mediate the hypotensive response in both species. The increased magnitude of antagonist responses in SHR and hypertensive patients could be explained by the known role of enhanced sympathetic outflow in hypertension (Tuck, 1986).

These data taken together suggest a compound such as fiduxosin may have an improved cardiovascular liability profile. The enhanced relative selectivity shown herein of tamsulosin compared with terazosin is consistent with the selectivity rank order reported in other models (Hancock et al., 2002; Witte et al., 2002) and in clinical studies (Djavan and Marberger, 1999; Schafers et al., 1999). The in vitro and in vivo profile of fiduxosin is similar to that of another _1A- and _1D-selective antagonist, A-131701 (Hancock et al., 1998a,b).

In this study, the uroselectivity of these ₁-adrenoceptor antagonists versus hypotensive effects exceeded their uroselectivity versus ₁-adrenoceptor agonist-induced increase in MAP (Table 1). One theoretical explanation is that hypotension and blockade of agonist-induced pressor effects are mediated by distinct receptor populations. For example, if the pressor responses to an exogenous intravenous agonist and the physiological release of endogenous agonist from sympathetic nerves are mediated by different subtypes or by receptors in different anatomic locations, the pharmacology of the chosen agonist could impact the findings, including perhaps implying a role for a particular receptor subtype not relevant to normal physiology. For example, although highly _1A-selective antagonists lack potency to decrease MAP (Blue et al., 1997), highly _1A-selective agonists potently increase it (Knepper et al., 1995; Taniguchi et al., 1996). A unifying hypothesis to explain these observations is that there may be _1A-adrenoceptors located extrajunctionally that are not involved in the tonic sympathetic noradrenergic control of arterial pressure but that mediate an exogenous _1A-adrenoceptor agonist-induced increase in pressure. Therefore, the pressor response to the exogenous administration of an _1A-agonist such as PE or its functional blockade by an _1A-antagonist is not necessarily indicative of a role for these receptors in the tonic sympathetic control of resting arterial pressure. If this extrajunctional hypothesis is accurate, antagonist affinity for _1A-adrenoceptors that mediate IUP effects would simultaneously result in blockade of _1A-adrenoceptor agonist-induced MAP pressor effects, thereby having a self-limiting effect on an estimate of selectivity. A study that compares the rank order of potency of subtype selective antagonists to block MAP pressor effects caused by stimulation of lumbar sympathetic nerves with their ability to block agonist-induced increases could further elucidate the functional role of ₁-adrenoceptor subtypes in the cardiovascular system.

In contrast to arterial pressure where multiple ₁-adrenoceptor subtypes are involved in its regulation, both agonist-induced increases and sympathetic nerve-mediated increases in urethral pressure appear mediated the same (_1A) subtype. For example, similar doses of REC 15/2739 (_1A-selective), tamsulosin, or terazosin blocked norepinephrine-induced and hypogastric nerve-induced increases in urethral pressure to a similar extent (Leonardi et al., 1997). Furthermore, the rank order of antagonist potency was the same as their affinity for the _1a- but not _1b- and _1d-subtypes. It would be expected that the selectivity profile of a mixed subtype agonist such as PE would not be a confounding factor in the case where a single subtype mediates the functional responses of the agonist.

For most ₁-adrenoceptor antagonists, including fiduxosin, there is a strong positive correlation between affinity for the LUT predominant (_1A) subtype and functional antagonist potency on LUT tissue in vitro and in vivo (Hancock, 1996; Hancock et al., 2002). However, some compounds have been described that have much weaker functional potency in prostatic tissue in vitro than would be predicted by their affinities for the recombinant _1a-subtype such as SNAP 5089, REC 15/2627 (Leonardi et al., 1997), and RS 17053 (Ford et al., 1996). This has lead to the hypothesis that contraction of prostatic (and urethral) tissue is mediated at least in part by an atypical ₁-adrenoceptor subtype, possibly the putative _1L-subtype (low affinity for prazosin) initially proposed by Flavahan and Vanhoutte (1986) and extended by Murumatsu et al. (1990, 1995) to explain the differences in the affinity constants for prazosin in different vascular tissue assays in vitro. Current data support the notion that the _1L-"subtype" may not be a distinct molecular entity but rather as a different "affinity state" of the _1A-adrenoceptor gene product. The fiduxosin in vitro data (Hancock et al., 2002) suggests that, unlike the outlier compounds described above and like most other ₁-adrenoceptor antagonists, the affinity of fiduxosin for the _1A-adrenoceptor is independent of its affinity state.

In a previous article on the effects of tamsulosin and terazosin in this model (Brune et al., 1996), the results were reported using PE at 16 µg/kg i.v., whereas 32 µg/kg i.v. is used herein. We routinely administered three PE doses in the protocol not knowing a priori where these three doses might lie on the dose-response curve in a particular dog. For example, if PE 32 µg/kg i.v. was a supramaximal IUP dose on a given day, an antagonist might cause less IUP blockade and therefore look less selective. Comparing the effects of multiple agonist doses helps evaluate compounds as to their ability to shift a dose response to the right instead of inhibition of effects at only a single dose. In hindsight, antagonist blockade of all PE doses was similar in different dogs on different days, indicating that these doses all lie on the "steep" portion of the dose-response curve and that compound potency and selectivity was not affected by such issues.

In this study, we demonstrated the utility of a conscious dog model to demonstrate selective functional ₁-adrenoceptor antagonism in the lower urinary tract (urethra and prostate) compared with the vascular system. This model appears relevant because 1) the _1A-adrenoceptor subtype is predominant in the LUT of both dog and human, 2) the pharmacology of dog lower urinary tract ₁-adrenoceptors is similar to that of human (Lepor et al., 1992, 1994), and 3) androgen-dependent macroscopic BPH occurs in both dog and human with increasing age (Johnston et al., 2000). Although the extent of similarity between dog and human with respect to distribution of ₁-adrenoceptor subtypes in the vasculature remains to be fully elucidated, the clinical observation that tamsulosin is better tolerated than terazosin due to less of an effect on arterial pressure was predicted by this study and by a similar PE challenge protocol in humans (Schafers et al., 1999). Conscious animals also enable the assessment of pharmacodynamic effects after oral dosing without the confounding effects of anesthesia and to relate those effects to pharmacokinetic parameters. However, the relationship between IUP as measured in this model, bladder outlet resistance, and ultimately, clinical symptom improvement is complex and not fully understood. Dynamic bladder outlet resistance is not routinely measured because it requires the difficult simultaneous measurement of pressure and flow (resistance = pressure/flow). Instead, IUP is used as a surrogate measure that directly reflects changes in resistance assuming flow is constant. The IUP measurement mostly reflects changes in the tone of smooth muscle surrounding the balloon (prostate and prostatic urethra) and not bladder or reflex effects because it is measured in the absence of a bladder contraction. Most of the agonist-induced increase in IUP can be attributed to effects on the prostate because agonist-induced increases were 60 to 80% smaller in the corresponding location in female dogs or in males when the balloon was placed just proximal or just distal to the prostatic urethra (Brune et al., 1995).

The relationship between the prostate, obstruction, and symptoms is also complex. LUT symptoms are classified as either obstructive such as weak stream and incomplete emptying or irritative such as frequency and urgency. Although in most patients surgical resection of the prostate relieves obstruction and improves both types of symptoms, about 30% of surgical patients do not show improvement in irritative symptoms. These data suggest that the amelioration of obstruction and the corresponding decrease in urethral resistance are not the only factors that determine symptom relief. This ultimate goal of therapy, symptom improvement, cannot be modeled easily, if at all, in laboratory animals. The relevance of ₁-adrenoceptor antagonist effects on IUP to therapeutic efficacy in LUTS suggestive of BPO remains to be fully elucidated.

A balanced antagonist profile across ₁-adrenoceptor subtypes implicated in the control of bladder function and outlet resistance (_1A and _1D) without cardiovascular effects at lower urinary tract-effective doses may result in a superior therapeutic agent. Fiduxosin demonstrates this balanced antagonist profile in radioligand binding and in vitro functional studies. In this current study, in an in vivo model that predicted the improved clinical uroselectivity of tamsulosin over terazosin, fiduxosin demonstrated selectivity superior to these agents. The improved uroselectivity of fiduxosin demonstrated herein, particularly versus hypotensive effects, suggest an ₁-adrenoceptor antagonist with this profile may be of therapeutic potential in the treatment of LUTS suggestive of BPO.