Effects of Prazosin in Patients with Benign Prostatic Obstruction

1 Electrical and mechanical properties of smooth muscle cells of the rabbit prostate capsule and the actions of the a,-adrenoceptor blocker, YM-12617, were investigated using microelectrode and isometric tension recording methods. 2 The capsular muscles comprised thick and thin muscle bundles. In the former, noradrenaline (NA; 0.1-10 M) provoked the phasic and tonic mechanical responses, with twitch contractions superimposed on the tonic response. YM-12617, in concentrations over 1 nM inhibited the contraction evoked by any given concentration of NA. Yohimbine (up to 1OpM) slightly inhibited the NA-induced contraction whilst clonidine (up to 10 pM) and acetylcholine (ACh; up to 1O gM) produced no mechanical response.3 In thin muscle bundles, NA (0.1-10 pM) produced a contraction but the phasic response was small and the tonic response was negligible. These changes were blocked by YM-12617. In contrast, ACh (0. 1-10 pM) produced atropine-sensitive, large phasic and tonic responses similar to those observed on application of NA to thick muscle bundles. 4 In thin and thick muscle bundles, the mean resting membrane potentials were -54 and -56 mV, respectively, values which were not statistically different. However, in thick muscle bundles, NA (over 0.1 pM) depolarized the membrane in a concentration-dependent manner and produced repetitive spike generation; ACh (up to 1 pM) did not modify the membrane potential. In thin muscle bundles, the above concentrations of NA hyperpolarized the membrane but ACh produced a large depolarization with repetitive spike generation. 5 In thick muscle bundles, nifedipine (0.3 AM) blocked twitch contractions generated spontaneously or provoked by application of NA with no effect on phasic and tonic responses. The NA-induced depolarization persisted after superfusion with nifedipine up to a concentration of 1.0 pM. In a Ca-free solution containing 2 mM EGTA, NA produced only the phasic responses, and re-addition of Ca (2.6 mM) restored the generation of a tonic response. 6 After application of 0.3 AM nifedipine, the effects of YM-12617 and prazosin were observed on the tonic component of the NA-induced contraction of thick muscle bundles. The ID50 values for YM-12617 and prazosin were 1 nM and 15 nM, respectively (n = 4). YM-12617 shifted the NA concentration-response curve to the right in a concentration-dependent and parallel manner. The Schild plot yielded a straight line with slope of 0.97 ± 0.05, (n = 4). The pA2 value for YM-12617 was 10.4 ± 0.05, (n = 4).7 In thiqk muscle bundles, the depolarization induced by NA (0I1OM) was blocked by YM-12617 (over 1 nM) to a greater extent than by prazosin (0.1 1AM). Half-inhibition of the NA (10 1AM)-induced maximum depolarization by YM-12617 or prazosin occurred at concentrations of 2 nm and 100 nM, respectively. 8 From these mechanical and electrical responses, the heterogeneous nature and distribution of a,-adrenoceptors and muscarinic receptors has been elucidated in capsular smooth muscles in the rabbit prostate. In both thick and thi...

Section: Methodsmentioning

confidence: 99%

Electrical and mechanical properties of the capsular smooth muscles of the rabbit prostate in relation to the actions of the α₁‐adrenoceptor blocker, YM‐12617

Seki

Nishiye

Itoh

et al. 1988

“…Following earlier studies with the alkylating agent phenoxybenzamine (Caine et al, 1978), competitive a 1 -adrenoceptor antagonists such as terazosin (Lepor, 1995), prazosin (Hedlund et al, 1983;Chapple et al, 1992) and alfuzosin (Buzelin et al, 1993) have been shown to be e ective in relieving urinary out¯ow obstruction and reducing symptom scores in patients with benign prostatic hyperplasia (BPH). However, the usefulness of a 1 -adrenoceptor antagonists in BPH is o set by their dose-limiting cardiovascular e ects, including postural hypotension, particularly with initial dosing.…”

Section: Introductionmentioning

confidence: 99%

In vitroα₁‐adrenoceptor pharmacology of Ro 70–0004 and RS‐100329, novel α_1A‐adrenoceptor selective antagonists

Williams¹,

Blue²,

Daniels³

et al. 1999

Bank, She eld, ST10 2TN and 4 8 Palace Garden, Royston, Hertfordshire, S68 5AD1 It has been hypothesized that in patients with benign prostatic hyperplasia, selective antagonism of the a 1A -adrenoceptor-mediated contraction of lower urinary tract tissues may, via a selective relief of outlet obstruction, lead to an improvement in symptoms. 2 The present study describes the a 1 -adrenoceptor (a 1 -AR) subtype selectivities of two novel a 1 -AR antagonists, Ro 70-0004 (aka RS-100975) and a structurally-related compound RS-100329, and compares them with those of prazosin and tamsulosin. Radioligand binding and second-messenger studies in intact CHO-K1 cells expressing human cloned a 1A -, a 1B -and a 1D -AR showed nanomolar a nity and signi®cant a 1A -AR subtype selectivity for both Ro 70-0004 (pK i 8.9: 60 and 50 fold selectivity) and RS-100329 (pK i 9.6: 126 and 50 fold selectivity) over the a 1B -and a 1D -AR subtypes respectively. In contrast, prazosin and tamsulosin showed little subtype selectivity. 3 Noradrenaline-induced contractions of human lower urinary tract (LUT) tissues or rabbit bladder neck were competitively antagonized by Ro 70-0004 (pA 2 8.8 and 8.9), RS-100329 (pA 2 9.2 and 9.2), tamsulosin (pA 2 10.4 and 9.8) and prazosin (pA 2 8.7 and 8.3 respectively). A nity estimates for tamsulosin and prazosin in antagonizing a 1 -AR-mediated contractions of human renal artery (HRA) and rat aorta (RA) were similar to those observed in LUT tissues, whereas Ro 70-0004 and RS-100329 were approximately 100 fold less potent (pA 2 values of 6.8/6.8 and 7.3/7.9 in HRA/RA respectively). 4 The a 1A -AR subtype selectivity of Ro 70-0004 and RS-100329, demonstrated in both cloned and native systems, should allow for an evaluation of the clinical utility of a`uroselective' agent for the treatment of symptoms associated with benign prostatic hyperplasia.

“…The present study confirmed the stereochemical specificity of the optical isomers of LY253352 in human prostatic adenomas using competitive binding assays. (Caine et al, 1978;Hedlund et al, 1983). The in vitro contractile properties of prostatic tissues are mediated by a-adrenoceptors (Honda et al, 1985).…”

Section: Methodsmentioning

confidence: 99%

The stereospecificity of LY253352 for α₁‐adrenoceptor binding sites in the brain and prostate

Lepor

Baumann

Shapiro

1988

The stereospecificity of the enantiomers of LY253352, a potent and selective α1‐adrenoceptor antagonist, were studied in the human prostate and canine brain using radioligand receptor binding methods. The mean equilibrium dissociation constant (KD) in the canine brain and human prostatic adenoma was 84.4 pM and 65.4 pM, respectively. The α1‐adrenoceptor density in the canine brain was approximately eight fold greater than in the human prostatic adenoma. The mean Ki values of (−)‐LY253352 and (+)‐LY253352 in the prostate were 0.19 nM and 5.79 nM, respectively. The mean Ki values of (−)‐LY253352 and (+)‐LY253352 in the brain were 0.29 nM and 34.7 nM, respectively. This study indicates that the stereochemical specificity of the optical isomers of LY253352 is a manifestation of differential affinities of the enantiomers for α1‐adrenoceptor binding sites. The differential affinities of (+)‐LY253352 in the brain and prostate are suggestive of subtle unique properties of adrenoceptor binding sites in these tissues.