BETA-ADRENOCEPTOR-MEDIATED INHIBITION OF ALPHA(1)-ADRENOCEPTOR-MEDIATED AND FIELD STIMULATION-INDUCED CONTRACTILE RESPONSES IN THE PROSTATEOF THE GUINEA-PIG

1 The prostate of the guinea pig responds to electrical field-stimulat ion (2 s trains, 0.1 ms pulses at 3-60 Hz, supramaximal voltage) with contractile responses. At 18 Hz these responses were inhibited (82 +/- 2%) by the L-type Ca2+ channel blocker, nifedipine (10 mu M) and (by 100%) by the neurotoxin, tetrodotoxin (500 nM). The alpha(1A)-selectiv e adrenoceptor antagonist, 5-methylurapidil, inhibited responses to fi eld stimulation in the absence and presence of nifedipine (10 mu M) wi th -log molar (p) IC50 (+/- s.e.mean) values of 7.95 +/- 0.14 and 7.01 +/- 0.07, respectively. 2 The non-selective beta-adrenoceptor agonist , isoprenaline, reduced (56 +/- 8%) field stimulation induced contract ile responses (pEC(50) 6.91 +/- 0.11). The non-selective beta-adrenoce ptor antagonist propranolol (50 nM) and the beta(1)-adrenoceptor selec tive antagonist, atenolol (3 mu M), but not the beta(2)-adrenoceptor a ntagonist ICI 118,551 ((+/-)-1 -inden-4-yl)oxyl]-3-[1-methylethyl)amin o]2-butanol HC1; 100 nM) antagonized this effect (apparent pK(B) value s 8.44 +/- 0.22 and 6.92 +/- 0.21, respectively) indicating an effect mediated through beta(1)-like adrenoceptors. In the presence of nifedi pine (10 mu M) isoprenaline (up to 10 mu M) did not inhibit the remain ing response to field-stimulation. 3 Phenylephrine elicited contractil e responses (pEC(50) 4.47 +/- 0.30) from preparations of guinea pig pr ostate which were reduced (63 +/- 25%) by nifedipine (10 mu M). This r esponse was antagonized by 5-methylurapidil (100 nM, apparent pK(B) 8. 24 +/- 0.33), but was not affected by preincubation chloroethylclonidi ne (50 mu M, 30 min). Responses to phenylephrine (30 mu M) were inhibi ted (by up to 52 +/- 5%) by isoprenaline (pIC(50) 6.40 +/- 0.35, the b eta(2)-adrenoceptor selective agonist, salbutamol was weakly effective ). Propranolol (300 nM), ICI 118,551 (100 nM) and atenolol (3 mu M) sh ifted isoprenaline concentration-response curves to the right (apparen t pK(B) +/- s.e. values 7.68 +/- 1.10; 8.00 +/- 0.72 and 6.62 +/- 0.95 , respectively). In the presence of nifedipine (10 mu M) responses to phenylephrine (30 mu M,) were inhibited (by up to 51 +/- 4%) by isopre naline (pIC(50) 6.88 +/- 0.17): propranolol (300 nM) and ICI 118,551 ( 100 nM), but not atenolol (3 mu M) antagonized this effect (apparent p K(B) values 8.85 +/- 1.53 and 8.35 +/- 1.18, respectively). Thus beta( 1)-like and beta(2)-like adrenoceptors may be involved in the isoprena line-stimulated inhibition of phenylephrine concentration-response cur ves. 4 Phenylephrine stimulated [H-3]-inositol phosphate accumulation (pEC(50) 4.47 +/- 0.83), an effect insensitive to chloroethylclonidine pre-treatment (50 mu M, 30 min) and to nifedipine (10 mu M), but inhi bited by 5-methylurapidil (apparent pK(D) 7.90 +/- 0.22). Isoprenaline (up to 1 mu M) did not affect the phenylephrine-stimulated maximal in crease in [H-3]-inositol phosphates but did increase [H-3]-cyclic aden osine monophosphate ([H-3]-cAMP) accumulation (pEC(50) 6.77 +/- 0.66); propranolol (30 nM) and ICI 118,551 (110 nM), but not atenolol (up to 3 mu M), antagonized this effect. These responses may therefore be me diated through beta(2)-like adrenoceptors. 5 These results show that t he alpha(1)-adrenoceptor mediated and field stimulation-induced contra ctions of the guinea pig prostate are partly dependent upon intracellu lar and extracellular sources of Ca2+. We conclude that both beta(1)- and beta(2)-like adrenoceptors inhibit responses to phenylephrine in t he prostate of the guinea pig. The beta(1)-like adrenoceptor-mediated inhibition of these responses is evident upon the field stimulation-in duced and nifedipine-sensitive component of the response to phenylephr ine and may not involve the activation of adenylyl cyclase. The beta(2 )-like adrenoceptor may inhibit both nifedipine sensitive and insensit ive components of the response to phenylephrine, possibly through the activation of adenylyl cyclase, but not through the inhibition of inos itol phosphate accumulation.