β-Adrenoceptor-mediated inhibition of α1-adrenoceptor-mediated and field stimulation-induced contractile responses in the prostate of the guinea pig

John M. Haynes, Stephen J. Hill

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Abstract

1. The prostate of the guinea pig responds to electrical field-stimulation (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 μM) and (by 100%) by the neurotoxin, tetrodotoxin (500 nM). The α(1A)-selective adrenoceptor antagonist, 5-methylurapidil, inhibited responses to field stimulation in the absence and presence of nifedipine (10 μM) with -log molar (p) IC50 (± s.e.mean) values of 7.95 ± 0.14 and 7.01 ± 0.07, respectively. 2. The non-selective β-adrenoceptor agonist, isoprenaline, reduced (56 ± 8%) field stimulation induced contractile responses (pEC50 6.91 ± 0.11). The non-selective β-adrenoceptor antagonist propranolol (50 nM) and the β1-adrenoceptor selective antagonist, atenolol (3 μM), but not the β2-adrenoceptor antagonist ICI 118,551 ((±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxyl]-3-[1-methylethyl)amino]-2 -butanol HCl; 100 nM) antagonized this effect (apparent pK(B) values 8.44 ± 0.22 and 6.92 ± 0.21, respectively) indicating an effect mediated through β1-like adrenoceptors. In the presence of nifedipine (10 μM) isoprenaline (up to 10 μM) did not inhibit the remaining response to field-stimulation. 3. Phenylephrine elicited contractile responses (pEC50 4.47 ± 0.30) from preparations of guinea pig prostate which were reduced (63 ± 25%) by nifedipine (10 μM). This response was antagonized by 5-methylurapidil (100 nM, apparent pK(B) 8.24 ± 0.33), but was not affected by preincubation chloroethylclonidine (50 μM, 30 min). Responses to phenylephrine (30 μM) were inhibited (by up to 52 ± 5%) by isoprenaline (pIC50 6.40 ± 0.35 the β2-adrenoceptor selective agonist, salbutamol was weakly effective). Propranolol (300 nM), ICI 118,551 (100 nM) and atenolol (3 μM) shifted isoprenaline concentration-response curves to the right (apparent 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 μM) responses to phenylephrine (30 μM,) were inhibited (by up to 51 ± 4%) by isoprenaline (pIC50 6.88 ± 0.17): propranolol (300 nM) and ICI 118,551 (100 nM), but not atenolol (3 μM) antagonized this effect (apparent pK(B) values 8.85 ± 1.53 and 8.35 ± 1.18, respectively. Thus β1-like and β2-like adrenoceptors may be involved in isoprenaline-stimulated inhibition of phenylephrine concentration-response curves. 4. Phenylephrine stimulated [3H]-inositol phosphate accumulation (pEC50 4.47 ± 0.83), an effect insensitive to chloroethylclonidine pre-treatment (50 μM, 30 min) and to nifedipine (10 μM), but inhibited by 5-methylurapidil (apparent pK(D) 7.90 ± 0.22). Isoprenaline (up to 1 μM) did not affect the phenylephrine-stimulated maximal increase in [3H]-inositol phosphates but did increase [3H]-cyclic adenosine monophosphate ([3H]-cAMP) accumulation (pEC50 6.77 ± 0.66); propranolol (30 nM) and ICI 118,551 (110 nM), but not atenolol (up to 3 μM), antagonized this effect. These responses may therefore be mediated through β2-like adrenoceptors. 5. These results show that the α1-adrenoceptor mediated and field stimulation-induced contractions of the guinea pig prostate are partly dependent upon intracellular and extracellular sources of Ca2+. We conclude that both β1- and β2-like adrenoceptors inhibit responses to phenylephrine in the prostate of the guinea pig. The β1-like adrenoceptor-mediated inhibition of these responses is evident upon the field stimulation-induced and nifedipine-sensitive component of the response to phenylephrine and may not involve the activation of adenylyl cyclase. The β2-like adrenoceptor may inhibit both nifedipine sensitive and insensitive components of the response to phenylephrine, possibly through the activation of adenylyl cyclase, but not through the inhibition of inositol phosphate accumulation.

Original languageEnglish
Pages (from-to)1067-1074
Number of pages8
JournalBritish Journal of Pharmacology
Volume122
Issue number6
DOIs
Publication statusPublished - 1 Dec 1997
Externally publishedYes

Keywords

  • α-adrenoceptor
  • β-adrenoceptor
  • cAMP
  • Guinea pig prostate
  • Inositol phosphate

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