Investigation of postjunctional alpha1- and alpha2-adrenoceptor subtypes in vas deferens from wild-type and alpha(2A/D)-adrenoceptor knockout mice.
1. The subtypes of alpha(1)- and alpha(2)-adrenoceptor mediating contractions of vas deferens have been examined in wild-type and alpha(2A/D)-adrenoceptor knockout mice. 2. Maximum contractions to noradrenaline but not phenylephrine were significantly greater in vas from wild-type. The alpha(1A)-adrenoceptor antagonist RS100329 (5-methyl-3-[3-[4-[2-(2,2,2,-trifluoroethoxy)phenyl]-1-piperazinyl]propyl]-2,4-(1H)-pyrimidinedione) (10 nM) significantly shifted the potency of noradrenaline. The alpha(2D)-adrenoceptor antagonist BRL 44408 (2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole) significantly reduced the maximum contraction to noradrenaline in wild-type but not in knockout. 3. Following prazosin (0.1 micro M), a component of the contraction to noradrenaline in wild-type but not in knockout was sensitive to the alpha(2)-adrenoceptor antagonist yohimbine. 4. Nifedipine (10 micro M) or suramin (100 micro M) reduced the contraction to 10 Hz stimulation for 4 s to an early peak and small maintained response. The peak was abolished by the alpha(1)-adrenoceptor antagonist prazosin. 5. RS100329 or prazosin inhibited 10 Hz stimulation evoked contractions with a U-shaped concentration-response curve: inhibiting responses up to 0.1 micro M, with a reversal of inhibition above this concentration. In the presence of suramin or nifedipine, the reversal of inhibition by high concentrations of prazosin was reduced. 6. The alpha(1D)-adrenoceptor selective antagonist BMY7378 (8-[2-(4-(2- methoxyphenyl)piperazin-1-yl)ethyl]-8-azaspiro[4,5]decane-7,9-dione) produced inhibition of 10 Hz evoked contractions only in high concentrations. 7. In conclusion, contractions to nerve stimulation in mouse vas deferens involve largely alpha(1A)-adrenoceptors and purinoceptors. alpha(1)-Adrenoceptor antagonists in high concentrations increase the purinergic response presumably by blocking prejunctional alpha(2)-adrenoceptor-mediated inhibition. In the presence of nifedipine, responses are predominantly alpha(1)-adrenoceptor mediated. Contractions to exogenous noradrenaline involved both alpha(1A)- and alpha(2A/D)-adrenoceptors in wild-type mice.
Cleary
Linda
L
Department of Physiology, Royal College of Surgeons in Ireland, 123 St Stephen's Green, Dublin 2, Ireland.
Vandeputte
Catherine
C
Docherty
James R
JR
D058668:Adrenergic alpha-1 Receptor Antagonists; D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D004558:Electric Stimulation; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D007537:Isometric Contraction; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D009638:Norepinephrine / Q000493:pharmacokinetics*; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000502:physiology*; D013498:Suramin / Q000494:pharmacology; D013941:Thymine / Q000494:pharmacology; D014649:Vas Deferens / Q000737:chemistry / Q000502:physiology*; D015016:Yohimbine / Q000494:pharmacology
D058668:Adrenergic alpha-1 Receptor Antagonists; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D010879:Piperazines; C120711:RS 100329; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D011983:Receptors, Purinergic; D010656:Phenylephrine; D015016:Yohimbine; D013498:Suramin; D003042:Cocaine; D009543:Nifedipine; C053428:BMY 7378; D013941:Thymine; D009638:Norepinephrine; D011224:Prazosin; C072125:BRL 44408