Alpha1-adrenoceptor subtypes involved in vasoconstrictor responses to exogenous and neurally released noradrenaline in rat femoral resistance arteries.
1. The alpha(1)-adrenoceptor subtypes involved in responses to exogenous and neurally released noradrenaline in rat femoral resistance arteries were characterised using a small vessel myograph, with antagonists prazosin (nonsubtype selective), 5-methyl-urapidil (alpha(1A)-selective), BMY 7378 (alpha(1D)-selective) and the alkylating agent chloroethylclonidine (preferential for alpha(1B)-). 2. Prazosin and 5-methyl-urapidil produced rightward shifts of the exogenous noradrenaline concentration - response curve (CRC) with pA(2) values of 9.2 and 9.1 respectively, in agreement with the presence of alpha(1A)-adrenoceptors. BMY 7378 (1 microm) shifted the noradrenaline CRC with an apparent pK(B) of 6.7, in agreement with the presence of alpha(1A)-, but not alpha(1D)-, adrenoceptors. Chloroethylclonidine at 1 microm had no effect and at 10 microm produced only a small reduction (c. 20%) in the maximum response to noradrenaline, indicating little, if any, contribution from alpha(1B)-adrenoceptors. 3. Responses of the rat femoral resistance arteries to electrical field stimulation (EFS) at 5-30 Hz for 10 s and 0.05 ms pulse width were principally due to alpha(1)-adrenoceptor stimulation. Prazosin and 5-methyl-urapidil inhibited EFS-mediated responses with pIC(50)s of 9.3 and 8.2, respectively, consistent with the alpha(1A)-adrenoceptor being the predominant subtype. Responses to EFS at 10-30 Hz were relatively insensitive to BMY 7378 (pIC(50), 6.5-6.7), while responses to 5 Hz were inhibited with a significantly higher pIC(50) of 8.02, suggesting the contribution of alpha(1D)-adrenoceptors. Chloroethylclonidine had no effect on responses to EFS, ruling out the contribution of an alpha(1B)-subtype. In the presence of cocaine, the predominant subtype involved in responses to EFS was the alpha(1A)-adrenoceptor, with a contribution from alpha(1D)-adrenoceptors at low frequency, as seen in the absence of cocaine. However, there was also a significant increase in the sensitivity to BMY 7378 at higher frequencies, suggesting that a further small alpha(1D)-adrenoceptor component may be uncovered in the presence of cocaine. 5. The present study has shown a predominant role of the alpha(1A)-adrenoceptor in contractions due to exogenous noradrenaline and to neurally released noradrenaline in rat femoral resistance arteries. alpha(1D)-Adrenoceptors are not involved in responses to exogenous noradrenaline but appear to be activated by neurally released noradrenaline at a low frequency of stimulation and at higher frequencies in the presence of neuronal-uptake blockade.
Department of Biological & Biomedical Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK.
Joseph
J
Zacharia
Chris
C
Hillier
Allan
A
MacDonald
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D003000:Clonidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003042:Cocaine; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005263:Femoral Artery / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply; D009638:Norepinephrine / Q000096:biosynthesis / Q000494:pharmacology / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology*; D014655:Vascular Resistance; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D014662:Vasoconstrictor Agents; C057446:5-methylurapidil; C051731:chlorethylclonidine; D003042:Cocaine; C053428:BMY 7378; D003000:Clonidine; D009638:Norepinephrine; D011224:Prazosin