The effect of pertussis toxin treatment on alpha-1-adrenoceptor-mediated pressor responses in the pithed rat: dependence on agonist efficacy but not chemical class.
The role of pertussis-toxin-sensitive guanine nucleotide regulatory proteins (G proteins) in the signal transduction processes involved in post-junctional vascular alpha 1-adrenoceptor-mediated vasoconstriction has been investigated in the pithed rat using two chemical classes of alpha-adrenoceptor agonists, the phenethylamines and imidazolines, in order to determine if they utilize different signal transduction mechanisms. Pertussis toxin pretreatment (50 micrograms/kg, i.v., 3 days prior to experimentation) slightly inhibited the pressor response to the full alpha 1-adrenoceptor agonist of the phenethylamine class (-)-norepinephrine (in the presence of rauwolscine, 1 mg/kg, i.v.), whereas it markedly inhibited the pressor response to the partial alpha 1-adrenoceptor agonist of the imidazoline class oxymetazoline (in the presence of rauwolscine, 1 mg/kg, i.v.). However, after elimination of the alpha 1-adrenoceptor reserve for (-)-norepinephrine with phenoxybenzamine (0.1 mg/kg, i.v.), the pressor response to this agonist became sensitive to inhibition by pertussis toxin treatment. The pattern of inhibition of alpha 1-adrenoceptor-mediated pressor responses produced by pertussis toxin was similar to that produced by the calcium channel antagonist nifedipine (1 mg/kg, i.a.). The results support the hypothesis that vascular alpha 1-adrenoceptors may be coupled to a G protein which is sensitive to pertussis toxin and which couples the alpha 1-adrenoceptor to the influx of extracellular calcium, which possibly another G protein that is insensitive to pertussis toxin that couples the alpha 1-adrenoceptor to the release of intracellular calcium. The intrinsic efficacy of the agonist, and not its chemical class, determines which signal transduction mechanisms will be utilized.
Motley
E D
ED
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa 19406-0939.
Ruffolo
R R
RR
Nichols
A J
AJ
D000316:Adrenergic alpha-Agonists / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D003655:Decerebrate State / Q000503:physiopathology; D019204:GTP-Binding Proteins / Q000502:physiology; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D037342:Pertussis Toxin; D051381:Rats; D017207:Rats, Sprague-Dawley; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D000316:Adrenergic alpha-Agonists; D011942:Receptors, Adrenergic, alpha; D010566:Virulence Factors, Bordetella; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D009543:Nifedipine