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.
Department of Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa 19406-0939.
E D
ED
Motley
R R
RR
Ruffolo
A J
AJ
Nichols
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