The effect of pertussis toxin on α 1 ‐adrenoceptor‐mediated vasoconstriction by the full agonist, cirazoline, and the partial agonist, (‐)‐dobutamine, in pithed rats

Summary— The role of pertussis toxin‐sensitive guanine nucleotide regulatory proteins (G‐proteins) in the signal transduction process(es) involved in postjunctional vascular α 1 ‐adrenoceptor‐mediated vasoconstriction produced by the full agonist, cirazoline, and the partial agonist, (‐)‐dobutamine, have been investigated in the cardiovascular system of the pithed rat. Pertussis toxin pretreatment (50 μg/kg, iv, 3 days prior to experimentation) only slightly inhibited the pressor response of cirazoline, and the degree of inhibition produced by pertussis toxin was roughly equivalent to the inhibition produced by the calcium channel antagonist, nifedipine (1 mg/kg, ia). In contrast, pertussis toxin pretreatment produced marked inhibition of the α 1 ‐adrenoceptor‐mediated pressor response to the partial agonist, (‐)‐dobutamine, and this large degree of inhibition was qualitatively and quantitatively similar to the degree of inhibition produced by nifedipine. The differential pattern of inhibition of full and partial α 1 ‐adrenoceptor agonists by pertussis toxin suggests that the vasoconstrictor response of an α 1 ‐adrenoceptor partial agonist, which is more dependent upon the translocation of extracellular calcium than a full agonist, as evidenced by its sensitivity to inhibition by nifedipine, involves a pertussis toxin‐sensitive G‐protein that couples the α 1 ‐adrenoceptor to the calcium channel. Furthermore, for α 1 ‐adrenoceptor‐mediated vasoconstriction by full agonists with high intrinsic efficacy, which involves both intracellular and extracellular pools of calcium, and particularly the former, pertussis toxin only inhibits that component of the α 1 ‐adrenoceptor response which is dependent upon the translocation of extracellular calcium, accounting for the limited degree of inhibition of the response to cirazoline by pertussis toxin and by nifedipine. By inference, the other component of the α 1 ‐adrenoceptor‐mediated pressor response to a full agonist, which is dependent upon the mobilization of intracellular stores of calcium through a process believed to involve the activation of phospholipase C, likely utilizes a pertussis toxin insensitive G‐protein that is distinct from that which we propose couples the α 1 ‐adrenoceptor to the calcium channel. We conclude, therefore, that the α 1 ‐adrenoceptor in the vasculature of the pithed rat may be coupled to 2 distinct G‐proteins, only one of which is sensitive to inhibition by pertussis toxin and links the α 1 ‐adrenoceptor to the membrane calcium channel, and which may be utilized by both full agonists and partial agonists.