EFFECTS OF PHENOXYBENZAMINE ON RESPONSES TO SOME RECEPTOR AGONISTS AND CALCIUM IN VITRO

Abstract

Noradrenaline-induced contractions of the rabbit and rat isolated aorta and guinea-pig spleen strips were inhibited by concentrations of phenoxybenzamine which did not affect responses to calcium. This may suggest a specific action on alpha-adrenoceptors. However, analysis of noradrenaline concentration-effect curves in guinea-pig spleen indicated that 1 mumol/l phenoxybenzamine should have reduced the available receptor population to 6% of control, but data from radioligand binding experiments on the same tissues using [3H]-prazosin indicated a reduction of the receptor population to only 82% of control. The reduced responsiveness observed in the organ bath study after phenoxybenzamine pretreatment, whilst not apparently related to effects on voltage-dependent calcium channels, could be due to the actions of phenoxybenzamine on other (non-receptor) processes such as receptor-operated calcium channels. Maximal contractile responses to histamine in rabbit isolated aorta but not those in guinea-pig isolated ileal preparations, were depressed by concentrations of phenoxybenzamine which depressed responses to calcium. Phenoxybenzamine produced parallel rightward shifts of curves to carbachol in guinea-pig ileal preparations but only depressed maximal responses to the agonist in higher concentrations which reduced responses to calcium. On the basis of the results obtained with calcium it is possible that the effects of phenoxybenzamine on receptor-mediated responses could be produced through the actions of this antagonist at less specific sites such as voltage-dependent calcium channels for histamine in rabbit aorta and carbachol in guinea-pig ileum. For alpha-receptor mediated responses in aortic and splenic strip preparations and for histamine-mediated responses in guinea-pig ileum, the actions of phenoxybenzamine may reflect an interaction of the antagonist with receptor-operated calcium channels.

Quantitative systems pharmacology analysis of drug combination and scaling to humans: the interaction between noradrenaline and vasopressin in vasoconstriction

“…The effect of phenoxybenzamine was characterized by two independent terms, which respectively refers to (i) the inactivation effect on α 1A -adrenoceptors and (ii) the inhibition effect on the common signal transducer for both noradrenaline and AVP stimulus to account for phenoxybenzamine caused contraction decrease for both noradrenaline and AVP. This is in accordance with the underlying mechanism that phenoxybenzamine as a nonselective irreversible α-adrenoceptor blocker has well-established inhibitory effect on noradrenaline through α 1A -adrenoceptors (Van der Graaf and , and phenoxybenzamine was also reported previously to have an inhibition effect on calcium channels (Gengo et al, 1984;McPherson et al, 1985) and calmodulin (Conant et al, 2003). These latter mechanisms were considered to contribute to phenoxybenzamine inhibition of AVP-induced contraction shown in Figure 2D as well as on noradrenaline, as calcium is a common signal transducer of noradrenaline and AVP (Mauger et al, 1984).…”

“…Experimental design. In general, SMAs were exposed in vitro to single or combined challenges of noradrenaline and AVP in varying concentrations, with or without pretreatment with phenoxybenzamine, a non-selective irreversible α-adrenoceptor blocker which also has a possible effect on calcium channels (Gengo et al, 1984;McPherson et al, 1985).…”

Effects of cervical sympathetic nerve stimulation and neuropeptide Y (NPY) on cranial blood flow in the cat

“…At high doses, phenoxybenzamine blocks not only alpha-adrenoceptors, but may also inhibit the responses to several other agents, such as acetylcholine, histamine and dopamine (see Gengo et al 1984). These effects of phenoxybenzamine have been attributed to an interference with Ca2' channels (Gengo et al 1984, McPherson et al 1985. As the vasoconstrictive effects of NPY can be reduced by Cazt antagonists (Edvinsson et al 1983, Pernow et al 1986, Mejia et al 1988, one may speculate that phenoxybenzamine in the present experiments could have diminished the effect of NPY due to interference with Ca2+ channels.…”