Role of the postsynaptic α2-adrenergic receptor subtypes in catecholamine-induced vasoconstriction

Abstract

Catecholamines induce direct vasoconstriction mediated by postsynaptic α-adrenergic receptors (α-ARs) of both the α₁ and α₂ type. To evaluate the contribution of each α₂-AR subtype (α_2A, α_2B, and α_2C) to this function, we used groups of genetically engineered mice deficient for the gene to each one of these subtypes and compared their blood pressure (BP) responses to their wild-type counterparts. Blood pressure responses to a bolus of norepinephrine (NE) were assessed before and after sequential blockade of α₁-ARs with prazosin and α₂-ARs with yohimbine. The first NE bolus elicited a brief 32 to 44 mm Hg BP rise (p < 0.001 from baseline) in all six groups. Prazosin decreased BP by 23 to 33 mm Hg in all groups, establishing a new lower baseline. Repeat NE at that point elicited lesser but still significant (p < 0.001) brief pressor responses between 32% and 45% of the previous BP rise in five of the six groups. Only the α_2A-AR gene knockouts differed, responding instead with a 20-mm Hg fall in BP, a significant change from baseline (p < 0.001) and different from the pressor response of their wild-type counterparts (p < 0.001). The addition of yohimbine produced no further BP change in the five groups, but it did produce a small 7.5-mm Hg fall (p < 0.05) in the α_2A-AR knockouts. Norepinephrine bolus during concurrent α₁ and α₂-AR blockade produced significant (p < 0.001) hypotensive responses in all subgroups, presumably attributable to unopposed stimulation of β₂-vascular wall ARs. We conclude that the α₂-AR-mediated vasoconstriction induced by catecholamines is attributable to the α_2A-AR subtype because mice deficient in any one of the other subtypes retained the capacity for normal vasoconstrictive responses. However, the α₁-ARs account for the major part (as much as 68%) of catecholamine-induced vasoconstriction.