Role of β 1-, β 2-, and β 3-adrenoceptors in contractile hypersensitivity in a model of small bowel transplantation

Chronic extrinsic denervation induced by small bowel transplantation (SBT) results in adrenergic hypersensitivity in rat ileum. This study evaluated the role of neuronal and/or muscular β 1-, β 2-, and β 3-adrenoceptor (AR) mechanisms on contractility. Ileal longitudinal muscle strips from Lewis rats ( n = 6 rats per group, 8 strips per rat): naïve controls (NC), 4 months after sham operation (SC) or after syngeneic orthotopic SBT were studied in vitro. Spontaneous contractile activity and dose responses (10 −8-10 −4 mol) to isoprenaline (IP), a nonspecific β-AR agonist were studied with or without selective antagonists (10 −5 mol), for β 1- (atenolol), β 2- (ICI 118551), or β 3- (SR 59230A) AR subtypes in the presence or absence of tetrodotoxin (TTX; 10 −6 mol; nerve blocker). pEC 50 (neg log of EC 50, which is the concentration where 50% of inhibition was observed) of IP was 7.2 ± 0.2 (mean value ± SEM) in SBT vs 6.3 ± 0.1 in SC and 6.3 ± 0.2 in NC (both P < .05 vs SBT), reflecting adrenergic hypersensitivity. β 1- and β 2-AR blockade induced a TTX-sensitive right shift of the curve only in SBT and normalized pEC 50 values from 7.2 ± 0.2 to 6.4 ± 0.1 and 7.2 ± 0.2 to 6.6 ± 0.1, respectively ( P < .05). β 3-AR blockade shifted the curve independent of the presence of TTX to the right in all groups (all P < .05). In rat ileum, adrenergic inhibition of contractility was dependent on muscular β 3-AR pathways, whereas posttransplant hypersensitivity was due to upregulated neuronal β 1- and β 2-AR mechanisms that were inactive before SBT.