Pharmacological characterization of alpha adrenoceptor-mediated motor responses in the rat colon.

Abstract

Background: Inhibitory neuromuscular transmission in the gastrointestinal tract is mediated by intrinsic nitrergic and purinergic neurons. Purines activate G protein-coupled receptor P2Y₁ receptors, increasing intracellular Ca²⁺ that activates small conductance calcium-activated potassium (SK_Ca) channels. Little is known about the effect of adrenergic receptor activation on intestinal smooth muscle. In vascular tissue, stimulation of α-adrenoceptors causes smooth muscle contraction, while their effect on intestinal tissue is poorly understood. This study aimed to pharmacologically characterize the effect of α-adrenoceptor activation in the rat colon, which shares similar inhibitory pathways to the human colon.

Methods: Muscle bath experiments were performed with the rat proximal, mid, and distal colon oriented both circularly and longitudinally.

Results: The α₁-adrenoceptor agonist phenylephrine (PE) (10^-8-10^-5 M) evoked concentration-dependent relaxations of the intestinal smooth muscle from all regions and orientations. However, in the mid-circular colon at low PE concentrations, a contraction sensitive to 10^-5 M phentolamine (non-selective α-adrenoceptor blocker), the neural blocker tetrodotoxin (TTX; 10^-6 M), and atropine (10^-6 M) was recorded. PE-induced relaxations were insensitive to TTX (10^-6 M) and the nonselective β-adrenoceptor blocker propranolol (10^-6 M). In contrast, PE-induced relaxations were blocked by phentolamine (10^-5 M), prazosin (10^-6 M) (α₁-adrenoceptor blocker), and RS17053 (10^-6 M) (α_1A-blocker), but not by yohimbine (10^-6 M) (α₂-adrenoceptor blocker). Apamin (10^-6 M), a SK_Ca channel blocker, abolished PE-induced relaxations.

Conclusions: Contractile responses in the circular muscle of the mid colon could be attributed to α-adrenoceptors located on enteric cholinergic neurons. Stimulation of α_1A-adrenoreceptors activates SK_Ca channels to cause smooth muscle relaxation, which constitutes a signaling pathway that shares similarities with P2Y₁ receptors.