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HORMONES AND SIGNALING

Angiotensin receptors and actions in guinea pig enteric nervous system

Department of Physiology and Cell Biology, The Ohio State University, College of Medicine and Public Health, Columbus, Ohio

Submitted 18 March 2005 ; accepted in final form 24 May 2005

Actions of ANG II on electrical and synaptic behavior of enteric neurons in the guinea pig small intestine were studied. Exposure to ANG II depolarized the membrane potential and elevated neuronal excitability. The number of responding neurons was small, with responses to ANG II in 32% of submucosal neurons and 25% of myenteric neurons. Hyperpolarizing responses were evoked by ANG II in 45% of the neurons. The hyperpolarizing responses were suppressed by ₂-noradrenergic receptor antagonists, which suggested that the hyperpolarizing responses reflected stimulation of norepinephrine release from sympathetic neurons. Exposure to ANG II enhanced the amplitude and prolonged the duration of noradrenergic inhibitory postsynaptic potentials and suppressed the amplitude of both fast and slow excitatory postsynaptic potentials. The selective ANG II₁ receptor (AT₁R) antagonists, ZD-7115 and losartan, but not a selective AT₂R antagonist (PD-123319), suppressed the actions of ANG II. Western blot analysis and RT-PCR confirmed expression of AT₁R protein and the mRNA transcript for the AT₁R in the enteric nervous system. No expression of AT₂R protein or mRNA was found. Immunoreactivity for AT₁R was expressed by the majority of neurons in the gastric antrum and small and large intestine. AT₁R immunoreactivity was coexpressed with calbindin, choline acetyltransferase, calretinin, neuropeptide Y, and nitric oxide synthase in subpopulations of neurons. The results suggest that formation of ANG II might have paracrine-like actions in the enteric nervous system, which include alterations in neuronal excitability and facilitated release of norepinephrine from sympathetic postganglionic axons. The enhanced presence of norepinephrine is expected to suppress fast and slow excitatory neurotransmission in the enteric microcircuits and to suppress neurogenic mucosal secretion.

gastrointestinal tract; enteric nervous system; myenteric plexus; submucosal plexus; sympathetic nervous system; angiotensin II; inflammation; irritable bowel syndrome