Essential Role of Hypothalamic Muscarinic and Alpha-adrenergic Receptors in Atrial Natriuretic Peptide Release Induced by Blood Volume Expansion

Expansion of the blood volume induces natriuresis, which tends to return the blood volume to normal. This response is mediated at least in part by the release of atrial natriuretic peptide (ANP) into the circulation. Previous experiments have shown the participation of the anterior ventral third ventricular (AV3V) region of the hypothalamus in the ANP release that follows volume expansion. When injected into the AV3V region, the cholinergic drug carbachol induces natriuresis and the release of ANP. In the present experiments, microinjection of norepinephrine into the AV3V region induced natriuresis and an increase in plasma ANP. To determine whether cholinergic and alpha-adrenergic pathways are crucial to the volume expansion-induced release of ANP, certain receptor-blocking drugs were injected into the AV3V region of conscious rats. Thirty minutes later blood volume was expanded by intravenous injection of 2.0 ml/100 g of body weight of hypertonic saline (0.3 M NaCl). Microinjection of isotonic saline (2 microliters) into AV3V region of control animals 30 min prior to volume expansion had no effect on the 3-fold increase in plasma ANP concentrations measured 5 min after volume expansion. In contrast, although the receptor-blocking drugs did not alter the initial concentrations of plasma ANP 30 min later, just prior to volume expansion, blockade of muscarinic cholinergic receptors by intraventricular injection of 5 nmol (2 microliters) of atropine sulfate or methylatropine markedly reduced the response to volume expansion but did not obliterate it. Microinjection of the alpha receptor blocker phentolamine (5 nmol) into the AV3V 30 min prior to volume expansion also markedly suppressed the ANP response. Intraperitoneal (i.p.) injection of methylatropine (0.01 mmol/100 g of body weight), which does not cross the blood-brain barrier, also did not affect the basal levels of ANP 30 min after i.p. injection. But, in striking contrast with the blockade of the response to volume expansion induced by intraventricular injection of methylatropine, the response to volume expansion was markedly enhanced by i.p. injection of methylatropine. The results therefore indicate that hypothalamic muscarinic and alpha-adrenergic synapses are essential to release of ANP in response to volume expansion. These results are consistent with a hypothetical pathway for physiological control of ANP release which involves distension of baroreceptors within the right atria, carotid and aortic sinuses, and kidney which alters afferent input to brain stem noradrenergic neurons with axons projecting to the AV3V region. There they activate cholinergic interneurons by an alpha 1-adrenergic synapse. The cholinergic neurons in turn stimulate ANP neurons in this brain region via muscarinic receptors. The stimulation of these neurons activates efferent pathways which induce the release of ANP.