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 retu rn the blood volume to normal. This response is mediated at least in p art by the release of atrial natriuretic peptide (ANP) into the circul ation. Previous experiments have shown the participation of the anteri or 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 re lease of ANP. In the present experiments, microinjection of norepineph rine into the AV3V region induced natriuresis and an increase in plasm a ANP. To determine whether cholinergic and alpha-adrenergic pathways are crucial to the volume expansion-induced release of ANP, certain re ceptor-blocking drugs were injected into the AV3V region of conscious rats. Thirty minutes later blood volume was expanded by intravenous in jection of 2.0 ml/100 g of body weight of hypertonic saline (0.3 M NaC l). Microinjection of isotonic saline (2 mul) into AV3V region of cont rol animals 30 min prior to volume expansion had no effect on the 3-fo ld increase in plasma ANP concentrations measured 5 min after volume e xpansion. In contrast, although the receptor-blocking drugs did not al ter the initial concentrations of plasma ANP 30 min later, just prior to volume expansion, blockade of muscarinic cholinergic receptors by i ntraventricular injection of 5 nmol (2 mul) of atropine sulfate or met hylatropine markedly reduced the response to volume expansion but did not obliterate it. Microinjection of the alpha receptor blocker phento lamine (5 nmol) into the AV3V 30 min prior to volume expansion also ma rkedly suppressed the ANP response. Intraperitoneal (i.p.) injection o f methylatropine (0.01 mmol/100 g of body weight), which does not cros s 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 block ade of the response to volume expansion induced by intraventricular in jection of methylatropine, the response to volume expansion was marked ly enhanced by i.p. injection of methylatropine. The results therefore indicate that hypothalamic muscarinic and alpha-adrenergic synapses a re essential to release of ANP in response to volume expansion. These results are consistent with a hypothetical pathway for physiological c ontrol of ANP release which involves distension of baroreceptors withi n the right atria, carotid and aortic sinuses, and kidney which alters afferent input to brain stem noradrenergic neurons with axons project ing to the AV3V region. There they activate cholinergic interneurons b y an al-adrenergic synapse. The cholinergic neurons in turn stimulate ANP neurons in this brain region via muscarinic receptors. The stimula tion of these neurons activates efferent pathways which induce the rel ease of ANP.