Increasing evidence supports the role of atrial natriuretic factor (ANF) in the modulation of gastrointestinal physiology. The effect of ANF on exocrine pancreatic secretion and the possible receptors and pathways involved were studied in vivo. Anesthetized rats were prepared with pancreatic duct cannulation, pyloric ligation, and bile diversion into the duodenum. ANF dose-dependently increased pancreatic secretion of fluid and proteins and enhanced secretin and CCK-evoked response. ANF decreased chloride secretion and increased the pH of the pancreatic juice. Neither cholinergic nor adrenergic blockade affected ANF-stimulated pancreatic secretion. Furthermore, ANF response was not mediated by the release of nitric oxide. ANF-evoked protein secretion was not inhibited by truncal vagotomy, atropine, or Nomega-nitro-l-arginine methyl ester administration. The selective natriuretic peptide receptor-C (NPR-C) receptor agonist cANP-(4-23) mimicked ANF response in a dose-dependent fashion. When the intracellular signaling coupled to NPR-C receptors was investigated in isolated pancreatic acini, results showed that ANF did not modify basal or forskolin-evoked cAMP formation, but it dose-dependently enhanced phosphoinositide hydrolysis, which was blocked by the selective PLC inhibitor U-73122. ANF stimulated exocrine pancreatic secretion in the rat, and its effect was not mediated by nitric oxide or parasympathetic or sympathetic activity. Furthermore, CCK and secretin appear not to be involved in ANF response. Present findings support that ANF exerts a stimulatory effect on pancreatic exocrine secretion mediated by NPR-C receptors coupled to the phosphoinositide pathway.
Abstract-Angiotensin (Ang)-(1-7) elicits a facilitatory presynaptic effect on peripheral noradrenergic neurotransmission, and because biological responses to the heptapeptide on occasion are tissue specific, the present investigation was undertaken to study its action on noradrenergic neurotransmission at the central level. In rat hypothalamus labeled with [ 3 H]-norepinephrine, 100 to 600 nmol/L Ang-(1-7) diminished norepinephrine released by 25 mmol/L KCl. This effect was blocked by the selective angiotensin type 2 receptor antagonist PD 123319 (1 mol/L) and by the specific Ang-(1-7) receptor antagonist ]Ang-(1-7) (1 mol/L) but not by losartan (10 nmol/L to 1 mol/L), a selective angiotensin type 1 receptor antagonist. The inhibitory effect on noradrenergic neurotransmission caused by Ang-(1-7) was prevented by 10 mol/L N -nitro-L-arginine methylester, an inhibitor of nitric oxide synthase activity, and was restored by 100 mol/L L-arginine, precursor of nitric oxide synthesis. Methylene blue (10 mol/L), an inhibitor of guanylate cyclase considered as the target of nitric oxide action, as well as Hoe 140 (10 mol/L), a bradykinin B 2 -receptor antagonist, prevented the inhibitory effect of the heptapeptide on neuronal norepinephrine release, whereas no modification was observed in the presence of 0.1 to 10 mol/L indomethacin, a cyclooxygenase inhibitor. Our results indicate that Ang-(1-7) has a tissue-specific neuromodulatory effect on noradrenergic neurotransmission, being inhibitory at the central nervous system by a nitric oxide-dependent mechanism that involves angiotensin type 2 receptors and local bradykinin production. Key Words: angiotensin Ⅲ norepinephrine Ⅲ nitric oxide Ⅲ angiotensin antagonist Ⅲ bradykinin Ⅲ prostaglandins A ngiotensin (Ang)-(1-7) is considered a bioactive end product of the renin-angiotensin system formed from Ang I metabolism through an enzymatic pathway independent of the angiotensin-converting enzyme. 1 It can be formed either from Ang I or Ang II by a prolyl-endopeptidase that cleaves the Pro-Phe bond. 1,2 Ferrario and coworkers 2 demonstrated the presence of Ang-(1-7) in several regions of the rat brain such as the hypothalamus, amygdala, and medulla oblongata but not in the cerebral cortex and cerebellum. In addition, type 1 (AT 1 ) and type 2 (AT 2 ) Ang receptors were described in several regions and nucleus of the central nervous system, including the hypothalamus. 3,4 Although Ang-(1-7) is not an agonist in terms of activating vasoconstriction, 5 stimulating thirst, 6 or promoting aldosterone secretion, 5 the heptapeptide causes neuronal excitation in the paraventricular nucleus of hypothalamus and dorsal vagal complex of the medulla oblongata, 7 facilitates the noradrenergic neurotransmission, 8 and stimulates prostaglandin 9 -11 and vasopressin release 12 with potency comparable to that of Ang II. Conversely, some of the effects of Ang-(1-7) are opposite to those elicited by Ang II, that is, it displays an antiproliferative action on vascular smooth muscle cells, 13 produ...
The cardiac polypeptide hormones atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) are synthesized and costored by atrial cardiocytes and share receptors and many biologic properties. Although some aspects of their synthesis and release are specific for each peptide, it is not clear whether they share intracellular sorting and secretory mechanisms. In the present work we take advantage of a stable isolated rat atrial preparation that allows, for the first time, long-term study of synthesis, trafficking, targeting, and secretion of ANF and BNP by adult atrial muscle. Three model stimuli of secretion were used: increased intra-atrial pressure, endothelin-1 (ET-1), and phenylephrine (PE), representing mechanical, hormonal, and α1-adrenergic stimuli, respectively. To gain further insight into the secretory process under basal and agonist-induced secretion, we employed agents known to inhibit protein synthesis (cycloheximide) or to interfere with the vectorial transport of protein targeted for secretion (brefeldin A and monensin). All these agents induced significant changes in ANF and BNP release. Cycloheximide decreased natriuretic peptide secretion under basal and stimulated conditions. Brefeldin A dramatically increased basal as well as stimulated secretion of ANF and BNP. Monensin partially decreased basal ANF and BNP secretion and completely blocked stimulated secretion. None of these agents modified proteolytic processing as assessed by reverse-phase HPLC analysis. Double-label pulse-chase experiments using [3H]- and [14C]leucine demonstrated that the secretory response to ET-1, in contrast to the response to muscle stretch, is based on peptide other than newly synthesized or relatively newly stored ANF. It is concluded that, in adult atrial cardiocytes, ANF and BNP are sorted to constitutive and regulated pathways in a manner that is substantially unique for atrial cardiocytes. In particular, it appears that basal and stimulated ANF and BNP secretion may have a large “constitutive-like” component, as previously defined in other endocrine systems. This type of secretion is based on the preferential release of hormone through vesicles arising from immature secretory granules. The capacity of the atria to release ANF and BNP in response to stimuli, therefore, may depend more on stimulation of the rate of formation of immature granules than on the amount of stored hormone.
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