To examine this hypothesis, the author's laboratory developed a fluorocarbon perfused rat heart—lung circuit in which venous return and right atrial stretch were regulated to simulate an increase in blood volume [16]. Hearts were perfused at both low and high levels of venous return and the atria were observed to expand markedly at the higher pressure.
Fluorocarbon perfusates from these two experiments were then infused into the abdominal aorta of anesthetized bioassay rats to assess natriuretic activity. As shown in the Fig. These experiments were the first to suggest that ANP is regulated by atrial distension and further suggested that cardiac innervation was not essential to natriuretic hormone secretion.
This hypothesis was strengthened shortly thereafter by both in vitro and in vivo studies. Lang et al. They also demonstrated that the plasma concentration of ANP increases in response to volume expansion in anesthetized rats [17]. Experiments in choralose-anesthetized dogs [18] demonstrated that mitral valve obstruction, which produces atrial distension, increased plasma ANP levels and this response was not attenuated by vagotomy.
These experiments again supported the atrial stretch hypothesis and further showed that the release of ANP from the heart did not require cardiac reflexes. ANP was found to increase in humans with water immersion [19] and in clinical conditions such as heart failure [20] and renal failure [21]. The elevated ANP concentrations in each of these conditions correlate with the degree of atrial distension. In addition, contraction rate has been suggested to stimulate ANP secretion [22].
However, this effect could be attributed to the effect of frequency of contraction on extracellular translocation of ANP which has been shown by Cho et al.
Cho et al. Atrial stretch enhanced natriuretic activity in rat heart perfusates. Gene expression is also an important determinate of ANP secretion since the total amount of ANP stored will ultimately effect the quantity of the molecule released into the plasma. ANP secretion is substantially augmented in experimental animals with cardiac hypertrophy or heart failure where gene expression of the hormone is increased in both the atria and ventricles [25].
ANP gene expression can be up-regulated by glucocorticoids and mineralocorticoids which also enhance ANP secretion [26,27]. By contrast, adrenomedullin inhibits ANP gene expression in rat cardiomyocytes [28]. Hypoxia or ischemia is one of the most potent stimuli for ANP secretion [29—31] and it has been suggested that release of atrial natriuretic peptides could play an important role in the nocturia associated with sleep apnea [32].
The release of ANP in response to cardiac ischemia can be viewed as an important homeostatic mechanism since ANP can produce cardiac vasodilatation to increase blood flow and oxygen delivery to the heart as well as peripheral vasodilatation to reduce arterial pressure. The reduction in cardiac afterload will then result in a beneficial reduction in cardiac oxygen demand.
This response has been attributed, at least in part, to both alpha and beta-adrenergic stimulation of ANP release [30] but more recently endothelins have been implicated in this response. Our laboratory demonstrated that much of the increase in ANP secretion induced by ischemia could be attributed to the release of endothelins [33]. It should also be pointed out that during the recovery normoxia period, ANP secretion returned to base line as did atrial hemodynamics.
Very recent studies attribute the nocturia seen with obstructive sleep apnea to increased secretion of ANP [34]. Plasma ANP levels in this sleep apnea study correlated directly with the degree of hypoxemia but also could be stimulated by hemodynamic mechanisms such as pulmonary hypertension, which elevates right heart pressures.
Also, myocardial infarction leads to acute cardiac ischemia and a profound increase in the release of ANP in both animals [35] and humans [36]. Atrial natriuretic peptide ANP secretion from isolated perfused rat atria was stimulated by hypoxia. One of the most potent stimuli for ANP secretion is the endothelial cell derived peptide, endothelin Lew and Baertschi [37,38] demonstrated this important relationship by co-culturing cardiac myocytes and endothelial cells, which resulted in enhanced ANP secretion.
Fukuda et al. Skvorak et al. Furthermore, they showed that a specific endothelin-1 receptor antagonist attenuates the ANP response to atrial stretch [40] , thus demonstrating that endothelin plays an essential paracrine role in the stretch-activated ANP secretory process.
High atrial pressure 8—10 mmHg produced a marked increase in ANP secretion 30—60 min compared to the low atrial pressure control period 30 min. Endothelin further augmented this response when added while atrial pressure was elevated 60—90 min.
Atrial natriuretic peptide ANP secretion from rat atria in response to atrial stretch High Press and 50 nM endothelin-1, redrawn from Pollack et al. Many years ago, experiments in animals showed that when acetylcholine was injected intravenously there was a pronounced vasodilatation and a significant drop in arterial blood pressure. This phenomenon was later attributed [42] to the release of an endothelial cell derived relaxing factor that has subsequently been identified as nitric oxide NO.
NO is a potent vasodilator which is produced from l -arginine and increases the production of cGMP in both cardiac muscle and vascular smooth muscle [43]. Stimulation of cGMP in the heart inhibits ANP secretion and decreases cardiac contractility and has been most recently shown as the mediator of the inhibitory action of C-type natriuretic peptide on ANP release [44]. Furthermore, inhibition of NO with methylene blue augments ANP secretion from isolated rat atria [46].
Experiments from our laboratory in the isolated perfused rat atria helped to confirm the hypothesis that NO inhibits ANP secretion [47]. We found Fig. Adding acetylcholine to the bath, which is known to stimulate NO synthesis, markedly attenuated the stretch-induced increase in ANP secretion [47].
In the same study [47] , acetylcholine did not depress basal ANP secretion in the isolated atria at low atrial pressure unstretched. There is some controversy as to whether these important regulatory hormones have significant direct effects on ANP secretion or alter secretion indirectly through their ability to produce vasoconstriction and affect venous return or cardiac afterload. Ruskoaho et al. Previous experiments from the author's laboratory using an isolated rat heart—lung preparation clearly showed that increasing venous return preload or increasing aortic pressure afterload would stimulate ANP secretion from the heart [49].
Katsube et al. However, Lachance and Garcia, [51] found an increase in plasma ANP in rats with angiotensin infusion at doses that did not alter atrial or left ventricular end-diastolic pressures. In vitro studies have also produced contradictory results. Several investigators failed to find any effect of angiotensin on ANP secretion in isolated tissues or primary cell cultures [52—54] while others have shown stimulation of ANP secretion by angiotensin [55—59]. There have been similar disagreements in regard to the effects of antidiuretic hormone vasopressin on ANP secretion in vitro.
Sonnenberg and colleagues [55,60,61] initially reported that vasopressin increased ANP secretion in cell cultures but later reported [51] that vasopressin inhibited ANP secretion from isolated rat hearts.
Our laboratory [52] found no significant effect of vasopressin on ANP secretion in the isolated rat heart—lung preparation. Clearly, several vasoconstrictor hormones including norepinephrine, epinephrine, angiotensin II and vasopressin can increase ANP secretion by indirect mechanisms related to vasoconstriction and increased atrial and ventricular stretch.
However, it has not been established conclusively whether these hormones possess direct inhibitory or stimulatory effects on ANP secretion. Thus, the physiological role of vasoconstrictors modulating ANP secretion is unclear and requires additional study. Opiods have been shown to increase ANP secretion in vivo and in isolated atria [62,63]. Crticotropin releasing factor also stimulates ANP secretion by what appears to be a direct receptor-mediated mechanism [64]. Although the precise physiological role for these hormones in regulating ANP release in not known, they could likely contribute to the marked stimulation of ANP secretion seen in ischemia and myocardial infarction.
Since atrial muscle stretch has been determined to be an important physiological mechanism controlling the secretion of ANP, the cellular mechanisms that transduce this response have been a topic of intensive study [48].
These lines of investigation have led to many seemingly contradictory results. However, what must be considered is the fact that the secretory process for ANP clearly involves at least four broadly defined steps: transduction of the signal at the cell membrane, integration of several intracellular messengers, processes involved in hormone packaging, trafficking and release and finally, extracellular fluid transport of the peptide.
All of these processes can potentially be affected by a given stimulus, for example, calcium or cyclic nucleotides. Laine et al. Recent evidence suggests that G proteins may act as important transducers of stretch activated ANP secretion. Bensimon et al. However, pertussis toxin did not block endothelin induced ANP secretion, which seems plausible since endothelin-1 is hypothesized to exert its effects on ANP secretion through a different G protein. Calcium clearly plays a central role in secretion mechanisms of many hormones but the evidence supporting a role for calcium in the secretion of ANP appears to be complex and not without significant contradictions.
Interestingly, BAY K , a calcium channel agonist that increases calcium entry into cardiac myocytes and increases cardiac contractility was found to stimulate ANP secretion in atrial myocyte cultures [71]. However, ryanodine, which inhibits calcium release from the sarcoplasmic reticulum, inhibited stretch-induced ANP secretion in atrial myocytes [74] and in the perfused rat atria [67] but did not affect basal release.
Thapsigargin, which inhibits sarcoplasmic reticulum calcium adenosine triphosphate and depletes intracellular calcium stores, does not alter basal ANP secretion but blocks stretch induced ANP release [75]. Based on their experiments in cultured rat atrial myocytes, Doubell and Thibault [76] postulated that calcium has a negative effect on ANP secretion under basal conditions but a positive modulatory role under conditions of stimulated sustained release.
Calcium depletion has been shown to decrease the stimulation of ANP secretion by phenylepherine and endothelin [54,77] in cultured myocytes but also attenuated the ANP inhibitory response to C-type natriuretic peptide and cGMP in vitro [44]. Calcium could potentially be involved at several points in the secretory process including transduction of the stretch signal, integration of multiple stimuli, granule formation, translocation, docking or release, prohormone processing and finally extracellular translocation of the hormone.
Further studies will be helpful in resolving the complex role of calcium in ANP release. It seems likely that basal ANP secretion may be regulated by calcium in a negative fashion as has been most clearly demonstrated for renin secretion from the kidneys [78]. Supporting this idea are two recent studies by Kim et al. Cyclic nucleotides act as important cellular messengers in the release of many hormones and in several cases cAMP and cGMP have opposing effects.
Gardner et al. Others have reported that prostaglandins are a potent stimulator of ANP secretion in rat ventricular myocytes [87,88] and rabbit atria sections [89]. The cyclooxygenase inhibitor, indomethacin, inhibits prostaglandin synthesis in vitro and reduces basal ANP secretion [61,90]. Another prostaglandin synthesis inhibitor, meclofenamate, had very similar inhibitory effects on ANP release [31,91].
Our laboratory demonstrated that indomethacin nearly completely blocked the ANP responses to ischemia and endothelin [33]. In a recent study, inhibition of cytochrome P arachidonate metabolites decreased basal ANP secretion in isolated perfused rat atria and inhibited endothelin stimulated ANP secretion in cultured rat myocytes [92].
Clearly, arachidonic acid metabolites play a key role in stimulus secretion coupling for ANP secretion. Several protein kinases have been implicated in the stimulus-secretion coupling for ANP secretion. Ruskoaho and Colleagues demonstrated that phorbol esters, which increase the cellular concentration of protein kinase C PKC , stimulate ANP secretion from the isolated rat heart [72]. Staurosporine, a protein kinase inhibitor, blocked Forskolin-induced inhibition of ANP secretion in the perfused rabbit atria [84].
Taskinen et al. However, in an earlier study they showed that another tyrosine kinase inhibitor, genistein, stimulated ANP release [94]. Studies suggest that calmodulin kinase is involved in a positive fashion in the secretory pathway [71,84]. In Fig. The lower panel of Fig. Thus, conversion of proANP to the various smaller peptides, including ANP, takes place during the secretion process and not at some peripheral site. In addition, there appears to be no significant differences in the processing of proANP into the smaller active peptides under either stretched or unstretched conditions [97].
High performance gel-permeation chromatography HP. Arrows indicate the elution positions of molecular weight calibrators, void V o and total volume V t. Each value represents the average of three experiments, from Dietz et al. Numerous studies focusing on the mechanisms regulating ANP secretion clearly show that, from a physiological standpoint, the most important factor affecting ANP secretion from the atria is mechanical stretch, which normally occurs when extracellular fluid volume or blood volume is increased.
A scheme for the stimulation of ANP secretion by atrial stretch or endothelin and inhibition of ANP secretion by nitric oxide is shown in Fig. Increases in atrial volume stimulate stretch-activated ion channels, which are most likely linked to a G o regulatory protein. One of the most dramatic increases in ANP release from the heart can be seen with cardiac ischemia, which appears to be mediated in part by endothelin The role of cell calcium on ANP secretion is less straightforward but basal ANP secretion appears to be inversely coupled to intracellular calcium release.
A more complete picture of the mechanical and cellular events regulating the release of ANP has provided a better understanding of its role in disease states such as cardiac ischemia and heart failure. Proposed scheme for stimulation of ANP secretion by stretch and endothelin and inhibition by acetylcholine. Field L. Veress A. Steinhelper M. Cochrane K. Sonnenberg H. Google Scholar. John S. Krege J. Oliver P. Hagaman J. Hodgin J. Pang S.
Genetic decreases in atrial natriuretic peptide and salt-sensitive hypertension Science Klinger J. Warburton R. Pietras L. Swift R. Hill N. Exaggerated pulmonary hypertensive responses during chronic hypoxia in mice with gene-targeted reductions in atrial natriuretic peptide Chest 79S 80S. Zhao L. Long L. Morrell N. Watkins M. NPR-A deficient mice show increased susceptibility to hypoxia-induced pulmonary hypertension Circulation 99 Lin K.
Chao J. Chao L. Atrial natriuretic peptide gene delivery attenuates hypertension, cardiac hypertrophy, and renal injury in salt-sensitive rats Hum Gene Ther 9 10 Stingo A. Clavell A. Aarhus L. Burnett J. Lopez M. Wong S. Kishimoto I. Dubois S. Mach V. Friesen J. Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide Nature 65 Fox J.
Kim R. Rockman H. Kim H. Reddick R. Hypertension, cardiac hypertrophy, and sudden death in mice lacking natriuretic peptide receptor A Proc Natl Acad Sci 94 26 Henry J.
Gauer O. Reeves J. Evidence of the atrial location of receptors influencing urine flow Circ Res 4 1 85 De Bold A. Borenstein H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats Life Sci 28 89 Flynn T. The amino acid sequence of an atrial peptide with potent diuretic and natriuretic properties Biochem Biophys Res Commun 3 Napier M.
Dewey R. Albers-Schonberg G. Bennett C. Rodkey J. Marsh E. Isolation and sequence determination of peptide components of atrial natriuretic factor Biochem Biophys Res Commun 3 Jamieson J. Palade G. Specific granules in atrial muscle cells J Cell Biol 23 Bencosme S. Studies on the relationship between the catecholamine distribution in the atrium and the specific granules present in atrial muscle cells: isolation of a purified specific granule subfraction Cardiovasc Res 7 3 Heart atria granularity: effects of changes in water-electrolyte balance Proc Soc Exp Biol Med Dietz J.
Release of natriuretic factor from rat heart—lung preparation by atrial distension Am J Physiol R R Lang R. Tholken H. Ganten D. Luft F. Ruskoaho H. Unger T. Atrial natriuretic factor—a circulating hormone stimulated by volume loading Nature Ledsome J. Wilson N. Courneya C. In the adrenal gland, ANF is a powerful inhibitor of aldosterone synthesis. ANF participates importantly in the natriuretic response to acute and chronic volume overload. ANF's property of shifting fluid from the vascular to the interstitial compartment acts as a buffering device, guarding against excessive plasma volume expansion in face of an increased total extracellular fluid volume.
ANF is also a physiological modulator of GFR, and mediates nephron hyperfiltration and natriuresis when salt excretion is threatened by a reduction in the number of nephrons. In addition to it's effect on blood pressure and volume, ANP appears to contribute to several other physiologic and pathologic processes, including inhibiting cardiac hypertrophy in the face of heart failure, promoting cardiomyocyte viability, and modulating a number of immune events.
Mice engineered to be incapable of secreting ANP develop chronic hypertension. ANP deficiencies have not been identified in humans, although some types of cardiac surgery can lead to at least temporary deficiency. ANP and espectially BNP have proven valuable as biomakers of heart failure and are used in monitoring the effect of therapies in such patients. Other Endocrine Tissues and Hormones. Updated Send comments to Richard. Bowen colostate.
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