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Atrial Receptors, Natriuretic Peptides, and the Kidney—Current Understanding

1986; Elsevier BV; Volume: 61; Issue: 7 Linguagem: Inglês

10.1016/s0025-6196(12)62010-2

1942-5546

Kenneth L. Goetz,

Ion Transport and Channel Regulation

An association between the cardiac atria and renal function was suggested 30 years ago by Henry, Gauer, and Reeves.1Henry JP Gauer OH Reeves JL Evidence of the atrial location of receptors influencingurine flow.Circ Res. 1956; 4: 85-90Crossref PubMed Scopus (216) Google Scholar These authors discovered that distention of the left atrium in anesthetized dogs usually produced an increase in urine flow. Because the renal response to left atrial distention could not be elicited in animals after the cervical vagi had been cooled to block nerve conduction, Henry and his colleagues concluded that stretch receptors in the left atrium were an important part of a reflex mechanism that linked changes in blood volume with homeostatic responses of the kidney. They postulated that atrial distention reflexly inhibited the secretion of antidiuretic hormone (vasopressin), an action that in turn caused a water diuresis. In that report, however, the authors did not suggest that the atria might influence the excretion of sodium. These observations generated considerable interest in the possible physiologic effects of atrial receptors on the kidney. Direct measurements of vasopressin, initially by bioassay2Baisset A Montastruc P Polyurie par distension auriculaire chez le Chien: role de l'hormone antidiurétique.J Physiol (Paris). 1957; 49: 33-36PubMed Google Scholar and later by radioimmunoassay,3De Torrente A Robertson GL McDonald KM Schrier RW Mechanism of diuretic response to increased left atrial pressure in the anesthetized dog.Kidney Int. 1975; 8: 355-361Crossref PubMed Scopus (42) Google Scholar confirmed that the plasma vasopressin concentration was reduced in response to several maneuvers that elevated left atrial pressure. In 1970, Gauer, Henry, and Behn4Gauer OH Henry JP Behn C The regulation of extracellular fluid volume.Annu Rev Physiol. 1970; 32: 547-595Crossref PubMed Scopus (156) Google Scholar summarized much of the previously published pertinent work and contended that "volume control" was primarily related to the control of excretion of water as regulated by vasopressin. A few years later, a more critical review of the relationship between atrial receptors and renal function was published.5Goetz KL Bond GC Bloxham DD Atrial receptors and renal function.Physiol Rev. 1975; 55: 157-205PubMed Google Scholar That review emphasized the nonspecific nature of most of the experimental interventions used to alter atrial receptor activity and pointed out that the important effect of sodium in determining the volume of extracellular fluid was largely ignored by the atrial volume receptor hypothesis. Several investigators had previously reported that atrial distention increased the excretion of sodium in conscious or chloralose-anesthetized dogs,6Lydtin H Hamilton WF Effect of acute changes in left atrial pressure on urine flow in unanesthetized dogs.Am J Physiol. 1964; 207: 530-536PubMed Google Scholar, 7Gillespie DJ Sandberg RL Koike TI Dual effect of left atrial receptors on excretion of sodium and water in the dog.Am J Physiol. 1973; 225: 706-710PubMed Google Scholar but the major focus at that time was on the inhibition of vasopressin and a water diuresis. Shortly thereafter, Reinhardt and colleagues8Reinhardt HW Kaczmarczyk G Eisele R Arnold B Eigenheer F Kuhl U Left atrial pressure and sodium balance in conscious dogs on a low sodium intake.Pflugers Arch. 1977; 370: 59-66Crossref PubMed Scopus (21) Google Scholar and other investigators9Schultz HD Fater DC Sundet WD Geer PG Goetz KL Reflexes elicited by acute stretch of atrial vs. pulmonary receptors in conscious dogs.Am J Physiol. 1982; 242: H1065-H1076PubMed Google Scholar demonstrated that distention of the left atrium of the conscious dog consistently produced a natriuresis as well as a reduction in the circulating level of vasopressin. Moreover, these responses seemed to depend on neural reflexes from the heart because they could not be elicited during atrial distention in conscious dogs with chronic cardiac denervation.10Kaczmarczyk G Drake A Eisele R Mohnhaupt R Noble MIM Simgen B Stubbs J Reinhardt HW The role of the cardiac nerves in the regulation of sodium excretion in conscious dogs.Pflugers Arch. 1981; 390: 125-130Crossref PubMed Scopus (28) Google Scholar, 11Fater DC Schultz HD Sundet WD Mapes JS Goetz KL Effects of left atrial stretch in cardiac-denervated and intact conscious dogs.Am J Physiol. 1982; 242: H1056-H1064PubMed Google Scholar Furthermore, selective distention of the pulmonary vasculature or the right atrium did not elicit changes in renal function in normal dogs;9Schultz HD Fater DC Sundet WD Geer PG Goetz KL Reflexes elicited by acute stretch of atrial vs. pulmonary receptors in conscious dogs.Am J Physiol. 1982; 242: H1065-H1076PubMed Google Scholar the response therefore seemed to arise specifically from an effect of left atrial distention. Possible mechanisms for mediating the increased excretion of sodium during left atrial distention include a reflex reduction in renal sympathetic nerve activity12DiBona GF The functions of the renal nerves.Rev Physiol Biochem Pharmacol. 1982; 94: 75-181Crossref Google Scholar or an inhibition of the renin-angiotensin system.13Reinhardt HW Kaczmarczyk G Mohnhaupt R Simgen B The possible mechanism of atrial natriuresis: experiments on chronically instrumented dogs.in: Lichardus B Schrier RW Ponec J Hormonal Regulation of Sodium Excretion. Elsevier-North Holland Biomedical Press, New York1980: 63-72Google Scholar With the discovery by de Bold and colleagues14De Bold AJ Borenstein HB Veress AT Sonnenberg H A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats.Life Sci. 1981; 28: 89-94Crossref PubMed Scopus (2650) Google Scholar that injection of extracts of atrial tissue into anesthetized rats produced an almost immediate natriuresis and diuresis, it was realized that the increase in excretion of sodium elicited by atrial distention might be caused by the release of a natriuretic substance from the atria. This natriuretic material soon was shown to be located in osmophilic granules that had originally been noted by Kisch15Kisch B Studies in comparative electron microscopy of the heart. II. Guinea pig and rat.Exp Med Surg. 1955; 13: 404-428PubMed Google Scholar and described in detail by Jamieson and Palade.16Jamieson JD Palade GE Specific granules in atrial muscle cells.J Cell Biol. 1964; 23: 151-172Crossref PubMed Scopus (429) Google Scholar The findings of de Bold and associates14De Bold AJ Borenstein HB Veress AT Sonnenberg H A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats.Life Sci. 1981; 28: 89-94Crossref PubMed Scopus (2650) Google Scholar were rapidly confirmed in laboratories throughout the world. Soon afterward, the active material in the atrial granules was shown to be a series of related peptides, the sequences of which were rapidly identified and synthesized. These peptides circulate in the bloodstream, perhaps as a single molecular form that is species-specific. Although factors that regulate secretion of the peptides from the atria have not been completely elucidated, the concentration of these peptides in plasma clearly is consistently increased by atrial distention.17Dietz JR Release of natriuretic factor from rat heart-lung preparation by atrial distension.Am J Physiol. 1984; 247: R1093-R1096PubMed Google Scholar, 18Goetz KL Wang BC Geer PG Leadley RJ Reinhardt HW Atrial stretch increases sodium excretion independently of release of atrial peptides.Am J Physiol. 1986; 250: R946-R950PubMed Google Scholar The foregoing synopsis leaves little doubt that the atria contain components of two mechanisms that are capable of altering renal function: (1) atrial stretch receptors that may reflexly alter vasopressin, renal nerve activity, and the renin-angiotensin system and (2) atrial peptides that can influence the renal excretion of sodium. Although most investigators to date have used pharmacologic doses of peptide to demonstrate the natriuretic action, the atrial peptides are widely assumed to exert physiologic and pathophysiologic effects on the maintenance of extracellular fluid balance. Certain clinical problems may be related to these atrial mechanisms, and several interesting possibilities have been suggested in patients and in animal models. The focus here will be on involvement of the atrial peptides. A strain of hamsters in which familial cardiomyopathy develops was shown to have a reduced content of bioassayable peptides in their atria, and it was hypothesized that retention of fluid in these animals might be related to a deficiency in circulating atrial peptides, which in turn causes retention of sodium.19Chimoskey JE Spielman WS Brandt MA Heidemann SR Cardiac atria of BIO 14.6 hamsters are deficient in natriuretic factor.Science. 1984; 223: 820-822Crossref PubMed Scopus (73) Google Scholar In this issue of the Proceedings (pages 517 to 521), Edwards and his colleagues confirm, by immunohistochemical techniques, that cardiomyopathic hamsters have a reduced content of peptide in their atria. More importantly, however, and in conflict with the earlier hypothesis, these investigators demonstrate that hamsters with congestive heart failure have elevated circulating levels of atrial peptides in their plasma. Thus, the retention of sodium and the formation of edema in this strain cannot be ascribed to a deficit of atrial peptides in plasma; an excess is present. Edwards and associates suggest that the retention of fluid in these animals may be attributable to a reduced renal response to the atrial peptides. Although this is a reasonable suggestion that is consistent with current opinion, another possibility will be considered here. Patients with congestive heart failure also have high circulating levels of atrial peptides, and a direct correlation exists between cardiac filling pressure and plasma concentrations of these peptides.20Burnett Jr, JC Kao PC Hu DC Heser DW Heublein D Granger JP Opgenorth TJ Reeder GS Atrial natriuretic peptide elevation in congestive heart failure in the human.Science. 1986; 231: 1145-1147Crossref PubMed Scopus (784) Google Scholar Does this finding indicate that the kidney becomes refractory to atrial peptides during decompensation of the heart? Perhaps, but one must keep in mind that the fundamental problem in these patients is a cardiac and not a renal disorder. If one were to attribute the retention of fluid associated with congestive heart failure to a reduced renal responsiveness to the atrial peptides, how could one explain the reduction in retention of salt and water that occurs after successful medical or surgical treatment of the underlying cardiac problem? Successful treatment of congestive heart failure almost always increases cardiac output and decreases cardiac filling pressure. Under these conditions, one would predict that the secretory rate of atrial peptides would be diminished. To explain how a decrease in circulating "natriuretic" peptides might contribute to an enhanced natriuresis in this situation, one would have to postulate that a change in renal hemodynamics (or some other factor) markedly augments the response of the kidneys to these peptides at the same time that the function of the heart is improving and the concentration of atrial peptides in plasma is diminishing. It may not be too preposterous, therefore, to postulate that atrial peptides are responsible for neither retention of fluid during the development of cardiac failure nor augmented loss of fluid when cardiac compensation is restored. Rather, one might consider that the atria are releasing peptides just as they do under normal conditions—that is, increasing their secretory rate when they are distended and decreasing their secretory rate when the distending force is lessened, but not necessarily affecting renal excretion of sodium. Does other evidence suggest that normal levels of atrial peptides, or even elevated levels comparable to those detected during heart failure, are not necessarily natriuretic? My colleagues and I recently obtained data18Goetz KL Wang BC Geer PG Leadley RJ Reinhardt HW Atrial stretch increases sodium excretion independently of release of atrial peptides.Am J Physiol. 1986; 250: R946-R950PubMed Google Scholar that are of interest in this regard. We distended the left atrium of conscious dogs by partially obstructing the mitral valve and observed the well-known renal and hemodynamic effects of this maneuver.9Schultz HD Fater DC Sundet WD Geer PG Goetz KL Reflexes elicited by acute stretch of atrial vs. pulmonary receptors in conscious dogs.Am J Physiol. 1982; 242: H1065-H1076PubMed Google Scholar We also measured circulating levels of atrial peptides by radioimmunoassay in plasma samples obtained before, during, and after the period of atrial distention. The circulating concentration of atrial peptides during atrial distention was increased more than 400% from a control value of 70 pg/ml.18Goetz KL Wang BC Geer PG Leadley RJ Reinhardt HW Atrial stretch increases sodium excretion independently of release of atrial peptides.Am J Physiol. 1986; 250: R946-R950PubMed Google Scholar On the basis of this experiment alone, one might assume that the increased concentration of circulating atrial peptides elicited by atrial distention was responsible for the natriuretic response. We also performed the same experiment, however, in a group of conscious dogs with chronic cardiac denervation. In these animals, circulating levels of atrial peptides also were increased more than 400% from the control level of 62 pg/ml.18Goetz KL Wang BC Geer PG Leadley RJ Reinhardt HW Atrial stretch increases sodium excretion independently of release of atrial peptides.Am J Physiol. 1986; 250: R946-R950PubMed Google Scholar Nevertheless, despite the fourfold increase in the plasma concentration of atrial peptides, no associated natriuresis or diuresis was noted. In other words, the renal response to atrial distention seemed to depend on cardiac nerves, not on the release of atrial peptides. Although several interpretations of these results are possible, the simplest explanation is that the atrial peptides were not natriuretic in these concentrations. As mentioned earlier, atrial peptides are widely believed to play a physiologic role in the renal regulation of excretion of sodium. Nevertheless, little solid evidence is available to support this point of view. Nearly all the reported natriuretic responses have been elicited by administration of atrial extracts or synthetic peptides in doses that almost certainly produced plasma concentrations of thousands of picograms per milliliter of plasma. Clearly, the atrial peptides elicit a rapid and brisk natriuresis in these high concentrations, but evidence that more normal concentrations of the hormone elicit substantial natriuretic effects is sparse. Normal concentrations range from perhaps 30 to 60 pg/ml in human subjects to slightly higher in laboratory animals. Many researchers are attempting to determine whether there is a threshold concentration at which atrial peptides become natriuretic. Therefore, the question of whether atrial peptides regulate normal sodium balance may be answered soon. Atrial peptides elicit multiple effects that may be important in physiologic or pathophysiologic situations. For example, they inhibit the secretion of renin21Burnett Jr, JC Granger JP Opgenorth TJ Effects of synthetic atrial natriuretic factor on renal function and renin release.Am J Physiol. 1984; 247: F863-F866PubMed Google Scholar and aldosterone22Atarashi K Mulrow PJ Franco-Saenz R Snajdar R Rapp J Inhibition of aldosterone production by an atrial extract.Science. 1984; 224: 992-994Crossref PubMed Scopus (371) Google Scholar and thereby could have a slower, indirect effect on excretion of sodium and perhaps on blood pressure. Atrial peptides and receptors to the peptides are located in the brain,23Needleman P Adams SP Cole BR Currie MG Geller DM Michener ML Saper CB Schwartz D Standaert DG Atriopeptins as cardiac hormones.Hypertension. 1985; 7: 469-482Crossref PubMed Scopus (318) Google Scholar, 24Quirion R Dalpé M De Lean A Gutkowska J Cantin M Genest J Atrial natriuretic factor (ANF) binding sites in brain and related structures.Peptides (Fayetteville). 1984; 5: 1167-1172Crossref PubMed Scopus (261) Google Scholar especially in hypothalamic areas that influence cardiovascular function and fluid balance. They stimulate guanylate cyclase and cyclic guanosine monophosphate,25Weil J Lang RE Suttmann H Rampf U Bidlingmaier F Gerzer R Concomitant increase in plasma atrial natriuretic peptide and cyclic GMP during volume loading.Klin Wochenschr. 1985; 63: 1265-1268Crossref PubMed Scopus (64) Google Scholar an effect that could produce numerous responses throughout the body. They reduce cardiac filling pressures,26Lappe RW Todt JA Wendt RL Mechanism of action of vasoconstrictor responses to atriopeptin II in conscious SHR.Am J Physiol. 1985; 249: R781-R786PubMed Google Scholar, 27Goetz KL Wang BC Geer PG Sundet WD Needleman P Effects of atriopeptin infusion versus effects of left atrial stretch in awake dogs.Am J Physiol. 1986; 250: R221-R226PubMed Google Scholar possibly by increasing venous compliance by a sodium nitroprusside-like action28Winquist RJ Faison EP Nutt RF Vasodilator profile of synthetic atrial natriuretic factor.Eur J Pharmacol. 1984; 102: 169-173Crossref PubMed Scopus (171) Google Scholar or, more intriguingly, by causing a rapid contraction of intravascular volume through an action on systemic capillaries.29Weidmann P Hasler L Gnädinger MP Lang RE Uehlinger DE Shaw S Rascher W Reubi FC Blood levels and renal effects of atrial natriuretic peptide in normal man.J Clin Invest. 1986; 77: 734-742Crossref PubMed Scopus (268) Google Scholar When one considers that the concentration of atrial peptides in plasma increases rapidly in response to increases in cardiac filling pressure, the observed decrease in cardiac filling pressure produced by infusion of the peptides may suggest that the heart has available a negative feedback system capable of influencing its own filling pressure by means of the effects of atrial peptides on venous compliance or on intravascular volume. The decrease in cardiac filling pressure produced by atrial peptides is accompanied by a decrease in stroke volume, possibly mediated by the Frank-Starling mechanism, and a resultant decrease in cardiac output. The lowered cardiac output contributes to the decrease in arterial pressure in conscious dogs,27Goetz KL Wang BC Geer PG Sundet WD Needleman P Effects of atriopeptin infusion versus effects of left atrial stretch in awake dogs.Am J Physiol. 1986; 250: R221-R226PubMed Google Scholar but the hypotensive effects of atrial peptides in human subjects seems to be more complex.29Weidmann P Hasler L Gnädinger MP Lang RE Uehlinger DE Shaw S Rascher W Reubi FC Blood levels and renal effects of atrial natriuretic peptide in normal man.J Clin Invest. 1986; 77: 734-742Crossref PubMed Scopus (268) Google Scholar The multiple responses observed after administration of atrial peptides suggest that they are important in the regulation of certain body functions. Will their primary target be identified as the kidney, the cardiovascular system, the brain, or some other organ? Until the dust has settled, it may be advisable to refer to them by a nonspecific term, such as "atriopeptins,"30Currie MG Geller DM Cole BR Siegel NR Fok KF Adams SP Eubanks SR Galluppi GR Needleman P Purification and sequence analysis of bioactive atrial peptides (atriopeptins).Science. 1984; 223: 67-69Crossref PubMed Scopus (407) Google Scholar a designation that does not imply a particular function. Finally, will these peptides or related synthesized analogues be useful clinically? Answers should be forthcoming.