Hypothalamic action of atrial natriuretic factor to inhibit vasopressin secretion

PeptMe~. Vol 8, pp 449-454 ~ Pergamon Journals Ltd, 1987 Printed m the U S A

01%-9781/87 $3 00 + 00

Hypothalamic Action of Atrial Natriuretic Factor to Inhibit Vasopressin Secretion WILLIS K. SAMSON, 1 M. CECILIA JOSE ANTUNES-RODRIGUES

AGUILA, JOVO AND MICHELE

MARTINOVIC, NORRIS

D e p a r t m e n t o f P h y s i o l o g y , U n i v e r s i t y o f T e x a s H e a l t h S c i e n c e C e n t e r at D a l l a s 5323 H a r r y H i n e s B o u l e v a r d , Dallas, T X 75235-9040 R e c e i v e d 22 J u n e 1986 SAMSON, W. K , M C AGUILA, J. MARTINOVIC, J ANTUNES-RODRIGUES AND M. NORRIS Hypothalamtc

action of atrial natrturetw factor to mhtbtt vasopressm secretion PEPTIDES 8(3) 449-454, 1987.--The ablhty of synthetic atrial natrmretlc factor (ANF) to inhibit vasopressin (AVP) release, as well as its action to inhibit water retake and salt preference in the rat, suggest a role for the peptlde in the hypothalam~c control of fired volume m ad&tlon to its established actions in the kidney. We report here evidence for a direct, hypothalamlc site of action of ANF to inhibit, specifically, AVP secretion. Third cerebroventncular infusion of 1 0 (p<0 05) and 2.0 (p<0.025) nmoles ANF s~gmficantly inhibited AVP release in euvolemlc, normally hydrated rats while IV doses of ANF failed to significantly alter AVP release except when 5 nmoles (p<0.05) were mfused. No slgmficant effects on oxytocm (OT) release were observed Vasopressm release from median eminence or pltmtary, neural lobe explants during static, tn vitro incubations was not slgmficantly altered by doses of ANF ranging from 10-lz to 10-7 molar Release of AVP during penfusmn of neural lobe explants m the presence of ANF was similarly unaffected. However, AVP and not OT release from hypothalamo-neurohypophysml system explants was significantly inhibited m the presence of 10-s and 10-7 M ANF, suggesting an action of the peptlde at the levels of the AVP-producmg cell bodies m the included supraoptlc nucleus either &rectly or via an action on an mterneuron, and not at the AVP-contammg terminal fields m the median eminence or neural lobe. Atrml natrluretlc factor

Vasopressln

Hypothalamus

direct, hypothalamic site of action of A N F to inhibit A V P release and suggest that this effect o f A N F is not e x e r t e d at the terminal fields of the A V P - c o n t a m i n g neurons which lie outside of the blood-brain-barrier, but instead either &rectly at the level o f their cell bodies or via interneurons located adjacent to the third cerebral ventricle.

T H E d e m o n s t r a t i o n o f the ability of a bolus, IV infusion of synthetic atrial natrmretic factor ( A N F ) to inh~blt e x p e r i m e n t a l l y - e l e v a t e d vasopressin (AVP) secretion in the rat [22] suggested, in ad&tion to their recognized renal [16, 18, 20] and adrenal [8] effects, central n e r v o u s system (CNS) actions of the cardiac peptides. In that original study, however, the possibility that the inhibition o f A V P release was secondary to s o m e peripheral action of the peptide could not be ruled out [22]. In o r d e r for A N F of cardiac origin to act &rectly within the C N S to alter A V P release, it would have to interact with neuronal e l e m e n t s positioned outside of the blood-brain-barrier at one of the c i r c u m v e n t r i c u l a r organs [31], or alternatively ~t would have to cross the barrier before exerting its effect. On the other hand, A N F - l i k e imm u n o r e a c t w l t y has been d e t e c t e d in extracts of specific C N S tissue sites [15, 23, 34] and its p r e s e n c e in neuronal e l e m e n t s within the hypothalamus [15, 26, 28], coupled with the presence of A N F - s p e c i f i c binding sites there [21] and the abdity of synthetic A N F to alter the electrical activity of smgle neurons m this region [9,32], suggest a n e u r o m o d u l a t o r y role for centrally p r o d u c e d peptide in the control o f A V P secretion. In vivo and in vitro studies described here in&cate the

METHOD

In Vtvo Studies Male rats (250--300 g, Sprague-Dawley, Holtzmann) were housed in individual cages under controlled conditions (23°C, lights on 05.00-19.00 hr) and p r o v i d e d Purina lab c h o w and w a t e r ad lib. Intravenous infusions of 0.1 ml sahne (0.9% NaCI) or A N F (atriopeptin III, Peninsula Labs) in saline w e r e c o n d u c t e d in conscious, freely m o v i n g rats via an indwelling jugular cannula implanted 24 hr earlier as previously described [22]. Central administration of saline control vehicle (2/zl, 0.9% NaCI) or A N F in vehicle was conducted also in conscious, freely m o v i n g rats via a chronic, indwelling, third c e r e b r o v e n t r i c u l a r (3V) cannula implanted one w e e k earlier [2]. Animals were left undisturbed for 15

1Requests for reprints should be addressed to W. K. Samson, Ph.D., Physiology, UTHSCD, 5323 Harry Hines Blvd , Dallas, TX 752359040

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nmoles ANF (intravenous infusion ) FIG I Plasma AVP concenlrat|ons (mean_+SEM) m unrestrained, euvolemlc rats 15 mm aftel IV rufus|on of 0 1 ml sahne (0 9% NaC1) alone or sahne containing ANF Group s~zes are indicated w~thm the bars (*p<0 05 versu~ ~ahne-mfused controls )

m m following injections and then killed by rapid decapltaUon, at which time trunk bloods w e r e collected in heparlnlzed tubes (4°C), centrifuged, and plasma stored frozen ( - 2 0 ° C ) for subsequent analysis of A V P content by RIA as described m detail e l s e w h e r e [20]. W h e n sufficient plasma remained after determination of A V P content, levels of o x y t o c m (OT) w e r e also ascertained by RIA [22]. In Vitro Studte,s In o r d e r to determine whether circulating A N F m~ght act at the level of the axon terminals of the A V P - c o n t a m m g neurons which are situated outside of the blood-bramb a m e r , explants o f two such fields, one m the median eminence (ME) and the other m the neural lobe of the pituitary (NL) w~th ~ts assocmted m t e r m e d m t e lobe attached, were incubated m vttso in the p r e s e n c e of A N F and the release of A V P monitored by R I A Median e m i n e n c e incubations w e r e c o n d u c t e d at 37°C m Krebs-Ringer bicarbonate as described m detail p r e w o u s l y [1]. Both static and dynamic incubations of N L tissue explants w e r e c o n d u c t e d at 37°C m m e d m m 199 ( D I F C O ) containing 2×10 -'~ M bacltracm (Sigma), 0.1% bovine serum albumin, 1% p e m c l l l i n - s t r e p t o m y c m (GIBCO), and 20 mM H E P E S buffer (GIBCO). This combination of B S A and bacltracin effectively prevents loss of either added or released peptide from the medium In the static incubation protocol, one N L explant per tube was incubated for 20 mln m 2 ml medium. After replacement w~th 2 ml fresh medium, the N L was incubated with shaking for an additional 20 mm preincubation period This medium was collected then for subsequent R I A o f neuropepUde content and test medium containing A N F added to the tubes The experimental period also lasted 20 mm after which time the medium was collected. In some e x p e r i m e n t s a third, 20 m m m c u b a u o n period followed the experimental test period

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nmoles ANF FIG 2 Plasma AVP concentrations (mean_+SEM) m unrestrained, euvolemlc rats 15 mm after third cerebroventncular infusion of 2 ~1 sahne (0.9cA NaCI) alone (control) or sahne containing ANF Group sizes are indicated w~thm the bars (~p<0 05, **p<0 025 versus sahne-mfused control values )

during which time the N L s were e x p o s e d to control medium alone Only those experiments m which no sigmficant differences existed b e t w e e n experimental groups m peptide release from N L s during the first 20 mm incubation period (premcubaUon) were analyzed, thus assuring homogeneity of variance b e t w e e n experimental groups In the dynamic protocol, 4 N L s each were loaded into a 13 mm d i a m e t e r S w m n e x - H A filter unit (0.45/zm) and perifused with medium for 50 mm at a flow rate of 0 5 ml/mln. Following this stabihzatmn period, fractions of perffusate w e r e collected at 1.5 mm intervals. During the first 15 min, medium alone perifused the N L tissues. This was followed by a 7.5 mln, lmtial test period and a subsequent 15 min e x p o s u r e period to medium alone F o u r umts were perifused m parallel m each experiment One umt was exposed to control medium alone during the initial test period, while the others were perlfused with log doses of A N F ranging from 10 12 to 10 7 M After the 15 mm washout period which followed the initial test, each umt was perifused for 7.5 m m with m e d i u m s~mdlar to that tested in the initial period for the unit, with the exception that a depolarizing concentration of KCI (60 mM) was also present. This second test period was followed by a 15 mln washout perffusion with incubation m e d m m alone In a second series of experiments, A N F e x p o s u r e during the second test period p r e c e d e d by 7.5 rain and continued during the add~tmn of KCI to the perffusate Data in Figs. 3 and 4 represent the m e a n _ S E A V P content for e a c h fraction of four rephcate perifuslons. Data were analyzed by paired t-test comparing the m e a n fractxon levels for 7.5 min prior to exposure and during e x p o s u r e to the peptides and by analyzing the areas under the curves by plammetry. In a final series of experiments the hypothalamoneurohypophysial system ( H N S ) , a tissue explant that contams the intact supraopt~c projection to the N L , was dissected and incubated at constant o s m o l a h t y as described by Sladek

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FIG 3 Vasopressm (AVP) release from perlfused neural lobe explants. Data are presented as the mean collection fraction content (sohd hne) of AVP of four rephcate experiments. Standard error of the mean ~s indicated by the gray borders Test substances were included m the perffusate as indicated

FIG 4 Same as Fig 3, except that ANF was penfused prior to, a, well as during, KCI exposure

RESULTS

In Vwo Studle~s [27]. Following one hour of preincubation in 25 ml Dulbecco's Minimum Essential Medium (Flow Laboratories) contaming 0.1% BSA and 2× 10-5 M bacitracin (37°C, gassed in 95% 02/5% CO.,), the medium was replaced w~th 25 ml of fresh medium and tissues incubated an additional 15 min. A final 15 rain preincubation period then followed during which time the HNS explants were incubated in 5 ml medium. Following removal of this final volume of prelncubahon medmm, four consecutive 30 min test periods were conducted with explants incubated in a volume of 5 ml (Control Period control medium alone; Test Period 1 control medium or medium containing A N F ; Test Period 2: control medmm, Test Period 3, medium plus a depolarizing concentration of KCI in controls or medium containing KCI and A N F in experimentals). Media from each test period were stored frozen until subsequent RIA of AVP or OT content and HNS explants weighed at the end of each experiment. Explant weights did not differ significantly between groups and averaged (18.7+0.6 mg, n=40). Peptlde release during test periods 1, 2, and 3 was expressed as a percent of the initial control period and differences between groups during each period were determined by analysis of variance and a Newman-Keuls multiple comparison procedure.

Intravenous infusion of 0.1 ml ~sotontc sahne failed to significantly alter circulating AVP or OT levels when compared to cannulated, non-injected controls (data not shown). Thus Infusion artifact was obviated. Similarly, plasma levels of OT were not significantly altered by any dose of A N F when compared to sahne-lnfused controls. Only in the rats receiving the highest dose of ANF, 5 nmoles, were plasma ANF levels significantly altered (Fig. 1) and then only when compared by t-test to saline-infused controls (p=0.046). When the data comparmg AVP levels present after infusion of saline (7.7_+1.7 pg/ml, n=10), 1 nmole A N F (7.8_+2 3, n=7), 2 nmoles A N F (5 7_+1 5, n=13) and 5 nmoles ANF (3.0_+0.1, n=6) were compared by analysis of variance, no significant differences existed, F(3,32)= 1.39. In contrast significant inhibluons of plasma AVP levels were seen in rats infused centrally with lower doses of A N F (Fig 2) Plasma AVP concentrations m rats receiving 2 ~1 saline vehicle were 8.4_+0.8 pg/ml (n=26). The lowest dose of A N F tested (0.2 nmoles) lowered, but did not significantly reduce plasma AVP levels (6.0_ + 1.2, n = 13). Significant inhibition of AVP values was observed following 3V infusion of 1.0 (4.4_+1.5, n=7, p<0.05) and 2 0 (4.3_+0.4, n=12, p<0.025) nmoles A N F (analysis of variance, F(3,54)=4.52; followed by Student-Newman Keuls multiple comparison)

S A M S O N ET AL.

452 TABLE 1 AVP RELEASE (PG AVP/FRACTION)FROM 4 PERIFUSION CHAMBERS, EACH CONTAINING4 NL EXPLANTSBEFORE, DURING, AND AFTER EXPOSURETO 10-7 M BETA ENDORPHIN Preexposure

Exposure

Postexposure

770 _+ 50

485 _+ 45*

670 _+ 70t

Hypothalamo-Neurohypophysial Explant AVP Release (Percent of Control Period) I

Test Period 2 44 9 t0 8

No statistically slgmficant differences m plasma a T levels were observed. In Vitro Studtes nence tissue explants to log doses of A N F ranging from l0 10 to l0 -7 M for 30 mm failed to significantly alter AVP release into the medium; however, dopamine (60/~M, dopamine hydrochloride, Sigma) slgmficantly inhibited AVP release (p<0.05) in two separate experiments (Experiment l" control, n=6, 255.0+46.9 pg AVP released/mg tissue, 60 p,M DA, n=6, 114.6+22 6. Experiment 2 control, n=5, 157.1_+40.6, 60 p,M DA, n=5, 50.2+9 9). Static neural lobe explants When N L explants were incubated in a static fashion m the presence of a depolarizing concentration of KC1, a significant, 2.7 fold, stimulation of AVP release occurred Compared to AVP release from N Ls exposed to control medium alone, no significant effects of A N F m log doses ranging from l0 -~2 to 10 7 M were observed The release of OT similarly was not significantly altered by A N F (data not shown). Dynarme neural lobe explants When NLs were perifused with medium containing log doses of A N F ranging from l0 ~2 to l0 -7 M, no significant effects on AVP release were observed Figures 3 and 4 demonstrate the lack of effect of doses ranging from l0 -9 to l0 ~ M. Similarly, simultaneous addition of A N F to the perifusate containing depolarizing concentratlons of KC1, failed to significantly reduce the magmtude of AVP release seen from N L s exposed to KCI alone (Fig. 3). Pretreatment of NLs with A N F prior to inclusion of 60 mM KCI in the perifusate also failed to reduce the AVP response (Fig 4) to potassium depolarization. The failure of A N F to inhibit AVP release in this perifusion model is not due to technical considerations alone since exposure of explants to 10 7 M beta-endorphm (human beta-lIpotropin, 61-91, Peninsula) (Table l) resulted in a significant and reversible inhibition of AVP release. Hypothalamo-neurohypophysial explants. No significant differences between experimental groups of H N S explants in amounts of neuropeptide released were observed during the control incubation period. AVP release during the control period ranged from 0.9+0.2 (for the group later exposed to 10-9 M ANF) to 1.2+0.1 ng (for the group later exposed to l0 -8 M ANF) released/explant, F(3,37)=0 53, p =0 66, and OT release ranged from 1.7_+0.3 to 3 . 6 +1.3 ng released/ explant, F(3,29)=0.95, p=0.43, for the same groups, respectively. Intermediate values were observed in the media from explants exposed to control medmm alone or later to

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Collection periods lasted 7 5 mm, during which time five, 1.5 mm fractions were collected Values presented are means (_+SEM) of AVP released per fraction per period F(2,9)=6.66, p =0 17 *Versus preexposure values a<0 025 ?Versus exposure values a<0 05.

Medmn eminence explants. Exposure of medmn emi-

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10 7 M ANF. Futhermore, no significant differences in AVP or a T release from the explants were observed during test periods I (when A N F was present in experlmentals) or 3 (when KC1 was present). Finally, no significant differences m a T release were observed among treatment groups during test periods I or 2. A significant inhibitory action of A N F on AVP release from H N S explants was observed (Fig. 5). Although present already during the initial test exposure period (test period 1) this inhibitory effect did not attain significance, F(3,37)=2.23, p=0.101 The expression of this inhibitory action of A N F was significant, however, during the followmg 30 min period when the test medium had been replaced with fresh control medium, F(3,37)=4.26, p=0.011. While prior exposure of the H N S explant to 10-9 M A N F failed to affect AVP release, exposure to 10-8 and 10 7 M peptlde significantly (p<0.05) suppressed subsequent secretion of vasopressln DISCUSSION These results suggest a direct, hypothalamlc site of A N F to inhibit AVP release. Cerebroventricular administration of atriopeptln III in the conscious, euvolemic rat sxgnificantly inhibited AVP secretion, at doses which did not during the time points examined alter mean arterial blood pressure (W. K Samson and J. H. Moltz, unpublished observations). The abilIty of centrally administered A N F to inhibit A V P release in the conscious, normally hydrated rat also has been reported recently by Iitaki et al. [11]. These authors employed doses of the twenty six amino acid A N F similar to those reported here for the twenty four amino acid A N F and similarly failed to observe any significant alterations in mean arterial blood pressure, hematocrlt, plasma osmolahty or plasma sodium concentration following central administration of the peptide. Only an even higher dose of A N F was effective to lower AVP when injected intravenously, suggesting either an ac-

A N F INHIBITS VASOPRESSIN R E L E A S E tion of the peptlde to alter cardiac vagal afferent flow and/or baroreceptor activity, the ability of peripherally infused A N F to act at CNS sites which lie outside of the classical blood-brain-barrier, or alternatively the penetration of circulating A N F into the brain. Controversy exists over the ability of circulating substances to cross the blood-brainbarrier and to date no direct evidence for or against the possibility that A N F penetrates the barrier has been presented. Additionally, the ability of circulating A N F to alter cardiac afferent activity or baroreceptor sensitivity has not been reported, however, an action to increase vagal afferent and decrease renal sympathetic nerve activity has been observed (M. J. Brody, personal communication) At least under the in v i t r o conditions described here, short term exposure of tissue explants containing AVP-posltlVe axon terminals situated outside of the blood-brain-barrier to A N F did not result in any significant alteration in AVP release. In contrast, inhibition of AVP release under the same conditions by DA and fl-endorphin from the median eminence and NL explants, respectively, could be demonstrated. It is possible that longer exposure of the tissue explants to A N F might result In suppression of AVP release m v i t r o , but extended exposure periods were not required to demonstrate the inhibitory action of A N F on AVP release from the intact, hypothalamo-neurohypophyslal unit tn v i t r o Similarly, single bolus infusions of ANF m v t v o resulted in significantly suppressed AVP secretion. Yet, under conditions of chronically elevated ANF secretion such as congestive heart failure [30] or hypertension [10] a significant action of the hormone on AVP secretion by an action in the ME or NL cannot be ruled out. Indeed controversy over a possible direct NL site of action of ANF to Inhibit AVP release does exist. Initial reports from one laboratory reported the ability of A N F to stimulate AVP release from quartered NLs m vuro [20], however, the authors concluded in the discussion that of that report that the overall physiologic effect of ANF on AVP release was probably inhibitory. Additionally, Obana e t a l . [19] reported the results of a single, perlfusxon experiment indicating the ability of ANF, after a much longer exposure period than reported here, to Inhibit basal and potassium-stimulated AVP release. The reason for the discrepancy between our results with NL incubations and those of Januszewlcz e t al. [12] and Obana e t a l . [19] is unclear; however, preliminary results in this laboratory using perifusion for longer time periods suggests that the critical factor was length of exposure period. Our results in the hypothalamoneurohypophysml explant Incubations also are discordant with those of Januszewtcz e t a l . [13] who reported no effect of A N F on basal AVP release when applied to the hypothalamlc side of a compartmentalized hypothalamo-neurohypophyslal explant. Their group did report, however, a lowerlng by A N F of osmotically-stimulated AVP release in that model. Apparently in both our studies and theirs an action on AVP release can be demonstrated, presumably at the hypothalamlc level. Our studies using the HNS explant are, however, in complete agreement with those of Crandall and Gregg [5] who, using a similar incubation protocol, also reported the inhibitory action of A N F on AVP release. In fact, our stu&es were designed to complement theirs. These data do not rule out the possibility that both the in v i t r o observations in the HNS explant incubations and the m w v o observations were due to an action of A N F on neuronal

453 elements present in one of the circumventricular organs. Binding sites for A N F have been described in the subfornical organ [21], and to a lesser degree in the organum vasculosum lamina terminalis. These sites have been strongly implicated in the mechanism of osmotic stimulation of AVP release [3 l]. Lesion studies examining the possible action of A N F via such "freeports" in the brain must be conducted to clarify this concept. The ability of centrally administered ANF to inhibit AVP release suggests a direct neuronal action of the peptide within the hypothalamus. Atrial natriuretlc factor-specific binding sites [21] have been identified in this region and ANF-hke lmmunoreactivity has been observed by several groups [15, 26, 28] in distinct neuronal populations in brain sites known to be important in the control of vasopressin secretion Indeed, one of the more densely staining terminal fields of these A N F containing neurons IS the paraventncular nucleus [28]. Recently, we have observed the ability of ANF when applied by pressure injection and mlcrolontophoresls to inhibit membrane excitabihty of single hypothalamic neurons [32] and J T. Haskins has demonstrated a similar action on paraventricular neurons [9]. Furthermore Saper's group has now demonstrated the inhibitory action of iontophoresed A N F on identified, AVP-produclng neurons [29]. Although the doses of ANF employed in v t v o in the present experiments and in those of Iitaki e t a l . [11] and also very recently Yamada e t a l [33] seem high in relation to total hypothalamlc content [23,34], the effective dose at the level of the synaptic cleft is unknown. Certainly the ICV infused A N F is first diluted in the CSF and then must diffuse or be transported into the brain lnterstxtium where its effective concentration is further decreased by some possible combination of binding, lntracellular sequestration or degradation before it can reach the receptors in the synaptlc cleft. Just what the Kd for A N F binding in the synaptic cleft is, is unknown. To be sure, the cells do not see the high levels infused It follows then that regardless of previously reported Kd's for brain A N F binding, the important point to examine is the concentration at the synaptic cleft. Unfortunately, that simply cannot be measured. Thus we [2,3] as well as the other groups [11,33], must infuse seemingly large doses into the CSF to assure ourselves that sufficient amounts reach the effector site. We do know however from our recording study [32], that ejection of ANF in quantities less than 10-1~ grams will result in significant inhibition of single neuron firing rates and that this effect can be demonstrated directly on AVP-containlng neurons [29]. All of these findings when taken together with the ability of centrally administered ANF to inhibit fluid [2,17] and salt [3] intake strongly argue m favor of a neuromodulatory role for A N F within the CNS. The actions of A N F described to date in the kidney (natriuresls, dluresls [4, 7, 16, 18]; inhibition of renm secretion [20], and possibly vasopressin's action [6,25]), and the brain (AVP release inhibiting; antidlpsogenlc [2, 3, 17]) seem well coordinated to result in a reduction in volume expansion, a potent stimulus for A N F release [18] because of the resultant increase in right atrial pressure. ACKNOWLEDGEMENT This work was supported by a grant from the American Heart Association (85G-087) to W K S

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ET AL.

REFERENCES

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