The Atrial Natriuretic Factor in Hypertension

The Atrial Natriuretic Factor in Hypertension BY JACQUES GENEST, CC, MO, PIERRE LAROCHELLE, MO, PHO, JEAN R. CUSSON, MO, RAUL GARCIA, MO, JOLANTA GUTKOWSKA, PHO, MARC CANTIN, MO, PHO

ABSTRACT: Plasma immunoreactive atrial natriuretic factor (IR-ANF) concentration measured by radioimmunoassay after extraction on Sep-Pak cartridges was studied in 64 control normotensive subjects, 25 patients with labile essential hypertension, 67 patients with mild essential hypertension (diastolic pressure between 90 and 105 mm Hg and no left ventricular hypertrophy) and 9 patients with moderate to severe essential hypertension (diastolic pressures between 105 and 120 mm Hg). An additional group of 16 patients under medication but without effective control of their blood pressure and with diastolic pressure above 110 mm Hg also was studied. Results show that plasma IRANF concentrations are within normal range in patients with labile, mild, and moderate hypertension. In view of the reported increased right and left atrial pressures and distension in patients with mild and moderate hypertension, these findings strongly suggest a state of hyporesponsiveness of the atria to release ANF. KEY INDEXING TERMS: Atrial Natriuretic Factor; Essential Hypertension; Experimental Hypertension. [Am J Med Sci 1988; 295(4):299-304.]

T

he atrial natriuretic factor (ANF) is present in plasma mainly as a 28 amino acid peptide released from granules in atrial cardiocytes, under the stimulus of increased pressure and/or stretch. Investigations in rats, dogs and humans have demonstrated that ANF has important properties in relation to blood pressure regulation: (1) selective vasodilation in many arterial territories, especially aortic, renal and carotid, by inhibition of the vasoconstrictor effects of norepinephrine and angiotensin II; (2) production of a massive diuresis and natriuresis of rapid onset and short duration; (3) decrease in cardiac output; (4) inhibition of aldosterone synthesis and of renin release, From the Clinical Research Institute of Montreal, affiliated with the University of Montreal, Montreal, Quebec, Canada. Reprint requests: Dr. Jacques Genest, 110 Pine Avenue West, Montreal, Quebec, Canada, H2W lR7. I

THE AMERICAN JOURNAL OF MEDICAL SCIENCES

and (5) shift of fluid from the vascular space to the extravascular space. 1,2 These findings led our group to study plasma IR-ANF concentrations in rats with various types of experimental hypertension and patients with essential hypertension. Further, the effects of intravenous administration of ANF to humans by bolus and continuous iv infusion were examined. Patients and Methods

Plasma IR-ANF was measured by radioimmunoassay after extraction on Sep-Pak (Waters Associates, Milford, MA) cartridges for human plasma or on Vycor glass beads for rat plasma.3 ,4 Human ANF (Ser 99-Tyr 126, METH 110) was purchased from Armand Frappier Productions, Montreal. Sixty-four members and employees of our institute were used as normotensive controls. One hundred and one patients with essential hypertension were studied. One-fifth of these were untreated; the others had their medication stopped for at least 3 weeks before study. Twenty-five of these had labile hypertension and had normal «140/90 mm Hg) blood pressures at the time of sampling of blood for ANF measurement. Sixtyseven had mild essential hypertension without evidence of left ventricular hypertrophy and with diastolic pressures between 90 and 105 mm Hg. Nine patients had moderate to severe essential hypertension with diastolic pressures between 105 and 120 mm Hg. An additional group of 16 patients with severe hypertension and diastolic pressures above 110 mm Hg also was studied. The patients in the latter group had blood pressures that were not well controlled with antihypertensive medications. Results ANF in Experimental HypertenSion in Rats. Six exper-

imental models of hypertension in rats were studied: SHR (at 16 weeks), 2K-1C and 1K-1C hypertensive rats, Dahl "S" rats, DOCA-salt and adrenal regeneration hypertensive rats were studied in comparison with control groups.5-10 In the five latter groups, all rats had blood pressures > 150 mm Hg for at least 1 month before study. All these groups of hypertensive rats showed a significant (p < 0.01) mean increase in plasma IR-ANF concentrations in comparison to

299

ANF In Hypertension

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Figure 1. Results of measurements of atrial tissue IR-ANF content and of plasma IR-ANF concentration In six groups of rats with various types of experimental hypertension In comparison to respective control groups: 2K-1C, 1K-1C, DOCA-NaCI, adrenal regeneration hypertension, SHR and Dahl "5" rats. All groups of hypertensive rats had blood pressure~ > 150 mm Hg for at least 4 weeks before study and had some degree of cardiac hypertrophy (Table 1). RA = right atrium; LA = left atrium.

their'respective control groups (Figure 1). There was a significant correlation between the plasma IR-ANF in these rats and the increase in heart weight (Table 1).5 Administration of h-ANF Ser 99-Tyr 126 as an iv bolus of 1 Ilg resulted in normalization of blood pressure in both the 2K-1C and 1K-1C hypertensive rats. l l •12 The duration of the fall in blood pressure was

longer (>40 minutes) in the 2K-1C hypertensive rats, which are renin-dependent, than in the 1K-1C rats, which are not. Infusions of ANF at 0.1 to 1llg/hour for up to 12 days to 2K-1C and 1K-1C hypertensive rats and to SHR resulted in significant lowering of blood pressure to normal levels, but had no effect in control and sham-operated rats. 10 ' ANF In Essential Hypertension. Bolus administration of ANF in doses of up to 25 Ilg iv to healthy volunteers had no effect on blood pressure, although plasma IRANF reached peak levels of 1100 pg/mL. Furthermore, no effect on diuresis and natriuresis was seen despite a significant increase in plasma ,cyclic GMP levels. Only with bolus injections of 50 Ilg iv and higher was there a significant decrease in both systolic and diastolic pressures (8/8 mm Hg and greater). Peak plasma IR-ANF concentrations were >1200 pg/mL, coinciding with a marked diuresis and natriuresis and a significant increase in plasma cyclic GMP concentrations. 13 Intravenous infusions of ANF at 0.8, 1.6, and 3.2 Ilg/minute for periods of 30 minutes each were administered to seven normal subjects and five patients with mild essential hypertension (diastolic pressures between 90 and 104 mm Hg). With the highest infusion dose, plasma levels of IR-ANF were between 230 and 250 pg/mL. No effect on blood pressure was noted despite significant diuresis and natriuresisP Weidmann et al,14 following a similar protocol but administering ANF at 6.5 and 12.5 Ilg/minute for 45 minutes, observed a significant fall in blood pressure in a group of 10 patients with essential hypertension from an average of 1811127 mm Hg to 165/110 mm Hg at plasma IR-ANF concentrations of 625 ± 87 pg/mL.14 Mean plasma IR-ANF concentrations measured in 25 patients with labile essential hypertension and 67 patients with mild essential hypertension were similar

TABLE 1 Relationship Between Plasma IR-ANF and Heart Weight in Experimental Hypertension in Rats·

Experimental Model 2K-1C 1K-1C DOCA-salt Adrenal regeneration hypertensive

Plasma IR-ANF % Above Control Group

Mean Heart Weight % Above Control Group

110t

63

256t

46

183t 317t

33 14

Correlation Plasma IR-ANF vs Heart, Weight O.83t O.73t O.69t O.71t

• From Garcia et al. 5 t p < 0,01. All Rats Hypertensive (systolic blood pressure above 150 mm Hg for 4 weeks).

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to that of a group of 64 control subjects. 15 Only two values were above the upper range of normal, one in the group of patients with labile hypertension and one in the group with mild essential hypertension. All other values were below 40 pg/mL. In the group of patients with diastolic pressures between 105 and 120 mm Hg, all plasma IR-ANF concentrations were normal except for one, which was slightly above the upper range of normal. In contrast, in the group of 16 patients with diastolic pressures above 110 mm Hg and receiving antihypertensive medication, six had values above the upper range of normal, and the mean value of the group was significantly elevatedI2 ,15,16 (Figure 2). Identical results were obtained by Zachariah et aP7 in a similar group of patients with mild essential hypertension and by Kohno et aps in borderline hypertension. Nakaoka et aP9 reported normal plasma IRANF values in World Health Organization class 1 and 2 patients with essential hypertension (N = 32), using affinity chromatography for purification of plasma ANF. As shown in Table 2, six other groups studying patients with hypertension of undefined etiology and severity could not find any significant difference in mean plasma IR-ANF concentration in comparison to control groups of normotensive subjects. 2o-25 In all of these studies, except for the group of Yamaji et al,25 plasma IR-ANF was measured after extraction with Sep-Pak cartridges. In contrast, several workers found mean plasma IR-ANF levels (after Sep-Pak extraction) to be slightly but significantly higher in hypertensive patients compared with control subjects IS,26-31 (Table 2). Arendt et al,31 using Amberlite o

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Figure 2. Results of measurements by RIA after SEP-PAK purification of plasma IR-ANF concentration In 64 control subjects. 24 patients with labile, borderline essential hypertension. 67 patients with mild essential hypertension (diastolic pressure between 90 and 105 mm Hg), nine patients with moderate and severe essential hypertension with diastolic pressures between 105-120 mm Hg at time of blood sampling, and 16 patients with severe essential hypertension whose blood pressure was not controlled by medication and In whom the diastOliC pressure was above 110 mm Hg. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

XAD-2 resin for extraction of plasma ANF, also reported significantly higher mean levels in an undefined group of hypertensive patients compared with control subjects. Our results and those of Burnett et aP7 are consistent with the findings of Ogawa et aP2 and Tsuchiga et al,33 who demonstrated normal levels of cGMP (a marker of ANF activity) in 68 patients with essential hypertension compared with control subjects. Discussion

These results and those previously reported indicate that plasma IR-ANF is within the normal range in mild to moderate essential hypertension and that it is increased in some patients (about one-third) with severe hypertension complicated by left ventricular hypertrophy.17,IS,34,35 Similar findings have been demonstrated in rats by Garcia et a1. 5 These findings and our experiments with bolus administration and iv infusion of ANF in patients with mild essential hyper.. tension suggest that plasma IR-ANF levels (corrected for recovery) must be greater than 325-350 pg/mL to exert a depressor effect. Such levels were not found in any of the patients studied by our group or others. Zimmerman et aP6 reported that h-ANF must be infused intravenously at a rate between 0.01 and 0.3 /-Lg/kg· minute with plasma IR-ANF levels (corrected for recovery) between 350 and 600 pg/mL to produce significant lowering of blood pressure in pentobarbital anesthetized dogs (Table 3). Weidmann et aP4 reported a significant fall in blood pressure in 10 normal subjects when infusions of ANF at 6.25 /-Lg/minute for 45 minutes resulted in ANF plasma levels of 625 ± 87 pg/mL (corrected for recovery). The plasma ANF concentration required by infusion of this peptide to lower blood pressure in normal subjects and hypertensive patients and the findings of normal plasma ANF values in mild and moderate essential hypertension strongly suggest a hyporesponsiveness of the atria to release ANF in mild to moderate essential hypertension. This hypothesis is reinforced by the findings of several workers of higher right and left atrial pressures in patients with mild and moderate essential hypertension in comparison to control subjects. 37-4o Goetz has calculated, on the basis of his studies of atrial distension in conscious dogs 41 and of the human studies of Raine et al,42 that each 1 mm Hg increase in left and right atrial pressure results in an average increase in plasma IR-ANF concentration of 10.5 to 14 pmol/L. The hypothesis of a specific hyporesponsiveness of the atria to release ANF in patients with mild and moderate essential hypertension is consistent with: (a) the recent findings of Larochelle, Thibault et al (written communication, December 1987) of normal N-terminal ANF (AA Asn 1-Arg 98) levels in plasma of patients with mild and moderate hypertension; (b) the reported normal plasma levels of cGMP (a marker 301

ANF In Hypertension

TABLE 2 Plasma IR-ANF (after Sep-Pak extraction) in Human Hypertension Patients with Mild Essential Hypertension pmollL (mean = SEM) Control subjects Larochelle et al 15 Zachariah et al 17

Nakaoka et al 19

3.6 ± 0.3 (N = 64) 11.8 ± 2.4 (N = 30)

Mild essential hypertension NS

4.2 ± 0.5 (N = 92)

p < 0.02

9.1 ±

1.8(N = 62)

Essential Hypertension WHO, CLASS 1 & 2 11.3 ± 5.5 (N = 32)

13.3 ±: 5

(Mean ± SD)

(N = 61)

Patients with Undefined (as to type or severity) Hypertension Naruse et al

20

Andersson et al 21 Hedner et al 22 Nlshluchl et al 23 Nozukl et al 24 Yamajl et al 25

•

No significant difference 58.8 ± 5.5 NS (N = 34) 11.4 ± 3.3 NS (N = 6) . 9.9 ± 2.9 NS (N = 29) 6.3 ± 0.3 (N = 54) No difference 12.4 ± 0.5 (N = 108)

65.7 ± 11.1 (N = 31) 9.5 ± 3.9 (N = 12) 10.8 ± 2.9 (N = 19) 13.7 ± 2.3 (N = 23) 12.6 ± 0.9 (N = 41)

Significant difference Sugawara et al 26 t Sugawara et al 27 Sagnella et al 28 MacGregor et al 29 Kohno et al 18 :j: Arendt et al 31 § Richards et al 30

12.3 ± 1.9 (N = 14) 11.8±1.6 (N = 20) 2.7 ± 1.2 (N = 24) 2.7 ± 0.2 (N;" 25) 10.6 ± 4 (N = 17) 8.5 ± 2.3 (N = 13) 7.5 ± 4.6 (N = 55)

P < 0.01 p < 0.05 p < 0.005

P < 0.001 p < 0.05 p < 0.02

25.4 ± 3.1 (N = 14) 22.9 ± 4.8 (N = 50) 5.6± 4.5 (N = 28) 5.2 ± 0.5 (N = 48) 16 ± 8 (N = 43) 58.8 ± 18.3 (N = 17) 17.3±16.3 (N = 33)

• Affinity chromatography on antlANF-coupled agarose, World Health Organization closs 1 and 2 patients. t Half of hypertensive patients studied were In World Health Organization classes 2 or 3. :j: No difference In patients with borderline hypertension (N = 16). § IR-ANF after extraction with Amberllte XAD-2 resin.

of ANF activity) in essential hypertension; (c) the decreased ability of the hypertensive kidney to excrete sodium loads, as postulated by Guyton et al,43 unless

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by increasing the blood pressure ("pressure natriuresis"), as demonstrated in rats by Tobian et a1 44 .45; (d) the decreased inhibition of aldosterone secretion and April 1988 Volume 295 Number 4

Genest et 01

TABLE 3 Relationship of IR-ANF Plasma Concentration and Mean Arterial Pressure in Oogs* h-ANF Infusion JLg/kg/mln Control

0.0025 0.005 0.01 0.3

IR-ANF Plasma Cone. (pg/mL)

68 ± 100 ± 163 ± 282 ± 519 ±

8 8 18 22 35

Mean AP (mm Hg)

120 ± 4 120 ± 4 121 ± 4 120 ± 4 106 ± 4

UNoV (JLEq/mln)

22 ± 66± 131 ± 171 ± 393 ±

6 15 26 26 151

• Modified from Zimmerman et 0/. 32

the inappropriately high secretion rates, plasma levels and excretion rates of aldosterone in patients with essential hypertension, especially during high sodium intake, as demonstrated by Collins et al,46 Luetscher et al,47 and Genest et al,48.49 and (e) the increased peripheral resistance characteristic of essential hypertension because insufficient concentrations of circulating ANF to prevent or to decrease the vasoconstrictor activity of pressor agents such as norepinephrine and angiotensin II. Conclusion

Plasma IR-ANF concentrations are increased in all models of experimental hypertension studied in rats. In patients with labile hypertension and mild to moderate essential hypertension, mean plasma IR-ANF concentration is similar to that of a control group of normotensive subjects, and almost all values are within normal range. Only in patients with more severe hypertension are plasma IR-ANF levels increased in about one-third of patients studied. In view of the reported increase in right and left atrial pressures and distension in patients with mild and moderate essential hypertension, an atrial hypo responsiveness to release ANF is postulated. References 1. Cantin M, Genest J: The heart and the atrial natriuretic factor. Endocr Rev 6:107-126,1985. 2. Genest J, Cantin M, eds: The Atrial Natriuretic Factor. Its Physiology and Biochemistry. Heidelberg, Springer-Verlag, in press. 3. Gutkowska J, Bourassa M, Roy D, Thibault G, Garcia R, Cantin M, Genest J: Immunoreactive atrial natriuretic factor (IRANF) in human plasma. Biochem Biophys Res Commun 128:1350-1357,1985. 4. Gutkowska J, Genest J, Thibault G, Garcia R, Larochelle P, Cusson JR, Kuchel 0, Hamet P, De Lean A, Cantin M: Circulating forms and radioimmunoassay of atrial natriuretic factor. THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES

Endocrinology and Metabolism Clinics of North America 16:183-198, 1987. 5. Garcia R, Thibault G, Cantin M: Correlation between cardiac hypertrophy and plasma levels of atrial natriuretic factor in non-spontaneous models of hypertension in the rat. Biochem Biophys Res Commun 145:532-541, 1987. 6. Gutkowska J, Horky K, Lachance C, Racz K, Garcia R, Thibault G, Kuchel 0, Genest J, Cantin M: Atrial natriuretic factor in spontaneously hypertensive rats. Hypertension 8(Suppl. 1):1137-1140, 1986. 7. Gutkowska J, Kuchel 0, Racz K, Buu NT, Cantin M, Genest J: Increased plasma immunoreactive atrial natriuretic factor concentrations in salt sensitive Dahl rats. Biochem Biophys Res Commun 136:411-416, 1986. 8. Garcia R, Gutkowska J, Genest J, Cantin M, Thibault G: Reduction of blood pressure and increased diuresis and natriuresis during chronic infusion of atrial natriuretic factor (ANF Arg 101-Tyr 126) in conscious one-kidney, one-clip hypertensive rats. Proc Soc Exp Bioi Med 179:539-545, 1985. . 9. Garcia R, Thibault G, Gutkowska J, Hamet P, Cantin M, Genest J: Effect of chronic infusion of synthetic atrial natriuretic factor (ANF 8-33) in conscious two-kidney, one-clip hypertensive rats. Proc Soc Exp Bioi Med 178:155-159, 1985. 10. Garcia R, Thibault G, Gutkowska J, Horky K, Hamet P, Cantin M, Genest J: Chronic infusion of low doses of atrial natriuretic factor (ANF Arg 101-Tyr 126) reduces blood pressure in conscious SHR without apparent changes in sodium excretion. Proc Soc Exp Bioi Med 179:396-401, 1985. 11. Larochelle P, Cusson JR, Hamet P, du Souich P, Gutkowska J, Schiffrin EL, Genest J, Cantin M: Pharmacodynamic effects of bolus administration of ANF in normal volunteers, in Brenner B, Laragh JH (eds): Proceedings, First World Congress on Biologically Active Atrial Pep tides. New York, Raven Press, 1987, pp 451-454. 12. Genest J, Larochelle P, Cusson JR, Gutkowska J, Cantin M, Garcia R, Thibault G, Kuchel 0, De Lean A, Hamet P: The atrial natriuretic factor in mild essential hypertension. Proceedings American Clinical and Climatological Association, Colorado Springs Meeting, Baltimore, Waverly Press, in press. 13. Cusson JR, Hamet P, Gutkowska J, Kuchel 0, Genest J, Cantin M, Larochelle P: Effects of atrial natriuretic factor on natriuresis and cGMP in patients with essential hypertension. J Hypertens 5:435-443, 1987. 14. Weidmann P, Hasler L, Gniidinger 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 77:734-742, 1986. 15. Larochelle P, Cusson JR, Gutkowska J, Schiffrin EL, Hamet P, Kuchel 0, Genest J, Cantin M: Plasma concentration of atrial natriuretic factor in essential and renovascular hypertension. Br Med J 294:1249-1252, 1987. 16. Genest J: The atrial natriuretic factor. Br Heart J 56:302-316, 1986. 17. Zachariah PK, Burnett JC, Ritter S, Strong CG: Atrial natriuretic peptide in human essential hypertension. Mayo Clin Proc 62:782-786, 1987. 18. Kohno M, Yasunari K, Matsuura T, Murakama K, Takeda T: Circulating atrial natriuretic polypeptide in essential hypertension. Am Heart J 113:1160-1163, 1987. 19. Nakuoka H, Kitahara Y, Amano M, Irmataka K, Fujii J, Ishibashi M, Yamaji T: Effect of {:1-adrenergic receptor blockade on atrial natriuretic peptide in essential hypertension. Hypertension 10:221-225, 1987. 20. Naruse N, Naruse K, Obana K, Kurimoto F, Sakurai H, Honda T, Higashida T, Demura H, Inagami T, Shizume K: Immunoreactive alpha-human atrial natriuretic polypeptide in human plasma. Pep tides 7:141-145, 1986. 21. Andersson OK, Persson B, Aurell M, Granerus G, Wysocky M, Hedner J, Hedner T: Basal and stimulated levels of immunoreactive atrial natriuretic peptide (a-hANP) levels in relation to

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