american society of hypertension symposium series volume 3
TRANSCRIPT
American Society of Hypertension Symposium Series Volume 3
Progress in Atrial Peptide Research
Editors
Barry M. Brenner, M.D. Director, R e n a l D i v i s i o n Department o f M e d i c i n e
B r i g h a m and Women's H o s p i t a l and H a r v a r d M e d i c a l School
Boston, Massachusetts
John H. Laragh, M.D. Director, Cardiovascular Center
and Department of M e d i c i n e C o r n e l l University M e d i c a l College
New York, New York
Raven Press «ü* New York
Contents
Preface v Contr ibutors x i x A u t h o r Index x x v
Chapters
1 Processing o f A t r i a l Nat r iu re t ic Fac to r Precursors 1 T a d a s h i I n a g a m i a n d T e r u a k i I m a d a
2 C a l c i u m Modula tes the Process ing o f A t r i opep t in Prohormone Cleavage in the Isolated Perfused Rat Hear t 13
T a k a y u k i I t o , Y u k i o T o k i , a n d P h i l i p Needleman
3 Compara t ive Study of the M o l e c u l a r F o r m o f A N P in H u m a n A t r i u m and P lasma 17
M i t s u h i d e N a r u s e y M i c h i a k i H i r o e , K i y o k o N a r u s e , M a k o t o N a g a t a , Z h e n g - P e i Zengy
A k i m a s a H a s h i m o t o , H i t o s h i K o y a n a g i , H i r o s h i D e m u r a , a n d K a z u o Shizume
4 Structural and Conformat ional Requirements of A N P Clearance Receptors 23
R . M . S c a r b o r o u g h , M . A . H s u , L - L . K a n g , G . A . M c E n r o e , K . S c h w a r t z , A . A r f s t e n , a n d J . A . L e w i c k i
5 Use of U r i n a r y C y c l i c G M P E x c r e t i o n as a Bio logie M a r k e r of the Rena l A c t i v i t y o f A t r i a l Nat r iure t ic Fac tor 31
M a r t i n G. C o g a n y C h o u - L o n g H u a n g , F u - Y i n g L i u , K e n n e t h R. W o n g , M i n g - H o n g X i e , L a n - B o Shi, H a r l a n E . Ives, a n d D a v i d G. G a r d n e r
6 A N o v e l M o d e l Depic t ing the Protein K i n a s e C Regulat ion o f A t r i a l Nat r iu re t ic Factor-Dependent 180-kDa Membrane Guanyla te Cyc l a se 43
Rameshwar K . S h a r m a , Teresa D u d a y a n d R a v i B . M a r a l a
v/7
v/77 C O N T E N T S
7 A t r i a l Nat r iure t ic Fac tor and C y c l i c A M P M o d i f y Protein Phosphory la t ion in Renal Pap i l l a ry Membranes o f Dah l Rats 53
A l e x a n d e r H i n k o a n d J o h n P . Rapp
8 A Physio logica l Ro le for A t r i a l Peptides in Endocr ine Con t ro l Mechan i sms 65
D a v i d J . Ramsay a n d T e r r y N . T h r a s h e r
9 Effects of H u m a n A t r i a l Nat r iure t ic Peptide on Renal Func t ion in Consc ious Dogs 77
H a n s - H e l l m u t Neumayer, M i c h a e l B i o s s e i , U t e S e h e r r - T h o h s , a n d K a r l W a g n e r
10 Dopamine and Rena l A c t i o n o f A t r i a l Nat r iure t ic Peptide 89
K i y o s h i K u r o k a w a , Samaisukh Sophasan, a n d Tetsuo K a t o h
11 Regulat ion o f E lec t ro ly te Transport in the Rena l Cor t i ca l Co l l ec t ing Duc t by Vasopress in and Natr iure t ic Peptides 95
M a r k A . K n e p p e r
12 Reversal o f the Hypo tens ive Effects o f A t r i a l Nat r iure t ic Fac to r in Anes the t ized Rats 111
Rodney W. L a p p e , N o b e r t K . M e t z , a n d R o b e r t L . Wendt
13 D r u g Effects and A t r i a l Nat r iure t ic Peptide in Exper imenta l Card iac Fai lure 121
C . l . J o h n s t o n , M . K o h z u k i , P . A . P h i l l i p s , a n d G.P. H o d s m a n
14 P lasma A N P in C h r o n i c Renal Fai lure and Effects of Changes in Die tary S o d i u m Intake 131
S. Spencer, G . A . S a g n e l l a , N . D . M a r k a n d u , M . A . M i l l e r , M . G . B u c k l e y , A . L . Sugden, D . R . J . Singer, a n d G . A . M a c G r e g o r
15 Amel io ra t ion of Pos t i schemic A c u t e Rena l Fa i lure in Consc ious Dogs by H u m a n A t r i a l Nat r iu re t ic Peptide 141
H a n s - H e l l m u t Neumayer, M i c h a e l B i o s s e i , U t e S e h e r r - T h o h s , a n d K a r l W a g n e r
16 A t r i a l Nat r iure t ic Peptide in N o r m a l H u m a n s : H e m o d y n a m i c and Rena l Effects after Single and Repeated B o l u s Injection 155
CONTENTS i x
Gert Müller-Esch, Jürgen Potratz, Michael Kentsch, Peter Ball, Rupert Gerzer, Sabine Klohs, Rüdiger Lawrenz, and Peter C . Scriba
17 C l i n i c a l Studies with A t r i a l Nat r iure t ic Peptides 169 M. Burnier, B. Waeber, J. Biollaz, J. Nussberger, and
H.R. Brunner
18 T h e R o l e of Resistance to A t r i a l Nat r iure t ic Peptide in the Pathogenesis o f S o d i u m Retent ion in Hepa t i c Ci r rhos i s 185
Leonard C . Warner, Wai-Ming Leung, Peter Campell, Judy M i l l e r , Alexander Logan, Laurence M. Blendis, and K a r l L . Skorecki
19 A t r i a l Nat r iure t ic Peptide in Patients wi th L i v e r Disease 205 Murray Epstein and Rodger Loutzenhiser
Extended Abstracts
Section I: ANP Synthesis, Storage, Secretion, and Radioimmunoassays
Effects of Calcium-free Condition and Hypoxia on A N P Release from Isolated Rat Hearts 213
Yuko Kato, M i t s u h i d e N a r u s e , Toshihiko H i g a s h i d a , Kiyoko N a r u s e , Z h e n g -Pei Zeug, H i r o s h i D e m u r a , Tadashi I n a g a m i , and Kazuo Shizume
Immunoenzymatic Assay of C- and N-Terminal Portions of A N F 217 Gaetan T h i b a u l t , P h i l i p p e Pradelles, Jacques Grassi, and M a r c C a n t i n
Atrial Natriuretic Peptide in Bovine Plasma and Urine 220 N a o y u k i T k e m u r a , K e n j i Ando, H i d e k a z u Koyama, T o s h i n o r i Sako,
T o m i y a U c h i n o , Shigekatsu Motoyoshi and F u m i a k i M a r u m o
Molecular Forms of Immunoreactive A N P in Human Plasma and Urine 223 K e n j i Ando, Kofi K i h i r a , Yoichi K a t o h , T a k a s h i M a s u d a , Toshiro Kurosawa,
and F u m i a k i M a r u m o
Infusion of Atr ial Natriuretic Peptide in Dogs on L o w and High N a C l Diets: Plasma Levels and Disappearance Times 227
D . B . Jennings, I . S a r d a , M . S . Douglas, and T . G . F l y n n
Effect of Morphine on Plasma A N P and Other Sodium Dependent Hormones in Normal Men 235
G. W a m b a c h , M . Weber, M . Stimpel, G. Bonner, and W. K a u f m a n n
X C O N T E N T S
Big A N F in Rabbit Plasma 239 N a d i n e W i l s o n , R a l p h Keeler, John R . Ledsome, Andrew Wong, and
V e r o n i c a Yakoleff
Identification and Characterization of Immunoreactive A N P - l i k e Material in Guinea Pig lntestine 241
A . M . V o l l m a r , A . F r i e d r i c h , and R . Schulz
Regulation of Plasma A N F Concentration in the Sheep Fetus 244 C e c i l i a Y. Cheung and Robert A . Bruce
Atrial Natriuretic Polypeptide-like Immunoreactive Substances (ANP-IR) in Fish Hearts 247
Z . H . Shao, C.Q. L i , L . Y . Z h a n g , J.K. L i u , S.S. Z h a n g , and S.Y. D o n g
Immunoreactive A N F and A N F Binding Site in Rat Olfactory Mucosa: Effect of Nasal Application of A N F on Urinary Secretion 252
J. Gutkowska, M . M a r c i n k i e w i c z , and L . P a n
Section II: ANP Receptors and Second Messengers
Tissue-specific Heterogeneity of the Atr ia l Natriuretic Factor Receptors 255 K a i l a s h N . Pandey and Tadashi I n a g a m i
Atria l Natriuretic Peptide Receptors are Increased in Supraoptic and Paraventricular Nuclei of Brattleboro Rats 260
E e r o Castren and J u a n M . Saavedra
Atrial Natriuretic Peptides in the Brain of Rats with Inherited Diabetes Insipidus (Brattleboro Rats) 264
Udo B a h n e r , H e l m u t Geiger, M i k l o s Palkovits, Detlev G a n t e n , Joachim M i c h e l , M a r i a n n Fodor, and August H e i d l a n d
Atrial Natriuretic Factor Binding Sites in the Jejunum 269 Cesario B i a n c h i , Edyta Wrobel-Konrad, Gaetan T h i b a u l t , A n d r e D e L e u n ,
M a r i e - C l a u d e G r e n i e r , Jacques Genest, and M a r c C a n t i n
Down Regulation of A N F Receptors by Phorbol Dibutyrate in Cultured Vascular Smooth Muscle Cells 273
P i e r r e Roubert, P i e r r e - E t i e n n e C h a b r i e r , Pascale Pias, and P i e r r e Braquet
Renal Structure - Activity Relationships of Ring-Deletion Analogs of Atrial Natriuretic Factor 276
Rodney W. Lappe, C h a r l o t t e M . H a r v e y , Robert L . Wendt, John A . Lewicki, G l e n A . M c E n r o e , and Robert M . Scarborough
Potentiation and Inhibition of A N F Activi ty by its Analogs 279 R . W i l l e n b r o c k , M . H e i m , P.W. Schiller, J. Tremblay, and P . H a r n e t
Glomerular and Vascular Atrial Natriuretic Factor Receptors in Adrenalectomized Rats: Correlation with the Peptide's Biological Effects 283
V i c t o r i a C a c h o f e i r o , M a r c C a n t i n , Ernesto L . Schiffrin, and R a u l G a r c i a
Effect of Chelators on the Binding of Atrial Natriuretic Factor to Human Placental Membranes: Identification of Multiple Forms of Atrial Natriuretic Factor Receptor 287
U l h a s N a i k , Pampa Roy, and I n d i r a Sen
C O N T E N T S x i
Atrial Natriuretic Factor Negatively Regulates Autophosphorylation of Protein Kinase C in Plasma Membranes of Murine Leydig Tumor Cells and Bovine Adrenal Cortical Cells 290
K a i l a s h N . Pandey and Tadashi I n a g a m i
The Sensitivity of Particulate Guanylate Cyclase to Atrial Natriuretic Factor is Increased by Amiloride and Triton X-100 294
K r a s s i m i r a I v a n o v a , Jörg-Martin H e i m , B a r b a r a Lückenga, and Rupert Gerzer
Characterization of ANF-Induced Inhibition of Adenylate Cyclase 297 M a d h u B . Anand-Srivastava and M a r c C a n t i n
Atrial Natriuretic Factor ( A N F ) Receptors are Coupled to Adenylate Cyclase in Rat Platelet Membranes 301
M a d h u B . Anand-Srivastava, J. Gutkowska, and M . C a n t i n
8-Br -cGMP Versus A N P in Conscious Dogs: Hemodynamic, Renal and Hormonal Effects 305
D i e t m a r Eisner, E c k h a r d F. Kromer, and Günter A . J . Riegger
Inhibition of A N F Vasorelaxation by E I P A : A Role for N a + / H + Exchange? 309 Sandeep G u p t a , E d w a r d J. Cragoe, Jr., and R i c h a r d C. D e t h
Section III: ANP and the Endocrine and Nervous Systems
Arginine Vasopressin (AVP)-enhanced Release of a-Atrial Natriuretic Factor From Unstretched Rat Atr ia Incubated In Vitro 315
G . A . Zeballos, C. Hoegler, M . H . Gewitz, and J . M . Stewart
Does Atrial Natriuretic Factor Inhibits Activation of Prorenin to Plasma Renin in Conscious Dogs? 318
D . H . Osmond, C T . Thompson, M . S . Douglas, and D . B . Jennings
Atrial Natriuretic Factor Inhibits Isoproterenol and Furosemide-stimulated Renin Release in Humans 328
John J M c M u r r a y and A l l a n D Struthers
Involvement of Atr ia l Natriuretic Peptide of the Brain A V 3 V Region in the Water and Salt Homeostasis 333
H e l m u t Geiger, Udo B a h n e r , M i k l o s Palkovits, C h r i s t i a n H u g o , Elisabeth N i k l a s , and August H e i d l a n d
Atrial Natriuretic Factor Constitutes an Intrinsic Functional Unit in Sympathetic Ganglia 338
W. Debinski, O. Kuchel, N . T . B u u , J. Tremblay, and P . H a r n e t
Atrial Natriuretic Factor Inhibits Adrenergic Neurotransmission in Rabbit Isolated Portal Veins 342
James G. Drewett, Gary R . M a r c h a n d , and George J. T r a c h t e
Inhibitory Act ion of Atrial Natriuretic Polypeptide and Other Vasoactive Neuropeptides on Neurotransmitter Release in Hypertension 351
Kazushi Tsuda, Seiko Tsuda, and Yoshiaki M a s u y a m a
Is a Hypophyseal Factor Required for Atrial Natriuretic Factor Secretion? 356 A a r o n H o f f m a n and H a r r y R . Keiser
x i i C O N T E N T S
The Role of Endogenous A N P in D O C A Salt Hypertension 359 C . H i r t h , S. Kazda, A . K n o r r , J . - P . Stasch, andS. Wohlfeil
Interaction Between Atrial Peptides and Endogenous Digitalis during the Development of Mineralocorticoid Hypertension: A New Axis? 363
John M . H a m l y n
Physiological Doses of Atr ial Peptide Inhibit Angiotensin II-stimulated Aldosterone Secretion in Conscious Dogs 368
C r a i g H . M e t z l e r and D a v i d J. Ramsay
Hormonal Effects of Alpha-Human Natriuretic Peptide in Patients with Primary Aldosteronism 371
Saleh Abdelhamid, P a u l Vecsei, R o l a n d Blomer, M i c h a e l Jansky, A r n o l d Rockel, Dieter W a l b , and Peter F i e g e l
Modulation of Na/K-ATPase Activi ty by Ouabain and Growth Hormone: Effects on Circulating Atrial Natriuretic Peptides 384
K. Peter O h m a n , M a r g a r e t Slover, H a r r y R . Keiser, and Nadav Z a m i r
Renal Action of Human Atrial Natriuretic Peptide in Active Acromegaly 388 E c k a r t J u n g m a n n , U n d i n e Schirmer, E r n s t - H . Scheuermann, Stefan Zeuzem,
and K a r l Schößling
Naloxone Does Not Antagonize the Clonidine-induced Increase In Plasma Atrial Natriuretic Peptides in Rats 392
Nadav Z a m i r , M a r g a r e t Slover, H a r r y Keiser, I r w i n K o p i n , and Peter O h m a n
Effects of STZ-induced Diabetes on Atrial Natriuretic Peptide Levels in Rats 396 Leslie Scale B l a c k and John C. Lee
Plasma Volume and Atrial Natriuretic Peptide Concentration during Pregnancy and Postpartum in Rats 400
A l a n L . A . B o u r a , Chaweewan Jansakul, Roger G. K i n g , S h a u n P . Brennecke, and Gwynneth M . H a n d b e r g
Atria l Natriuretic Peptide in the Puerperium as Compared with Pregnancy in Healthy Women: Increased Plasma Concentrations Postpartum Possibly Participating in the Stimulation of Natriuresis Immediately after Delivery 403
Lorenzo S. M a l a t i n o , Benedetta Stancanelli, Giuseppe Greco, L u i s a G i t t o , Giuseppe E t t o r e , Paolo Scollo, and Giacomo T a m b u r i n o
Thyroid Hormone and Glucocorticoid Modulate the Release of Atrial Natriuretic Peptides from Cardiac Atr ia 407
Nadav Z a m i r , M a r k u s Haass, M a r g a r e t Slover, and Peter O h m a n
A N F Involvement in the Diuresis of Hyperthyroidism 412 D o n a l d F. Sellitti, P h i l l i p A . Passarelli, and Keith R . L a t h a m
Relationships between Atrial Natriuretic Peptides and Amphetamine in Idiopathic (Orthostatic) Edema 416
John J. C a n a r y , Sam J. B h a t h e n a , P a t r i c i a M . S m i t h , M y r a L . G l e n , C a r o l A . G a n n o n , and Bruce W. Kennedy
Lack of Inhibiting Effect of Human Atrial Natriuretic Peptide on Pituitary and Adrenal Hormone Stimulation during Insulin-induced Hypoglycemia 420
E c k a r t J u n g m a n n , Thomas H a a k , C h r i s t i n e Konzok, Edmond H o l l , and K a r l Schößling
C O N T E N T S x i i i
Raised A N F Concentrations in Normotensive Obese Patients: Discrepancy between Radioreceptor and Radioimmunoassay Measurements 423
L . H e i n e m a n n , P . T . Sawicki, A . H o h m a n n , K. Rave, W. Mensel, and M . Berger
Plasma Atrial Natriuretic Peptide Concentration (p-ANP-c) during Licorice Ingestion in Healthy Volunteers 426
Ter je F o r s l u n d , F r e j Fyhrquist, B e r t i l Fr<ßseth and l l k k a T i k k a n e n
A N P and Other Fluid-Regulating Hormones during Space Flight 431 N . M . Cintrön, CS. L e a c h , J . M . K r a u h s , and J . B . Charles
Atrial Natriuretic Factor in Fetal Alcohol Syndrome in Rats 435 Lawrence M . D o l a n , C a r o l y n A . Young, and Charles V. Vorhees
Atrial Natriuretic Factor in Chronic Hypoxie Pulmonary Hypertension: Physiological Correlates and Responses to Peptide Infusion 438
Serge Adnot, P i e r r e Andrivet, P i e r r e - E t i e n n e C h a b r i e r , Jacques Piquet, P i e r r e Braquet, and C h r i s t i a n Brun-Buisson
Section IV: ANP in Heart Disease and Hypertension
Atrial Natriuretic Factor Release during Angiotensin II Infusion in Right and Left Atr ia l Appendectomized Rats 441
D a n i e II e L a c h a nee and R a u l G a r c i a
Plasma Atr ia l Natriuretic Peptide Level and Molecular Forms in Dogs with Acute Heart Failure Induced by Experimental Aort ic Regurgitation 445
T a k a s h i M a s u d a , Kiyotaka Satoh, Yoshihiko M a s a k i , K e n j i Ando, and F u m i a k i M a r u m o
Plasma Atr ial Natriuretic Peptide Level and Molecular Forms in Dogs with Acute Heart Failure Induced by Experimental Mitral Regurgitation 447
Kiyotaka Satoh, T a k a s h i M a s u d a , Yoshihiko M a s a k i , K e n j i Ando, N o b u h i r o Hasegawa, R y u i c h i K i k a w a d a , and F u m i a k i M a r u m o
Natriuretic and Urinary Cycl ic Guanosine Monophosphate Responses to Infused Atrial Natriuretic Peptide in Rats with Chronic Myocardial Infarction 449
M a s a h i r o Kohzuki, G. Peter H o d s m a n , and C o l i n I . Johnston
I n V i v o and I n V i t r o Effects of Atrial Natriuretic Factor on Renal Cycl ic G M P Production in Rats with Experimental Heart Failure 453
Joseph Winaver, Z a i d Abassi, A a r o n H o f f m a n , O r i S. Better, and Aviad H a r a m a t i
Attenuated Diuretic and Natriuretic Effect of Atrial Natriuretic Peptide in Rats with Heart Failure 458
l l k k a T i k k a n e n , T u u l a T i k k a n e n , H a n n u S a r i o l a , M a r g a r e t a Svartström-Fraser, and F r e j F y h r q u i s t
Renal and Adrenal Resistance against Exogenous A N P in Congestive Heart Failure: Effect of Enalapril 461
G. W a m b a c h , U. Schittenhelm, S. Degenhardt, G. Bonner, and W. K a u f m a n n
xiv C O N T E N T S
Effects of Atrial Natriuretic Peptide on Voltage-dependent Inactivation of T-Type Calcium Channel Current 464
R i c h a r d T. M c C a r t h y , Carlos M . Isales, and P a u l a Q. B a r r e t t Limited Role of Right Atr ial Pressure in the Acute Control of Circulating
Atrial Natriuretic Factors. Volume Expansion and Lower Body Negative Pressure in Young and Aged Healthy Men 468
H e r m a n n Saxenhofer, Christoph Cottier, Susanne Suda, Sidney Shaw, C l a u d i a F e r n e r , and Peter W e i d m a n n
Evidence for the Sidedness in the Baroceptorial Regulation of At r ia l Natriuretic Peptide in Normal Human Subjects 476
A n n a Santucci, Vincenzo M a r i g l i a n o , l l i o C a m m a r e l l a , C l a u d i o F e r r i , Riccardo Leonetti L u p a r i n i , C l a u d i o D e Angelis, Antonio M u s c a , and Francesco Balsano
Plasma Levels of Atrial Natriuretic Peptide and its Correlates in a Male Working Population 480
Francesco P . Cappuccio, G r a h a m A . M a c G r e g o r , Pasquale Strazzullo, Giuseppe A . S a g n e l l a , L i c i a I a c o v i e l l o , M a r t i n G. Buckley, E d u a r d o F a r i n a r o , and M a r i o M a n c i n i
Increased Atrial Natriuretic Peptide and Decreased Vasopressin during Supraventricular Tachycardia 483
M i t s u h i d e N a r u s e , Satoshi O h n i s h i , Kiyoko N a r u s e , H i r o s h i Kasanuki, Tamotsu Shibasaki, H i r o s h i D e m u r a , Koshichiro H i r o s a w a , Tadashi I n a g a m i , and Kazuo Shizume
Role of Right Atrial Wall Stress in A N P Release in Patients with Heart Disease 492
Thomas A . Fischer, M a r k u s Haass, R u d o l f E . L a n g , and R a i n e r Dietz
Does the Determination of Atrial Natriuretic Peptide Replace Diagnostic Right Heart Catheterization during Treadmill Exercise? 496
T. Eisenhauer, J. T a l a r t s c h i k , K . - H . Scholz, and K . L . Neuhaus
Change of Molecular Forms of Atr ia l Natriuretic Peptide in Treated Congestive Heart Failure 501
T Kurosawa, S. T a k e da, N . Hasegawa, K. Ando, R . K i k a w a d a , and F. M a r u m o
Atrial Natriuretic Peptide in Patients with Acute Cerebroocclusion and Heart Failure 503
C.Q. L i , Z . H . Shao, S.Y. L i u , C.X. Z h a o , Q.Y. H e , and L . Y . Z h a n g
Plasma A N P Changes in Patients with Heart Failure and Cerebroocclusion Treated with Isometric Dilution Therapy 509
C.Q. L i , Z . H . Shao, S.Y. L i u , C.X. Z h a o , Q.Y. H e , and L . Y . Z h a n g
Persistent Elevation of A N P and Cyc l ic G M P Concentrations in Plasma of Patients after Cardiac Surgery 511
Klaus P . Kohse, Klaus H e l l b e r g , and H e r r m a n n Wisser
Plasma Levels of Atr ial Natriuretic Peptide in Cardiac Transplant Recipients during Dynamic Exercise 515
D i e t m a r H . Petzl, Engelbert H a r t t e r , Gregor W o l l e nek, Wolf gang Schuller, Wolfgang Woloszczuk, C h r i s t i a n Wolf, W e r n e r Scheithauer, and Oswald J a h n
C O N T E N T S xv
Peripheral Vascular Effects of Atr ia l Natriuretic Peptide after Total Artificial Heart Implantation 519
Timothy E . Oaks, James A . M a g o v e r n , W a l t e r E . Pae, and W i l l i a m S. Pierce
Atrial Natriuretic Peptide and Atr ial Pressure in Calves with Total Artificial Hearts 523
James A . M a g o v e r n , W a l t e r E . Pae, Jr., Timothy E . Oaks, W i l l i a m S. Pierce, John A . Waldhausen, and Roscoe E . Hersey
Plasma Atr ial Natriuretic Factor during the Week after Orthotopic Heart Transplantation 525
D . F a r g e , R . G u i l l e m a i n , D . Rayen, C. A m r e i n , G. D r e y f u s , I . Viossat, P . E . C h a h r i e r , and P . Braquet
Atrial Natriuretic Peptide Prevents Hypoxia-induced Pulmonary Hypertension in Rats 529
R e n - H u i Yang, H o n g k u i J i n , Y i u - F a i C h e n , Robert M . Jackson, and Smanne O p a r i l
Silicosis and Atr ia l Natriuretic Polypeptides 533 Z . H . Shao, C.Q. L i , L . Y . Z h a n g , Y . L . J i n g , Y . M . Cheng, J.K. L i u ,
S.Y. D o n g , and S.S. Z h a n g
Free and Bound Forms of Atrial Natriuretic Peptide in Rat Plasma: A Comparison of Spontaneously Hypertensive Rats and Wistar Kyo to Rats 541
J o h j i Kato, Osamu K i d a , T o s h i h i r o K i t a , Shigeru N a k a m u r a , A k i r a Sasaki, K e n j i Kodama, and K e n j i r o T a n a k a
Central Atrial Natriuretic Peptides in Young (Prehypertensive) Spontaneously Hypertensive Rats 545
Udo B a h n e r , H e l m u t Geiger, Miklös Palkovits, C s i l l a Pammer, Klaus Schafferhans, and August H e i d l a n d
Regulation of Brain Atr ia l Natriuretic Peptide Binding Sites in Spontaneously Hypertensive Rats after Chronic Antihypertensive Treatment with Enalapril 549
A J . N a z a r a l i , J.S. G u t k i n d , F . M . C o r r e a , a n d J . M . Saavedra
The Distribution, Origin and Possible Role of Neural A N F in Spontaneously Hypertensive Rats 554
Otto Kuchel, W a l d e m a r Debinski, G a c > t a n T h i b a u l t , M a r c C a n t i n , and Jacques Genest
Glomerular Atr ial Natriuretic Factor Receptors in Spontaneously Hypertensive Rats 557
R a u l G a r c i a , Guillemette G a u q u e l i n , Gaetan T h i b a u l t , M a r c C a n t i n , and Ernesto L . Schiffrin
Atrial Natriuretic Factor Attenuates Hypertension Induced by Acute Unilateral Renal Artery Clipping in Rats 561
Massimo Volpe, R . Ernest Sosa, Steven A . Atlas, M a r i a J. C a m a r g o , C a r l a S a l a , F r a n c o B . M u l l e r , E . D a r r a c o t t V a u g h a n , Jr., and John H . L a r a g h
Vascular Receptors for Atrial Natriuretic Peptide in Spontaneously Hypertensive Rats 564
Ernesto L . Schiff r i n , Jean St-Louis, Pavel H a r n e t , and R a u l G a r c i a
x v i C O N T E N T S
Important Role of Brain A N P in the Development of DOCA-Sa l t Hypertension in Rats 567
H e l m u t Geiger, Udo B a h n e r , M i k l o s Palkovits, Jürgen H u p e , Klaus Schafferhans, and August H e i d l a n d
Mechanism Mediating the Hypotensive Effect of Atrial Natriuretic Factor in Sodium-depleted Dogs: Role of Renin Suppression 572
Joey P . Granger, Elizabeth Meadows, Soheil Sooudi, and D . L o w e l l Stacy
Influence of Acute Venodilation by Captopril on the A N P and Pressor Modifications in Borderline Hypertension 575
C. B o r g h i , S. Boschi, A . Mussi, F.V. Costa, and E . Ambrosioni
Influence of D A 3 Receptor Blockade on Plasma A N F and on Its Humoral and Renal Effects in Human Hypertensives 580
A . R . L u c a r i n i , P . A r r i g h i , S. F a v i l l a , N . S i m o n i n i , and A . Salvetti
N o Changes in Plasma Insulin and Cortisol during A N F Infusions in Essential Hypertension 584
G i a n c a r l o T o n o l o , Paolo M a n u n t a , A . M a r k Richards, Aldo Soro, M a r i o M a i o l i , and N i c o l a Glorioso
Section V: A N P Effects on the Kidney and Liver
Atrial Natriuretic Peptide Reverses Norepinephrine-induced Afferent Arteriolar Vasoconstriction 589
Rodger Loutzenhiser, K o i c h i H a y a s h i , and M u r r a y Epstein
Vasopressin and Norepinephrine Potentiate the Renal Effects of Synthetic Atrial Natriuretic Factor in a Model of Experimental Cirrhosis 598
D a n i e l R . Ganger, Jeanne Gott stein, and Andres T. B l e i
Norepinephrine Attenuates the Renal Effects of Atrial Natriuretic Factor in Men 602
John J. M c M u r r a y , Peter H . Seidelin, and A l l a n D . Struthers
Arginine Vasopressin Dissociates the Natriuresis and Diuresis Due to Atrial Natriuretic Factor in Men 606
John J. M c M u r r a y and A l l a n D . Struthers
Clinical Studies on the Effects of Atrial Natriuretic Peptide on Antidiuretic Hormone and Urinary Dilution 610
Yasunobu H i r a t a , M a s a o fshii, Kazushige F u k u i , T o k u i c h i r o Sugimoto, H i r o a k i M a t s u o k a , Tsuneaki Sugimoto, K e n j i K a n g a w a , and H i s a y u k i M a t s u o
Effect of Atrial Natriuretic Peptide on Renal Sodium Handling in Unilaterally Kidney-denervated Rats 614
W l a d i m i r o Jimenez and D a n i e l C. B a t l l e
Hemodynamic Responses to Atrial Natriuretic Factor in Nephrectomized Rabbits 618
Massimo Wölpe, F i l i p p o Vecchione, Giuseppe Lembo, Alberto Cuocolo, S i l v a n a Pignalosa, G i a n L u i g i Condorelli, and B r u n o T r i m a r c o
C O N T E N T S x v i i
Atrial Natriuretic Factor Release in Diabetic Uremic Patients with Severe Combined Sympathetic Parasympathetic Dysfunction 621
C a r m i n e Zoccali, Francesco M a l l a m a c i , M a u r i z i o C i c c a r e l l i , F i l i p p a S a l n i t r o , Saverio P a r l o n g o , and Adalgisa C u r a t o l a
Changes in the Molecular Forms of Atr ial Natriuretic Peptide by a Single Hemodialysis 625
F u m i a k i M a r u m o , Atsushi Yoshida, A k i r a K u r o k a w a , M i y o k o K a m i y a m a , and K e n j i Ando
Prevention of Uranyl Nitrate-induced Acute Renal Failure by Renal Denervation and Atrial Natriuretic Peptide: A Comparative Study 627
K. Schafferhans, H . Geiger, R . Herzog, and A . H e i d l a n d
Additive Protective Action of Atrial Natriuretic Peptide and Verapamil in Gentamicin-induced Acute Renal Failure 632
K. Schafferhans, LI. B a h n e r , R . Schmatz, and A . H e i d l a n d
Atrial Natriuretic Peptide Reverses Experimental Acute Renal Failure Induced by Arginin Vasopressin 636
E k k e h a r t Heidhreder, Klaus Schafferhans, Thomas Z o l l n e r , Rüdiger Götz, and August H e i d l a n d
Excretion Patterns for Inulin and Sodium in Rat Kidneys: Effect of Atrial Natriuretic Peptide on Papillary Necrosis 640
R a l p h Keeler and A n a M a r i a Azzarolo
Atrial Natriuretic Factor Increases Urinary Albumin Excretion in Men 643 John J. M c M u r r a y , Peter H . Seidelin, Jaquie Howey, and A l l a n D . Struthers
Effects of the Calcium Channel Blocker Nifedipine on A N P Secretion and Renal Excretory Function During Head-Out Water Immersion 647
H . M e y e r - L e h n e r t , C . Till, H . G . Predel, and H J . K r a m e r
A N F and Renal Excretory Functions Related to Changes in Intrathoracic Pressure 650
P i e r r e Andrivet, Serge Ad not, P i e r r e - E t i e n n e C h a b r i e r , P i e r r e Braquet, and C h r i s t i a n Brun-Buisson
Effect of Auricul in on the Salt Gland of the Duck 653 H e r b e r t G. L a n g f o r d and K a t i e H o l d e r
Atrial Natriuretic Factor in Ascites of Patients with Cirrhosis of the Liver or with Malignant Neoplasms 656
Alexander L . Gerbes, A n g e l i k a M . Wollmar, Y i n i n g X i e , and R a i n e r M . Arendt
Subject Index 661
P r o g r e s s i n A t r i a l P e p t i d e Research. V o l . I I I : A m e r i c a n Society of H y p e r t e n s i o n Symposium Series. cd i ted by B. M . Brenner , and J. H . La ragh . Raven Press. L t d . . N e w York © 1989.
CHAPTER 16
Atrial Natriuretic Peptide in Normal Humans: Hemodynamic and Renal Effects after Single and Repeated Bolus Injection
*Gert Müller-Esch, * Jürgen Potratz, ^Michael Kentsch, **Peter Ball, tRupert Gerzer, *Sabine Klohs,
* Rüdiger Lawrenz, and * Peter C. Scriba
Departments of * M e d i c i n e and **Biochemical Endocrinology, M e d i c a l University Lübeck, and tDepartment of M e d i c i n e , University München,
F e d e r a l Republic o f Germany
To study cardiovascular and diuretic effects and to establish whether there is an attenuation of response after repeated application, we gave a single or two 30-min-apart bolus injections of 200 |xg human atrial natriuretic peptide (a-hANP). Before and after a - h A N P bolus injections, echocardiography was performed and plasma atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) as well as urinary c G M P excretion were deter-mined. Plasma c G M P rose from basal 3.4 ± 1.1 to 25.0 ± 6.7 nmol/liter within 10 min after the first injection and from 20.0 ± 6.0 before the second administration to 32.7 ± 11.1 nmol/liter another 10 min later. Urine volume (30-min sampling periods) increased from 2.1 ± 2.5 to 16.1 ± 5.3 after the first and to 22.6 ± 7.0 ml/min after the second bolus. Urine sodium excretion increased from 6.2 ± 2.9 to 43.0 ± 18.5 and 38.7 ± 21.0 mmol/hr. After each a - h A N P bolus, there was a significant decrease in mean arterial blood pressure and increase in heart rate. The ejection fraction increased from 66.2 ± 3.7 to 76.4 ± 4.0% after the first bolus and from 66.8 ± 3.8 before the second to 76.9 ± 5.0 after the second a - h A N P bolus. A l l reported changes are significant (/? < 0.01).
Single and repeated bolus applications of 200 |mg of a - h A N P in healthy volunteers increases plasma and urinary c G M P , diuresis, and natriuresis as well as echocardiographically determined ejection fraction and decreases arterial blood pressure. Reproducible diuretic effects and improved cardiac Performance after repeated bolus application of a - h A N P may be beneficial in the treatment of congestive heart failure.
155
156 C H A P T E R 16
a - h A N P is a cardiac hormone with diuretic, natriuretic, and vasodilating properties (1-3). When given either as a bolus or as an infusion intravenously in normal humans, a - h A N P causes a rise in urinary volume and sodium excretion (1,2). The hemodynamic actions of a - h A N P are yet not well de-fined. After an a - h A N P bolus, Richards et al. observed an increase of heart rate and adecrease of blood pressure (1). During infusion of a - h A N P , Cuneo et al. could not detect changes of heart rate or blood pressure (4), but Indolfi et al. reported decreased blood pressure while the heart rate was kept con-stant by cardiac pacing (5). Vasodilating actions (4) as well as other hemodynamic and diuretic effects of a - h A N P depend on the application scheme and the given dose (6).
In this study, our aim was to investigate the effects of Single and repeated high dose a - h A N P bolus injections in normal humans on (a) c G M P response, (b) hemodynamic parameters detectable by echocardiography, and (c) di-uresis and natriuresis.
MATERIALS AND METHODS
The first part of the study (protocol 1) was performed in seven healthy volunteers (six men and one woman; 27.7 ± 1.8 years) without any evidence of heart disease. After an overnight fast and bed rest, 200 |xg of a - h A N P (Bissendorf Peptide, Wedemark, FRG) were given as a bolus injection intravenously.
Heart rate and blood pressure were monitored noninvasively by an auto-matic device (DynamapR). M-mode echocardiography was performed 40 and 20 min before as well as 5, 10, 15, 30, 45, 60, 120, and 180 min after the injection of a -hANP.
Venous blood samples were drawn for the determination of A N P , c G M P , hematocrit, sodium, potassium, and serum osmolality at - 2 0 , ± 0 , +2, +5, + 10, +20, +35, +60, +90, and + 180 min. Urine was collected at 30-min-ute intervals for measuring the excretion of sodium, potassium, and c G M P . Urine Output was replaced throughout the study by oral water.
Informed consent was given; the study was approved by a local ethics committee.
Echocardiography
A n I R E X III (m-mode) echocardiograph together with a C A R D I O 200 Computer for the elaboration of the data was used. The left ventricular di-mensions were obtained when the ultrasonic beam was directed at the Chamber between the mitral valve echos and the papillary muscle echos (7). The end-diastolic diameter (EDD) was taken at the peak of the R-wave and from the trailing edge of the left side of the intraventricular septum to the leading edge of the posterior endocardial echo. The end-systolic diameter (ESD)
a - h A N P I N N O R M A L H U M A N S 1 5 7
was taken at the peak downward motion of the intraventricular septum. Ven-tricular volumes—end-diastolic volume (EDV) and end-systolic volume (ESV) , stroke volume (SV), and cardiac index (CI)—were obtained utilizing the formula of Teicholz et al. (8). The ejection fraction (EF) was calculated according to the method of Quinones et al. (9).
A N P (without prior extraction; I B L , Hamburg, F R G ) a n d cGMP(10) were measured by radioimmunoassay.
Data are given as means ± Standard deviation (SD). For Statistical anal-ysis, Studenfs Mest for paired data and the analysis of variance for repeated measures over time (11) were used.
In the second part of the study (protocol 2), 200 jxg of a - h A N P were given twice as intravenous boluses at a 30-minute interval in six healthy volunteers (five men, one woman; 27.5 ± 2.4 years). Again, echocardiography was performed 40 and 20 min before the first administration as well as 5, 10, 15, and 30 min after each bolus and finally at 90, 120, and 180 min. As before, venous blood samples were drawn ( - 4 0 , - 2 0 , ± 0 , +2, +5, +10, +20, + 32, +35, +40, +50, +60, +90, + 120, +150, + 180 min) and urine was collected at 30-minute intervals.
Within 2 min after each injection, a transient heart rate increase together with a fall of mean arterial pressure occurred (Tables 1 and 2). These
TABLE 1. Hemodynamic, echocardiographic, and laboratory findings after a Single bolus injection of <x-hANPa
Analytical Methods
Calculation and Statistics
RESULTS
Basal Max/min Time (min)
Heart rate (min ') Mean arterial pressure (mm Hg) Stroke volume (ml) Cardiac index (liters/min/m 2) Urinary cGMP (nmol/min) Hematocrit (%)
58.6 ± 4.67 91.3 ± 5.7 77.5 ± 15.1 2.44 ± 0.41 0.71 ± 0.25 41.7 ± 3.3
79.1 ± 7.4 81.7 ± 6.4 90.3 ± 10.2 2.88 ± 0.41 5.56 ± 1.94 44.8 ± 3.2
+ 4 + 2 + 10 + 10
+ 35 0 -30
a Time: time of maximal deviation from baseline values. The significance of all differences between basal and maximal or minimal values (max/min): p < 0.01.
1 5 8 C H A P T E R 16
TABLE 2. Hemodynamic, echocardiographic, and laboratory Undings after repeated bolus injections of a-hANPa
Basal Max/min Time (min)
Heart rate ( m i n - 1 ) A65 .5 ± 8.6 79.5 ± 6.4 + 3 B 60.2 ± 7.9 83.3 + 6.7 + 3
Mean arterial pressure (mm Hg) A 9 0 . 0 3.9 82.5 6.4 + 4 B 8 9 . 8 5.8 81.2 ± 5.3 + 2
Stroke volume (ml) A83 .4 11.0 95.8 13.0 + 10 B 7 8 . 6 13.1 90.2 ± 23.7 + 15
Cardiac index (liters/min/m 2) A 2 . 9 7 ± 0.51 3.20 0.67 + 10 B 2.63 0.46 3.28 ± 0.93 + 15
Urinary cGMP (nmol/min) 0.62 0.42 5.68 1.75 30-Hematocrit (%) 42.5 + 2.5 46.7 ± 2.3 + 40
8 A: first a-hANP bolus; B: second a-hANP bolus. Time: t ime of maximal deviation from baseline values. The significance of all differences between basal and maximal or minimal values (max/min): p < 0.01.
changes had disappeared another 5 min later. A l l subjects experienced mild to moderate facial flushing; no severe side effects were observed.
Hemodynamic Findings
In general, echocardiographic changes were most pronounced 10 to 15 min after the injection of a - h A N P and reached baseline values another 15 to 20 min later.
S i n g l e B o l u s ( P r o t o c o l 1)
The results are given in Figs. 1 and 2 and in Table 1. E S D decreased mark-edly. As E D D (basal, 5.06 ± 0.37 cm) remained constant, this resulted in an increase of the calculated EF . Correspondingly, S V and CI were augmented by about 17%.
Repeated B o l u s I n j e c t i o n ( P r o t o c o l 2 )
Figures 3 and 4 and Table 2 give the results. Again, E S D decreased sig-nificantly while E D D remained unchanged, leading to an increase of calculated E F , SV, and C I . Two-way analysis of variance did not disclose differences between the effects of a Single A N P bolus (protocol 1) and the first of two bolus injections (protocol 2). Repeated injection after 30 min provoked comparable hemodynamic responses; an attenuation or waning effect could not be demonstrated.
3.5
3.4
3.3 H
3.2
3.1
3.0 -I
2.9
2.8-
2.7-
2.6-
ESD [cm]
-40 -20 »051015 30 45 60 90 180
FIG. 1 . End-systolic diameter (ESD) after a Single bolus injection of 200 |xg of a-hANP in volunteers; 'p < 0.01.
75
70
65
60-
EF ro/.i
200,ug 4-hANP
^40 -20 t05t t t5 30 45 60 90 120 180 min
FIG. 2. Ejection fraction (EF) after Single bolus injection of 200 p.g of a-hANP in volunteers; *p < 0 .01 .
1 6 0 C H A P T E R 16
L.Q
3.5
3.0
2.5
2.0
ESD Lern]
t t 200 w <rf-hANP
i i I | i I r r n 1 1 r— -40 -20 0 10 3040 60 75 90 5 15 3545
120 150 180 min
6.0
5.5 i
5.0 J
*.5
EDD [cm]
t t 200 ug o(-hANP
-40 -20 ÖSo' 3oVo' 60 75 90 llo" 5 15 3545 150 180 min
FIG. 3. End-systolic diameter (ESD) and end-diastolic diameter (EDD) after repeated bolus injections of 200 \x,g of a-hANP at a 30-min interval; *p < 0.01.
a - h A N P I N N O R M A L H U M A N S 1 6 1
FIG. 4. Ejection fraction (EF) after repeated bolus injections of 200 p,g of a-hANP at a 30-minute interval; *p < 0.01.
Renal Findings
Single Bolus
Within the first 30 min after injection, urinary volume increased ninefold and sodium excretion increased fivefold (Fig. 5), whereas potassium excretion only doubled. Enhanced diuresis and natriuresis were still present at least 60 min later.
Repeated Bolus Injections
Again, the first injection of 200 \xg of a - h A N P produced clear-cut diuresis and natriuresis together with a moderate increase of potassium excretion. These effects were not different from those in protocol 1. Repeated injection
162 C H A P T E R 16
U Na* [ml/min] [mmol/h]
|-60 200/ug oC-hANP # -
I 50
-40
30
-20
10
E3 Urinary excretion of NA*
| Urinary volume (U)
U1 •0min
U6 180min
FIG. 5. Urinary volume (U) and urinary sodium excretion ( N a + ) after a Single bolus injection of 200 jxg of a-hANP in volunteers; *p < 0.01.
of a - h A N P evoked prolonged renal actions when compared to Single bolus application (Fig. 6; Table 2).
cGMP
There was a marked rise of plasma c G M P in protocol 1, maximal values being observed between 10 and 20 minutes after injection (Fig. 7). Corre-spondingly, urinary c G M P excretion increased nearly eightfold during the second collection period (0 to 30 min) (Table 1).
The second a - h A N P bolus resulted in a further increase of plasma c G M P (Fig. 8) together with a more pronounced and persisting c G M P excretion up to the third collection period (30 to 60 minutes) (Table 2). During protocol 2, urinary excretion rose from a basal value of 0.62 ± 0.42 to 4.70 ± 1.99 mmol/min after the first bolus and to 5.68 ± 1.75 mmol/min after the second bolus.
Other Findings
A N P (basal value, 195 ± 94 pg/ml) rose nearly 15-fold after each injection and had nearly normalized 30 min later. After a Single bolus injection, the
a - h A N P I N N O R M A L H U M A N S 163
[ml/minj [mmol/h] •70
U1 -60-i0
200/ug oC-hANP
Urinary volume [ml/min] I | Sodium excretion Immol/h] • I Potassium excretion [mmol/h]
U7 150-180 min
FIG. 6. Urinary volume and urinary sodium and potassium excretion after repeated bolus injections of 200 |xg of a-hANP at a 30-min interval; *p < 0 .01.
venous hematocrit had risen after half an hour by 7% and not yet returned to a basal value by the end of the study. Repeated injection produced a slightly greater rise of 10% (Tables 1 and 2). Serum concentrations of sodium and potassium remained unchanged during both protocols. Apart from a moderate, symptomatic flush, no side effects were observed in the healthy volunteers.
DISCUSSION
The data demonstrate reproducible transient increases of heart rate and a reduction of blood pressure after single and repeated bolus injections of 200 |xg of a -hANP. These results correspond well with previous observations after a single bolus of 100 |xg of a - h A N P (1).
Intravenous A N P in humans produces an increase of plasma c G M P and of urinary c G M P excretion (10). Probably because of the higher a - h A N P bolus dose of 200 jxg in the present study, the plasma and urinary response was more pronounced than previously reported after a bolus of 50 |xg (10).
Cycl ic G M P seems to be not only a marker but also a mediator of A N P
1 6 4 C H A P T E R 16
FIG. 7. Serum cyclic guanosine monophosphate (C GMP) after a Single bolus injection of 200 ixg of a-hANP in volunteers; *p < 0 .01.
activity in vascular smooth muscle cells and endothelial cells (12). In v i t r o the Stimulation of c G M P production by A N P seems to be relatively irreversible and the responsiveness to A N P is downregulated by prior exposure to A N P (12). Interestingly, we could not demonstrate any attenuation of plasma c G M P or urinary c G M P excretion after the second of two consecutive a-h A N P bolus injections. After the second bolus, plasma c G M P rose from a still elevated level to an even higher peak concentration (Fig. 8). Corre-spondingly, urinary c G M P excretion was also higher after the second than after the first a - h A N P bolus. Thus, there seems to be no evidence of a di-minished c G M P response after high dose a - h A N P bolus applications at a 30-min interval.
Echocardiography after a - h A N P application revealed significant de-creases of E S D which, with E D D remaining unchanged, led to an increase of computed E F after each a - h A N P injection. Also , S V and CI increased after a - h A N P . Similar to the c G M P response, there was no diminution of the echocardiographic effects of the second of two consecutive bolus injections in protocol 2.
a - h A N P I N N O R M A L H U M A N S 165
FIG. 8. Serum cyclic guanosine monophosphate (cGMP) after repeated bolus injections of 200 |xg of a-hANP at a 30-min interval; *p < 0.01.
In healthy volunteers, there seems to be no evidence for a cardiodepres-sive effect of the drug, which had been reported earlier in animals (13). In-stead, the data point toward improved cardiac Performance which may, be-cause of reported vasodilating effects of a - h A N P (3), be due to reductions of preload and afterload. Apart from possible direct myocardial effects, tem-porarily elevated catecholamine levels as a consequence of vasodilatation (14) may contribute to improvement of cardiac Performance.
L ike others (1,2,4,10), we observed increased diuresis and natriuresis after a - h A N P application in non-salt restricted healthy volunteers. Increases of diuresis and natriuresis in this study were larger than those previously reported after bolus injections, probably because of the higher dose of a-h A N P (1,2,4,10). The recorded renal effects of a - h A N P persisted up to 60 min after a bolus injection, which is remarkably longer than the duration of the cardiovascular effects.
166 C H A P T E R 16
Because of the prolonged renal action of a single dose, the second bolus in protocol 2 was given with an overlap of the renal effect of the first bolus. Nevertheless, there was no attenuation of diuretic and natriuretic effects after the second bolus.
Endogenous plasma a - h A N P is elevated in patients with congestive heart failure and may have regulatory functions (15,16). Studies in small numbers of patients with congestive heart failure showed beneficial effects of a - h A N P due to its vasodilating and diuretic properties. Responses to a - h A N P in those patients has been varying. Although Riegger et al. (17) and Saito et al . (18) observed vasodilatory as well as diuretic effects after bolus injections, Firth (19) found only renal but no cardiovascular effects. After continuous infusion of a - h A N P in patients with heart failure, Mol l ina et al . (20) observed beneficial effects in cardiovascular and renal parameters, but several others (21-23) could not confirm diuretic effects after a - h A N P infusion.
In the present study, reproducible improvement of cardiac Performance and prolonged diuretic effects could be demonstrated in healthy volunteers after single and two consecutive bolus injections of 200 jxg of a - h A N P . A l though conclusions from data obtained in healthy volunteers must be drawn with care, one can speculate that improved cardiac Performance together with sustained diuresis and natriuresis after repeated high dose bolus application of a - h A N P might be beneficial in the acute treatment of congestive heart failure.
CONCLUSIONS
Single and repeated bolus applications of 200 jxg of a - h A N P in healthy volunteers produces increases of plasma c G M P concentrations and urinary c G M P excretion, diuresis and natriuresis, heart rate and echocardiographi-cally determined ejection fraction, and decreases in arterial blood pressure. Comparing the effects of two consecutive bolus injections of a - h A N P at a 30-minute interval, there was no evidence for attenuation of c G M P response, diuresis, natriuresis, or cardiovascular effects.
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