Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart.
Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily of cytokines, possesses hypertrophic actions and atrial natriuretic peptide (ANP)-producing activity in vitro. The goal of our study is to elucidate whether CT-1 affects the cardiovascular system in vivo. Intravenous injection of CT-1 (4-100 microg/kg) in conscious rats evoked significant declines in blood pressure and reflex increases in heart rate (HR) in a dose-dependent manner. CT-1 induced no significant change in cardiac output (from 260.7 +/- 11.0 to 264.7 +/- 26.6 ml. min(-1). kg(-1), P = not significant), which was compatible with the results from isolated perfused rat hearts; HR, change in pressure over time, left ventricular developed pressure, and perfusion pressure were unaffected. Northern blot and RT-PCR analyses revealed that CT-1 increased expression of inducible nitric oxide synthase (iNOS) in lung and aorta but not in heart or liver. Pretreatment with aminoguanidine, a specific iNOS inhibitor, inhibited both iNOS mRNA production and the depressor effect of CT-1. Interestingly, CT-1 increased ventricular expression of ANP and brain natriuretic peptide (BNP). The data demonstrate that CT-1 elicits its hypotensive effect via a nitric oxide-dependent mechanism and that CT-1 induces ANP and BNP mRNA expression in vivo.
Hamanaka
I
I
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan 606-8507.
Saito
Y
Y
Nishikimi
T
T
Magaribuchi
T
T
Kamitani
S
S
Kuwahara
K
K
Ishikawa
M
M
Miyamoto
Y
Y
Harada
M
M
Ogawa
E
E
Kajiyama
N
N
Takahashi
N
N
Izumi
T
T
Shirakami
G
G
Mori
K
K
Inobe
Y
Y
Kishimoto
I
I
Masuda
I
I
Fukuda
K
K
Nakao
K
K
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009320:Atrial Natriuretic Factor / Q000235:genetics; D002302:Cardiac Output / Q000187:drug effects; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000008:administration & dosage / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006131:Growth Inhibitors / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006439:Hemodynamics / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D007276:Injections, Intraventricular; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008168:Lung / Q000201:enzymology; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D020097:Natriuretic Peptide, Brain / Q000235:genetics; D019001:Nitric Oxide Synthase / Q000235:genetics*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016207:Cytokines; D006131:Growth Inhibitors; D006146:Guanidines; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines; D011994:Recombinant Proteins; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; C092073:cardiotrophin 1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester