Nitric oxide-dependent hypotensive effects of adrenomedullin in rats

Matsunaga, Kazuki; Iwasaki, Takanori; Yonetani, Yukio; Kïtamura, Kazuo; Eto, Tanenao; Kangawa, Kenji; Matsuo, Hisayuki

doi:10.1002/(sici)1098-2299(199601)37:1<55::aid-ddr4>3.0.co;2-l

Cited by 17 publications

(10 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, the vasodilation of hindlimb peripheral vasculature after AM administration in cats is mediated by increases in smooth muscle cAMP levels (Champion et al, 1997a). Furtherm ore, the vasodilation effect of AM reduced by the blockade of nitric oxide synthase activity with N G -nitro-L-arginine methyl ester indicates a partial contribution of NO to AM-induced vasodilation (Matsunaga et al, 1996). These results suggest that AM-induced hypotensive effects could be mediated by a cAMP-dependent or independent cascade.…”

Section: Discussionmentioning

confidence: 89%

Human Adrenomedullin Gene Delivery Protects against Cardiac Hypertrophy, Fibrosis, and Renal Damage in Hypertensive Dahl Salt-Sensitive Rats

et al. 2000

View full text Add to dashboard Cite

Adrenomedullin (AM) is a potent vasodilator expressed in tissues relevant to cardiac and renal functions. Our previous study showed that delivery of the human AM gene in the form of naked DNA caused a prolonged reduction of blood pressure in genetically hypertensive rats. In this study, we evaluated potential protective effects of adenovirus-mediated AM gene delivery on salt-induced cardiorenal lesions in hypertensive Dahl saltsensitive (DSS) rats. Adenovirus carrying the human AM cDNA under the control of the cytomegalovirus promoter-enhancer (Ad.CMV-hAM) was generated by homologous recombination of E. coli. Expression of recombinant human AM was detected by a radioimmunoassay in the medium of human embryonic kidney 293 cells transfected with Ad.CMV-hAM. A single intravenous injection of Ad.CMV-hAM caused a significant reduction of systolic blood pressure for 4 weeks in DSS rats compared with control rats with or without injection of adenovirus carrying the green fluorescent protein gene. AM gene delivery significantly reduced left ventricular mass and urinary protein, increased cAMP levels, and enhanced renal function as evidenced by increases in glomerular filtration rate and renal blood flow. Morphological investigations showed that AM gene transfer reduced cardiomyocyte diameter and interstitial fibrosis in the heart as well as glomerular sclerosis, tubular disruption, and protein cast accumulation in the kidney. Expression of human AM mRNA was identified in rat heart, kidney, lung, liver, and aorta, and immunoreactive human AM levels were measured in rat plasma and urine. These results indicate that human AM gene delivery protects against salt-induced hypertension and cardiac and renal lesions in DSS rats via activation of cAMP as a second messenger. These findings provide new insights into the role of AM in salt-induced hypertension and may have implications in therapeutic applications to salt-related cardiovascular and renal diseases.

show abstract

Section: Discussionmentioning

confidence: 89%

Human Adrenomedullin Gene Delivery Protects against Cardiac Hypertrophy, Fibrosis, and Renal Damage in Hypertensive Dahl Salt-Sensitive Rats

et al. 2000

View full text Add to dashboard Cite

show abstract

“…Furthermore, the study by Szokodi (Szokodi et al , 1996) observed no change in cardiac rate in isolated hearts, suggesting that ADM is unlikely to produce a direct cardiac chronotropic effect in vivo . A recent study by Matsunaga has also demonstrated that the tachycardia associated with ADM administration in normal and spontaneously hypertensive (SHR) rats is abolished during concurrent treatment with hexamethonium (Matsunaga et al , 1996).…”

Section: Discussionmentioning

confidence: 99%

Direct cardiac and vascular actions of adrenomedullin in conscious sheep

Parkes

May

1997

British J Pharmacology

View full text Add to dashboard Cite

1 Adrenomedullin (ADM) is a recently characterized circulating hormone which a ects haemodynamic, renal and pituitary function in mammals. We have shown previously that in sheep, ADM produces vasodilatation together with increases in cardiac output and contractility. However, whether these e ects are direct or mediated by autonomic re¯exes is unclear. The present study examined the cardiovascular actions of an intravenous infusion of ADM in conscious, chronically instrumented sheep with either sympathetic, parasympathetic or autonomic ganglion blockade, to determine the role of the autonomic nervous system in mediating these cardiovascular changes. 2 Human ADM (1 ± 52) was infused for 60 min at 2 mg kg 71 h 71 following: (1) saline control, (2) combined a/b-adrenoceptor (sympathetic) blockade (proporanolol 0.4 mg kg 71 h 71 +phentolamine 0.15 mg kg 71 h 71 for 20 h), (3) muscarinic (parasympathetic) blockade (methscopolamine 0.05 mg kg 71 h 71 for 20 h) or (4) ganglion blockade (hexamethonium 3 mg kg 71 h 71 for 4 h). Measurements were made of mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), stroke volume (SV), total peripheral conductance (TPC), maximal aortic¯ow (Fmax) and maximal rate of change of aortic¯ow (dF/dt). 3 ADM reduced MAP by 3+1 mmHg, and increased CO (1.2+0.2 l min 71 ), HR (14+2 beats min 71 ), TPC (21+3 ml min 71 mmHg 71 ), Fmax (2.3+0.8 l min 71 ) and dF/dt (86+21 l min 71 s 71 ) in normal sheep. In animals with a/b blockade, similar changes were observed with ADM. However, during muscarinic blockade, the increases in HR (32+4 beats min 71 ), CO (2.1+0.4 l min 71 ), TPC (31+4 ml min 71 mmHg 71 ), Fmax (4.0+0.6 l min 71 ), and dF/dt (150+12 l min 71 s 71 ) produced by ADM were enhanced. During ganglion blockade, ADM produced a greater reduction in MAP (710+2 mmHg) compared to controls (73+1 mmHg). However, there was no increase in HR. The changes in CO, TPC and contractility were similar to those observed in control animals. 4 These results suggest that the vasodilator e ects of ADM on the periphery and its ability to increase CO and cardiac contractility are not mediated by the autonomic nervous system, but are probably the result of direct actions of ADM on the heart and vasculature.

show abstract

“…Several papers show that the vasodilating effect by AM is abrogated by blockade of nitric oxide (NO) synthase activity (L-NAME), suggesting that the decrease in total peripheral resistance subsequent to AM infusion is in part due to NO generation (Feng et al, 1994;Matsunaga et al, 1996;Santiago et al, 1995). However, the diminution of vasodilation by L-NAME seems to vary greatly from study to study.…”

Section: In Vivo Cardiovascular Effectsmentioning

confidence: 99%

Adrenomedullin and PAMP: Discovery, structures, and cardiovascular functions

Kïtamura

Kangawa

Eto

2002

Microscopy Res & Technique

Self Cite

112

View full text Add to dashboard Cite

We discovered adrenomedullin (AM) from human pheochromocytoma tissue by monitoring the elevating activity of intracellular cyclic AMP (cAMP) in rat platelets in 1993. Since the discovery of AM, it has attracted intense interest from cardiovascular researchers because AM elicits multiple biological activities, including a potent and powerful hypotensive activity caused by dilatation of resistance vessels. AM is biosynthesized and secreted from tissues, including cardiovascular organs. In addition to AM, "proadrenomedullin N-terminal 20 peptide (PAMP)," another biologically active peptide, was found to be processed from the AM precursor. Plasma AM levels are increased in various cardiovascular and renal diseases. AM, therefore, seems to function as a novel system that controls circulation and body fluid, and may be involved in pathophysiological changes in cardiovascular diseases. Therefore, in this review we will focus on the structure of AM and its gene, distribution, receptor, and the physiological and pathological roles of AM in cardiovascular disease.

show abstract

Nitric oxide-dependent hypotensive effects of adrenomedullin in rats

Cited by 17 publications

References 20 publications

Human Adrenomedullin Gene Delivery Protects against Cardiac Hypertrophy, Fibrosis, and Renal Damage in Hypertensive Dahl Salt-Sensitive Rats

Human Adrenomedullin Gene Delivery Protects against Cardiac Hypertrophy, Fibrosis, and Renal Damage in Hypertensive Dahl Salt-Sensitive Rats

Direct cardiac and vascular actions of adrenomedullin in conscious sheep

Adrenomedullin and PAMP: Discovery, structures, and cardiovascular functions

Contact Info

Product

Resources

About