Renal responses to intra-arterial administration of adrenomedullin in dogs

Majid, Dewan S. A.; Kadowitz, Philip J.; Coy, David H.; Navar, L. Gabriel

doi:10.1152/ajprenal.1996.270.1.f200

Cited by 68 publications

(72 citation statements)

References 11 publications

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“…This complete prevention of the vasodilator response, in comparison with the partial prevention reported in other studies, may reflect a more complete inhibition of NOS by the 2 h pretreatment with L-NNA given directly into the coronary arteries in our study. Our observation that NOS inhibition prevented the vasodilator action of ADM in the coronary arteries of sheep is consistent with the reports that NOS inhibition blocks the effect of ADM in most, but not all, vascular beds (Feng et al, 1994;Majid et al, 1996;Nossaman et al, 1996). In the present study, ADM (0.5 mg kg À1 h À1 ) infused i.c., but not i.v., caused a small increase in HR, suggesting that ADM has a direct chronotropic action.…”

Section: R De Matteo and Cn Maysupporting

confidence: 93%

“…It has been proposed that the vasodilator action of ADM is mediated by a number of mechanisms, including a direct action on vascular smooth muscle cells via cAMP and Ca 2 þ mobilisation (Ishizaka et al, 1994;Shimekake et al, 1995), and by stimulation of nitric oxide (NO). Inhibition of nitric oxide synthase (NOS) has been shown to prevent the vasodilator action of ADM in dog kidney (Majid et al, 1996), rat hindquarters (Feng et al, 1994) and in the pulmonary circulation of the rat but not the cat (Nossaman et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Direct coronary vasodilator action of adrenomedullin is mediated by nitric oxide

Matteo

May

2003

British J Pharmacology

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1 Increased circulating levels of adrenomedullin (ADM) cause peripheral vasodilatation and hypotension, accompanied by cardiac actions including tachycardia and increases in cardiac contractility, cardiac output, coronary conductance (CC) and coronary blood flow (CBF). It is unclear to what extent these cardiac effects are direct actions of ADM or secondary to the hypotension and altered cardiac loading. 2 The direct cardiac actions of ADM were examined in conscious sheep previously implanted with aortic and coronary flow probes, and an indwelling left coronary artery cannula. Responses to infusion of ADM (0.5 mg kg À1 h À1 for 1 h) into the left coronary artery or jugular vein were compared (n ¼ 6). The effect of blockade of nitric oxide (NO) synthase with intracoronary (i.c.)), infused for 2 h before and during ADM infusion, was assessed to determine whether the responses to ADM were mediated by NO (n ¼ 5). 3 I.c. ADM caused large and sustained increases in CC (0.3570.07 -0.5570.13 ml min À1 mmHg À1 , Po0.05) and CBF (2876-4279 ml min À1 , Po0.05), but had no effect on arterial pressure or indices of cardiac contractility (first differential of the upstroke of systole and peak aortic flow rate). Intravenous infusion of ADM had no effects. 4 I.c. L-NNA, at a dose that abolished the coronary vasodilator action of acetylcholine, blocked ADM-induced coronary vasodilatation. 5 In conclusion, ADM had a direct coronary vasodilator action that was mediated by release of endogenous NO and resulted in increased CBF. There was no evidence for a direct inotropic action of ADM.

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Section: R De Matteo and Cn Maysupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Direct coronary vasodilator action of adrenomedullin is mediated by nitric oxide

Matteo

May

2003

British J Pharmacology

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“…A similar range of responses have previously been observed in animals 8 and humans with HF 10 after short-term AM administration, and are likely to be owing to the actions of AM to directly reduce tubular sodium reabsorption and renal vascular resistance and to increase renal blood flow. [21][22][23] A persistent increase in glomerular filtration rate, as assessed by the rise in creatinine clearance, also appears to have contributed to the sustained natriuretic effect observed in the current study. The maintenance of sodium excretion in association with the protracted reduction in MAP (and presumably renal perfusion pressure) points to a shift in the pressure-natriuresis curve with prolonged AM administration.…”

Section: Chronic Effects Of Adrenomedullin In Sheep With Experimentalmentioning

confidence: 55%

Long-Term Adrenomedullin Administration in Experimental Heart Failure

et al. 2002

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Abstract-Short-term administration of adrenomedullin, a recently discovered peptide with potent vasodilator, natriuretic, and aldosterone-inhibitory actions, has beneficial effects in experimental and clinical heart failure. The effects of prolonged adrenomedullin administration have not previously been assessed in this setting. Consequently, in 16 sheep with pacing-induced heart failure, we infused either adrenomedullin (10 ng/kg per minute; nϭ8) or a vehicle control (Hemaccel; nϭ8) for 4 days. Compared with control data, infusion of adrenomedullin persistently increased circulating levels of the peptide (by Ϸ9.5 pmol/L; PϽ0.001), in association with prompt (15 minutes) and sustained (4 days) increases in cardiac output (day 4, 27%), and reductions in peripheral resistance (30%), mean arterial pressure (13%), and left atrial pressure (24%; all, PϽ0.001). Adrenomedullin also significantly enhanced urinary sodium excretion (day 4, 3-fold; PϽ0.05), creatinine excretion (1.2-fold; PϽ0.001), and creatinine clearance (1.4-fold; PϽ0.001) over the 4 days of treatment, whereas urine volume and cAMP excretion tended to be elevated (both, 0.1ϾPϾ0.05). Plasma renin activity was increased (PϽ0.05), whereas aldosterone levels were reduced in a sustained fashion (PϽ0.01). Plasma endothelin rose transiently (hours 1 to 6) after initiation of treatment (PϽ0.05). Despite substantial cardiac unloading, plasma concentrations of the natriuretic peptides were not significantly different from control. In conclusion, long-term administration of adrenomedullin induces pronounced and sustained cardiovascular and renal effects in experimental heart failure, including reductions in cardiac preload and afterload, as well as augmentation of cardiac output, sodium excretion, and glomerular filtration. These findings support the concept of adrenomedullin as a protective hormone during hemodynamic compromise with therapeutic potential in heart failure.

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“…16 Intrarenal infusion of AM had marked diuretic and natriuretic effects and increased the glomerular filtration rate. 17 Plasma AM was found to be elevated in patients with impaired renal function, and an intimate correlation was noted between levels of plasma AM and those of norepinephrine and atrial natriuretic peptide. 9,18 Taken together, these findings strongly suggest that AM contributes to the modulation of kidney function that counterregulates volume expansion in the face of a high salt diet.…”

Section: Discussionmentioning

confidence: 94%

Chronic Salt Loading Upregulates Expression of Adrenomedullin and Its Receptors in Adrenal Glands and Kidneys of the Rat

Cao

Kïtamura²,

Kato³

et al. 2003

Hypertension

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Abstract-The vasodilator peptide adrenomedullin (AM) elicits diuresis and natriuresis and inhibits aldosterone secretion.The aim of this study was to better understand the role of AM in maintaining water and electrolyte balance during chronic salt loading. Male Wistar rats were divided into a high salt (HS) group that received a diet containing 8% sodium chloride (NaCl) and a normal salt group that received a diet containing 0.4% NaCl. Plasma AM concentrations as well as expression of AM mRNA in the adrenal gland and kidney were then measured after 3, 7, 14, and 28 days. After 28 days, sodium and water excretion were significantly higher in HS rats than in control, although blood pressure and fluid volume were not significantly affected. Moreover, although plasma AM remained unchanged for up to 14 days, it was increased 2.5-fold in HS rats after 28 days on a high salt diet, and there were corresponding 3-fold and 1.5-fold increases in the levels of AM mRNA in the adrenal gland and kidney, respectively. At the same time, expression of calcitonin receptor-like receptor mRNA was significantly upregulated in both kidney and adrenal gland, as was expression of receptor activity-modify protein 1 (RAMP1) and RAMP2 mRNA in the adrenals and expression of RAMP3 in kidneys. Taken together, these results suggest that AM plays a role in the regulation of water and electrolyte balance in animals chronically ingesting high levels of salt. Key Words: adrenomedullin Ⅲ diuresis Ⅲ natriuresis Ⅲ gene expression Ⅲ sodium A drenomedullin (AM) is a potent vasodilatory peptide discovered in the extract of human pheochromocytoma based on its capacity to elevate rat platelet cAMP levels. AM is composed of 52 amino acids and shows slight structural homology with calcitonin gene-related peptide (CGRP) and amylin: it shares a disulfide bridge and C-terminal amide structure. 1 In addition to its vasodilatory action, AM also exerts multiple biological effects by serving as a circulating and autocrine/paracrine hormone. 2 In the kidney, for example, AM exerts diuretic and natriuretic effects, whereas in adrenal gland it inhibits angiotensin II-stimulated and potassium-stimulated secretion of aldosterone. 3,4 AM thus appears to play a role in maintaining appropriate electrolyte and water balance. 5 The receptor activity-modifying proteins (RAMP1, RAMP2, and RAMP3), which have a single transmembrane domain, are required for transport of calcitonin receptor-like receptor (CRLR), an orphan receptor with 7-transmembrane domains, to the plasma membrane and for definition of its agonist selectivity. RAMP1 shares Ϸ30% identity with RAMP2 and RAMP3. Coexpression of RAMP1 with CRLR produces a CGRP receptor, which can be blocked by CGRP(8 -37), whereas coexpression of RAMP2 or RAMP3 with CRLR produces an AM receptor, which can be blocked by AM(22-52). 6 Notably, our recent findings indicate that AM, too, can bind with RAMP1/CRLR, though it has 8-fold less affinity than does CGRP. 7 It was previously shown that plasma AM levels are elevated in patients wi...

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Renal responses to intra-arterial administration of adrenomedullin in dogs

Cited by 68 publications

References 11 publications

Direct coronary vasodilator action of adrenomedullin is mediated by nitric oxide

Direct coronary vasodilator action of adrenomedullin is mediated by nitric oxide

Long-Term Adrenomedullin Administration in Experimental Heart Failure

Chronic Salt Loading Upregulates Expression of Adrenomedullin and Its Receptors in Adrenal Glands and Kidneys of the Rat

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