Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep

Westphal, Martin; Stubbe, Henning D.; Bone, Hans G.; Daudel, Fritz; Vocke, Sebastian; Aken, Hugo Van; Booke, Michael

doi:10.1016/s0006-291x(02)00821-5

Cited by 29 publications

(19 citation statements)

References 22 publications

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“…When s eps is is accompanie d b y hypotension plus organ dysfunction, the condition is known as septic shock. Despite significant progress in understanding the pathophysiology of sepsis and septic shock, these conditions continue to be the most causes of morbidity and mortality in intensive care units (Westphal et al 2002). Endotoxin has harmful effects on various organs including kidney through the induction of inflammatory mediators (Cadenas and Cadenas 2002;Taniguchi et al 2003).…”

confidence: 99%

Protective Effects of Vitamin C, Alone or in Combination with Vitamin A, on Endotoxin-Induced Oxidative Renal Tissue Damage in Rats

Kanter

Çoşkun

Armutçu

et al. 2005

Tohoku J. Exp. Med.

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confidence: 99%

Protective Effects of Vitamin C, Alone or in Combination with Vitamin A, on Endotoxin-Induced Oxidative Renal Tissue Damage in Rats

Kanter

Çoşkun

Armutçu

et al. 2005

Tohoku J. Exp. Med.

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“…Bolus injection or infusion of AM in humans (5-10) and in several animal species (11)(12)(13)(14)(15)(16)(17) causes prolonged, dosedependent vasorelaxation and hypotension. Yet the dose, route, and duration of exogenous administration required to elicit a systemic effect on blood pressure (BP) varies widely among published studies (8)(9)(10).…”

mentioning

confidence: 99%

Adrenomedullin gene expression differences in mice do not affect blood pressure but modulate hypertension-induced pathology in males

Caron¹,

Hagaman

Nishikimi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Adrenomedullin (AM) is a potent vasodilator peptide in plasma at picomolar levels. Polymorphisms in the human AM gene have been associated with genetic predisposition to diabetic nephropathy and proteinuria with essential hypertension, and numerous studies have demonstrated that endogenous AM plays a role in protecting the heart and kidneys from fibrosis resulting from cardiovascular disease. Elevated plasma levels of AM are associated with pregnancy and sepsis and with cardiovascular stress and hypertension. However, there are no reports of the effects of genetic differences in the expression of the endogenous AM gene and of gender on blood pressure in these circumstances or on the pathological changes accompanying hypertension. To address these questions, we have generated mice having genetically controlled levels of AM mRNA ranging from Ϸ50% to Ϸ140% of wild-type levels. These modest changes in AM gene expression have no effect on basal blood pressure. Although pregnancy and sepsis increase plasma AM levels, genetically reducing AM production does not affect the transient hypotension that occurs during normal pregnancy or that is induced by treatment with lipopolysaccharide. Nor does the reduction of AM affect chronic hypertension caused by a renin transgene. However, 50% normal expression of AM enhances cardiac hypertrophy and renal damage in male, but not female, mice with a renin transgene. These observations suggest that the effect of gender on the role of AM in counteracting cardiovascular damage in humans merits careful evaluation. cardiovascular ͉ pregnancy ͉ cardiac hypertrophy ͉ renal fibrosis ͉ gene targeting A drenomedullin (AM) is a 52-aa peptide vasodilator which circulates in the plasma as a protein-bound hormone and can influence many biological processes (1). The gene coding for AM is widely expressed throughout the body, most highly in endothelial cells and vascular smooth muscle cells (2, 3). Consequently, highly vascularized tissues, such as the placenta, lung, heart, and kidney cause elevated plasma AM levels when their secretion of AM peptide is stimulated by conditions such as pregnancy, sepsis, and cardiovascular disease or by inflammatory cytokines or hypoxia.AM is most widely known for its vasodilatory properties (4). Bolus injection or infusion of AM in humans (5-10) and in several animal species (11-17) causes prolonged, dosedependent vasorelaxation and hypotension. Yet the dose, route, and duration of exogenous administration required to elicit a systemic effect on blood pressure (BP) varies widely among published studies (8-10). Moreover, it is possible that bolus infusions of the unbound peptide may not accurately replicate the functions of the endogenous protein-bound peptide. Consequently, it is important to determine whether modest changes in expression of the endogenous AM gene affect the maintenance of BP during health and disease.Endogenous AM plays a role in protecting the heart and kidneys from damage during cardiovascular stresses such as hypertension and its associated ...

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“…Similarly to what has been observed in animal studies [12], intravenous infusion of adrenomedullin in patients with pulmonary hypertension contributed to a reduction in vascular resistance of both the systemic and pulmonary circulation [16]. Recently, NAGAYA et al [17] have provided evidence that intratracheal delivery of aerosolised adrenomedullin (10 mg?kg -1 ) has likewise beneficial effects in patients with idiopathic pulmonary hypertension.…”

mentioning

confidence: 80%

“…In a recent study by WESTPHAL et al [12], the effects of exogenous adrenomedullin infusion on systemic and pulmonary haemodynamics were investigated in endotoxaemic sheep. While adrenomedullin reduced the endotoxaemia-associated pulmonary vasopressive effect, it aggravated the hypotensive-hyperdynamic circulatory state [12], a side-effect that may limit its clinical use in sepsis.In the current issue of the European Respiratory Journal (ERJ), VON DER HARDT et al [13] report the results of a carefully conducted study on the effects of aerosolised adrenomedullin on pulmonary hypertension in a surfactantdepleted piglet model. The major finding was that nebulisation of adrenomedullin (50 ng?kg -1 ?min -1 for 2 h) resulted in a sustained reduction in mean pulmonary arterial pressure (MPAP).…”

mentioning

confidence: 99%

“…Another important effect of adrenomedullin is the decrease in peripheral vascular resistance and the ensuing reduction in afterload, which may stimulate heart rate and cardiac output via reflex mechanisms [11]. In a recent study by WESTPHAL et al [12], the effects of exogenous adrenomedullin infusion on systemic and pulmonary haemodynamics were investigated in endotoxaemic sheep. While adrenomedullin reduced the endotoxaemia-associated pulmonary vasopressive effect, it aggravated the hypotensive-hyperdynamic circulatory state [12], a side-effect that may limit its clinical use in sepsis.…”

mentioning

confidence: 99%

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Adrenomedullin: a smart road from pheochromocytoma to treatment of pulmonary hypertension

Westphal¹

2004

Eur Respir J

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In 1993, KITAMURA et al.[1] isolated a new peptide from human pheochromocytoma cells, stimulating cAMP production in human platelets and inducing systemic hypotension in rats. Due to its origin of discovery, i.e. the medulla of the adrenal gland, it was named adrenomedullin [1]. Adrenomedullin is a 52-amino acid peptide hormone with structural homology to calcitonin gene-related peptide [2]. Together with pro-adrenomedullin N-terminal 20-peptide, adrenomedullin is generated by post-translational splicing from its precursor, pro-adrenomedullin [3]. Initially, it was believed that adrenomedullin is only expressed in tumour cells, but subsequent studies revealed that it is a multifunctional peptide, synthesised by a huge variety of mammalian tissues, including myocardium, central nervous system, kidney, and reproductive and digestive organs [2,4]. In addition, adrenomedullin is produced by endothelial and smooth muscle cells of both the systemic and pulmonary circulation [5]. Adrenomedullin regulates cardiopulmonary functions and vascular tone as both a circulating hormone and as a local autocrine/ paracrine mediator [6].The haemodynamic effects of adrenomedullin are predominantly mediated by cAMP production resulting from activation of two Gs-protein-coupled plasma membrane receptors of the calcitonin peptide family: the calcitonin receptor-like receptor and the receptor activity-modifiying protein-2 or -3 [2]. Moreover, adrenomedullin mediates smooth muscle cell hyperpolarisation by activating ATPsensitive K z channels [7], stimulates the release of vasodilatory prostaglandins [8], and elicits endothelium-dependent vasorelaxation secondary to nitric oxide (NO) formation [8,9].Inasmuch as adrenomedullin reduces pulmonary vascular tone and improves tissue oxygenation [10], supplementation of exogenous adrenomedullin may be a rationale in the management of acute respiratory distress syndrome (ARDS) associated with pulmonary hypertension. When discussing the usefulness of intravenous adrenomedullin infusion to treat pulmonary hypertension, it has to be taken into consideration that the effects are not restricted to the pulmonary circulation. Another important effect of adrenomedullin is the decrease in peripheral vascular resistance and the ensuing reduction in afterload, which may stimulate heart rate and cardiac output via reflex mechanisms [11]. In a recent study by WESTPHAL et al. [12], the effects of exogenous adrenomedullin infusion on systemic and pulmonary haemodynamics were investigated in endotoxaemic sheep. While adrenomedullin reduced the endotoxaemia-associated pulmonary vasopressive effect, it aggravated the hypotensive-hyperdynamic circulatory state [12], a side-effect that may limit its clinical use in sepsis.In the current issue of the European Respiratory Journal (ERJ), VON DER HARDT et al. [13] report the results of a carefully conducted study on the effects of aerosolised adrenomedullin on pulmonary hypertension in a surfactantdepleted piglet model. The major finding was that nebulisation of adre...

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Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep

Cited by 29 publications

References 22 publications

Protective Effects of Vitamin C, Alone or in Combination with Vitamin A, on Endotoxin-Induced Oxidative Renal Tissue Damage in Rats

Protective Effects of Vitamin C, Alone or in Combination with Vitamin A, on Endotoxin-Induced Oxidative Renal Tissue Damage in Rats

Adrenomedullin gene expression differences in mice do not affect blood pressure but modulate hypertension-induced pathology in males

Adrenomedullin: a smart road from pheochromocytoma to treatment of pulmonary hypertension

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