Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin 2 in Experimental Heart Failure

Rademaker, Miriam T.; Charles, Christopher J.; Nicholls, M. Gary; Richards, A. Mark

doi:10.1161/circheartfailure.107.755504

Cited by 11 publications

(19 citation statements)

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“…Although the mechanisms underlying these renal actions of AM5 are yet to be established, it is possible that an increase in glomerular filtration may have contributed in light of the accompanying rise in creatinine clearance, as well as the observed decrease in circulating aldosterone levels. A similar enhancement of renal function has been demonstrated previously following identical doses of AM and AM2 in experimental ovine HF [11,12] (Table 2), with modes of action reported to include reductions in renal vascular resistance and increases in renal blood flow (via pre- and post-glomerular arteriolar vasodilation) and glomerular filtration rate, together with inhibition of proximal and distal fractional sodium reabsorption [37,39,40]. Similar direct actions of AM5 in the kidney might also be a possibility given the significant increase in urine cAMP levels.…”

Section: Discussionsupporting

confidence: 81%

“…Although this effect is probably attributable in part to the attendant reduction in cardiac afterload (evidenced by falls in CTPR and MAP), it is plausible that AM5 also exhibits positive inotropic activity as the rise in CO was associated with prominent increases in LV d P /d t (max). Similar increases in CO and d P /d t (max) have been observed with AM and AM2 administration (Table 2) (in conjunction with enhanced coronary artery perfusion flow) [11,12,27], and both peptides are reported to have direct inotropic actions in isolated perfused rat hearts [8,9]. The AM5-induced rise in CO in the present study presumably contributed to the fall in LAP, although it is also possible that AM5 possesses venodilator actions as has been demonstrated for AM2 [28].…”

Section: Discussionsupporting

confidence: 61%

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Haemodynamic, endocrine and renal actions of adrenomedullin 5 in an ovine model of heart failure

et al. 2012

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AM5 (adrenomedullin 5), a newly described member of the CGRP (calcitonin gene-related peptide) family, is reported to play a role in normal cardiovascular physiology. The effects of AM5 in HF (heart failure), however, have not been investigated. In the present study, we intravenously infused two incremental doses of AM5 (10 and 100 ng/min per kg of body weight each for 90 min) into eight sheep with pacing-induced HF. Compared with time-matched vehicle control infusions, AM5 produced progressive and dose-dependent increases in left ventricular dP/dt(max) [LD (low dose), +56 mmHg/s and HD (high dose), +152 mmHg/s] and cardiac output (+0.83 l/min and +1.81 l/min), together with decrements in calculated total peripheral resistance (−9.4 mmHg/min per litre and −14.7 mmHg/min per litre), mean arterial pressure (−2.8 mmHg and −8.4 mmHg) and LAP (left atrial pressure; −2.6 mmHg and −5.6 mmHg) (all P<0.001). HD AM5 significantly raised PRA (plasma renin activity) (3.5-fold increment, P<0.001), whereas plasma aldosterone levels were unchanged over the intra-infusion period and actually fell in the post-infusion period (70% decrement, P<0.01), resulting in a marked decrease in the aldosterone/PRA ratio (P<0.01). Despite falls in LAP, plasma atrial natriuretic peptide and B-type natriuretic peptide concentrations were maintained relative to controls. AM5 infusion also induced significant increases in urine volume (HD 2-fold increment, P<0.05) and urine sodium (2.7-fold increment, P<0.01), potassium (1.7-fold increment, P<0.05) and creatinine (1.4-fold increment, P<0.05) excretion and creatinine clearance (60% increment, P<0.05). In conclusion, AM5 has significant haemodynamic, endocrine and renal actions in experimental HF likely to be protective and compensatory in this setting. These results suggest that AM5 may have potential as a therapeutic agent in human HF.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionsupporting

confidence: 61%

Haemodynamic, endocrine and renal actions of adrenomedullin 5 in an ovine model of heart failure

et al. 2012

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“…In addition, AM2/ IMD had no suppressive effects on aldosterone response to angiotensin II in conscious sheep in contrast to AM (Charles et al 2010). In experimental heart failure sheep, however, plasma aldosterone levels were not significantly altered during the infusion of human AM2/IMD 1-47 despite the increase in renin activity, and therefore, the aldosterone/ plasma renin activity ratio was reduced (Rademaker et al 2008). Thus, AM2/IMD may have a relative inhibition of angiotensin II induced aldosterone secretion in heart failure.…”

Section: Effects Of Adrenomedullin 2/intermedin On the Adrenal Hormonmentioning

confidence: 81%

Adrenomedullin 2/Intermedin in the Hypothalamo–Pituitary–Adrenal Axis

et al. 2010

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Adrenomedullin 2/intermedin (AM2/IMD) is a new member of the calcitonin/calcitonin gene-related peptide (CGRP) family. CGRP, adrenomedullin (AM), and AM2/IMD share the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMP). The CRLR/RAMP2 or CRLR/RAMP3 complex forms the AM receptor, whereas the CRLR/RAMP1 forms the CGRP receptor. AM2/IMD binds non-selectively to all three CRLR/RAMP complexes. AM2/IMD has various actions, such as a potent vasodilator action and a protective action against oxidative stress, like AM and CGRP. When administered intracerebroventricularly, AM2/IMD stimulates the sympathetic nervous system and increases blood pressure. In human hypothalamus, AM2/IMD is expressed in the paraventricular and supraoptic nuclei and colocalized with arginine vasopressin. Anterior pituitary cells were diffusely immunostained for AM2/IMD. AM2/IMD stimulates the release of ACTH, prolactin, and oxytocin, but suppresses GH release. Some of these pituitary actions of AM2/IMD have been supposed to be mediated by an unidentified unique receptor for AM2/IMD. In the adrenal gland, immunoreactive (IR)-AM2/IMD and IR-AM were detected in the medulla, while the degree of IR-AM2/IMD and IR-AM in the cortex was relatively weak or undetectable. Furthermore, AM2/IMD and AM were expressed in adrenocortical tumors, such as aldosterone-secreting adenomas, and pheochromocytomas. CRLR and RAMPs are expressed in the hypothalamus, pituitaries, adrenal glands, and adrenal tumors. Thus, AM2/IMD is expressed in every endocrine organ of the hypothalamo-pituitary-adrenal axis together with its receptor. AM2/IMD may act as a neurotransmitter or modulator in the brain and as a paracrine/autocrine regulator in the hypothalamo-pituitary-adrenal axis.

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“…6,7 We have previously reported the hemodynamic, hormonal, and renal actions of AM-2 in both normal conscious sheep 8 and sheep with pacinginduced heart failure. 9 These studies showed that AM-2 (as with AM) has favorable effects on cardiovascular, endocrine, and renal indices in heart failure and identify the peptide as a potential therapeutic target in this disease.…”

Section: Introductionmentioning

confidence: 99%

Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin-5 in Normal Conscious Sheep

Charles

Rademaker

Richards

2011

Journal of Cardiovascular Pharmacology

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Although blood pressure effects have been reported for adrenomedullin 5 (AM-5), a newly identified member of the calcitonin gene-related peptide superfamily, little is known about other biological actions. We report the integrated hemodynamic, hormonal, and renal actions of AM-5 (10 and 100 ng·kg·min each for 90 minutes) in normal conscious sheep. AM-5 reduced the mean arterial pressure by 12 mm Hg at the end of the high dose (P < 0.001) in association with dose-dependent increments in the heart rate (40 beats/min--high dose, P < 0.001) and cardiac output (50%-high dose, P < 0.001) and dose-dependent falls in calculated total peripheral resistance (P < 0.001). Plasma renin activity (4-fold increment, P < 0.001), aldosterone (2-fold increment, P = 0.014), and cyclic adenosine monophosphate (50% increment, P < 0.001) all rose in response to high dose AM-5. Urine volume and sodium excretion were unchanged. In conclusion, it is observed that intravenous infusions of AM-5 administered to normal conscious sheep induced significant hemodynamic actions including reduced mean arterial pressure and calculated total peripheral resistance and increased heart rate and cardiac output. Concurrently, AM-5 activated plasma cyclic adenosine monophosphate, plasma renin activity, and aldosterone. These actions are similar to those previously reported for AM and AM-2. Thus, AM-5 may be an another important regulator of volume and pressure homeostasis and may play a role in the pathophysiology of heart disease.

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Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin 2 in Experimental Heart Failure

Cited by 11 publications

References 51 publications

Haemodynamic, endocrine and renal actions of adrenomedullin 5 in an ovine model of heart failure

Haemodynamic, endocrine and renal actions of adrenomedullin 5 in an ovine model of heart failure

Adrenomedullin 2/Intermedin in the Hypothalamo–Pituitary–Adrenal Axis

Hemodynamic, Hormonal, and Renal Actions of Adrenomedullin-5 in Normal Conscious Sheep

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