Species Variability in Cardiovascular Research: The Example of Adrenocorticotrophin‐induced Hypertension

Whitworth, Judith A.; Zhang, Yi; Mangos, George; Kelly, John J.

doi:10.1111/j.1440-1681.2006.04460.x

Cited by 6 publications

(7 citation statements)

References 53 publications

(75 reference statements)

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“…One important observation is that in all species tested, the rise in blood pressure can be prevented by prior adrenalectomy and is therefore dependent to a substantial degree on adrenally produced steroids. In humans and rats, for example, administration of the primary glucocorticoid (cortisol and corticosterone, respectively) can in large part reproduce the hypertensive state (30). We found that corticosterone increased dramatically in response to ACTH treatment in both ouabainsensitive and -resistant mice and that the magnitude of this response was not different between the genotypes.…”

Section: Discussionsupporting

confidence: 47%

ACTH-induced hypertension is dependent on the ouabain-binding site of the α₂-Na⁺-K⁺-ATPase subunit

Lorenz¹,

Loreaux²,

Dostanic-Larson³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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-ACTH-inducedhypertension is commonly employed as a model of stress-related hypertension, and despite extensive investigation, the mechanisms underlying elevated blood pressure (BP) are not well understood. We have reported that ACTH treatment increases tail-cuff systolic pressure in wild-type mice but not in mutant mice expressing ouabainresistant ␣ 2-Na ϩ -K ϩ -ATPase subunits (␣2 R/R mice). Since tail-cuff measurements involve restraint stress, the present study used telemetry to distinguish between an effect of ACTH on resting BP vs. an ACTH-enhanced stress response. We also sought to explore the mechanisms underlying ACTH-induced BP changes in mutant ␣2 R/R mice vs. wild-type mice (ouabain-sensitive ␣ 2 -NaS/S mice). Baseline BP was not different between the two genotypes, but after 5 days of ACTH treatment, BP increased in ␣2 S/S (104.0 Ϯ 2.6 to 117.7 Ϯ 3.0 mmHg) but not in ␣2 R/R mice (108.2 Ϯ 3.2 to 111.5 Ϯ 4.0 mmHg). To test the hypothesis that ACTH hypertension is related to inhibition of ␣2-Na ϩ -K ϩ -ATPase on vascular smooth muscle by endogenous cardiotonic steroids, we measured BP and regional blood flow. Results suggest a differential sensitivity of renal, mesenteric, and cerebral circulations to ACTH and that the response depends on the ouabain sensitivity of the ␣ 2-Na ϩ -K ϩ -ATPase. Baseline cardiac performance was elevated in ␣2 S/S but not ␣2 R/R mice. Overall, the data establish that the ␣2-Na ϩ -K ϩ -ATPase ouabain-binding site is of central importance in the development of ACTH-induced hypertension. The mechanism appears to be related to alterations in cardiac performance, and perhaps vascular tone in specific circulations, presumably caused by elevated levels of circulating cardiotonic steroids.

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Section: Discussionsupporting

confidence: 47%

ACTH-induced hypertension is dependent on the ouabain-binding site of the α₂-Na⁺-K⁺-ATPase subunit

Lorenz¹,

Loreaux²,

Dostanic-Larson³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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“…It has been argued that these endogenous ouabain-like compounds contribute to other forms of hypertension as well, including essential hypertension (2,15), preeclampsia (12,33), and DOCA-salt hypertension (14,19,32). Although ACTH-induced hypertension is commonly regarded as a stress-related form of hypertension involving multiple regulatory pathways, the pathogenesis of this form of high blood pressure remains somewhat enigmatic, and there appears to be a substantial amount of species heterogeneity (37). It therefore became important to determine whether resistance to hypertension in the ␣1 R/R ␣2 R/R animals was a general phenomenon, or alternatively, whether the resistance was peculiar to this form of stress-related hypertension.…”

Section: Role Of Nka ␣-Subunit and Its Endogenous Ligands In Renovascmentioning

confidence: 98%

Renovascular hypertension using a modified two-kidney, one-clip approach in mice is not dependent on the α1 or α2 Na-K-ATPase ouabain-binding site

Lorenz

Lasko²,

Nieman³

et al. 2011

American Journal of Physiology-Renal Physiology

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Endogenous cardiotonic steroids, through their interaction with the ouabain-binding site of the Na-K-ATPase α-subunit, have been implicated in a variety of cardiovascular disease states including hypertension. We have previously shown that ACTH-induced hypertension is abolished in mutant mice expressing ouabain-resistant α1- and α2-subunits. To further evaluate hypertension resistance in these mutant mice, we examined blood pressure changes in a modified model of 2-kidney, 1-clip (2K1C) renovascular hypertension. To reliably generate 2K1C hypertension, we used polyvinyl tubing (inner diameter: ∼0.27 mm) to accurately gauge the degree of renal artery stenosis. Using this method, virtually all of the clipped mice became hypertensive and there was no incidence of apparent renal ischemia. By telemetry, in response to renal artery clipping, blood pressure in wild-type mice (α1 ouabain-resistant, α2 ouabain-sensitive) increased from 97 ± 3 to 136 ± 7 mmHg. In α1-resistant, α2-resistant mice, pressure increased from 93 ± 2 to 123 ± 4 mmHg, and in α1-sensitive, α2-resistant mice, blood pressure increased from 95 ± 2 to 139 ± 5 mmHg. Blood pressure changes were equivalent in all three groups. In sham mice, blood pressure did not change (96 ± 1 to 95 ± 2 mmHg). Renin mRNA expression was dramatically elevated in the left vs. the right kidney, and plasma renin concentration was elevated similarly in all genotypes. These data indicate that sensitivity of the α1- or α2-Na-K-ATPase binding site to cardiotonic steroids is not a prerequisite for the development of 2K1C renovascular hypertension. In addition, use of a polyurethane cuff to constrict the renal artery provides a reliable method for producing 2K1C hypertension in mice.

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“…ACTH-induced hypertension depends on intact adrenal gland function since adrenal insufficiency or adrenalectomy prevents increased BP in subjects with high levels of ACTH [13]. Although the mechanisms by which ACTH raises BP regulation are still unclear, sodium and water retention secondary to adrenal secretion of glucocorticoids/mineralocorticoid hormones appears to play an important role [12, 14].…”

Section: Pomc Melanocortin Peptides and Blood Pressure Regulationmentioning

confidence: 99%

“…ACTH also greatly enhances the chronic BP effects of norepinephrine or angiotensin II through mechanisms that are independent of increased glucocorticoids [12]. Although the kidneys are importantly involved in mediating the chronic cardiovascular actions of the ACTH-adrenocortical axis, the complex mechanisms involved are still the subject of investigation and have been extensively reviewed by others [13]. …”

Section: Pomc Melanocortin Peptides and Blood Pressure Regulationmentioning

confidence: 99%

Role of the brain melanocortins in blood pressure regulation

Carmo

Silva

Wang

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Melanocortins play an important role in regulating blood pressure (BP) and sympathetic nervous system (SNS) activity as well as energy balance, glucose and other metabolic functions in humans and experimental animals. In experimental models of hypertension with high SNS activity, blockade of the melanocortin-4 receptor (MC4R) reduces BP despite causing marked hyperphagia and obesity. Activation of the central nervous system (CNS) pro-opiomelanocortin (POMC)–MC4R pathway appears to be an important link between obesity, SNS activation and hypertension. Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, urinary catecholamine excretion and SNS responses to cold stimuli compared to obese subjects with normal MC4R function. In this review we discuss the importance of the brain POMC-MC4R system in regulating SNS activity and BP in obesity and other forms of hypertension. We also highlight potential mechanisms and brain circuitry by which the melanocortin system regulates cardiovascular function.

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Species Variability in Cardiovascular Research: The Example of Adrenocorticotrophin‐induced Hypertension

Cited by 6 publications

References 53 publications

ACTH-induced hypertension is dependent on the ouabain-binding site of the α₂-Na⁺-K⁺-ATPase subunit

ACTH-induced hypertension is dependent on the ouabain-binding site of the α₂-Na⁺-K⁺-ATPase subunit

Renovascular hypertension using a modified two-kidney, one-clip approach in mice is not dependent on the α1 or α2 Na-K-ATPase ouabain-binding site

Role of the brain melanocortins in blood pressure regulation

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Species Variability in Cardiovascular Research: The Example of Adrenocorticotrophin‐induced Hypertension

Cited by 6 publications

References 53 publications

ACTH-induced hypertension is dependent on the ouabain-binding site of the α2-Na+-K+-ATPase subunit

ACTH-induced hypertension is dependent on the ouabain-binding site of the α2-Na+-K+-ATPase subunit

Renovascular hypertension using a modified two-kidney, one-clip approach in mice is not dependent on the α1 or α2 Na-K-ATPase ouabain-binding site

Role of the brain melanocortins in blood pressure regulation

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About

ACTH-induced hypertension is dependent on the ouabain-binding site of the α₂-Na⁺-K⁺-ATPase subunit

ACTH-induced hypertension is dependent on the ouabain-binding site of the α₂-Na⁺-K⁺-ATPase subunit