Neurohumoral mechanisms in deoxycorticosterone acetate (DOCA)–salt hypertension in rats

Yemane, Henok T; Busauskas, Marius; Burris, Sarah K; Knuepfer, Mark M.

doi:10.1113/expphysiol.2008.046334

Cited by 64 publications

(81 citation statements)

References 40 publications

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“…Consistent with previous reports in other models of cardiomyopathy, these DOCA‐treated nonischemic HF mice showed reduced ejection fraction and reduced systolic cytoplasmic Ca 2+ transients 14, 15, 42, 43, 44. Similar to other myopathic models, these nonischemic HF mice showed electrical remodeling with prolonged QTc intervals and APDs 1.…”

Section: Discussionsupporting

confidence: 90%

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Xie

Song

Liu

et al. 2018

JAHA

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BackgroundHeart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis.Methods and ResultsA model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol‐induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L‐type Ca2+ currents, increased Na+‐Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 μmol/L Ru360, a mitochondrial Ca2+ uniporter–specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+‐Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L‐type Ca2+ current, consistent with the experimental observations.ConclusionsMitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition.

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Section: Discussionsupporting

confidence: 90%

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Xie

Song

Liu

et al. 2018

JAHA

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“…Furthermore, the administration of NKCC1 inhibitor during DOCA-salt treatment partially blocked the development of hypertension and the associated rise in plasma AVP level. These findings indicate that GABAergic excitation plays a crucial role in the development and maintenance of hypertension in this model but that other mechanisms (eg, increases in plasma osmolality, renal sodium and water retention, and sympathetic activity) 20 must be involved. Our results raise the possibility that GABAergic excitation in AVP neurons contributes to the increase in blood pressure by altering the baroreflexive control of these cells.…”

Section: Discussionmentioning

confidence: 97%

“…In the present study, rats were made hypertensive by administration of DOCA and exposure to 1% NaCl drinking water after uninephrectomy. 20 We then sought to test the hypothesis that, in this DOCA-salt model of hypertension, GABA excites AVP neurons to increase the release of AVP and consequently raise blood pressure. Here, we present experimental results supporting this hypothesis.…”

mentioning

confidence: 99%

GABAergic Excitation of Vasopressin Neurons

Kim

et al. 2013

Circulation Research

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Rationale: Increased arginine-vasopressin (AVP) secretion is a key physiological response to hyperosmotic stress and may be part of the mechanism by which high-salt diets induce or exacerbate hypertension. Objective: Using deoxycorticosterone acetate-salt hypertension model rats, we sought to test the hypothesis that changes in GABA A receptor–mediated inhibition in AVP-secreting magnocellular neurons contribute to the generation of Na + -dependent hypertension. Methods and Results: In vitro gramicidin-perforated recordings in the paraventricular and supraoptic nuclei revealed that the GABAergic inhibition in AVP-secreting neurons was converted into excitation in this model, because of the depolarization of GABA equilibrium potential. Meanwhile, in vivo extracellular recordings in the supraoptic nuclei showed that the GABAergic baroreflexive inhibition of magnocellular neurons was transformed to excitation, so that baroreceptor activation may increase AVP release. The depolarizing GABA equilibrium potential shift in AVP-secreting neurons occurred progressively over weeks of deoxycorticosterone acetate-salt treatment along with gradual increases in plasma AVP and blood pressure. Furthermore, the shift was associated with changes in chloride transporter expression and partially reversed by bumetanide (Na + -K + -2Cl – cotransporter inhibitor). Intracerebroventricular bumetanide administration during deoxycorticosterone acetate-salt treatment hindered the development of hypertension and rise in plasma AVP level. Muscimol (GABA A agonist) microinjection into the supraoptic nuclei in hypertensive rats increased blood pressure, which was prevented by previous intravenous V1a AVP antagonist injection. Conclusions: We conclude that the inhibitory-to-excitatory switch of GABA A receptor–mediated transmission in AVP neurons contributes to the generation of Na + -dependent hypertension by increasing AVP release. We speculate that normalizing the GABA equilibrium potential may have some utility in treating Na + -dependent hypertension.

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“…Here, the regenerating gland is relatively deficient in 11b-hydroxylase, so corticosterone production is depressed whereas DOC becomes elevated (Brown et al 1972a, Holzbauer et al 1972: 19-nor-DOC and other DOC derivatives may also be increased and implicated in the development of hypertension in these animals (Dale et al 1982, Gomez-Sanchez et al 1983. Additionally, the salt-fed DOCA-treated rat is a standard model for hypertension, and although this could be assumed to be an adjunct to its mineralocorticoid action, the effect is complex and central, and other actions are implicated (Schenk & McNeill 1992, Pinto et al 1998, Yemane et al 2010) -as indeed is also the case for aldosterone (Xue et al 2011). The salt-DOCA rat model of hypertension must be the most widely used application of DOCA treatment -a search of the key words in Web of Science produces a count of some 1700 relevant papers.…”

Section: Other Actions and Doc In Other Speciesmentioning

confidence: 99%

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

Vinson¹

2011

Journal of Endocrinology

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Over the 70 or so years since their discovery, there has been continuous interest and activity in the field of corticosteroid functions. However, despite major advances in the characterisation of receptors and coregulators, in some ways we still lack clear insight into the mechanism of receptor activation, and, in particular, the relationship between steroid hormone structure and function remains obscure. Thus, why should deoxycorticosterone (DOC) reportedly be a weak mineralocorticoid, while the addition of an 11b-hydroxyl group produces glucocorticoid activity, yet further hydroxylation at C18 leads to the most potent mineralocorticoid, aldosterone? This review aims to show that the field has been confused by the misreading of the earlier literature and that DOC, far from being relatively inactive, in fact has a wide range of activities not shared by the other corticoids. In contrast to the accepted view, the presence of an 11b-hydroxyl group yields, in corticosterone or cortisol, hormones with more limited functions, and also more readily regulated, by 11b-hydroxysteroid dehydrogenase. This interpretation leads to a more systematic understanding of structure-function relationships in the corticosteroids and may assist more rational drug design.

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Neurohumoral mechanisms in deoxycorticosterone acetate (DOCA)–salt hypertension in rats

Cited by 64 publications

References 40 publications

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

GABAergic Excitation of Vasopressin Neurons

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

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Neurohumoral mechanisms in deoxycorticosterone acetate (DOCA)–salt hypertension in rats

Cited by 64 publications

References 40 publications

Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Mitochondrial Ca 2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

GABAergic Excitation of Vasopressin Neurons

The mislabelling of deoxycorticosterone: making sense of corticosteroid structure and function

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Product

Resources

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Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy

Mitochondrial Ca ²⁺ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy