Low-Renin and Nonmodulating Essential Hypertension

Warnock, David G.

doi:10.1161/01.hyp.34.3.395

Cited by 23 publications

(27 citation statements)

References 22 publications

(22 reference statements)

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“…Patients in the lowest quartile of renin activity had lower serum creatinine levels than the other 3 quartiles. Interestingly, serum aldosterone level did not differ according to quartile of renin activity but, as expected, 4,21 there was a graded reduction in the aldosterone/ renin ratio with increasing renin activity.…”

Section: Baseline Clinical Characteristicssupporting

confidence: 66%

“…This variable has been used as a screen for adrenal adenomas and hyperplasia and may be moderately elevated in low-renin hypertension (30 to 100 ng/dL per ng/mL per hour). 4 We therefore investigated the relation between quartile of aldosterone to renin ratio and vascular function in hypertensive and normotensive participants. In the hypertensive group, patients with the highest quartile of aldosterone to renin ratio (19.7 to 155 ng/dL per ng/mL per hour) had lower vasodilator responses to peak methacholine (9.5Ϯ7.3 mL/min per dL) compared with the first, second, and third quartiles (15.0Ϯ5.9, 14.1Ϯ5.9, and 12.8Ϯ6.3 mL/min per dL, respectively, PϽ0.001) (Figure 4).…”

Section: Aldosterone To Renin Ratio and Vascular Functionmentioning

confidence: 99%

“…Key Words: aldosterone Ⅲ blood flow Ⅲ endothelium Ⅲ mineralocorticoids Ⅲ renin A pproximately one-third of patients with hypertension have "low-renin hypertension," 1 and such patients are more likely to be salt-sensitive and may respond better to diuretic therapy. [2][3][4] The spectrum of low-renin hypertension includes patients with normokalemic primary hyperaldosteronism (mostly idiopathic hyperaldosteronism), which occurs in up to 15% of hypertensive subjects 5-8 and may represent an end-stage in the evolution of neurohormonal changes in "essential" hypertension. 7,8 Despite early evidence that patients with low renin levels might have a relatively favorable prognosis, 1,9 more recent epidemiological studies suggest that patients with low-renin and/or salt-sensitive hypertension have increased risk of endorgan damage, cardiovascular events, and mortality compared with other hypertensives.…”

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Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation

et al. 2005

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Abstract-Recent studies suggest that hypertension associated with low renin status and hyperaldosteronism is associated with increased risk for end-organ damage and cardiovascular events compared with other forms of hypertension.Additionally, experimental studies have demonstrated impaired nitric oxide-mediated bioactivity in these states. To investigate the relation between renin/aldosterone status and resistance vessel function, we examined plasma renin activity, serum aldosterone level, and forearm blood flow responses to the endothelium-dependent vasodilator methacholine and the endothelium-independent vasodilators sodium nitroprusside and verapamil using venous occlusion plethysmography in 130 volunteers (43 hypertensive, 87 normotensive). Key Words: aldosterone Ⅲ blood flow Ⅲ endothelium Ⅲ mineralocorticoids Ⅲ renin A pproximately one-third of patients with hypertension have "low-renin hypertension," 1 and such patients are more likely to be salt-sensitive and may respond better to diuretic therapy. [2][3][4] The spectrum of low-renin hypertension includes patients with normokalemic primary hyperaldosteronism (mostly idiopathic hyperaldosteronism), which occurs in up to 15% of hypertensive subjects 5-8 and may represent an end-stage in the evolution of neurohormonal changes in "essential" hypertension. 7,8 Despite early evidence that patients with low renin levels might have a relatively favorable prognosis, 1,9 more recent epidemiological studies suggest that patients with low-renin and/or salt-sensitive hypertension have increased risk of endorgan damage, cardiovascular events, and mortality compared with other hypertensives. 3,10 -12 These observations might seem difficult to reconcile with our current understanding of the vascular consequences of neurohormonal activation. For example, experimental and clinical studies strongly suggest that activation of the reninangiotensin-aldosterone system leads to endothelial dysfunction, 13,14 which contributes importantly to the pathogenesis of cardiovascular events in hypertension. 15,16 In this regard, treatment with angiotensin II, aldosterone, or deoxycorticosterone and salt in rats reduces the bioavailability of endothelium-derived NO, increases superoxide production, and produces other pathological changes in the vasculature. [17][18][19] In humans, patients with elevated aldosterone levels 20,21 or renovascular hypertension 20 have impaired endotheliumdependent vasodilation in forearm microvessels, and intra-arterial aldosterone infusion impairs endothelium-dependent vasodilation. 22 Finally, treatment of hypertensive patients with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor blockers generally improves endothelial function in hypertensive patients, providing further support for a link between endothelial dysfunction and increased activity of the renin-angiotensin system in hypertension. 21,23 On the basis of this experimental and clinical work, we hypothesized that increased activity of the renin-aldo...

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Section: Baseline Clinical Characteristicssupporting

confidence: 66%

Section: Aldosterone To Renin Ratio and Vascular Functionmentioning

confidence: 99%

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confidence: 99%

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Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation

et al. 2005

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“…1 Indeed, the genetic basis of some forms of hypertension with mendelian inheritance is understood: glucocorticoid remediable hyperaldosteronism, Liddle's syndrome, and apparent mineralocorticoid excess come readily to mind. 1,2 Less drastic damage to the genes involved in these disorders may contribute to essential hypertension in some populations. 3,4 Research into the etiology of essential hypertension has been facilitated by the development of the genetically hypertensive inbred rat strains.…”

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confidence: 99%

Neither the New Zealand Genetically Hypertensive Strain nor Dahl Salt-Sensitive Strain Has an A1079T Transversion in the α1 Isoform of the Na ⁺ ,K ⁺ -ATPase Gene

Barnard

Kelly²,

Manzetti³

et al. 2001

Hypertension

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Abstract-A putative 1079A3 T mutation in the ␣1 isoform of the Na ϩ , K ϩ -ATPase (Atp1a1) gene of the Dahl salt-sensitive rat inbred by John Rapp (SS/Jr) strain was projected to cause a conformation change in the membrane hydrophobic region of the protein product, possibly resulting in hypertension. The existence of the mutation was challenged, but the challenge was apparently rebutted. The New Zealand genetically hypertensive (GH) rat is known to have a blood pressure quantitative trait locus on chromosome 2 containing the gene for the ATPase. Thus, we sought to determine whether the GH rat carried the 1079A3 T transversion. We chose a method, first nucleotide change analysis, that can detect point mutations in a mixed population of polymerase chain reaction (PCR) products, even in the presence of PCR bias, and confirmed our analysis by restriction enzyme digestion of PCR products. To ensure the validity of our analyses, we used site-directed mutagenesis to create positive controls containing the mutation. Surprisingly, we found that neither the GH nor the SS/Jr strain had the A1079T transversion. Indeed, the transversion was not found in any strain tested. As an incidental observation, we have sequenced the intron preceding the exon containing the putative A1079T transversion. Within this intron, a single-base C/T polymorphism was observed at base 132. Our results definitively eliminate the putative A1079T transversion in Atp1a1 as a causative factor underlying hypertension in the GH, spontaneously hypertensive, and SS/Jr rat strains and indicate that alternative candidate genes in the region defined by the chromosome 2 hypertension quantitative trait locus should be examined.

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“…Low renin hypertension is characterized by a suppressed plasma renin and normal plasma aldosterone level, together with saltsensitive hypertension and possible relative volume expansion. 44 Plasma K + is usually normal, but levels of ≤5.3 mmol/L have been reported. 45 There is a good response to thiazides.…”

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confidence: 99%

Pseudohypoaldosteronism Type II

Healy

2014

Hypertension

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K + during a NaHCO 3 infusion. As will be discussed below, we now know that there are 5 levels of severity of PHAII so that the response to PRAN may differ between individual cases. Given the hyperkalemia of these patients, one might have expected even a supranormal response to PRAN as seen below in the mouse model of PHAII.32 PRAN were used in 11 of the studies surveyed here and although some had a reduced kaliuretic response, in none was there a response greater than the normal controls. 3,5,[7][8][9][11][12][13]17,19,20 Therefore, given the hyperkalemia, these results indicate a mild degree of depression of ENaC function. This might have been expected to lead to a compensatory increase in activity of the major K + secretory mechanism, the renal outer medullary K + (ROMK) channels. 34,35 This might imply that ROMK also was not functioning normally (Figure, Theory 1).Another factor that could have suppressed the K + secretion, particularly ROMK, 31 was the acidosis, which is known to be because of hyperkalemia in PHAII. 5,7,11,12 If PHAII is reversed by drug treatment (thiazide) and the drug is stopped, the hyperkalemia returns in 10 days before a return of the acidosis at 17 days, 8 indicating the primacy of the hyperkalemia. If the ENaC is compromised to a degree, this period without acidosis would provide ROMK with a window of opportunity to control the rising plasma K + ; this clearly does not happen. DeFronzo et al 33 studied K + secretion in sickle cell disease that damages the renal papillae and the medulla. They found a negligible response in K + secretion to PRAN, yet hyperkalemia did not occur (average plasma K + , 3.78±0.01 mmol/L). This difference from PHAII might be explained by the fact that although ROMK shares the late DT, the connecting tubule and the collecting duct sites with ENaC, functioning isoforms ROMK 2 and 3 are present as well in the whole of the distal convoluted tubule (DCT). 34 Therefore, in sickle cell disease, these isoforms may have been intact in the DCT before the late DCT but perhaps not so in PHAII. PHAII and sickle cell disease cannot be compared pathologically, but these results reflect on the way the effects of PRAN are interpreted because they show that a negligible response in K + secretion to PRAN is not obligatorily associated with hyperkalemia in humans.Finally, Golbang et al 26 (see below) have described a father and son with PHAII caused by a mutant gene shown by genetic testing to inhibit ROMK substantially.The second view of the cause of hyperkalemia in PHAII is that a Cl -shunt may play a role 3 by increasing paracellular Cl -absorption in the early DT (Figure, Theory 2). Schambelan et al 3 in 1981 showed that with mineralocorticoid pretreatment, intravenous Na 2 SO 4 and NaHCO 3 could both invoke an increase in K + excretion in PHAII, but that intravenous sodium chloride (NaCl) was much less able to do so. They postulated that a Cl -shunt proximal to the ENaC would result in less Cl -delivery and thus less negativity at the ENaC, resulting in decreased K + sec...

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Low-Renin and Nonmodulating Essential Hypertension

Cited by 23 publications

References 22 publications

Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation

Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation

Neither the New Zealand Genetically Hypertensive Strain nor Dahl Salt-Sensitive Strain Has an A1079T Transversion in the α1 Isoform of the Na ⁺ ,K ⁺ -ATPase Gene

Pseudohypoaldosteronism Type II

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Low-Renin and Nonmodulating Essential Hypertension

Cited by 23 publications

References 22 publications

Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation

Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation

Neither the New Zealand Genetically Hypertensive Strain nor Dahl Salt-Sensitive Strain Has an A1079T Transversion in the α1 Isoform of the Na + ,K + -ATPase Gene

Pseudohypoaldosteronism Type II

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Neither the New Zealand Genetically Hypertensive Strain nor Dahl Salt-Sensitive Strain Has an A1079T Transversion in the α1 Isoform of the Na ⁺ ,K ⁺ -ATPase Gene