The Molecular Basis of Hypertension

Garbers, David L.; Dubois, Susan K.

doi:10.1146/annurev.biochem.68.1.127

Cited by 71 publications

(56 citation statements)

References 259 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An explanation for the acquisition of salt sensitivity in ANP genedeficient animals but not in GC-A gene-deficient animals remains unresolved (comprehensively discussed in ref. 35). ANP regulates arterial blood volume not only chronically but also in an acute fashion, for instance, in situations of acute volume expansion or sudden increases in blood pressure that cause the release of atrial granules from the heart (1, 4, 36).…”

Section: Discussionmentioning

confidence: 99%

Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide

Sabrane¹,

Kruse²,

Fabritz³

et al. 2005

J. Clin. Invest.

146

148

View full text Add to dashboard Cite

Atrial natriuretic peptide (ANP), via its vasodilating and diuretic effects, has an important physiological role in the maintenance of arterial blood pressure and volume. Its guanylyl cyclase-A (GC-A) receptor is highly expressed in vascular endothelium, but the functional relevance of this is controversial. To dissect the endothelium-mediated actions of ANP in vivo, we inactivated the GC-A gene selectively in endothelial cells by homologous loxP/Tie2-Cre-mediated recombination. Notably, despite full preservation of the direct vasodilating effects of ANP, mice with endothelium-restricted deletion of the GC-A gene (EC GC-A KO) exhibited significant arterial hypertension and cardiac hypertrophy. Echocardiographic and Doppler flow evaluations together with the Evan's blue dilution technique showed that the total plasma volume of EC GC-A KO mice was increased by 11-13%, even under conditions of normal dietary salt intake. Infusion of ANP caused immediate increases in hematocrit in control but not in EC GC-A KO mice, which indicated that ablation of endothelial GC-A completely prevented the acute contraction of intravascular volume produced by ANP. Furthermore, intravenous ANP acutely enhanced the rate of clearance of radio-iodinated albumin from the circulatory system in control but not in EC GC-A KO mice. We conclude that GC-A-mediated increases in endothelial permeability are critically involved in the hypovolemic, hypotensive actions of ANP.

show abstract

Section: Discussionmentioning

confidence: 99%

Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide

Sabrane¹,

Kruse²,

Fabritz³

et al. 2005

J. Clin. Invest.

146

148

View full text Add to dashboard Cite

show abstract

“…Thus, we investigated the participation of gene polymorphisms of the RAAS and SNS. The gene polymorphisms were selected from previous studies investigating the correlation between BP regulation and gene polymorphisms (33). Although Sciarrone et al (34).…”

Section: Discussionmentioning

confidence: 99%

The Thiazide-Sensitive Na+-Cl- Cotransporter Gene, C1784T, and Adrenergic Receptor-β3 Gene, T727C, May Be Gene Polymorphisms Susceptible to the Antihypertensive Effect of Thiazide Diuretics

Matayoshi¹,

Kamide²,

Takiuchi³

et al. 2004

Hypertens Res

View full text Add to dashboard Cite

IntroductionThiazide diuretics (TZDs) have been most widely used as a first line antihypertensive drug (1,2). Recently, the ALLHAT study confirmed the usefulness of TZDs for the reduction of blood pressure (BP) and cardiovascular diseases in comparison with newer antihypertensive drugs, including Ca channel blockers (CCBs) such as amlodipine and angiotensin converting enzyme inhibitors (ACEIs) such as lisinopril in about 40,000 hypertensive patients with high risk factors (3). TZDs are not only effective as a monotherapy for hypertension, but are also very useful for combination therapy with other antihypertensive drugs (4). Moreover, the use of a TZD as a drug therapy for hypertension, which is a chronic and lifelong disease, would be very good from the viewpoint of the cost of drugs, because TZDs are the cheapest of all antihypertensive drugs. However, the response of BP to TZDs differs among individuals, and TZDs often induce side effects, such as hypokalemia and lipid, glucose and uric acid metabolism abnormalities (4). Therefore, it would be useful to determine the individual sensitivity to a TZD before prescribing it.Regarding previous findings about gene polymorphisms that influence TZD-sensitivity, Turner et al. (5) reported that the β3-subunit of the G protein (GNB3) C825T polymorphism was related to the antihypertensive effect of a TZD in Caucasian and African-American subjects with essential hypertension (EHT). Glorioso et al. (6) also demonstrated that the α-adducin (ADD1) Gly460Trp polymorphism is the gene conferring susceptibility to the antihypertensive effect of TZDs in Italian hypertensives. This ADD1 Gly460Trp polymorphism was also suggested to confer susceptibility to saltsensitivity in Caucasians and Asians with EHT (7).Mutations of causative genes have recently been detected in several monogenic electrolyte disorders, such as mutations in the thiazide-sensitive Na-Cl cotransporter (TSC) gene for Gitelman syndrome (8, 9), the WNK1 and 4 genes for Gordon syndrome (pseudohypoaldosteronism type II) (10) and the mineral corticoid receptor (MLR) for pseudohypoaldosteronism type I (PHA I) (11). TZDs are commonly effective for treating Gitelman syndrome and Gordon syndrome. We also focused on the Na /Ca 2 exchanger gene (NCX1), because its impairment was recently reported in mesangial cells from salt-sensitive hypertensive rats (12). TZDs are known to be effective for salt-sensitive hypertension. It is also known that the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS) are activated in response to changes in circulating blood volume after TZD administration. Therefore, it is expected that gene polymorphisms related to the RAAS and SNS might be involved in the antihypertensive effect of TZDs. The present study investigated the gene polymorphism influencing the TZD-sensitivity by analyzing mainly single nucleotide polymorphisms (SNPs) of several water-electrolyte-related genes, including GN3B, ADD1, TSC, MLR, NCX1, WNK1, WNK4 and RAAS-and SNS-related genes, to antici...

show abstract

“…Hypertension remains a major risk factor for coronary artery disease and stroke, and yet there is little information regarding the molecular basis for this relatively common condition (23). Furthermore, in a large proportion of patients, high blood pressure remains difficult to control with currently available therapies.…”

Section: Discussionmentioning

confidence: 99%

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

Gros²,

You³

et al. 2001

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

View full text Add to dashboard Cite

We cloned a rat vascular chymase (RVCH) from smooth muscle cells (SMCs) that converts angiotensin I to II and is up-regulated in SMC from spontaneously hypertensive vs. normotensive rats. To determine whether increased activity of RVCH is sufficient to cause hypertension, transgenic mice were generated with targeted conditional expression of RVCH to SMC, with the use of the tetracyclinecontrolled transactivator (tTA). We confirmed conditional expression of RVCH by mRNA, protein, and chymase activity in the absence, but not in the presence, of dietary doxycycline. The systolic blood pressure (mmHg), measured by carotid artery cannulation at 10 -12 weeks of age, was higher in tTA؉͞RVCH؉ mice than in nonbinary transgenic littermates (136 ؎ 4 vs. 109 ؎ 3) (P < 0.05), as were the diastolic and mean pressures. Hypertension was completely reversed by doxycycline, suggesting a causal link with chymase expression. Medial thickening of mesenteric arteries from tTA؉͞RVCH؉ mice vs. littermates (0.82 ؎ 0.1 vs. 0.42 ؎ 0.02) (P < 0.05) was associated with increased SMC proliferation, as judged by positive immunoreactivity, with the use of an antibody to the proliferating cell nuclear antigen. These structural changes were prevented by doxycycline. Perfusion myography of mesenteric arteries from tTA؉͞RVCH؉ mice also revealed increased vasoconstriction in response to phenylephrine and impaired metacholine-induced vasodilatation when compared with littermate controls or with the doxycyline-treated group. Our studies suggest that up-regulation of this vascular chymase is sufficient to cause a hypertensive arteriopathy, and that RVCH may be a candidate gene and a therapeutic target in patients with high blood pressure.smooth muscle cells C hymases are serine proteinases that were thought to be produced exclusively by mast cells in blood vessels and the myocardium. These enzymes generate angiotensin (Ang) II in large and resistance vessels (1-3) and in the heart (4) and also can convert big-endothelin-1 to endothelin-1 in vitro (5) and inactivate the vasodilator bradykinin (6). That chymase-dependent Ang II formation can occur in the intact animal is evident from studies in the baboon, where it was shown that Ang-converting enzyme inhibitors could not prevent the hemodynamic response to [Pro11, Da1a12]Ang I, which produces Ang II upon incubation with chymase (7). In addition to blood pressure regulation, both Ang II and endothelin-1 are involved in the stimulation of vascular smooth muscle cell (SMC) growth and proliferation, vascular remodeling, and cardiac hypertrophy (8, 9). Chymases also can influence structural remodeling through their ability to degrade extracellular matrix proteins, including fibronectin and collagen type IV, possibly through activation of matrix metalloproteinases (MMPs) (MMP-1, MMP-3, and MMP-9) (10-12). Chymases also stimulate collagen fibirillogenesis by cleavage of type I procollagen (13).Several studies have provided compelling data to suggest that chymases could play a central role in cardiovascular di...

show abstract

The Molecular Basis of Hypertension

Cited by 71 publications

References 259 publications

Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide

Vascular endothelium is critically involved in the hypotensive and hypovolemic actions of atrial natriuretic peptide

The Thiazide-Sensitive Na+-Cl- Cotransporter Gene, C1784T, and Adrenergic Receptor-β3 Gene, T727C, May Be Gene Polymorphisms Susceptible to the Antihypertensive Effect of Thiazide Diuretics

Conditional and targeted overexpression of vascular chymase causes hypertension in transgenic mice

Contact Info

Product

Resources

About