Hypertension最新文献

Background: Ang II (angiotensin II) causes hypertension and vascular inflammation both directly and indirectly via cytokines, including TNFα (tumor necrosis factor-α). In vascular smooth muscle cells (VSMCs), Ang II and TNFα activate Nox1 (NADPH oxidase 1) to produce superoxide. TNFα receptors associate with Nox1 and LRRC8A (leucine-rich repeat containing 8A) anion channels to modulate inflammation and contractility in a RhoA-dependent manner. VSMC-specific LRRC8A knockout mesenteric arteries are protected from TNFα-induced injury, and vasodilation is preserved. We hypothesized that LRRC8A knockout would preserve vascular function and decrease blood pressure (BP) in Ang II-infused mice.

Methods: Wild-type and knockout mice received Ang II infusions for 14 days. BP was measured by radiotelemetry, and aortic and mesenteric artery function was measured by wire myography. VSMCs were isolated from male wild-type and knockout mice.

Results: Systolic BP was not different, but knockout mice had more BP dipping during inactive periods at baseline, and dipping was preserved after Ang II. The function of knockout aortic and mesenteric vessels was less impaired by Ang II, as reflected by less augmented contraction to norepinephrine and serotonin and preserved relaxation to acetylcholine and sodium nitroprusside. Western blotting revealed increased soluble guanylate cyclase alpha and reduced CPI-17 in hypertensive knockout aortae. Consistent with lower Rho kinase activity, phosphorylation of ERM (ezrin/radixin/moesin) and cofilin was reduced in knockout VSMCs. Ang II caused less proliferation (lower PCNA [proliferating cell nuclear antigen]) and less induction of senescence in knockout vessels.

Conclusions: LRRC8A anion channels support VSMC inflammation and the associated vascular dysfunction, which impairs BP dipping in hypertension.

Background: The rice diet (RD), a low-sodium (<200 mg/d), low-protein (≈20 g/d), and low-fat (<5 g/d) diet was used to treat patients with malignant hypertension beginning in the 1940s, before any effective antihypertensive drugs were available. We retrospectively analyzed a curated cohort of RD patients with malignant hypertension to assess factors, including dietary adherence, associated with blood pressure (BP) reduction.

Methods: From 17 487 RD charts, we identified 544 malignant hypertension patients (baseline systolic BP ≥170 mm Hg and with concurrent retinal hemorrhage or papilledema), excluding those with diabetes, brain tumor, or prior sympathectomy. Outcome data were censored after any 30-day break in consecutive data. Baseline features, BP changes from baseline to week 4, and diet adherence (assessed by urinary chloride, UCl) were evaluated using summary statistics, univariate, and multivariable analyses.

Results: Most patients participated in the RD program before antihypertensive drugs were available; only 48 (8.8%) received any antihypertensive medications in the first month. The cohort (68.9% male) had a median baseline BP of 213/128 mm Hg and body mass index of 23.6 kg/m². Median time in the program before censoring was 109 days; median total time in the RD program was 333 days. BP declined significantly within the first week, reaching 179/108 mm Hg at week 4. UCl dropped from 217 to 21 mg/dL by week 4. Lower UCl, higher baseline BP, and female sex, but not retinal hemorrhage or papilledema, were associated with greater systolic BP reduction.

Conclusions: The low-sodium, low-fat, low-protein RD effectively lowered BP in malignant hypertension patients in 4 weeks, independent of antihypertensive medications.

Background: Chronic unfolded protein response due to endoplasmic reticulum stress has been proposed as a therapeutic target for hypertension. Here, we tested our hypothesis that inactivation of one of the central unfolded protein response effectors, inositol-requiring enzyme 1α, mitigates hypertension and vascular remodeling in mice infused with angiotensin II.

Methods: C57BL6 mice were infused with angiotensin II for 2 weeks with or without an inositol-requiring enzyme 1α inhibitor KIRA6 treatment to evaluate blood pressure and cardiovascular remodeling. Mouse small mesenteric arteries were used to assess vascular reactivity. Rat vascular smooth muscle cells were used to assess inositol-requiring enzyme 1α activation, intracellular Ca²⁺ concentration, and secretory phenotype via proteomics.

Results: KIRA6 treatment mitigated hypertension induced by angiotensin II infusion. KIRA6 treatment also prevented angiotensin II-induced vascular thickening and perivascular fibrosis. Immunohistochemical staining of aortas indicated that phosphorylated inositol-requiring enzyme 1α signal in vascular smooth muscle cells was elevated with angiotensin II infusion and attenuated with KIRA6 treatment. Vasoconstriction in small mesenteric arteries after incubation with angiotensin II was attenuated by KIRA6 coincubation. Angiotensin II-induced elevation in intracellular Ca²⁺ concentration was partially reduced by KIRA6 pretreatment in vascular smooth muscle cells. Proteomic analysis demonstrated that angiotensin II induced a unique secretory phenotype in vascular smooth muscle cells, which was mitigated by KIRA6.

Conclusions: Targeting inositol-requiring enzyme 1α is a potential therapy for hypertension and vascular remodeling by reducing vascular resistance, mitigating intracellular Ca²⁺ elevation, and protecting against secretory phenotype in vascular smooth muscle cells.