scholarly journals High Dose Vardenafil Blunts the Hypertensive Effects of Toll-Like Receptor 3 Activation During Pregnancy

2021 ◽  
Vol 1 ◽  
Author(s):  
Dakshnapriya Balasubbramanian ◽  
Sathish Dharani ◽  
Mohammad Tauseef ◽  
Mansoor A. Khan ◽  
Ziyaur Rahman ◽  
...  

The maternal innate immune system plays a central role in preeclampsia (PE). Toll-like receptors (TLRs) are innate immune system receptors that recognize characteristics of extracellular endogenous ligands or pathogens, and their activation leads to a pro-inflammatory immune response. We and others have reported that excessive activation of TLRs causes pregnancy-dependent hypertension in animals and is associated with PE in women. Activation of TLR3 by poly I:C mimics the innate immune system activation by viruses that women who develop PE encounter during pregnancy. Vardenafil was approved by the FDA for erectile dysfunction but has recently been examined as a potential PE medication due to studies done with a similar drug, sildenafil. Preclinical as well as recent clinical studies demonstrate the potential effectiveness of sildenafil for PE. However, vardenafil is more potent than sildenafil and acts by increasing expression of placental growth factor in addition to increasing cGMP levels. We hypothesized that vardenafil will be more potent and effective in reducing the negative health effects in a mouse model of virus-induced PE. Pregnant mice were injected with the TLR3 agonist poly I:C (PPIC) on gestational days 13, 15, and 17. We treated PPIC mice with a high dose of vardenafil (50 mg human equivalent), a lower dose of vardenafil (20 mg human equivalent), or sildenafil (50 mg human equivalent) on gestational days 15–17 after hypertension was established. Daily i.p. injections of either high dose or low dose vardenafil significantly decreased systolic blood pressure in PPIC mice whereas sildenafil had no effect. There were no differences in body weight between the groups. The splenomegaly induced in PPIC mice was ameliorated in high dose vardenafil-treated PPIC mice, while low dose vardenafil-treated and sildenafil-treated PPIC mice still exhibited splenomegaly. High dose vardenafil-treated PPIC mice also did not exhibit any fetal demise characteristic of PPIC mice, while low dose vardenafil-treated and sildenafil-treated PPIC mice still had significantly increased incidences of fetal demise. These data support the notion that high dose vardenafil may be safe and effective at reducing blood pressure during a virus-associated hypertensive pregnancy.

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Cameron G McCarthy ◽  
Camilla F Wenceslau ◽  
Styliani Goulopoulou ◽  
Safia Ogbi ◽  
Takayuki Matsumoto ◽  
...  

HBPR 2014 Circulating mitochondrial DNA (mtDNA) is elevated in spontaneously hypertensive rats (SHR) and the enzyme responsible for its degradation, DNase II, has decreased activity in SHR tissues. Moreover, a synthetic mtDNA mimetic, specific for TLR 9, causes endothelial dysfunction and elevated blood pressure. Therefore, we sought to inhibit the contribution of mtDNA on innate immune system activation, via inhibition of Toll-like receptor (TLR)9, in SHR. We treated 12-15 week old SHR and Wistar-Kyoto rats (WKY) with chloroquine (CQ; 40mg/kg/day) or vehicle (veh; saline) for 21 days via intraperitoneal injection ( i.p. ). We hypothesized that CQ treatment would improve endothelial function and decrease blood pressure in SHR. Blood pressure was measured pre- and post-treatment via tail cuff and endothelial function was measured via mesenteric resistance artery (MRA) relaxation to acetylcholine (ACh; 10 -9 -10 -5 M) using a wire myograph. Treatment with CQ lowered post-systolic blood pressure in SHR (mmHg, Veh: 201±2 vs. CQ: 185±5 mmHg; p<0.05). No effects of treatment were observed on blood pressure in WKY (p>0.05). CQ abolished the contractile effect to high concentrations of ACh [AUC (%NE pre-contraction), Veh: 160±25 vs. CQ: 277±20; p<0.05] in MRA from SHR. However, no differences were observed in endothelium-independent relaxation to NO-donor sodium nitroprusside [E max (%NE pre-contraction), Veh: 97±12 vs. CQ: 102±26; p<0.05] in MRAs from SHR. Again, no effects of treatment were observed for endothelium-dependent or -independent relaxation in WKY (p>0.05). These data demonstrate the inhibition of endosomal TLRs, including TLR9, improves blood pressure and endothelial function in SHR. Inhibition of TLR9 abrogates the potentially deleterious contribution of increased mtDNA and impaired DNase II activity on innate immune system activation in hypertension.


2015 ◽  
pp. 71-85
Author(s):  
María Isabel Cuartero ◽  
Ignacio Lizasoain ◽  
María Ángeles Moro ◽  
Ivan Ballesteros

2018 ◽  
Vol 104 (4) ◽  
pp. 1187-1199 ◽  
Author(s):  
Ahmed Iqbal ◽  
Lynne R Prince ◽  
Peter Novodvorsky ◽  
Alan Bernjak ◽  
Mark R Thomas ◽  
...  

Abstract Context Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting Single-blinded, prospective study of three independent parallel groups. Participants and Interventions Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main Outcome Measures We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P &lt; 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P &lt; 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P &lt; 0.01; vs sham-saline 26.20 ± 3.86/μL, P &lt; 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P &lt; 0.001; vs sham-saline 19.05 ± 3.81/μL, P &lt; 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P &lt; 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P &lt; 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P &lt; 0.05; vs sham-saline 3.81± 1.42/μL, P &lt; 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P &lt; 0.01; vs sham-saline 3.08 ± 1.01/μL, P &lt; 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P &lt; 0.05). Conclusions Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.


Virology ◽  
2016 ◽  
Vol 488 ◽  
pp. 169-178 ◽  
Author(s):  
M. Kondili ◽  
M. Roux ◽  
N. Vabret ◽  
M. Bailly-Bechet

2014 ◽  
Vol 306 (2) ◽  
pp. H184-H196 ◽  
Author(s):  
Cameron G. McCarthy ◽  
Styliani Goulopoulou ◽  
Camilla F. Wenceslau ◽  
Kathryn Spitler ◽  
Takayuki Matsumoto ◽  
...  

Low-grade systemic inflammation is a common manifestation of hypertension; however, the exact mechanisms that initiate this pathophysiological response, thereby contributing to further increases in blood pressure, are not well understood. Aberrant vascular inflammation and reactivity via activation of the innate immune system may be the first step in the pathogenesis of hypertension. One of the functions of the innate immune system is to recognize and respond to danger. Danger signals can arise from not only pathogenic stimuli but also endogenous molecules released following cell injury and/or death [damage-associated molecular patterns (DAMPs)]. In the short-term, activation of the innate immune system is beneficial in the vasculature by providing cytoprotective mechanisms and facilitating tissue repair following injury or infection. However, sustained or excessive immune system activation, such as in autoimmune diseases, may be deleterious and can lead to maladaptive, irreversible changes to vascular structure and function. An initial source of DAMPs that enter the circulation to activate the innate immune system could arise from modest elevations in peripheral vascular resistance. These stimuli could subsequently lead to ischemic- or pressure-induced events aggravating further cell injury and/or death, providing more DAMPs for innate immune system activation. This review will address and critically evaluate the current literature on the role of the innate immune system in hypertension pathogenesis. The role of Toll-like receptor activation on somatic cells of the vasculature in response to the release of DAMPs and the consequences of this activation on inflammation, vasoreactivity, and vascular remodeling will be specifically discussed.


2014 ◽  
Vol 111 (2) ◽  
pp. S109-S110
Author(s):  
Moin Vera ◽  
Steven Le ◽  
Shih-hsin Kan ◽  
Patricia Dickson ◽  
Raymond Y. Wang

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