Autoimmune therapeutic chloroquine lowers blood pressure and improves endothelial function in spontaneously hypertensive rats

Abstract

It has been suggested that hypertension results from a loss of immunological tolerance and the resulting autoimmunity may be an important underlying factor of its pathogenesis. This stems from the observations that many of the features involved in autoimmunity are also implicated in hypertension. Furthermore, the underlying presence of hypertension and cardiovascular disease are frequently observed in patients with autoimmune diseases. Antimalarial agents such as chloroquine are generally among the first line treatment options for patients with autoimmune diseases; however, whether they can improve a hypertensive phenotype in a genetic model of essential hypertension remains to be clarified. Therefore, we hypothesized that chloroquine treatment would improve endothelial function and lower blood pressure in spontaneously hypertensive rats (SHR). We treated adult SHR and Wistar-Kyoto rats (12 weeks old), as well as a group of young SHR (5 weeks old), with chloroquine (40 mg/kg/day via intraperitoneal injection) for 21 days. Chloroquine lowered blood pressure in adult SHR, but did not impede the development of high blood pressure in young SHR. In isolated mesenteric resistance arteries from SHR of both ages, chloroquine treatment inhibited cyclooxygenase-dependent contraction to acetylcholine, lowered vascular and systemic generation of reactive oxygen species, and improved nitric oxide bioavailability. Overall, these data reveal the anti-hypertensive mechanisms of chloroquine in the vasculature, which may be important for lowering risk of cardiovascular disease in patients with autoimmune diseases. Furthermore, it adds to the growing body of evidence suggesting that autoimmunity underlies hypertension.

UDP-induced relaxation is enhanced in aorta from female obese Otsuka Long–Evans Tokushima Fatty rats

“…Since NO is a major endothelium-derived relaxing factor in thoracic aorta and NO bioavailability and/or signaling are impaired in various pathophygiological states, including obesity, hypertension, and diabetes [20][21][22]29], we investigated the effects of a NOS inhibitor on UDP-and ACh-induced relaxation (Fig. 1c, g, respectively).…”

“…To regulate vascular tone, endothelial cells release relaxant [such as endothelium-derived relaxing factors (EDRFs)] and contractile factors [such as endothelium-derived contracting factors (EDCFs)], and the balance between these factors is altered at various disease states [20][21][22][29][30][31][32][33]. Moreover, purinoceptor ligands release EDCFs [30,33].…”

“…Moreover, purinoceptor ligands release EDCFs [30,33]. Among these factors, vasoconstrictor prostanoids play an important role in regulating vascular tone by functioning as EDCFs [24,25,29,31,32]. In addition, in male OLETF rats, EDCF-mediated contraction has been reported to increase in superior mesenteric arteries [20][21][22].…”

Chloroquine is a potent pulmonary vasodilator that attenuates hypoxia‐induced pulmonary hypertension

“…In addition to its anti-autophagic effects, chloroquine induced vasodilation and decreased BP following treatment for malaria in humans (Looareesuwan et al, 1986;Anigbogu et al, 1993) and animals (Musabayane et al, 1994;McCarthy et al, 2016). In thoracic aortas precontracted by noradrenaline or high K + , treatment with chloroquine resulted in a concentration-dependent relaxation (Aziba and Okpako, 2003).…”

Paying the Toll for Inflammation

“…To understand if TLR9 could be involved in the development and/or maintenance of hypertension, our initial experiments focused on whether TLR9 could alter vascular function using a pharmacological approach and standard myograph procedures 42,47 . Specifically, we incubated isolated aortic segments from normotensive rats with TLR9 agonist, oligonucleotide (ODN)2395 (10 μmol/L) for 12 or 16 hours.…”