Jessica Watson

Introduction. Hypertension is defined as blood pressure persistently elevated above 130/80 mmHg.^1,2 It is the most important modifiable risk factor for cardiovascular disease and affects 874 million people worldwide.­­¹ Thirty to fifty percent of hypertensive patients exhibit salt sensitive hypertension, which is best defined as a direct correlation between salt intake and blood pressure.^3,4 The mechanism of salt-sensitive hypertension is becoming clearer. In response to high sodium levels, inflammatory mediators are released, prompting the cyclooxygenase-2 (COX-2) enzyme to produce Prostaglandin E2 (PGE2).^4,5 PGE2 then binds to E-prostanoid (EP) receptors.^6-10 In salt-resistant individuals, vasodilatory EP2 and EP4 receptors predominate.⁷ However, mutations to EP2 and EP4 cause salt sensitivity by allowing vasoconstrictive EP1 and EP3 receptors to act unopposed.⁷ While there are many medications available for standard hypertension, none are designed to specifically treat salt-sensitive hypertension.³ This study evaluates the use of COX-2 and EP3 receptor inhibitors in the treatment of salt-sensitive hypertension. Methods. Salt sensitive hypertension was modelled in genetically altered mice that were fed a controlled sodium diet.^6,7,9,10 As sodium levels were varied and pharmaceutical agents added, salt sensitivity was evaluated by measuring blood pressure, lymphatic flow, inflammatory cell population and distribution, cell receptor profiles, and cardiac hypertrophy.^6-10 Blood pressure was measured with tail-cuff plethysmography.^7-9 Inflammatory cells were analyzed using flow cytometry and microbeads.^6,8 Lymphatic flow was measured through fluorescent microscopy.⁸ Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to evaluate EP, COX-2, and inflammatory receptor levels.^6,8,9 Results. Salt-resistant mice undergoing COX-2 inhibition developed salt-labile hypertension, reduced lymphatic flow, and higher macrophage numbers with an M1 phenotype predominance.⁸ When salt-sensitive mice underwent EP3 inhibition, through pharmaceutical agents or genetic modification, salt-sensitivity was reduced. Blood pressure lability, antigen presenting cell activation, and inflammatory cell infiltration all decreased.^6,7,9 Furthermore, inhibition of EP3 receptors in the paraventricular nucleus reduced blood pressure, reactive oxygen species release, and cardiac hypertrophy.¹⁰ Conclusions. The use of COX-2 inhibitors in salt-resistant individuals induces salt sensitivity by both preventing the release of PGE₂ and its action on vasodilatory EP2 and EP4 receptors as well as reducing vascular endothelial growth factor release, hindering lymphatic flow.⁸ Since COX-2 inhibitors reduce PGE₂ levels, they could be useful in the treatment of genetically salt-sensitive individuals by minimizing EP3 activation.⁸ EP3 inhibition is a promising treatment for salt sensitive hypertension, as it prevents vasoconstriction and inflammation in response to increased sodium.^6,7,9 Central EP3 administration can prevent long term hypertensive adverse events, including cardiac hypertrophy.¹⁰

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