Thebination treatment also improved endothelium dependent relaxation of resistance mesenteric arteries. In rats with L NAME induced hypertensi caused by nitric oxide Troxerutin synthase inhibiti pound alone or inbination with olmesartan reduced pulse wave velocity. Moreov only thebination treatmentpletely prevented collagen accumulation in the aor which resulted in a profound reduction of aortic stiffness. Most interesting the effects of AT R stimu lation in both these studies seemed to be independent of the changes in blood pressu suggesting that binations of this agent with antihypertensive treatment might lead to vasculoprotective effects even beyond the blood pressure reducing effect.

Dual inhibitors AT R blockade and vasopeptidase inhibition Neutral endopeptidase is a Neohesperidin 13241-33-3 metallopeptidase that metabo lizes various vasodilatory and vasoconstrictive sub stanc leading to variable effects on blood pressure. Howev if this enzyme is inhibited in the presence of coitant vasoconstrictor blocka the effect of reduced degradation of vasodilatory substrates might outweigh that of vasoconstrictive substrat leading to a net vasodilatory effect. The OCTAVE and OVERTURE trials of the dual ACE”neutral endopeptidase inhibitor omaptrilat were encouraging in terms of efficacy in hypertension and heart failure. Howev they highlighted an increased incidence of angioedema after treatment with dual ACE and neutral endopeptidase inhibitorspared with buy Fostamatinib the ACE inhibitor enalapril. Consequent atten tion has shifted to dual AT R and neutral endopeptidase antagonism.

The putative first in class dual AT R and neutral endopeptidase antagonist LCZ achieved a blood pressure reductionparable to an  in a phase randomiz double bli placebo controll and active treatment controlled clinical trial in patients with mild to moderate essen tial hypertension. After weeks of treatme the two highest doses of LCZ achieved a larger Salidroside inhibitor reduction in sitting systolic and diastolic blood pressures than was achieved usingparable doses of valsartan . The mg dose of LCZ also resulted in superior blood pressure control and pulse pressure reductionpared with valsartan. In contrast to the results of trials of dual ACE and neutral endopeptidase inhibito no angioedema was reported in this study. With these encouraging da LCZ is now the most promising dual AT R and neutral endo peptidase inhibitor in clinical trials for the treatment of hypertensi as the development of the dual AT R and neutral endopeptidase antagonist VNP seems to be halted .

AT R and endothelin A receptor blockade Endothelin is one of the most potent vasoconstricto and also has prominent roles in fibrogenes inflam mati oxidative stre atheroscleros salt and water homeostas and pulmonary hypertension. Several endothelin receptor antagonists have been investi gated for the treatment of hypertension. The hexamine selective endothelin A antagonist darusentan achieved promis ing blood pressure reductions in patients with resis tant hypertension in the DAR tri and a larger reduction in mean h systolic and dia stolic blood pressure than either placebo or the sym patholytic antihypertensive agent guanfacine in the DAR trial. Howev adverse .