NITRATE-CIN Study: Protocol of a Randomized (1:1) Single-Center, UK, Double-Blind Placebo-Controlled Trial Testing the Effect of Inorganic Nitrate on Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography for Acute Coronary Syndromes

Background: Contrast-induced nephropathy (CIN), an acute kidney injury resulting from the administration of intravascular iodinated contrast media, is a significant cause of morbidity/mortality following coronary angiographic procedures in high-risk patients. Despite preventative measures intended to mitigate the risk of CIN, there remains a need for novel effective treatments. Evidence suggests that delivery of nitric oxide (NO) through chemical reduction of inorganic nitrate to NO may offer a novel therapeutic strategy to reduce CIN and thus preserve long term renal function. Design: The NITRATE-CIN trial is a single-center, randomized, double-blind placebo-controlled trial, which plans to recruit 640 patients presenting with acute coronary syndromes (ACS) who are at risk of CIN. Patients will be randomized to either inorganic nitrate therapy (capsules containing 12 mmol KNO3) or placebo capsules containing potassium chloride (KCl) daily for 5 days. The primary endpoint is development of CIN using the Kidney Disease Improving Global Outcomes (KDIGO) criteria. A key secondary endpoint is renal function over a 3-month follow-up period. Additional secondary endpoints include serum renal biomarkers (e.g. neutrophil gelatinase-associated lipocalin) at 6 h, 48 h and 3 months following administration of contrast. Cost-effectiveness of inorganic nitrate therapy will also be evaluated. Summary: This study is designed to investigate the hypothesis that inorganic nitrate treatment decreases the rate of CIN as part of semi-emergent coronary angiography for ACS. Inorganic nitrate is a simple and easy to administer intervention that may prove useful in prevention of CIN in at-risk patients undergoing coronary angiographic procedures.

Nitrite-stimulated Gastric Formation of S-nitrosothiols As An Antihypertensive Therapeutic Strategy

Hypertension is usually associated with deficient nitric oxide (NO) bioavailability, and therefore stimulating NO activity is an important antihypertensive strategy. Recently, many studies have shown that both nitrite and nitrate anions are not simple products of NO metabolism and indeed may be reduced back to NO. While enzymes with nitrite-reductase activity capable of generating NO from nitrite may contribute to antihypertensive effects of nitrite, another mechanism involving the generation of NO-related species in the stomach from nitrite has been validated. Under the acidic conditions of the stomach, nitrite generates NO-related species that form S-nitrosothiols. Conversely, drugs that increase gastric pH may impair the gastric formation of S-nitrosothiols, which may mediate antihypertensive effects of oral nitrite or nitrate. Therefore, it is now becoming clear that promoting gastric formation of S-nitrosothiols may result in effective antihypertensive responses, and this mechanism opens a window of opportunity in the therapy of hypertension. In this review, we discuss the recent studies supporting the gastric generation of S-nitrosothiols as a potential antihypertensive mechanism of oral nitrite. We also highlight some drugs that increase S-nitrosothiols bioavailability, which may also improve the responses to nitrite/nitrate therapy. This new approach may result in increased nitrosation of critical pharmacological receptors and enzymes involved in the pathogenesis of hypertension, which tend to respond less to their activators resulting in lower blood pressure.

Impact of nitrate therapy on the expression of caveolin-1 and its phosphorylated isoform in lungs in the model of monocrotaline induced pulmonary hypertension

Aim: Nitric oxide signalling pathway showed to be one of the crucial factors in the treatment and pathogenesis of pulmonary arterial hypertension. The aim of this study was to determine the effect of administration of inorganic nitrate, NaNO3, on the expression of caveolin-1 and its phosphorylated isoform (pTyr14Cav-1) in lungs in the experimental model of monocrotaline induced pulmonary hypertension. Methods: 10 weeks old male Wistar rats were subcutaneously injected with 60 mg/kg dose of monocrotaline (MCT) or vehicle (CON). Twelve days after the injection, part of the MCT group was receiving 0.3 mM NaNO3 (MCT+N0.3) daily in the drinking water and rest was receiving 0.08% NaCl solution. Four weeks after MCT administration, the rats were sacrificed in CO2. Protein expression in lungs was determined by western blot. Results: We observed a significant decrease in the caveolin-1 expression and a significant shift towards the expression of pTyr14Cav-1 in the group treated with nitrate (p < 0.05). Conclusion: NaNO3 administration affected the expression of caveolin-1 and the ratio of its active (phosphorylated) isoform increased.

HFrEF pharmacological treatment: hydralazine and isosorbide dinitrate

The use of hydralazine and isosorbide dinitrate in combination with renin–angiotensin blockade and evidence-based beta-blocker therapy is an accepted therapy for heart failure with reduced ejection fraction (HFrEF). However, differing assessments of the evidence base and the strength of recommendation are noted between the heart failure guideline writing committees in America and Europe, so much so that this may the largest digression of opinion between the two august groups. Three randomized clinical trials in the United States provide the cornerstone evidence for use of hydralazine and nitrates in selected patients with HFrEF. The explanation of the potential mechanism of action for combination hydralazine and nitrate therapy in certain HFrEF populations has shifted from a haemodynamic to a neurohormonal model based on better understanding of the role of nitric oxide and oxidative stress imbalances in the pathogenesis of HFrEF. The differing professional interpretations of the data and the unique cohort studied most avidly (i.e. those of African descent), have resulted in unusually low use of this regimen despite evident salutary benefits. Moreover, the available preparation requires thrice-daily dosing and important side effects limit its tolerability. The future of hydralazine and isosorbide dinitrate use in patients with HFrEF will be informed by ongoing research allowing for more precise alignment of treatment and response. Even more so, further research to explore how best to modulate nitric oxide in cardiovascular disease including the application of pharmacogenomics may expose new therapeutic directions in the treatment of heart failure.