LETTERS to the EDITOR

L-arginine-induced hypotension

Blood pressure (BP) and the incidence and severity of hypertension are affected by the intake of many nutrients as well as the person’s nutritional status, and particularly the presence or absence of obesity. Excessive energy intake and obesity are major causes of hypertension. Obesity is associated with alterations of many physiological processes that promote hypertension. These include increased activity of the renin–angiotensin–aldosterone and sympathetic nervous systems, probably increased activity of other mineralocorticoids, insulin resistance, salt-sensitive hypertension, excessive intake of sodium and chloride, and kidney disease that can reduce the glomerular filtration rate. High sodium chloride intake also strongly predisposes to hypertension. Excessive imbibing of ethyl alcohol may acutely elevate BP. On the other hand, higher intakes of potassium, polyunsaturated fatty acids, protein, and possibly vitamin D and physical exercise may lower BP. Other studies, of a less conclusive nature, suggest that certain amino acids, tea, green coffee bean extract, dark chocolate, and foods high in nitrates may reduce BP. Short-term studies indicate that specialized diets may prevent or ameliorate mild hypertension, most notably the dietary approaches to stop hypertension (DASH) diet, which is high in fruits, vegetables, and low-fat dairy products and the DASH low-sodium diet, which may lower BP even further. The Mediterranean diet is also reported to lower BP. This diet consists mainly of vegetables, fresh fruit, whole grains, fish and other kinds of seafood, legumes, nuts, olive oil, and red wine. However, long-term adherence to the foregoing diets may not be easy for many people because of food preferences. Growing evidence indicates that for many obese individuals with hypertension, bariatric surgery in association with lifestyle and diet counseling provides a reliable and effective method for reducing their BP.

At the moment, little treatment options are available for Duchenne muscular dystrophy (DMD). The absence of the dystrophin protein leads to a complex cascade of pathogenic events in myofibres, including chronic inflammation and oxidative stress as well as altered metabolism. The attention towards dietary supplements in DMD is rapidly increasing, with the aim to counteract pathology-related alteration in nutrient intake, the consequences of catabolic distress or to enhance the immunological response of patients as nowadays for the COVID-19 pandemic emergency. By definition, supplements do not exert therapeutic actions, although a great confusion may arise in daily life by the improper distinction between supplements and therapeutic compounds. For most supplements, little research has been done and little evidence is available concerning their effects in DMD as well as their preventing actions against infections. Often these are not prescribed by clinicians and patients/caregivers do not discuss the use with their clinical team. Then, little is known about the real extent of supplement use in DMD patients. It is mistakenly assumed that, since compounds are of natural origin, if a supplement is not effective, it will also do no harm. However, supplements can have serious side effects and also have harmful interactions, in terms of reducing efficacy or leading to toxicity, with other therapies. It is therefore pivotal to shed light on this unclear scenario for the sake of patients. This review discusses the supplements mostly used by DMD patients, focusing on their potential toxicity, due to a variety of mechanisms including pharmacodynamic or pharmacokinetic interactions and contaminations, as well as on reports of adverse events. This overview underlines the need for caution in uncontrolled use of dietary supplements in fragile populations such as DMD patients. A culture of appropriate use has to be implemented between clinicians and patients’ groups.

Increased matrix metalloproteinases activity and reduced nitric oxide (NO) bioavailability contributes to development of hypertension and this may be associated with a defective l-arginine-NO pathway. Exogenous l-arginine improves endothelial function to prevent the onset of cardiovascular disease, but the mechanism by which this is accomplished remains unclear. We determined the effects of exogenous l-arginine infusion on vascular biomarkers in patients with hypertension.

Venous blood samples were obtained from seven patients with hypertension (45 ± 5 yrs., HT group) and eleven normotensive men (37 ± 3 yrs., CT group) before and during a 30-min intravenous l-arginine or saline infusion. Nitrite concentration was evaluated by ozone-chemiluminescence method; metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) activities were detected by zymography; tissue inhibitor of metalloproteinases-1 (TIMP-1) and 8-isoprostane concentrations were measured by enzyme-linked immunosorbent assay (ELISA); and thiobarbituric acid reactive substances (TBARS) were determined by colorimetric assay.

At baseline, nitrite, TIMP-1, and MMP-2 activity were similar between the groups (P > 0.05), but MMP-9, TBARS and 8-isoprostane were higher in HT group (P ≤ 0.03). During l-arginine infusion, nitrite increased only in control group (P = 0.01), while MMP-2, MMP-9 activities, MMP-9/TIMP-1 ratio and 8-isoprostane decreased in HT group (P ≤ 0.02). There were no significant changes in vascular biomarkers between groups during the saline infusion (P > 0.05).

Exogenous l-arginine diminished metalloproteinase-2 and -9 activities and MMP-9/TIMP-1 ratio along with restoring the oxidative stress balance in patients with hypertension.

l-arginine administration decreases mean arterial blood pressure (MABP), presumably by excess nitric oxide (NO) synthesis. However, some reports indicate that d-arginine, not a substrate of NO synthase (NOS), also induces hypotension. To clarify this phenomenon, the hemodynamic effects of l- and d-arginine and their modification by NOS inhibition with l-nitroarginine methyl ester (l-NAME) were assessed. MABP, cardiac output, stroke volume, heart rate and systemic vascular resistance were recorded in Sprague-Dawley rats under urethane or ketamine/diazepam anesthesia, with or without blockade of NO synthesis by l-NAME. Both stereoisomers of arginine induced a dose-related drop in MABP of similar magnitude and time course, but recovery from hypotension was slower in l-arginine than in d-arginine. The hypotension induced by both stereoisomers was due to a decrease in systemic vascular resistance (SVR) with increase in cardiac output (CO) and stroke volume (SV). Administration of l-NAME induced a pronounced increase in MABP and SVR, with decreases in CO and heart rate (HR). Infusion of l-arginine after l-NAME significantly decreased MABP and SVR at the highest dose while d-arginine failed to do so. After l-NAME, MABP was significantly lower under l-arginine than under d-arginine at all doses. These experiments suggest a dual mechanism in the hypotensive effect of l-arginine: a NO independent action on vascular resistance shared with d-arginine, and a NO dependent mechanism that becomes evident in the presence of NOS inhibition with l-NAME. Cardiac effects of NO do not appear to play a role in l-arginine hypotension.

Cardiovascular diseases (CVD) are the leading cause of death globally (World Health Organisation, 2011). Many of the risk factors for CVD are modifiable, including overweight and obesity. Numerous strategies have been proposed to fight CVD, with a special focus being placed on dietary interventions for weight management. The literature suggests that two nutrients, fiber and protein, may play significant roles in weight control and hence cardiovascular health. Increasing both protein and fiber in the diet can be difficult because popular low-carbohydrate and high-protein diets tend to have considerably low-fiber intakes (Slavin, 2005). One approach to obtain both is to develop functional foods using unique ingredients. Lupin flour is a novel food ingredient derived from the endosperm of lupin. It contains 40–45% protein, 25–30% fiber, and negligible sugar and starch (Petterson and Crosbie, 1990). Research conducted to date reveals that lupin-enriched foods, which are naturally high in protein and fiber, may have a significant effect on CVD risk factors. This review explores whether there is a role for fiber-, protein-, and lupin-enriched foods in improving cardiovascular health.