Do nitric oxide-releasing drugs offer a potentially new paradigm for the management of cardiovascular risks in diabetes?

Abstract

Cardiovascular complications are frequently observed in diabetic patients and are mostly caused by endothelial dysfunction associated with a decline in biosynthesis of nitric oxide (NO). In response to this concern, a remarkable increase in the interest for development of NO-releasing hybrid drugs has been observed. The NO-donating entity was linked to known drugs with the belief that NO is a vasorelaxant and an inhibitor of platelet aggregation or reduces thrombotic events. Many of these NO-releasing hybrid drugs have shown significant improvement in cardiovascular safety. In this editorial the potential roles of NO-releasing drugs for the treatment of cardiovascular complications in diabetes will be discussed.

Keywords::

• cardiovascular complications
• diabetes
• endothelial dysfunction
• nitric oxide
• nitric oxide releasing drugs

Diabetes mellitus (DM) is a metabolic disease that affects about 347 million individuals worldwide. This number is expected to increase by more than 50% in the next 10 years. Approximately 5–10% of diabetics have Type 1 (insulin-dependent) and 90–95% have Type 2 (non-insulin-dependent) DM. A number of life-threatening complications are often associated with DM, making it a complex disease. In this regard, DM is most frequently accompanied by micro- and macrovascular diseases caused by endothelial dysfunction that is associated with a diminished biosynthesis of nitric oxide (NO) in endothelial cells [1–4]. The negative impact of endothelial dysfunction in diabetic patients results in the development of high blood pressure (hypertension) in conjunction with other adverse cardiovascular complications. For example, numerous studies suggest that diabetic patients with elevated blood pressure are at high risk to blood vessel damage, stroke, heart failure, heart attack or kidney failure [5]. All these implications add additional burden to the diabetes patient that requires a multi-drug treatment regimen. For example, diabetic patients using anti-diabetic drugs (e.g., sulfonylureas, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, meglitinides) regularly require drugs to treat hypertension (angiotensin-converting enzyme inhibitors, calcium channel blockers, sartans, vasodilators) and dyslipidemia (statins, fibrates, niacin/nicotinic acid) [6–8] Consequently, numerous multi-target drugs (pharmacodynamic hybrids) have been investigated in recent years as an alternative to the traditional ‘one drug–one target’ model, and numerous multi-target drugs (pharmacodynamic hybrids) have been discovered [9–11]. These pharmacodynamic hybrid compounds were rationally designed with the expectation that a single drug molecule would modulate manifold targets concurrently. In comparison to the administration of multiple drug cocktails, the use of a single multi-target drug offers potential advantages that include a lower risk of drug–drug interactions, easier monitoring of pharmacokinetic/pharmacodynamic relationships and enhanced efficacy and safety profiles [9,12]. In view of the beneficial properties of NO and frequent occurrence of cardiovascular complications during DM, it is our hope that this brief article will attract the attention of medicinal chemists and aid in the development of new NO-releasing hybrid chemical entities with superior cardiovascular efficacy and safety profiles.

The free radical NO, for many years, has continued to surprise medicinal chemists, pharmacologists and physicians where its pharmacological effects have been labeled as both hero and villain. For example, in biological systems, NO exerts special beneficial effects in low concentrations while being damaging at higher concentrations [13,14]. The discovery that the ‘NO molecule’ is involved in numerous bioregulatory pathways resulted in it achieving status as a molecule of great interest. Accordingly, NO was proclaimed ‘Molecule of the Year’ in 1992. In 1998, the importance of NO was underscored by the award of the Nobel Prize to three outstanding cardiovascular investigators Robert Furchgott, Louis Ignarro and Ferid Murad.

In the scientific literature, there are more than 85,000 publications reporting on NO. Today, attention is mostly focused on various NO-mediated pharmacological applications to lower the incidence of adverse drug effects, particularly for the management of thrombotic events, myocardial infarctions and strokes.

NO, collectively with H₂S and CO, belongs to a family of endogenous low-molecular-weight gaseous molecules which are also termed as gasotransmitters. NO is one of the most prevalent signaling molecules in mammalian biology. NO carries out various biological tasks due to its rapid passage across cell membranes. Endogenous NO plays an imperative role in regulation of blood flow by means of vascular smooth muscle relaxation (blood vessel relaxation and vasodilation). NO reduces the risk of blood clot formation (thrombosis) by inhibiting platelet aggregation and adhesion; and it is also known to participate in neurotransmission, muscle contraction, leukocyte adhesion and angiogenesis [13,14]. Under normal conditions, endothelial cells constitutively biosynthesize endogenous metastable free radical NO by oxidizing the guanidine group in L-arginine [15] This firmly controlled process involves the participation of three specialized isoforms of NO synthases (NOSs). Two isoforms are constitutively expressed (cNOS), and one is an inducible isoform (iNOS). All enzymes are named according to their site of action or tissue type in which they were first expressed. Endothelial (eNOS or NOS3 or cNOS) and neuronal (nNOS or NOS1) NOSs are constitutively expressed and biosynthesize NO in response to an increased level of calcium. NO produced via nNOS and eNOS isoenzymes is lower in concentration and is usually associated with physiological functions. In contrast, inducible isoforms (iNOS or NOS2) are expressed in response to stress or inflammatory mediators, and they are calcium-independent [16,17].

Endogenous release of NO by the endothelium plays a crucial role in the regulation of vascular functions, which include homeostasis between vasodilation and vasoconstriction, thrombogenesis and fibrinolysis, immunological reactions and penile erection [14]. It is common knowledge that endothelium-derived relaxing factor, the regulatory agent found in the endothelium, was in fact NO. The discovery of its biosynthetic pathway opened new therapeutic avenues for a better understanding of various cardiovascular complications and their possible prevention.

Endothelial dysfunction is a pathological state which is associated with a decline in biosynthesis or bioavailability of the beneficial vasodilator NO. Endothelial dysfunction has been shown to occur in many disorders, including DM [1,18]. However, it has also been observed that patients with diabetic or prediabetic conditions, such as impaired fasting glucose and impaired glucose tolerance, are at increased risk of endothelial dysfunction. When endothelial dysfunction is operative, there is a higher probability of platelet adhesion and aggregation compared to normal endothelial function, and arteries become unable to dilate properly. Hence, endothelial dysfunction represents a strong predictor for adverse cardiovascular complications and related fatalities. Therefore, enhancement of the availability of NO, or recovery from a state of endothelial dysfunction, represents an attractive strategy for the treatment of cardiovascular complications in diabetic or other patients. In this regard, several classes of structurally and chemically diverse NO-releasing drug candidates were designed for biological investigation. These NO-releasing drug candidates include NO-angiotensin-converting enzyme inhibitors, NO-non-steroidal anti-inflammatory drugs and NO-antidiabetic drugs [10,11,19,20]. Accumulating evidence indicates that a decline in the production of endogenous NO can be counterbalanced by the administration of exogenous NO through NO-releasing drugs.

In contrast to other disease states, only a few reports are known where this strategy has been implemented for lowering cardiovascular complications in diabetic patients [20,21]. In our recent report, the commercial Type 2 anti-diabetic drugs nateglinide and meglitinide were elaborated into hybrid ‘NO-releasing anti-diabetic’ prodrugs [20]. The main conclusions from this study [20] were that these novel hybrid NO-donor analogues of nateglinide and meglitinide simultaneously improved anti-diabetic potency; induced a hypotensive effect (decrease in blood pressure) and provided vascular relaxation due to the endogenous release of NO. In a similar type of study, a group of NO-glibenclamide prototypical derivatives was reported. In this case, the hybrid drug exhibited both hypoglycemic effects and vasorelaxing effects [21]. Hence, positive preliminary findings provided by these studies support the belief that a slow release of NO from hybrid NO-releasing antidiabetic drug can sufficiently deliver NO to circumvent the endogenous NO deficiency (endothelial dysfunction) in diabetic patients. Furthermore, with respect to diabetes, it has been postulated that a low-level production of NO from β-cells by the cNOS isoform contributes to the regulation of insulin release. There are several reports which support the hypothesis that L-arginine-derived NO mediates the release of insulin, or that inhibition of NOSs produces an inhibitory effect on insulin secretion [22]. Several reports indicated that both NO and NO donors exert beneficial actions in DM. For example, it was demonstrated that oral administration of L-arginine (precursor of NO) can increase insulin secretion and reduce hyperglycemia [23]. Nevertheless, there are also research reports discussing contradicting results related to NO release and insulin secretions. According to these reports, depletion of NOS expression resulted in a stimulatory [24] or no effect [25] upon insulin release.

The outcomes of these preliminary studies and other research work on diabetes have demonstrated the possibility that release of NO from anti-diabetic drugs may help to restore NO bioavailability, and therefore has the potential to improve the clinical status of diabetic patients.

In conclusion, during the last decade, various ‘NO-releasing pharmacodynamic hybrid drugs’ have generated great interest in the scientific community. It can be expected that future developments will include more new NO-donating drugs for lowering cardiovascular morbidity and mortality in patients with diabetes. However, long-term clinical studies with this type of drugs, including short- and long-term toxicity assessment, are still pending. In this regard, the use of NO donors possesses some potential theoretical pitfalls in abrogating endothelial dysfunction in diabetics since they are unlikely to mimic the physiological temporospatial regulation of NO, and that excess NO may react with endogenous ROS to form other toxic-free radicals, such as peroxynitrite. Therefore, a conclusive answer on the risk/benefit profile of NO/NO-releasing hybrid drugs cannot be given yet. The discussion is at an early stage, and more data are needed to unveil additional physiological and pharmacological aspects to validate the application of NO/NO-releasing hybrid drugs. This will ultimately lead to a better understanding of mechanisms related to endogenous and exogenous NO release.

Financial & competing interests disclosure

The authors were supported by the Dianne and Irving Kipnes Foundation and the Canadian Institutes of Health Research (Grant no. MOP-14712 to E.E.K.). J Kaur and F Wuest thank the Alberta Cancer Foundation for a postdoctoral fellowship. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.