 |
|
 |
 |
| |
|
|
| |
| Hypertension research- past, future, and beyond. |
 |
by Nitin Aggarwal, M.Pharm., Ph.D. - December 19, 2011
|
Hypertension is a complex disease, which can be associated with several comorbidities (called secondary hypertension) and may exist alone without any known cause (called essential hypertension). Various systems contribute towards regulation of hypertension such as the renin-angiotensin system, the heart, the blood vessels and its endothelium derived vasodilators, the sympathetic and parasympathetic tone, the electrolyte concentrations in blood, and the blood volume regulation by the kidneys. A number of therapeutic approaches targeting these systems are available to ameliorate hypertension such as reducing the blood volume by the use of diuretics, and reducing the cardiac contractility by using b-blockers. However, these approaches can only provide symptomatic relief of hypertension and can-not cure the primary cause. As it was mentioned earlier, for most of the (95%) of hypertension cases the primary cause is unknown anyways. Therefore, for a long time, the primary cause of hypertension has been a focus of research by academic and industry scientist with only marginal success so far. However, considerable strides have been made in the past 25-30 years with the description of endothelium and its role in hypertension. This is one of the hot subjects of research these days and; although, not many scientist are involved, it is a promising approach.
The endothelium consists of a single layer of cells on the luminal surface of all vessels of the vascular system. Initially, it was thought that the endothelium functioned only as an antithrombotic surface to prevent aggregation of blood products and as a barrier to prevent exchange of molecules between plasma and tissue. Early in 1976 John Vane and his team had already established that cyclooxygenase (COX) in the blood vessels cels (including endothelium), synthesizes several prostanoids that may relax or contract the blood vessels to control the blood pressure. In 1979, Robert Furchgott reported the critical role of endothelium in regulating the vascular relaxations and thus regulating blood pressure. After this discovery, it became apparent that the endothelium synthesizes several molecules that regulate the relaxing and contractile state of vascular smooth muscles. In late eighties, Luois Ignarro proposed that nitric oxide (NO), which is a potent mediator of vascular relaxations, is an endothelial derived relaxing factor. This research was furthered by Furchgott, and Fareed Murad to show that NO indeed is a potent vasodilator in humans, bioavailability of which can be regulated to control blood pressure, arterial diameter, and thus blood supply to the heart. Together these two discoveries form one of the basis of hypertension therapy in todays world. Needless to say that we have had drugs such as VioxxTM (a COX inhibitor) and nitroglycerine preparations (nitric oxide therapy) that are widely used to regulate blood pressure and to restore blood supply in angina by dilating the blood vessels. For their vital contribution, John Vane received the Nobel prize in 1982, and Furchgott, Ignarro, and Murad, received Nobel prize in 1995. Research thereafter suggested that, such non-prostaglandin endothelium dependent relaxations of isolated arteries are also caused by other agonists such as A23187, bradykinin, substance P, adenosine triphosphate (ATP), adenosine diphosphate, uridine triphosphate, vasopressin, and histamine, or shear stress. However, the ability of these agents to cause relaxations differed in various arteries from various species indicating that a single compound or mechanism is not responsible for the relaxations. After several years of research and numerous important discoveries, it is now widely accepted that (i) endothelium synthesizes and releases a number of factor that relax vessels and, (ii) there are more than one such factors that cause relaxations and these factors may work by different pathways. These substances that are synthesized in the endothelium and cause relaxations upon release are called endothelium-derived relaxing factors (EDRFs).
In his first paper Furchgott did report that there is a third mediator, apart from NO and prostacyclin, from the endothelium that also regulates blood pressure, and that it is possibly a Lipoxygenase (LO) derived molecule. Years of research on this third pathway summarized that agonists such as acetylcholine, act on the muscarinic receptor of the endothelium, activate a reaction sequence in which arachidonic acid (a fatty acid present in all the cells) is liberated and then oxidized by LO to a product that is responsible for the relaxations of vascular smooth muscle cells. These findings were the first to indicate the role of LO metabolites in vasorelaxations. In the studies by Weston and coworkers, it was revealed that a group of endogenous factor, distinct from NO and prostacyclin, is also released from the endothelium, which causes hyperpolarization in the vascular smooth muscle cells. This factor was termed as endothelium-derived hyperpolarizing factor (EDHF; notice the difference between EDRF and EDHF). The smooth muscle cells hyperpolarization by EDHF causes decreased intracellular Ca+2 through closure of voltage-operated Ca+2 channels in the membranes and this leads to the relaxations. However, various EDHFs, their synthesis and release from endothelium, and mechanism by which they cause vascular smooth muscle cells hyperpolarization is still under investigation. The major factors currently being considered to explain EDHF relaxations are (i) the monovalent cation K+, (ii) gap junctions, (iii) hydrogen peroxide (iv) C-type natriuretic peptide (CNP), and (v) arachidonic acid-metabolites.
With regards to LO recently William Campbell and Nitin Aggarwal have collectively published several reports describing the role of arachidonic acid metabolites by 15-LO-1 (an isoform that is predominantly expressed in the endothelium) that regulate the vascular relaxations and thus blood pressure. Various lipoxygenases initiate the production of diverse products from arachidonic acid such as leukotrienes (LT), hydroxyeicosatetraenoic acid (HETEs), lipoxins (LX), hepoxilins (HX), trihydroxyeicosatrienoic acid (THETA) and hydroxyepoxyeicosatrienoic acid (HEETAs). Extensive studies, which include genetic animal models and various pharmacological compounds, by Campbell and Aggarwal indicated that THETA and HEETA from 15-LO-1 pathway mediate NO and prostacyclin resistant relaxations and that THETA and HEETA are actually one of the EDHF. They have also reported that in diseases such as hypercholesterolemia and hypoxia 15-LO-1 expression increases as a protective mechanism to regulate the blood pressure, and with age the expression decreases that might be responsible for increasing blood pressure with aging. Further, investigations are under way to find a receptor of these EDHFs (THETA and HEETA) and potentially find a molecule that could mimic the effect of TEHTA and HEETA to regulate hypertension. Although, the studies are in very basic stages and are still preclinical the potential of these studies are very promising. Interest in vascular lipoxygenases has been increasing as a potential cure for essential hypertension that actually needs attention for the 95% of the total hypertensive population. Besides the lipoxygenase metabolites another groups of endothelium derived vasodilating compounds called EETs (epoxyeicosatrienoic acids) have made considerable progress. So much so that the pharmaceutical companies are developing the epoxide hydrolase (enzyme that degrade EETs) inhibitors as potential therapeutic hypertensive drugs.
The future is ahead for the cure of essential hypertension but leaders in research agree that there is a lot of work to be done to take lipoxygenases and epoxide hydrolase based therapy to the clinics. Nevertheless, current success in research pertaining to the endothelium and its ability to synthesize anti-hypertensive molecules provide hope for a promising future.
Dr. Nitin Aggarwal is a Pharmacist and PhD is Pharmacology and Toxicology. He has been in cardiovascular pharmacology research for sometime and has contributed significantly to understanding the some of the basic cardiovascular science. His main research focus is in hypertension, cardiac failure, and myocardial Ischemia. With his clinical and basic science experience he has extensively contributed to several peer reviewed scientific Journals as an author, reviewer, and an editor.
The viewpoint expressed in this article is the opinion of the author and is not necessarily the viewpoint of the owners or employees at Healthcare Staffing Innovations, LLC.
RECOMMEND THIS ARTICLE
You must be logged in
to recommend articles
|
|
|
|
| |
|
|
 |
 |
|
 |
 |
 |
|
