Current Vascular Pharmacology - Volume 4, Issue 2, 2006

The oral phosphodiesterase type 5 (PDE5) inhibitors have made a valuable contribution to the treatment of erectile dysfunction (ED). PDE5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, PDE5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of PDE5 inhibitor failure. Tachyphylaxis may also occur. This is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug. Treatment failure may cause considerable distress. If dose titration, more attempts and continuous dosing of PDE5 inhibitors (taken on a daily basis) fail to resolve the initial PDE5 inhibitor failure, clinicians need to consider alternative treatments. These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery. Combination therapy like prostaglandin E1 (PGE1) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT2 antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/ losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide (NO) donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low. The early use of PDE5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of PDE5 inhibitors may be maintained. Targeting the risk factors of ED (similar to those for arteriosclerosis) in the early stages of the disease may prevent the development or decrease the severity of ED.

Angiographic no reflow is a recognized phenomenon during percutaneous coronary intervention (PCI). It usually follows successful lesion dilation and, by definition, it represents a reduction in epicardial coronary blood flow in the absence of identifiable dissection, obstruction or distal vessel cut off (indicative of distal embolisation). No reflow appears to be more commonly associated with PCI for acute myocardial infarction and PCI for saphenous vein graft occlusions. While the exact mechanism of no reflow is unknown, theoretical causes include local humoral and microembolic effects leading to microcirculatory dysfunction. As the process is multifactorial, various therapeutic strategies are required in different situations. The present day pharmacological management involves the use of vasodilators including nitrates, verapamil, papaverine, adenosine, nicardipine and sodium nitroprusside, but interestingly a vasoconstrictor like epinephrine may also have a role. Glycoprotein IIb/IIIa platelet receptors antagonist have shown a powerful de-thrombotic effect, and the intracoronary administration appears to be particularly promising. We review the pathogenesis of a reduced epicardial flow during PCI and focus on those drugs that have been studied for the treatment of no reflow. Although no double blind, randomized trial has been conducted to assess any of these agents, or to determine the appropriate dosage, we try to identify some useful conclusions from the published evidence.

Vascular diseases, such as atherosclerosis, thromboembolic disorders and stroke, in addition to surgical procedures such as restenosis, all share the plasminogen activator system as a central component in the pathogenesis of vascular injury. Since the development of plasminogen deficient mice our knowledge of the effects of this proteolytic system in cardiovascular disease has vastly increased. The plasminogen activator system plays a key role in vascular homeostasis and constitutes a critical response mechanism to cardiovascular injury. The central components of the PA system are the proteolytic activators, urokinase-plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA), plasminogen (plg) and its degradation product, plasmin, together with the major inhibitors of this system, plasminogen activator inhibitor- 1 and -2 (PAI-1, PAI-2). An extensive network of additional proteases, inhibitors, receptors and modulators directly associate and are influenced by the PA system, the largest group being the Matrix Metalloproteinases (MMPs) and their respective inhibitors the Tissue inhibitors of MMPs (TIMPS).

Migraine is characterized by attacks of intense pulsatile and throbbing headache, typically unilateral in nature with or without aura. Migraine affects a substantial fraction (10-20 %) of the world population (more women than men). With regard to the pathophysiology of migraine, several theories have been proposed; the major three are vascular (due to cerebral vasodilatation), neurological (abnormal neurological firing) and neurogenic dural inflammation (release of inflammatory neuropeptides). The drugs used to treat migraine can be divided into two groups: agents that abolish the acute migraine headache and agents aimed at prevention. The acutely acting antimigraine agents (5-HT1B/1D receptor agonists) stimulated research interest in the field of migraine. Currently prophylactic treatments for migraine include calcium channel blockers, 5-HT2 receptor antagonists, beta-adrenoceptor blockers and γ-amino butyric acid (GABA) agonists. Unfortunately, many of these treatments are non-specific and not always effective. Despite progress, the complex etiology of migraine requires further research, the condition often remains undiagnosed and available therapies are underused. In this review, the evidence that linked the different theories of migraine with its pathophysiology is considered. Furthermore, the present therapeutic targets and future approaches for the acute and prophylactic treatment of migraine are critically evaluated.

Aortic aneurysms account for 10,000 deaths annually in the UK, due to rupture. At present the only effective therapeutic strategy to treat abdominal aortic aneurysms is to surgically repair them; this carries an elective mortality of up to 10%. Recent advances in vascular biology have led to a greater understanding of the pathophysiological process that causes aortic aneurysms to expand and rupture. Key pathological processes include widespread aortic inflammation, proteolytic degradation of the extracellular matrix, neovascularisation and generation of reactive oxygen species. Identification of these processes has lead to pharmacological strategies to prevent aneurysm expansion and rupture. Many of these strategies have undergone proof of concept in animal models and some have now entered clinical trials. This review outlines current thinking regarding the molecular events leading to aneurysm expansion and explains how these processes may be inhibited. Experimental data on agents retarding aneurysm expansion in animal models are discussed. A significant proportion of the review details pharmacological agents that have undergone or are undergoing clinical trials. Pharmacological treatment for abdominal aneurysms is urgently required given the number of small aneurysms being diagnosed by screening programmes. This is a rapidly evolving field and one in which translation from experimental research to clinical practice is anticipated within 5 years.

The accumulation of sphingolipids, including sphingomyelin and glycosphingolipids, in atherosclerotic lesions is well known. Plasma sphingomyelin concentration is correlated with atherosclerosis development and is an independent predictor of coronary artery disease. Similarly, plasma glycosphingolipid levels are increased in conditions associated with atherosclerosis risk. Recent studies have focused on understanding the mechanisms by which specific intermediates and end-products of the sphingolipid biosynthetic pathway, such as sphingomyelin, glycosphingolipids, ceramide and sphingosine-1-phosphate may modulate vascular biology and atherosclerosis. Here we focus on recent work indicating that pharmacological modulation of the sphingolipid biosynthetic pathway could offer a novel treatment for atherosclerosis or, at the very least, provide mechanistic insights concerning the eitiology of this disease which is the major cause of death in developed countries.

Control of hypertension is well established for the primary prevention of stroke. Prior studies, on the other hand, conflict over whether hypertension remains a risk factor for recurrent stroke and if blood pressure reduction is associated with better outcomes in this subset of patients. We review current evidence regarding the role of BP lowering for primary and secondary prevention of stroke. Current evidence amassed from both primary and secondary prevention trials demonstrate that BP reduction is a crucial common element in overall reduction of stroke risk.

Postprandial hypotension is a frequent disorder, occurring in ∼ 40% of nursing-home residents, and represents a major cause of morbidity and mortality. Current approaches to management are suboptimal. While it has been generally assumed that ingestion of carbohydrate has the greatest effect, the fall in blood pressure (BP) does not appear to be mediated by the consequent elevations in blood glucose and insulin. Moreover, there is evidence that fat may decrease BP to a comparable extent to carbohydrate, although onset of the response may be slower, and that the response is affected by the type of carbohydrate. It has recently been established that the rate of nutrient delivery from the stomach into the small intestine is an important determinant of the hypotensive response to carbohydrate, so that the magnitude of the fall in BP and rise in heart rate is greater when gastric emptying is relatively more rapid. In both healthy elderly subjects and patients with type 2 diabetes, the fall in BP is attenuated when gastric emptying and small intestinal carbohydrate absorption are slowed by dietary (e.g. guar) or pharmacological (e.g. acarbose) means. Conversely, gastric distension attenuates the postprandial fall in BP. Strategies for the treatment of postprandial hypotension should, therefore, potentially be directed at (i) meal composition, particularly carbohydrate type and content, (ii) slowing gastric emptying and/or small intestinal carbohydrate absorption and/or (iii) increasing postprandial gastric distension.