Current Medicinal Chemistry - Cardiovascular & Hematological Agents - Volume 3, Issue 1, 2005

Bloodfeeding (hematophagous) parasites have evolved effective means of inhibiting mammalian thrombosis, thereby facilitating the acquisition and digestion of a bloodmeal. To date, specific inhibitors of coagulation and platelet function have been identified from numerous invertebrate species, representing an impressive array of convergent functional strategies. These parasite antithrombotics, in addition to playing a critical role in the diseases caused or transmitted by bloodfeeding invertebrates, may also serve as potentially useful therapeutic agents for the treatment of a variety of conditions associated with activation of thrombosis. A number of naturally occurring anticoagulants and platelet inhibitors have been evaluated in vivo, with some currently in varying stages of preclinical and clinical development. Because of the unique specificity and potency of parasite antithrombotics, these invertebrate natural products hold great promise for improving the treatment of a variety of human illnesses, including heart disease, stroke, and cancer.

The Natriuretic Peptide (NP) family, especially its best-characterized member Atrial Natriuretic Peptide (ANP), plays an important role in the regulation of blood pressure homeostasis and salt and water balance. Besides their action in cardiovascular physiology, NPs have been described as anti-inflammatory regulators of macrophage function: they have been reported to inhibit the induction of inflammatory mediators, such as iNOS, COX-2, and TNF-α. In the following review we will focus on a rather novel aspect of NP action: NPs, especially ANP, will be presented as vasoprotective agents. We will specifically focus on ANP's interaction with the complex intracellular signalling networks responsible for proliferation, vascular permeability, attraction and adhesion of leukocytes, and the induction of cytoprotective proteins. We will also discuss the critical mediator systems involved in mediating ANP's benefical actions. Recently, ANP as well as BNP, another member of the NP family, have been introduced as cardiovascular therapeutics. In this context, we will highlight the physiological and pharmacological relevance of NPs, particularly ANP, as endogenous vasoprotective agents.

The renin-angiotensin system is a key target for drugs combating cardiovascular disease. Angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor type-1 (AT1 receptor) blockers are well known. However, angiotensin peptides can be generated through a number of pathways besides the classic system. This review outlines some of these pathways, their relation to the classic system and the likely effect of inhibiting them. Renin is still the key enzyme in angiotensin peptide generation and seems to be the only route to angiotensin I formation in vivo. Renin inhibitors may have some advantages in terms of specificity. Also, by blocking angiotensin I generation, the production of downstream bioactive angiotensin I metabolites should also be blocked. Chymase, a mast cell serine protease, cleaves angiotensin I to produce angiotensin II and may be important at sites of inflammation such as atherosclerotic plaque. Angiotensin-converting enzyme 2 (ACE2), a carboxypeptidase structurally related to ACE but resistant to ACE inhibitors, has a protective effect on cardiac function. Neutral endopeptidase 24.11 breaks down both atrial natriuretic peptide and angiotensin II. Inhibiting it potentiates the action of endogenous atrial peptide but only affects circulating angiotensin II when basal levels are above normal. Dual inhibitors of ACE and endopeptidase 24.11 may be of value where there is both sodium retention and increased angiotensin II. Targeting the renin-angiotensin system by gene therapy or antibody treatment may provide a longer-term treatment for hypertension.

Bradykinin and Lys-bradykinin are potent peptide mediators implicated in several physiopathological effects in mammals. They act through activation of G-protein-coupled constitutive B2 or inducible kinin B1 receptors linked to signaling pathways involving increased intracellular Ca++ concentrations and / or release of mediators including arachidonic acid metabolites, NO and EDHF. In the cardiovascular system, the kallikrein-kinin system exerts a fine control of vascular smooth muscle tone and arterial blood pressure, and plays a significant cardioprotective effect. This has been lately confirmed in experimental studies employing transgenic mice overexpressing human tissue kallikrein and animals with knockout of kinin B1 and B2 receptor gene. Disturbances in this system are associated with arterial hypertension, myocardial ischaemia and other clinical complications. Inhibitors of kininase II (angiotensin-converting enzyme) have been prescribed successfully to patients with cardiovascular diseases, but there is still a great interest in developing drugs or pharmacological strategies that augment the activity of kininogen-kallikrein-kinin system in pathological conditions. Delivery of adenovirus vector containing the human tissue kallikrein gene (gene kallikrein therapy) has emerged as a great potential to satisfy these conditions. This review provides a summary of plasma and tissue kallikrein-kinin system, focusing on the pharmacological properties, kinin receptors and drugs reported to interfere with their actions. The modulatory effects of the kallikrein-kinin system on cardiovascular system, particularly in regulating smooth muscle tone and arterial blood pressure and in preventing myocardium ischaemia have also been explored in the review.

Many women receiving hormone replacement therapy (HRT) smoke; in the Women's Health Initiative (WHI), one of the largest interventional studies on HRT to date and which recently had to be discontinued, 50% of the 8,500 women on HRT had smoked before or continued to smoke during the study. Remarkably, there is little knowledge about the impact smoking has on the efficacy and side effects of HRT. However, it has been proven that, depending on the type, duration and intensity of nicotine consumption, smoking can reduce or completely cancel the efficacy of orally administered estrogens. Not only does smoking diminish the otherwise well-established beneficial effects of estrogen on hot flashes and urogenital symptoms and its positive effects on lipid metabolism, i.e. by reducing cholesterol, but smoking also specifically reduces estrogen's ability to prevent osteoporosis. The reduction or loss of therapeutic efficacy is mainly caused by dose-dependent elevated hepatic clearance, partially in conjunction with lower estrogen levels, and has been demonstrated only with oral estrogen applications. This failure of therapeutic action should not be compensated for by increasing the dose in smokers as this might result in the production of toxic, even potentially mutagenic estrogen metabolites - compounds recently associated with a higher risk of breast cancer. The favorable effects of estrogens are not lost in smokers when they are applied transdermally. This route enables low dosage and also avoids the formation of unphysiological metabolites by bypassing the liver. Women who continue to smoke despite all warnings should therefore only be treated via the transdermal route. Oral contraceptives, but not HRT, are contraindicated in elderly smokers. However, the principal conclusion of the WHI study was that the lowest dose possible should be chosen, especially in patients with an increased cardiovascular risk, as is the case in smokers.

Recently published guidelines recognize the relevance of the development of chronic kidney disease in the stratification of risk of the hypertensive patient. Adequate assessment of renal function, including estimation of glomerular filtration rate, is mandatory in order to ensure an adequate evaluation of global cardiovascular risk in the hypertensive patient. The presence of subtle elevations of serum creatinine concentrations is a potent predictor of a poor cardiovascular prognosis. Clustering of associated risk factors seems to justify the elevated cardiovascular risk observed in patients with essential hypertension and mild renal function derangement. Chronic kidney disease is associated with a significant increase in cardiovascular risk attributable to the simultaneous existence of other risk factors related to the metabolic syndrome. The inhibition of the effects of angiotensin II is necessary to ensure the best degree of renal protection. It has demonstrated to improve the long-term renal outcome of patients with nephrosclerosis and to reduce the appearance of cardiovascular complications in high risk patients The high prevalence of chronic kidney disease in the general and in the hypertensive populations forces the recognition of its relevance and the need for an integrative therapeutic approach to protect simultaneously renal and cardiovascular systems.

Angiotensin II plays a significant role in cell growth and proliferation in model systems and in humans. Numerous studies have shown that left ventricular hypertrophy (LVH) increases the risk of coronary heart disease, congestive heart failure, stroke or transient ischemic attack; all-cause deaths, and sudden death. The use of angiotensinconverting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has provided beneficial effects on LVH regression and on cardiac remodeling in the presence of hypertension and heart failure. The new class of ARBs appears to provide cardioprotective effects that are similar to those of the ACE inhibitors. Most of the beneficial effects provided by these agents appear to be related to a more complete blockade of the angiotensin II type 1 (AT1) receptor. However, costimulation of the angiotensin II type 2 (AT2) receptor appears to increase nitric oxide and thus causes some bradykinin-like effects. Evidence for the role of angiotensin II in promoting LVH as well as abnormal regulation of the angiotensin II signal transduction pathways in model systems and in humans has been reviewed. Secondly, the mechanisms for the beneficial effects of angiotensin II receptor blockers studied in model systems and in humans, including possible involvement in the formation of reactive oxygen species by mononuclear cells, are presented. Finally, results from large-scale interventions such as the Losartan Intervention For Endpoint reduction (LIFE) study, as well as an overview of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial involving the use of ARB in highrisk patients, are presented.

Dopamine plays an important role in the pathogenesis of hypertension by regulating epithelial sodium transport and reactive oxygen and by interacting with vasopressin, renin-angiotensin, and the sympathetic nervous system. Decreased renal dopamine production and / or impaired dopamine receptor function have been reported in hypertension. Disruption of any of the dopamine receptors (D1, D2, D3, D4, and D5) results in hypertension. In this paper, we review the mechanisms by which hypertension develops when dopamine receptor function is perturbed.