Milestones in antihypertensive drug treatment.

Hypertension provoked since the beginning of the 19th century a medical debate between physicians. The early antihypertensive agents were poorly tolerated. Progress towards more effective drugs, appeared after the 2nd World War. Thiocyanates, dehydrogenated alkaloids of ergot, barbiturates, bismuth and bromides, were soon replaced by phenoxbenzamine, hexamethonium, pentolinium, and mecamylamine. Thiazide diuretics were the biggest breakthrough during the early 1960's. Then Beta(ß)-blockers and angiotensin-converting enzyme inhibitors heralded a new era, until 1995, when losartan, the first non-peptide anti-hypertensive drug, was introduced. The plethora of the antihypertensive drugs changed the relationship between physicians and patients, pushed medicine towards prevention, and altered the medical marketing forever.

Synergy between medicinal chemistry and biological research.

Salvador Moncada studied medicine at the University of El Salvador (El Salvador) before coming to the UK in 1971 to work on a PhD with Professor John Vane at the Institute of Basic Medical Sciences, Royal College of Surgeons (UK). After a short period of research at the University of Honduras (Honduras), he joined the Wellcome Research Laboratories (UK) where he became Head of the Department of Prostaglandin Research and later, Director of Research. He returned to academic life in 1996 as founder and director of the Wolfson Institute for Biomedical Research at University College London (UK). Moncada played a role in the discovery of the mechanism of action of aspirin-like drugs and later led the teams which discover prostacyclin and identified nitric oxide as a biological mediator. In his role as a Director of Research of the Wellcome Laboratories, he oversaw the discovery and development of medicines for epilepsy, migraine, malaria and cancer. Currently, he is working on the regulation of cell proliferation as Director of the Institute of Cancer Sciences at the University of Manchester (UK). Moncada has won numerous awards from the international scientific community and in 2010, he received a knighthood from Her Majesty Queen Elizabeth II for his services to science.

[Evolution of treatment options for hypertension].

In the early 20th century hypertension became a medical problem because of the prevalence. The process of clinical research of the etiopathogenesis of hypertension is associated with a scientific and technical progress and state of medical science at every historical stage. The first stage (end of the 19th century--beginning of the 20th (century) was characterised by a research of hypertension and monitoring of its natural history. The second stage (early--mid 20th century) was characterised by attempts to influence on the natural history of hypertension. The basis of the attempts was neurohumoral concept. The third stage (end of 50s--beginning of 70s)--was characterised by the application of angiotensin-converting enzyme inhibitor, calcium channel blocker and thiazide diuretic along with beta-adrenergic blockers. The fourth stage (end of 20th century--beginning of 21st) was characterised by discovery of the renin-angiotensin-aldosterone system, development of complex treatment options for hypertension, based on stratification of risk factors of cardiovascular complication. Clinical picture of hypertension haven't changed significally during the last 100 years. Cerebral and cardiac manifestations of hypertension remain dominat in 21st century as well as in 20th century. In the beginning of 21st century such systems as eyes and kidneys are not affected by the hypertension. Hypertension remains the main cause of progression of cardiac muscle and vessel wall structural changes.

[Achievements and problems of modern trials of antihypertensive drugs].

Most important value of lowering of substantially elevated arterial pressure (AP) for improvement of outcomes in patients with arterial hypertension (AH) was convincingly confirmed by large truly placebo controlled randomized clinical trials (RCT) with the use of mainly diuretics, and/or beta-adrenoblockers in the 60-80ths. Later comparative RCT confirmed equal antihypertensive efficacy of 5 main drug classes relative to AP level in brachial artery. In this review we discuss merit of auxiliary class-specific properties of antihypertensive agents potentially affecting prognosis besides AP lowering. We also discuss problems related to decline of significance of quantitative criteria of AH and consideration of AP level in general context of cardiovascular risk; problems of external validity of RCT; extrapolation of RCT results obtained in patients with complicated AH and very high cardiovascular risk on young patients with uncomplicated AH; significance of hard and surrogate end points.

The evolution of renin-angiotensin blockade: angiotensin-converting enzyme inhibitors as the starting point.

The renin-angiotensin system has been a target in the treatment of hypertension for close to three decades. Several medication classes that block specific aspects of this system have emerged as useful therapies, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and, most recently, direct renin inhibitors. There has been a natural history to the development of each of these three drug classes, starting with their use as antihypertensive agents; thereafter, in each case they have been employed as end-organ protective agents. To date, there has been scant evidence to favor angiotensin receptor blockers or direct renin inhibitors over angiotensin-converting enzyme inhibitors in treating hypertension or in affording end-organ protection; thus, angiotensin-converting enzyme inhibitors remain the standard of care when renin-angiotensin system blockade is warranted.

Cilnidipine: a new generation Ca channel blocker with inhibitory action on sympathetic neurotransmitter release.

Cilnidipine is a unique Ca(2+) channel blocker with an inhibitory action on the sympathetic N-type Ca(2+) channels, which is used for patients with hypertension in Japan. Cilnidipine has been clarified to exert antisympathetic actions in various examinations from cell to human levels, in contrast to classical Ca(2+) channel blockers. Furthermore, renoprotective and neuroprotective effects as well as cardioprotective action of cilnidipine have been demonstrated in clinical practice or animal examinations. After the introduction of nifedipine as an antihypertensive drug, many Ca(2+) channel blockers with long-lasting action for blood pressure have been developed to minimize sympathetic reflex during antihypertensive therapy, which have been divided into three groups; namely, first, second, and third generation based on their pharmacokinetic profiles. Since cilnidipine directly inhibits the sympathetic neurotransmitter release by N-type Ca(2+) channel-blocking property, the drug can be expected as fourth generation, providing an effective strategy for the treatment of cardiovascular diseases.