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Discovery and Development of Calcium Channel Blockers
#MMPMID28611661
Godfraind T
Front Pharmacol
2017[]; 8
(?): 286
PMID28611661
show ga
In the mid 1960s, experimental work on molecules under screening as coronary
dilators allowed the discovery of the mechanism of calcium entry blockade by
drugs later named calcium channel blockers. This paper summarizes scientific
research on these small molecules interacting directly with L-type
voltage-operated calcium channels. It also reports on experimental approaches
translated into understanding of their therapeutic actions. The importance of
calcium in muscle contraction was discovered by Sidney Ringer who reported this
fact in 1883. Interest in the intracellular role of calcium arose 60 years later
out of Kamada (Japan) and Heibrunn (USA) experiments in the early 1940s. Studies
on pharmacology of calcium function were initiated in the mid 1960s and their
therapeutic applications globally occurred in the the 1980s. The first part of
this report deals with basic pharmacology in the cardiovascular system
particularly in isolated arteries. In the section entitled from calcium
antagonists to calcium channel blockers, it is recalled that drugs of a series of
diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin
were initially named calcium antagonists on the basis of their effect in
depolarized arteries contracted by calcium. Studies on arteries contracted by
catecholamines showed that the vasorelaxation resulted from blockade of calcium
entry. Radiochemical and electrophysiological studies performed with
dihydropyridines allowed their cellular targets to be identified with L-type
voltage-operated calcium channels. The modulated receptor theory helped the
understanding of their variation in affinity dependent on arterial cell membrane
potential and promoted the terminology calcium channel blocker (CCB) of which the
various chemical families are introduced in the paper. In the section entitled
tissue selectivity of CCBs, it is shown that characteristics of the drug,
properties of the tissue, and of the stimuli are important factors of their
action. The high sensitivity of hypertensive animals is explained by the partial
depolarization of their arteries. It is noted that they are arteriolar dilators
and that they cannot be simply considered as vasodilators. The second part of
this report provides key information about clinical usefulness of CCBs. A section
is devoted to the controversy on their safety closed by the Allhat trial (2002).
Sections are dedicated to their effect in cardiac ischemia, in cardiac
arrhythmias, in atherosclerosis, in hypertension, and its complications. CCBs
appear as the most commonly used for the treatment of cardiovascular diseases. As
far as hypertension is concerned, globally the prevalence in adults aged 25 years
and over was around 40% in 2008. Usefulness of CCBs is discussed on the basis of
large clinical trials. At therapeutic dosage, they reduce the elevated blood
pressure of hypertensive patients but don't change blood pressure of normotensive
subjects, as was observed in animals. Those active on both L- and T-type channels
are efficient in nephropathy. Alteration of cognitive function is a complication
of hypertension recognized nowadays as eventually leading to dementia. This
question is discussed together with the efficacy of CCBs in cognitive pathology.
In the section entitled beyond the cardiovascular system, CCBs actions in
migraine, neuropathic pain, and subarachnoid hemorrhage are reported. The final
conclusions refer to long-term effects discovered in experimental animals that
have not yet been clearly reported as being important in human pharmacotherapy.
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