Most of what we know about the origin of humans comes from the research of paleoanthropologists, scientists who study human fossils. Paleoanthropologists identify the sites where fossils can be found. They determine the age of fossils and describe the features of the bones and teeth discovered. Recently, paleoanthropologists have added genetic technology to test their hypotheses. In this article, we will tell you a little about prehistory, a period of time including pre-humans and humans and lasting about 10 million years. During the Prehistoric Period, events were not reported in writing. Most information on prehistory is obtained through studying fossils. Ten to twelve million years ago, primates divided into two branches, one included species leading to modern (current) humans and the other branch to the great apes that include gorillas, chimpanzees, bonobos, and orangutans. The branch leading to modern humans included several different species. When one of these species—known as the Neanderthals—inhabited Eurasia, they were not alone; Homo sapiens and other Homo species were also present in this region. All the other species of Homo have gone extinct, with the exception of Homo sapiens, our species, which gradually colonized the entire planet. About 12,000 years ago, during the Neolithic Period, some (but not all) populations of H. sapiens passed from a wandering lifestyle of hunting and gathering to one of sedentary farming, building villages and towns. They developed more complex social organizations and invented writing. This was the end of prehistory and the beginning of history.

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.

OPINION article Front. Pharmacol., 03 February 2015Sec. Cardiovascular and Smooth Muscle Pharmacology Volume 6 - 2015 | https://doi.org/10.3389/fphar.2015.00010

This paper summarizes the pharmacological properties of calcium channel blockers (CCBs), their established therapeutic uses for cardiovascular disorders and the current improvement of their clinical effects through drug combinations. Their identification resulted from study of small molecules including coronary dilators, which were named calcium antagonists. Further experiments showed that they reduced contraction of arteries by inhibiting calcium entry and by interacting with binding sites identified on voltage-dependent calcium channels. This led to the denomination calcium channel blockers. In short-term studies, by decreasing total peripheral resistance, CCBs lower arterial pressure. By unloading the heart and increasing coronary blood flow, CCBs improve myocardial oxygenation. In long-term treatment, the decrease in blood pressure is more pronounced in hypertensive than in normotensive patients. A controversy on the safety of CCBs ended after a large antihypertensive trial (ALLHAT) sponsored by the National Heart, Lung, and Blood Institute. There are two main types of CCBs: dihydopyridine and non-dihydropyridine; the first type is vascular selective. Dihydropyrines are indicated for hypertension, chronic, stable and vasospastic angina. Non-dihydropyridines have the same indications plus antiarrythmic effects in atrial fibrillation or flutter and paroxysmal supraventricular tachycardia. In addition, CCBs reduced newly formed coronary lesions in atherosclerosis. In order to reach recommended blood pressure goals, there is a recent therapeutic move by combination of CCBs with other antihypertensive agents particularly with inhibitors acting at the level of the renin-angiotensin system. They are also combined with statins. Prevention of dementia has been reported in hypertensive patients treated with nitrendipine, opening a way for further studies on CCBs’ beneficial effect in cognitive deterioration associated with aging.

BACKGROUND:Stroke is the second most common cause of death and a major cause of disability worldwide. Risperidone is an atypical antipsychotic drug that may increase the risk of stroke. The present work examined whether risperidone enhances the vulnerability to stroke in hypertensive rats and the potential mechanisms underlying such action.METHODS:Experiment 1: Wistar-Kyoto (WKY) rats, spontaneously hypertensive rats (SHRs) and stroke-prone SHRs (SHR-SPs) were treated with risperidone (0.8 and 2.4 mg/kg/d) or vehicle for 30 consecutive days. Tissue damage in response to middle cerebral artery occlusion (MCAO) was measured microscopically. The activity of superoxide dismutase, glutathione peroxidase, the levels of malondialdehyde were also determined. Experiment 2: Survival data were recorded in SHR-SPs that received daily risperidone perpetually. Experiment 3: Effect of risperidone on interleukin-6 and tumor necrosis factor-α was examined in quiescent or LPS-activated cortical microglias from WKY rats. Experiment 4: Potential damage of risperidone exposure to neurons was examined in primary neuronal culture obtained from WKY rats, SHRs, and SHR-SPs.RESULTS:Risperidone increased infarct areas upon MCAO in SHR-SPs and SHRs, but not in WKY rats. Survival time in SHR-SPs was shortened by risperidone. Apoptosis was augmented by risperidone through enhanced Bax. Risperidone also increased endothelial injury.CONCLUSIONS:Risperidone enhances the vulnerability to stroke in hypertensive rats through increasing neuronal apoptosis and endothelial injury.

FIELD GRAND CHALLENGE article Front. Pharmacol., 22 November 2010 Volume 1 - 2010 | https://doi.org/10.3389/fphar.2010.00134

Setsuro Ebashi, a pioneer of muscle research, died on July 17, 2006 at the age of 83 years. He was an exceptional scientist and had an outstanding personality. Dr Ebashi was born in Tokyo on August 31, 1922. In September 1944, he graduated as Doctor of Medicine from the Faculty of Medicine of the University of Tokyo, where he spent most of his professional life. In June 1954, he obtained the Doctor of Medical Sciences (PhD) degree from the same university. From January to December 1959, he was Guest Investigator of the Rockefeller Institute in the laboratory of Fritz Lipmann, Nobel Laureate in Medicine. In May 1959, he was offered the Chair of Pharmacology in the Faculty of Medicine of the University of Tokyo and kept this position until March 1983. From May 1971 to March 1983, he was also Chair of Biophysics at the Faculty of Sciences of the University of Tokyo. After retiring from the University of Tokyo and becoming Professor Emeritus, he was offered a professorship in the National Institute for Physiological Sciences in Okazaki. In April 1985, he became Director-General of the National Institute for Physiological Sciences. Prof Ebashi left this position in March 1991, after being nominated as President of Okazaki National Institutes. After retiring from this position, he became Professor Emeritus of the National Institute for Physiological Sciences in March 1993.FIGURE: Setsuro Ebashi (1922-2006).While preparing his PhD thesis under the supervision of Prof H. Kumagai, he purified choline-acetylase and took special pride in the study of the “relaxing factor,” discovered by B.B. Marsh in 1951, which in the presence of adenosine triphosphate (ATP) relaxed glycerinated muscles of rabbits. Ebashi found that this factor existed in particulates with Mg-activated ATPase. He demonstrated that the fractions that strongly took up Ca2+ in the presence of ATP consisted of fragmented sarcoplasmic reticulum, suggesting a regulatory function for the calcium pump of the sarcoplasmic reticulum. This built upon Emil Bozler's observation that sequestration of Ca by EDTA caused muscle relaxation. W.H. Hasselbach and Anne-Marie Weber, who explained how the endoplasmic reticulum (ER) could accumulate Ca2+, confirmed the importance of intracellular Ca2+ pumps associated with the endomembranes. At the same time, the first indications of ER-residing regulated ion channels, which could provide a means of Ca2+ release, were reported by Clara Franzini-Armstrong. In the early 1940s, Heilbrunn in the United States and Kamada in Japan demonstrated the role of Ca2+ as a contraction signal. In the early 1960s, studying actomyosin prepared directly from whole muscle, Setsuro Ebashi discovered that in the absence of Ca ions, no contractile reaction occurs, even when ATP is added to the myosin-actin system, but that with even a minute amount of calcium (on the order of 1 μmol), ATP induces a vigorous sensitivity to actomyosin. Clearly, the muscle extracts contained a factor that conferred Ca2+ sensitivity to actomyosin. This factor turned out to be the tropomyosin-troponin complex. Ebashi's concept of Ca receptor protein was extended to other cell types, for instance, with calmodulin, which plays a role in various cellular regulations from muscle to nerve cells. Setsuro Ebashi presented a clear picture for factors regulating onset and offset of the Ca2+ signal in skeletal muscles. He reported that Ca2+-related regulatory processes were different in the various types of muscles. This elucidation of the role of the calcium ion in mechanisms that regulate muscle contraction-relaxation and the demonstration of differences among muscles paved the way for studies of the pharmacological control of the Ca2+ signal that emerged as a therapeutic principle. A by-product of his research included studies related to alterations of calcium regulatory mechanism and proteins dysfunction in muscle pathologies such as muscular dystrophy and malignant hyperthermia. His seminal research attracted a large number of research fellows and associates, a pattern that continued after his move from Tokyo to Okazaki, thus allowing Japanese scientific research to become a world leader. At the risk of leaving out numerous associates who benefited from his creative critical scientific approach, I would like to mention the following people who are well known in the fields of skeletal muscle and cardiovascular research as well as neuroscience: Masanori Otsuka, Makoto Endo, Yosiaki Nonomura, Tomoh Masaki, Iwao Ohtsuki, Yoshiki Hotta, Yasuo Ogawa, Eijiro Ozawa, and Takeyuki Wakabayashi. From 1978-1981, Setsuro Ebashi was President of the International Union for Pure and Applied Biophysics (IUPAB), but his major international activity was devoted to IUPHAR, the International Union of Pharmacology (now the International Union of Basic and Clinical Pharmacology). He organized and chaired the Eighth World Congress of Pharmacology held in Tokyo in July 1981. This Congress is considered an international model because of its perfect organization and the high quality of its scientific program. Dr Ebashi was elected president of IUPHAR for the period 1990-1994 and officiated as Immediate Past-President until December 1998. During this time, he devoted himself to fundraising for IUPHAR, and because of his commitment, the Japanese Pharmacological Society initiated an increase of Member Society contributions to IUPHAR with the purpose of allowing the establishment and the development of scientific research activities operated by the Union (eg, Receptor Characterization and Classification, which has become a major receptor database). Dr Ebashi was awarded the Order of Cultural Merit (Bunka-Kunsho) and received numerous major honors from diverse scientific and civic organizations and academies throughout the world. A few of these stand out: the 1965 Prize of the Yamaji Science-Promoting Foundation, the 1968 Asahi Prize (issued by Asahi Newspaper Publishing Co), and the 1972 Imperial Prize of the Japan Academy. In 1999, he was awarded the International Prize for Biology for outstanding developments in biomedical sciences and fundamental developments in the field of calcium's role in the physiological regulation of skeletal muscle. Dr Ebashi was very proud that the awards ceremony was attended by the Emporer and Empress of Japan. Setsuro Ebashi was a member of the Japan Academy and a foreign member of several academies including the Deutsche Akademie Leopoldina, the Royal Academy of Medicine of Belgium, the American Academy of Arts and Sciences, the National Academy of Sciences (US), the Academia Europaea, and the Royal Society of London. He was also an honorary professor at the Shanghai Institute of Biochemistry, Chinese Academy of Sciences. Bob Furchgott introduced me to Setsuro Ebashi in 1969. Since then, I met him several times around the world. I met with him more regularly during the period 1990-1998. He was a modest person with a rich and complex personality. As a scientist, he proved to be rational and imaginative. He had a great memory even for small details; this allowed him to identify existing connections between facts apparently disparate. His scientific creativity was enhanced by his rejection of any dogmatism. He sometimes appeared imposing. In fact, Setsuro Ebashi was unusual in being outspoken; when he was critical about something or somebody, he said so. Yet, he was among the most cultured scientists I have ever met, able to sing a capella Bach chorals. When writing about Setsuro Ebashi, it is not possible to forget his wife, who provided him with great support. In the early years, she was efficiently active in his laboratory. At the end of his life, she had been vigilant, maintaining an affectionate environment and contacts with his friends abroad. Dr Setsuro Ebashi made many lifelong friendships. His many friends from many different continents will miss him dearly. Théophile Godfraind Théophile Godfraind Past-President, IUPHAR

Objectives: Amlodipine is a calcium channel blocker (CCB) known to stimulate nitric oxide production from endothelial cells. Whether this ancillary property can be related to the capacity of amlodipine to concentrate and alter the structure of cholesterol-containing membrane bilayers is a matter of investigation. Here, we reasoned that since the endothelial nitric oxide synthase is, in part, expressed in cholesterol-rich plasmalemmal microdomains (e.g., caveolae and rafts), amlodipine could interfere with this specific locale of the enzyme and thereby modulate NO production in endothelial cells.Methods and results: Using a method combining lubrol-based extraction and subcellular fractionation on sucrose gradient, we found that amlodipine, but not verapamil or nifedipine, induced the segregation of endothelial NO synthase (eNOS) from caveolin-enriched low-density membranes (8 +/- 2% vs. 42 +/- 3% in untreated condition; P < 0.01). We then performed co-immunoprecipitation experiments and found that amlodipine dose-dependently disrupted the caveolin/eNOS interaction contrary to other calcium channel blockers, and potentiated the stimulation of NO production by agonists such as bradykinin and vascular endothelial growth factor (VEGF) (+138 +/- 28% and +183 +/- 27% over values obtained with the agonist alone, respectively; P < 0.01). Interestingly, we also documented that the dissociation of the caveolin/eNOS heterocomplex induced by amlodipine was not mediated by the traditional calcium-dependent calmodulin binding to eNOS and that recombinant caveolin expression could compete with the stimulatory effects of amlodipine on eNOS activity. Finally, we showed that the amlodipine-triggered, caveolin-dependent mechanism of eNOS activation was independent of other pleiotropic effects of the CCB such as superoxide anion scavenging and angiotensin-converting enzyme (ACE) inhibition.Conclusions: This study unravels the modulatory effects of amlodipine on caveolar integrity and the capacity of caveolin to maintain eNOS in its vicinity in the absence of any detectable changes in intracellular calcium levels. The resulting increase in caveolin-free eNOS potentiates the NO production in response to agonists including VEGF and bradykinin. More generally, this work opens new avenues of treatment for drugs able to structurally alter signaling pathways concentrated in caveolae. (c) 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

It is generally accepted that hypertension doubles the risk of cardiovascular disease, of which coronary heart disease is the most common and lethal. Hypertension is a predisposing factor for the development of stroke, peripheral arterial disease, heart failure and end-state renal disease. Atherosclerosis-causing coronary heart disease is related to the severity of hypertension. Inhibition of calcium entry reduces the active tone of vascular smooth muscle and produces vasodilatation. This pharmacological action has been the basis for the use of calcium-channel blockers (CCBs) for the management of hypertension. Other drug families may achieve this: diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists. Cardiovascular hypertrophy and atherosclerosis are major complications related to high blood pressure. Cardiac hypertrophy is considered as an independent risk factor associated with abnormalities of diastolic function and can result in heart failure. Atherosclerosis is associated with activation of innate immunity. Atherosclerosis is expressing itself not only as coronary heart disease, but as a cerebrovascular and peripheral arterial disease. By impairing physiological vasomotor function, atherosclerosis includes ultimately necrosis of myocardium. CCBs reduce blood pressure. Do they prevent the progress of the main complications of hypertension? This major question is the matter of the present paper.

Calcium channel blockers slow the progression of atherosclerosis. The purpose of the present experiments was to examine the action of lacidipine in a condition that accelerates the development of atherosclerosis in order to test the hypothesis that the protective action of lacidipine in atherosclerosis is unrelated to the reduction of blood pressure. Male ApoE-deficient mice (6 weeks old) were exposed either to normal chow (ND) or to a Western-type diet (WD, adjusted calorie diet containing 42% from fat) for 8 weeks. Western-type diet induced a reduction of nitric oxide (NO)-mediated endothelium-dependent relaxation to acetylcholine (Max relaxation % = 55.8 ± 2 for ND and 46.6 ± 2 for WD, n = 8, p < 0.05). Dose-relaxation curves to S-nitroso-N-acetylpenicillamine (SNAP) NO donor were also significantly rightward-shifted (n = 7, ANOVA, p < 0.01) in WD compared with ND arteries. Chronic treatment of WD mice with lacidipine (1 and 3 mg/kg/day) increased significantly the acetylcholine-evoked relaxation (to 76.6 ± 3.5%, n = 6, ANOVA, p < 0.001) and prevented the loss of responsiveness to SNAP in mice exposed to WD. Plasma renin activity and endothelin-1 plasma levels as well as thiobarbituric acid-reactive substance levels in kidneys were significantly lower in WD mice treated with lacidipine than in untreated ones. In mice exposed to WD lacidipine reduced extension of atherosclerotic lesions, renal injury and increase in blood pressure. Experimental data indicate that inhibition of Western-type diet-evoked alterations is related to both antioxidant and vasoactive properties of lacidipine.

Drugs currently known as calcium channel blockers (CCB) were initially called calcium antagonists because of their ability to inhibit calcium-evoked contractions in depolarized smooth muscles. Blocking the entry of calcium reduces the active tone of vascular smooth muscle and produces vasodilatation. This pharmacological property has been the basis for the use of CCBs in the management of hypertension and coronary heart disease. A major question is whether drugs reducing blood pressure have other effects that help prevent the main complications of hypertension, such as atherosclerosis, stroke, peripheral arterial disease, heart failure and end-state renal disease. Experimental studies that focus on this question are reviewed in the present paper.

To better understand excitation-contraction coupling in cardiac muscle, we investigated the main Ca2' channels involved in that process in adult and neonatal rat ventricle. Voltagedependent (L-type) Ca2' channels and sarcoplasmic reticulum Ca2' release channels were labeled by means of [3H](+)-PN200-110 and [3Hlryanodine, respectively. The number of [3HIryanodine binding sites (per gram tissue) increased more than that of [3H] (+)-PN200-110 binding sites over the postnatal period (2.1-fold versus 1.35-fold, respectively). After equilibration of microsomal fractions in density gradient, ryanodine receptors were characterized by a heavy distribution pattern that did not change appreciably between days 1 and 30 after birth. In neonatal tissue, 1,4-dihydropyridine receptors were found mainly in low-density subfractions, together with other sarcolemmal constituents, whereas in adult tissue, they were recovered predominantly in high-density subfractions, together with ryanodine receptors. Thus, after birth, and in parallel with the development of T tubules, there was a progressive concentration of L-type Ca2' channels in junctional structures of high equilibrium density, where they were situated close to the Ca2+ release channels of the sarcoplasmic reticulum. In adult ventricle, L-type channels were, on an average, threefold more abundant in T tubules than in external sarcolemma. In parallel mechanical studies, we found that the inhibitory action of ryanodine on systolic contraction was much more pronounced in adult than in neonatal right ventricle, and that, conversely, neonatal tissue was more sensitive than adult tissue to inhibitors of L-type channels. We conclude that, in view of the presumed mechanism of Ca2' release from the sarcoplasmic reticulum, that is, Ca2+-induced Ca2+ release, the predominant localization in adult rat ventricle of the major Ca2' entry pathway in the vicinity of the Ca2+ release pathway is of great functional significance. Furthermore, owing to the relative stoichiometry of Ca21 entry and Ca2+ release channels in junctional structures (about 1: 9), a physical link between these channels is not likely to be involved in the modulation of Ca2+ release from the sarcoplasmic reticulum in cardiac muscle. (Circulation Research 1991;68:662-673)

Experimental pharmacology studies consider short- and long-term effects of CCBs. The most obvious short-term action is the reduction of blood pressure that has prompted the use of calcium antagonists in cardiovascular medicine. This action is the result of a decrease of peripheral resistance due to vasodilatation within the arterial beds. Therefore, a large body of experimental work has been concerned with studies of the mechanism of action of CCBs in arteries. Analytical pharmacology studies of various CCBs have supported the concept of tissue and action selectivity, which has some interest for pharmacotherapy. Studies of the long-term effects have enlightened their action in the prevention of the complications of hypertension including the development of atherosclerosis. Earlier studies have addressed the mechanism of action of calcium antagonists in the vasculature by considering their interaction with Ca2+ activator of the contractile machinery. Such approach has required the characterization of calcium movements in the absence and in the presence of calcium antagonists.

The hypothesis that the reduction of elevated blood pressure is not the only mechanism of tissue protection has not reached full acceptance because of poor evidence from clinical studies. In a recent paper, Ruilope and Schiffrin [41] debated the question of whether blood pressure lowering alone is responsible for the benefits accrued from antihypertensive therapy as demonstrated in many multicenter randomized clinical trials with different antihypertensive agents or whether there is evidence that some agents have special properties that result in benefits that go beyond those resulting from lowering blood pressure. The authors pointed out that over the past 30 years, it has been demonstrated that lowering blood pressure in severe forms of hypertension, and more recently in systolic and even mild hypertension, will result in reduced incidence of stroke and slower progression of heart and renal failure. These effects have been easier to demonstrate in sicker patients, because enough end points may be counted in the three to five years that these clinical trials last. However, better prevention by a specific drug, of risk attributable to high blood pressure has not been identified in the much larger group of hypertensive individuals, who have less severe forms of hypertension. With agents such as reninangiotensin system inhibitors or calcium channel blockers, it has been demonstrated that hypertensive vascular remodeling and endothelial dysfunction may be corrected. However, only specifically designed clinical trials could indicate that benefits beyond blood pressure lowering may be achieved with the use of specific drugs to lower blood pressure. Although some evidence suggests that this may be the case, the question remains for the time being largely unanswered.