The catecholamines comprise the endogenous substances dopamine, noradrenaline (norepinephrine) and adrenaline (epinephrine) as well as numerous artificially synthesized compounds such as isoprenaline. Their investigation constitutes a prominent chapter in the history of physiology, biochemistry and pharmacology. Adrenaline was the first hormone extracted from itsendocrine gland and obtained in pure form, before the word hormone was coined.^[1] It was also the first hormone the structure and biosynthesis of which were clarified. Apart fromacetylcholine, adrenaline and noradrenaline were the first neurotransmitters to be discovered and the first intercellular biochemical signals to be found in intracellular vesicles. The β-adrenoceptor was the first G protein-coupled receptor the gene of which was cloned.

Nerve fibers with noradrenaline in the iris

Goal-directed catecholamine research began with the preparation by George Oliver and Edward Albert Sharpey-Schafer of a pharmacologically active extract from the adrenal glands.

Contents

  [hide] 

• 1 Adrenaline in the adrenal medulla
  • 1.1 Forerunners
  • 1.2 Oliver and Schäfer 1893/94
  • 1.3 Independent discoverers
• 2 Chemistry
• 3 Adrenaline as a transmitter
• 4 Formation and destruction
• 5 Noradrenaline
• 6 Dopamine
• 7 Membrane passage
• 8 Receptors
• 9 References
• 10 Notes

Adrenaline in the adrenal medulla[edit]

Forerunners[edit]

In the best book on asthma of the 19th century, first published in 1860,^[2] the British physician and physiologist Henry Hyde Salter (1823–1871) included a chapter on treatment ″by stimulants″. Strong coffee was very helpful, presumably because it dispelled sleep, which favoured asthma. Even more impressive, however, was the response to ″strong mental emotion″: ″The cure of asthma by violent emotion is more sudden and complete than by any other remedy whatever; indeed, I know few things more striking and curious in the whole history of therapeutics. … The cure … takes no time; it is instantaneous, the intensest paroxysm ceases on the instant.″ ″Cure″ due to release of adrenaline from the adrenals is the retrospective interpretation.

At the same time that Salter unwittingly made use of the adrenal medulla, the French physician Alfred Vulpian found that there was something unique about it:^[3] material scraped from it coloured green when ferric chloride was added. This did neither occur with the adrenal cortex nor with any other tissue. The adrenal medulla hence contained "une matière spéciale, inconnue jusqu’ici et qui constitue le signe particulier de ces organes". Vulpian even came to the insight that the substance entered "le torrent circulatoire", for blood from the adrenal veins did give the ferric chloride reaction.

Members of University College London around 1895. Schäfer in middle of forefront, Oliver to his left in light coat.

In the early 1890s, the German pharmacologist Carl Jacobj (1857–1944) in the laboratory of Oswald Schmiedeberg in Strasbourg studied the relationship between the adrenals and the intestine. Electrical stimulation of the vagus nerve or injection of muscarine elicited peristalsis. This peristalis was promptly abolished by electrical stimulation of the adrenals.^[4] The experiment has been called "the first indirect demonstration of the role of the adrenal medulla as an endocrine organ <and> actually a more sophisticated demonstration of the adrenal medullary function than the classic study of Oliver and Schäfer".^[5] While this may be true, Jacobj did not envisage a chemical signal secreted into the blood to influence distant organs, in other words a hormone, but nerves running from the adrenals to the gut, "Hemmungsbahnen für die Darmbewegung".

Oliver and Schäfer 1893/94[edit]

George Oliver was a physician practicing in the spa town of Harrogate in North Yorkshire. Edward Albert Schäfer was Professor of Physiology at University College London. In 1918, he prefixed the surname of his physiology teacher William Sharpey to his own to become Edward Albert Sharpey Schafer. The canonical story, told by Henry Hallett Dale, who worked at University College London from 1902 to 1904, runs as follows:^[6]

Dr Oliver, I was told, … had a liking and a ′flair′ for the invention of simple appliances, with which observations and experiments could be made on the human subject. Dr Oliver had invented a small instrument with which he claimed to be able to measure, through the unbroken skin, the diameter of a living artery, such as the radial artery at the wrist. He appears to have used his family in his experiments, and a young son was the subject of a series, in which Dr Oliver measured the diameter of the radial artery, and observed the effect upon it of injecting extracts of various animal glands under the skin. … We may picture, then, Professor Schafer, in the old physiological laboratory at University College, … finishing an experiment of some kind, in which he was recording the arterial blood pressure of an anaesthetised dog. … To him enters Dr Oliver, with the story of the experiments on his boy, and, in particular, with the statement that injection under the skin of a glycerin extract from calf’s suprarenal gland was followed by a definite narrowing of the radial artery. Professor Schafer is said to have been entirely sceptical, and to have attributed the observation to self-delusion. … He can hardly be blamed, I think; knowing even what we now know about the action of this extract, which of us would be prepared to believe that injecting it under a boy’s skin would cause his radial artery to become measurably more slender? Dr Oliver, however, is persistent; he … suggests that, at least, it will do no harm to inject into the circulation, through a vein, a little of the suprarenal extract, which he produces from his pocket. So Professor Schafer makes the injection, expecting a triumphant demonstration of nothing, and finds himself standing ′like some watcher of the skies, when a new planet swims into his ken,′ watching the mercury rise in the manometer with amazing rapidity and to an astounding height.

Antiquity

Main article: History of ancient Israel and Judah

Further information: Israelites, Kingdom of Israel (united monarchy), Kingdom of Israel (Samaria) and Kingdom of Judah

Kingdom of Israel, 1020 BCE–930 BCE

The notion of the "Land of Israel", known in Hebrew as Eretz Yisrael, has been important and sacred to the Jewish people since Biblical times. According to the Torah, God promised the land to the three Patriarchs of the Jewish people.^[46][47] On the basis of scripture, the period of the three Patriarchs has been placed somewhere in the early 2nd millennium BCE,^[48] and the first Kingdom of Israel was established around the 11th century BCE. Subsequent Israelite kingdoms and states ruled intermittently over the next four hundred years, and are known from various extra-biblical sources.^{[49][50][51][52]}

The first record of the name Israel (as ysrỉꜣr) occurs in the Merneptah stele, erected for Egyptian Pharaoh Merneptah c. 1209 BCE, "Israel is laid waste and his seed is not."^[53] This "Israel" was a cultural and probably political entity of the central highlands, well enough established to be perceived by the Egyptians as a possible challenge to their hegemony, but an ethnic group rather than an organised state;^[54] Ancestors of the Israelites may have included Semites native to Canaan and the Sea Peoples.^[55] McNutt says, "It is probably safe to assume that sometime during Iron Age a population began to identify itself as 'Israelite'", differentiating itself from the Canaanitesthrough such markers as the prohibition of intermarriage, an emphasis on family history and genealogy, and religion.^[56]

Villages had populations of up to 300 or 400,^[57][58] which lived by farming and herding, and were largely self-sufficient;^[59] economic interchange was prevalent.^[60] Writing was known and available for recording, even in small sites.^[61] The archaeological evidence indicates a society of village-like centres, but with more limited resources and a small population.^[62] Modern scholars see Israel arising peacefully and internally from existing people in the highlands of Canaan.^[63]

The Iron Age kingdom of Israeland kingdom of Judah (8th century BCE)

Around 930 BCE, the kingdom split into a southern Kingdom of Judah and a northern Kingdom of Israel. From the middle of the 8th century BCE Israel came into increasing conflict with the expanding neo-Assyrian empire. UnderTiglath-Pileser III it first split Israel's territory into several smaller units and then destroyed its capital, Samaria (722 BCE). An Israelite revolt (724–722 BCE) was crushed after the siege and capture of Samaria by the Assyrian kingSargon II. Sargon's son, Sennacherib, tried and failed to conquer Judah. Assyrian records say he leveled 46 walled cities and besieged Jerusalem, leaving after receiving extensive tribute.^[64]

In 586 BCE King Nebuchadnezzar II of Babylon conquered Judah. According to the Hebrew Bible, he destroyed Solomon's Temple and exiled the Jews to Babylon. The defeat was also recorded by the Babylonians^[65][66] (see theBabylonian Chronicles).

In 538 BCE, Cyrus the Great of Persia conquered Babylon and took over its empire. Cyrus issued a proclamation granting subjugated nations (including the people of Judah) religious freedom (for the original text see the Cyrus Cylinder). According to the Hebrew Bible 50,000 Judeans, led by Zerubabel, returned to Judah and rebuilt the temple. A second group of 5,000, led by Ezra and Nehemiah, returned to Judah in 456 BCE although non-Jews wrote to Cyrus to try to prevent their return.

§Classical period

Main articles: Hasmonean kingdom and Herodian kingdom

Further information: Maccabean Revolt and Jewish-Roman wars

Hasmonean Kingdom

Treasures, including the Menorah, carried in a Roman triumph after the 70 CE Siege of Jerusalem (original relieffrom the Arch of Titus, Rome).

With successive Persian rule, the region, divided between Syria-Coele province and later the autonomous Yehud Medinata, was gradually developing back into urban society, largely dominated by Judeans. The Greek conquests largely skipped the region without any resistance or interest. Incorporated into Ptolemaic and finally Seleucid Empires, southern Levant was heavily hellenized, building the tensions between Judeans and Greeks. The conflict erupted in 167 BCE with the Maccabean Revolt, which succeeded in establishing an independent Hasmonean Kingdom in Judah, which later expanded over much of modern Israel, as the Seleucids gradually lost control in the region.

The Roman Empire invaded the region in 63 BCE, first taking control of Syria, and then intervening in the Hasmonean civil war. The struggle between pro-Roman and pro-Parthian factions in Judea eventually led to the installation of Herod the Great and consolidation of the Herodian Kingdom as a vassal Judean state of Rome.

Herodian Kingdom of Israel

Kfar Bar'am, an ancient Jewish village,^{[citation needed]} abandoned some time between the 7th-13th centuries AD.^[67]

With the decline of Herodians, Judea, transformed into a Roman province, became the site of a violent struggle of Jews against Greco-Romans, culminating in the Jewish-Roman Wars, ending in wide-scale destruction, expulsions, and genocide. Jewish presence in the region significantly dwindled after the failure of the Bar Kokhba revolt against the Roman Empire in 132 CE.^[68] Nevertheless, there was a continuous small Jewish presence and Galilee became its religious center.^[69][70] The Mishnah and part of the Talmud, central Jewish texts, were composed during the 2nd to 4th centuries CE in Tiberias and Jerusalem.^[71] The region came to be populated predominantly by Greco-Romans on the coast and Samaritans in the hill-country. Christianity was gradually evolving over Roman paganism, when the area under Byzantine rule was transformed into Deocese of the East, as Palaestina Prima and Palaestina Secunda provinces. Through the 5th and 6th centuries, dramatic events of Samaritan Revolts reshaped the land, with massive destruction to Byzantine Christian and Samaritan societies and a resulting decrease of the population. After the Persian conquest and the installation of a short-lived Jewish Commonwealth in 614 CE, the Byzantine Empire reinstalled its rule in 625 CE, resulting in further decline and destruction.

§Middle Ages and caliphates

Further information: Old Yishuv, Pre-Zionist Aliyah and History of the Jews and the Crusades

Beit Knesset Abuhav, is a 15th-century synagogue in Safed, Israel.^[72]

In 635 CE, the region, including Jerusalem, was conquered by Arabs. It remained under Muslim control and predominately Muslim occupancy for the next 1300 years under various caliphates.^[73]Control of the region transferred between the Umayyads,^[73] Abbasids,^[73] and Crusaders throughout the next six centuries,^[73] before the area was conquered in 1260 by the Mamluk Sultanate.^[74]

Siege and Capture of Jerusalem in 1099, where the Jews had participated in its defense

In 1099, the Jews were among the rest of the population who tried in vain to defend Jerusalem against the Crusaders. When the city fell, a massacre of 6,000 Jews occurred when the synagogue they were seeking refuge in was set alight. Almost all perished.^[75] The Jews almost single-handedly defended Haifa against the crusaders, holding out in the besieged town for a whole month (June–July 1099) in fierce battles. At this time, a full thousand years after the fall of the Jewish state, there were Jewish communities all over the country. Fifty of them are known and include Jerusalem, Tiberias, Ramleh, Ashkelon, Caesarea, and Gaza.^[76][77]

In 1165 Maimonides visited Jerusalem and prayed on the Temple Mount, in the "great, holy house".^[78] In 1141 Spanish poet, Yehuda Halevi, issued a call to the Jews to emigrate to the Land of Israel, a journey he undertook himself. In 1187 Ayyubid Sultan Saladin defeated the Crusaders in the Battle of Hattin and took Jerusalem and most of Palestine. In time, Saladin issued a proclamation inviting all Jews to return and settle in Jerusalem,^[79] and according to Judah al-Harizi, they did: "From the day the Arabs took Jerusalem, the Israelites inhabited it."^[80] al-Harizi compared Saladins decree allowing Jews to re-establish themselves in Jerusalem to the one issued by the Persian Cyrus the Great over 1,600 years earlier.^[81]

In 1211, the Jewish community in the country was strengthened by the arrival of a group headed by over 300 rabbis from France and England,^[82] among them Rabbi Samson ben Abraham of Sens.^[83] Nachmanides, the 13th-century Spanish rabbi and recognised leader of Jewry greatly praised the land of Israel and viewed its settlement as a positive commandment incumbent on all Jews. He wrote "If the gentiles wish to make peace, we shall make peace and leave them on clear terms; but as for the land, we shall not leave it in their hands, nor in the hands of any nation, not in any generation."^[84]

In 1260, control passed to the Egyptian Mamluks. In 1266 the Mamluk Sultan Baybars converted the Cave of the Patriarchs in Hebron into an exclusive Islamic sanctuary and banned Christians and Jews from entering, which previously would be able to enter it for a fee. The ban remained in place until Israel took control of the building in 1967.^[85][86]

In 1470, Isaac b. Meir Latif arrived from Ancona and counted 150 Jewish families in Jerusalem.^[87] Thanks to Joseph Saragossi who had arrived in the closing years of the 15th century, Safed and its environs had developed into the largest concentration of Jews in Palestine. With the help of the Sephardic immigration from Spain, the Jewish population had increased to 10,000 by the early 16th century.^[88]

In 1516, the region was conquered by the Ottoman Empire; it remained under Turkish rule until the end of the First World War, when Britain defeated the Ottoman forces and set up a military administration across the former Ottoman Syria. In 1920 the territory was divided under the mandate system, and the area which included modern day Israel was named Mandatory Palestine.^[74][89][90]

§Zionism and the British mandate

Further information: Zionism, Mandate for Palestine, Balfour Declaration and Aliyah

Theodor Herzl, visionary of the Jewish State

Since the Jewish diaspora, some Jews have aspired to return to "Zion" and the "Land of Israel",^[91] though the amount of effort that should be spent towards such an aim was a matter of dispute.^[92][93] The hopes and yearnings of Jews living in exile are an important theme of the Jewish belief system.^[92] After the Jews were expelled from Spain in 1492, some communities settled in Palestine.^[94] During the 16th century, Jewish communities struck roots in the Four Holy Cities—Jerusalem, Tiberias, Hebron, and Safed—and in 1697, Rabbi Yehuda Hachasid led a group of 1,500 Jews to Jerusalem.^[95] In the second half of the 18th century, Eastern European opponents of Hasidism, known as the Perushim, settled in Palestine.^[96][97][98]

"I believe that a wondrous generation of Jews will spring into existence. The Maccabeans will rise again. Let me repeat once more my opening words: The Jews who wish for a State will have it. We shall live at last as free men on our own soil, and die peacefully in our own homes. The world will be freed by our liberty, enriched by our wealth, magnified by our greatness. And whatever we attempt there to accomplish for our own welfare, will react powerfully and beneficially for the good of humanity."

Theodore Herzl, concluding words of The Jewish State, 1896^[99]

The first wave of modern Jewish migration to Ottoman-ruled Palestine, known as the First Aliyah, began in 1881, as Jews fled pogroms in Eastern Europe.^[100] Although the Zionist movement already existed in practice, Austro-Hungarian journalist Theodor Herzl is credited with founding political Zionism,^[101] a movement which sought to establish a Jewish state in the Land of Israel, by elevating the Jewish Question to the international plane.^[102] In 1896, Herzl published Der Judenstaat (The State of the Jews), offering his vision of a future Jewish state; the following year he presided over the first World Zionist Congress.^[103]

The Second Aliyah (1904–14), began after the Kishinev pogrom; some 40,000 Jews settled in Palestine, although nearly half of them left eventually.^[100] Both the first and second waves of migrants were mainly Orthodox Jews,^[104]although the Second Aliyah included socialist groups who established the kibbutz movement.^[105] During World War I, British Foreign Secretary Arthur Balfour sent the Balfour Declaration of 1917 to Baron Rothschild (Walter Rothschild, 2nd Baron Rothschild), a leader of the British Jewish community, that stated that Britain intended for the creation of a Jewish homeland within the Palestinian Mandate.^[106][107]