Åke Wennmalm

Publisher Summary

This chapter provides an overview of prostaglandins (PGs) and the heart. PGs are fatty acid derivatives. Prostanoic acid, a saturated C-20 fatty acid with cyclization between carbon atoms 8 and 12, is the theoretical mother substance. PGs are subgrouped by the letters A–I, depending on their chemical structure. Prostaglandins are formed in most tissues in the body. The chief precursor in the bioformation of PGs is arachidonic acid (AA). AA, liberated into the cytoplasm, can be transformed oxidatively via a variety of metabolic routes. The PG endoperoxides, although possessing a biological activity of their own, are generally regarded as intermediates in PG bioformation. Agents that apparently initiate or accelerate PG formation by activating phospholipase A may be chemical, neuronal, or physical in nature. The cardiac tissue accelerates its synthesis of PG when it is exposed to ischemia. Below a certain level of tissue oxygen tension, hypoxia counteracts rather than stimulates PG bioformation.

I A Historical Outline

Prostaglandin (PG) research entered its most expansive phase in the early 1960s, but its origins lie in the beginning of the present century. The possibility that the male genital glands, apart from producing a nutritive transport solvent for the male gametes, also form biologically active agents attracted several investigators. The first observation that may be ascribed to the action of a prostaglandin or related compound was made by Camus and Gley in 1907. These authors injected the secretion from the internal prostate of the hedgehog intravenously into rabbits and found that the animals became severely dyspnoic and died. Götzl (1910) reported analogously that pressed juice from human prostate glands (autopsy material) on iv injection killed rabbits, apparently by inducing intravascular clotting. These early observations deserve attention since they suggest that products formed in the prostate gland may be related in some way to blood clotting, an idea that is of considerable current interest.

Experiments with extracts from fresh human prostate gland were carried out by Battez and Boulet (1913). The material was obtained from a 20-year-old man who had been executed. Injection of the extract intravenously in the dog led to a pronounced fall in blood pressure. This was probably the first observation to indicate the occurrence of a depressor substance in the male prostate gland. The first communication on a pharmacodynamic action of human seminal fluid originates from Kurzrok and Lieb (1931). They observed, after addition of seminal fluid to an isolated human uterine strip, an increase or a decrease in spontaneous movement or tone. The conclusion, apparently erroneous, was that the active agent in the seminal fluid was acetylcholine.

The occurrence of a depressor and smooth-muscle-stimulating substance in human seminal fluid was reported independently by Goldblatt (1933) and von Euler (1934). Initially the active principle was indistinctly separated from substance P, likewise a strong depressor agent. However, the chemical disparity between the new agent and substance P was rapidly elucidated, and the substance was given the name prostaglandin (von Euler, 1935a). Chemically it was defined as an acid soluble in ether and chloroform. It was clearly separated from other vasoactive substances (von Euler, 1935b). Later its entire blood-pressure-lowering action was shown to be due to a relaxing influence in the resistance vascular bed, the mammalian heart being completely unaffected by prostaglandin (von Euler, 1936). That prostaglandin is not a general vasodilator was pointed out; both qualitative and quantitative organ and species differences exist (von Euler, 1939).

The lack of suitable chemical methods at that time rendered further prostaglandin studies difficult. Not until the late 1940s was a second wave of research begun. It was then that the fruitful work of the Bergström group started, initiated by von Euler. This resulted in the important discovery that prostaglandin, rather than being a single compound, is a whole family of active agents. One of the first consequences of this discovery was the isolation of two prostaglandins in crystalline form (Bergström and Sjövall, 1957). Subsequently, research activity in the prostaglandin field has snowballed.

Von Euler focused his interest at an early stage on the cardiovascular effects of prostaglandin. Today, 45 years later, prostaglandins appear as significant as ever before in connection with cardiac function in health and disease.

II Chemistry and Biochemistry of Prostaglandins