In dogs, Crawford (1905, 1911, 1914) reported a temporary fall of blood pressure, even if both vagus nerves were cut, followed by a marked and sustained raise together with increases in pulse rate and diuresis by the intravenous injection of an extract from American mistletoe (Phoradendron flavescens); the initial fall of blood pressure was prevented by the acetylcholine inhibitor atropine. Thus, Crawford and Watanabe (1914) suggested the presence of choline or acetylcholine. Both, Phoradendron flavescens and Phoradendron villosum produced temporary hypotension, and an initial increase in respiration and pulse rate, peripheral vasoconstriction, reduction of the volume of peripheral organs, and decrease of the cardiac volume and urine output (Hanzlik and Frech, 1924). After that, a quick recovery of the blood pressure was observed, while the pulse rate remained accelerated; however, respiration was reduced in rate and amplitude, or even stopped. As also the intestines and uteri of non-pregnant animals responded with increased tonus and contractility, Hanzlik and French (1924) suggested a direct stimulation of muscle cells by the drug.
The hypotensive effects of European mistletoe were investigated by Gaultier and Chevalier in man and animals (Gaultier, 1907, 1910). Injection of an aqueous extraction from Viscum album leaves in frogs produced bradycardia, negative dromotropic effects resulting in irregularities of heart rhythm, and arrest of the heart in systole (Ebster and Jarisch, 1929). Also in cats and rabbits, intravenous application of Viscum album resulted in hypotension, bradycardia, arrhythmia and cardiac arrest in systole (Ebster and Jarisch, 1929; Jarisch und Henze, 1937; Henze and Ludwig, 1937; Jarisch, 1938; Enders, 1940; Zipf, 1950), and constriction of the intestine and uterus (Enders, 1940). A continuous decrease of the arterial blood pressure was associated with a constant raise of the venous blood pressure until cardiac arrest (Enders, 1940). 3 to 4 mg of the Viscum album extract (VA-E) killed cats and rabbits (Enders, 1940); however, rats were killed by an intravenously applied aqueous VA-E from leaves at 60 to 800 mg/kg body weight (BW) (Ebster and Jarisch, 1929). These results indicate a distinct affection of heart activity by compounds from Viscum album. However, affection of the heart by Viscum album was suggested not to depend on the sympathic or parasympathic system but to be due to a direct affection of the heart muscle cells (Enders, 1940).
Apart from the hypotensive effect of aqueous VA-E from the dried leaves of mistletoe grown on different host trees in dogs, cardioxicity was prevented by oral application, and by heating (Pora et al., 1957), indicating a proteinic-nature of the relevant compounds. Indeed, oral application of Viscum album concentration 3x higher than those applied intravenously did not result in cardiac arrest (Enders, 1940), indicating the degradation of the toxic compound in the stomach and/or intestine.
It became evident, that the effects of mistletoe on blood pressure and heart activity may be due to distinct compounds present in Viscum album. The hypotension-inducing substance present in Viscum album was suggested to be acetylcholine (Müller, 1932). Indeed, Winterfeld and Kronenthaler (1942) verified the presence of acetylcholine and choline. Later on, Winterfeld and Rink (1948) were able to attribute the cardiotoxic effects of VA-E to a compound termed "viscotoxin". The lethal concentration of this toxin was found to be 0.5 mg/kg BW in rabbits (Winterfeld and Bijl, 1948), and 0.2 to 0.4 mg/kg BW in rats (Zipf, 1950). The animals died with dyspnoe, cramps, and systolic heart arrest. The cardiotoxic component was recognised by Zipf (1950) to be identical with the necrosis-inducing compound described by Koch (1938a). Samuelsson (1959) reported that the transient hypotensive effects of VA-E were caused by choline and 7-aminobutyric acid, while the main effect was a toxic manifestation which could be attributed to the viscotoxins. Later on, also flavonoids such as quercitrin, rhamnetin-3-O-rhamnoside, rhamnocitrin-3-O-rhamnoside, homo-flavoyadorinin-B and acetylcholine, isolated from Japanese mistletoes (Taxillus yadoriki DANSER, Hyphear tanakae HOSOKAWA, and Viscum album LINNE var. coloratum OHWI), were suggested to be responsible for the temporary hypotensive response (Fukunaga et al., 1989).
Viscotoxin when applied intravenously in cats at 35 ^g/kg BW, and also a thionin from Phoradendron serotinim, termed Phoratoxin, at 400 ^g/kg BW, resulted in vasoconstriction of blood vessels, reflex bradycardia, negative inotropic effect on the heart and thus, hypotension (Rosell and Samulesson, 1966). However, viscotoxin-induced bradycardia was completely prevented by bilateral vagotomy, indicating its reflex origin, while the decrease of the contractile force of the heart was only transiently influenced by vagotomy, indicating that viscotoxin exerts its negative inotropic effect directly upon the heart muscle (Rosell and Samuelsson, 1966). Indeed, a thionin from Phoradendron tomentosum macrophyllum (Phoratoxin B) was found to irreversible depolarise the membranes of frog skeletal and heart muscles as well as papillary heart muscle (Sauviat et al., 1985).
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