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Hemmung der Lipolyse durch α- und β-Sympathicolytica, Nicotinsäure und Prostaglandin E1

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Zusammenfassung

An Ratten wurde die Wirkung von α-Sympathicolytica (Phentolamin, Phenoxybenzamin), β-Sympathicolytica [Dichlorisoproterenol, Pronethalol, Methylphenoxy-isopropylaminopropanol (Kö 592), Propranolol], Nicotinsäure und Prostaglandin E 1 auf die Lipolyse untersucht.

1. An unvorbehandelten, gefütterten Ratten wurde der Plasmaspiegel an unveresterten Fettsäuren durch Injektion von Dichlorisoproterenol, Pronethalol, Phentolamin und Phenoxybenzamin erhöht, blieb dagegen nach Injektion 10–100 fach höherer Dosen von Kö 592 oder Propranolol praktisch unbeeinflußt und wurde durch Nicotinsäure signifikant erniedrigt.

2. Vorbehandlung der Tiere mit β-Sympathicolytica (z. B. Kö 592) verhinderte die lipolytische Wirkung des Noradrenalins ohne diejenige des ACTH zu beeinflussen. Demgegenüber wurde durch α-Sympathicolytica (z. B. Phenoxybenzamin) die lipolytische Wirkung von Noradrenalin und ACTH etwa gleichstark gehemmt, durch Nicotinsäure aber vollständig aufgehoben. — Die verstärkte Lipolyse im Hungerzustand, beim Alloxan-Diabetes, sowie nach Injektion von Physostigmin wurde durch Nicotinsäure, nicht aber durch Kö 592 verhindert, während der Fettsäureanstieg beim Kälte-Stress auch durch Kö 592 stark abgeschwächt wurde.

Durch Anwendung von β-Sympathicolytica und Nicotinsäure ist es somit möglich, bei einer verstärkten Lipolyse unbekannter Genese zwischen adrenergischen und nicht-adrenergischen Mechanismen zu unterscheiden.

3. Am isolierten, epididymalen Fettgewebe der Ratte verhinderten β-Sympathicolytica (Kö 592, Propranolol) die lipolytische Wirkung des Noradrenalins schon in Konzentrationen, welche die lipolytische Wirkung des ACTH noch unbeeinflußt ließen, während α-Sympathicolytica (Phentolamin, Phenoxybenzamin) die Wirkung des Noradrenalins und des ACTH etwa gleich stark hemmten.

4. In vitro hemmte Prostaglandin E1 die „spontane“ Lipolyse, die gesteigerte Lipolyse alloxandiabetischer Ratten und auch die lipolytische Wirkung des Noradrenalins; es war jedoch nicht imstande, die erhöhte Lipolyse hungernder Ratten zu beeinflussen.

5. Als Angriffspunkt der β-Sympathicolytica kommt die Adenylcyclase des Fettgewebes in Frage, denn es spricht vieles dafür, daß die Triglyceridlipase — ähnlich wie die Phosphorylase — durch cyclisches Adenosin-3′,5′-monophosphat aktiviert wird.

Summary

In rats the antilipolytic effects of α-adrenolytics (phentolamine, phenoxybenzamine), β-adrenolytics (dichloroisoproterenol, pronethalol, propranolol, Kö 592 [1-(3-methylphenoxy)-3-isopropylaminopropanol-2], nicotinic acid and prostaglandin E 1 have been studied.

1. In untreated fed rats the plasma level of free fatty acids (FFA) was increased by subcutaneous injection of dichloroisoproterenol, pronethalol, phentolamine and phenoxybenzamine, while 10 to 100 times higher doses of Kö 592 or propranolol had no significant effect; in contrast plasma FFA were lowered by nicotinic acid.

2. In vivo, the FFA mobilizing effect of norepinephrine was blocked by pretreatment with Kö 592 at a dose which had no effect upon the lipolytic action of ACTH. In contrast, both the effects of norepinephrine and ACTH were inhibited to about the same degree by the α-adrenolytic phenoxybenzamine and completely blocked by pretreatment with nicotinic acid. Unlike FFA mobilization during cold exposure, increased lipolysis in fasting or diabetic rats, or following the injection of physostigmine was not inhibited by pretreatment with Kö 592; increase of plasma FFA after the injection of theophylline was only reduced by Kö 592, while all effects were completely blocked by nicotinic acid.

Using Kö 592 — or any potent β-adrenolytic — and nicotinic acid resp. it is thus possible to differentiate between adrenergic and nonadrenergics mechanisms leading to lipolysis.

3. In vitro, i. e. upon incubation with epididymal adipose tissue of rats, the lipolytic effect of norepinephrine was inhibited by both α- and β-adrenolytics. To obtain 50% inhibition of a standard dose of norepinephrine (6×10−7 M), however, more than 100 times higher concentrations of the α-adrenolytics phentolamine or phenoxybenzamine were required as compared to the β-adrenolytics Kö 592 or propranolol. Pronethalol was 40 times less avtive than Kö 592, while iproveratril had only weak antilipolytic activity.

If ACTH was the lipolytic stimulant α- and β-adrenolytics were equally effective; however, the concentrations of the β-adrenolytics necessary to block a standard dose of ACTH by 50% were up to 500 times higher than those used in the experiments with norepinephrine as the lipolytic stimulant.

4. Unlike the β-adrenolytics, prostaglandin E1 (PGE) inhibited in vitro spontaneous lipolysis as well as lipolysis induced by norepinephrine, ACTH or alloxan diabetes. PGE had no inhibitory effect in fat pads of fasting rats.

5. The possible sites of action of the various inhibitors are discussed, particularly the possibility that adenyl cyclase might be the site of action of the β-adrenolytics. This assumption is favored by evidence that lipolysis is induced in much the same manner as glycogenolysis, i.e. through the formation of cyclic adenosine-3′,5′-monophosphate.

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  1. Pharmakologisches Institut der Universität Frankfurt a. M., Germany

    K. Stock & E. Westermann

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Herrn Professor Dr. O. Schaumann zum 75. Geburtstag gewidmet.

Ausgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft (We 272). Über einen Teil der Ergebnisse wurde auf Tagungen der Deutschen Pharmakologischen Gesellschaft (Westermann u. Stock, 1963, 1965; Stock u. Westermann, 1966b) und der Deutschen Gesellschaft für Endokrinologie (Westermann, 1966) berichtet, sowie in einer kurzen Mitteilung (Stock u. Westermann, 1965c).

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Stock, K., Westermann, E. Hemmung der Lipolyse durch α- und β-Sympathicolytica, Nicotinsäure und Prostaglandin E1 . Naunyn-Schmiedebergs Arch. Pharmak. u. Exp. Path. 254, 334–354 (1966). https://doi.org/10.1007/BF00538805

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