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Nerve growth factor (NGF), substance P (SP) and thymopoietin all caused shape change reactions of rapid onset in rabbit platelets. NGF had the highest maximal effect, and SP the lowest EC50 (concentration causing half maximal shape change). The action of SP was reversible within 5 min, whereas that of NGF lasted for at least 1 h. A series of other peptides were inactive. After preincubation of platelets with SP, a second application of SP no longer caused a shape change reaction, whereas the effect of NGF was not influenced. An oxidized NGF‐derivative without biological activity did not cause a shape change reaction, neither did epidermal growth factor. Prostaglandin E1 (PGE1) and pretreatment of the platelets with 3% butanol, which counteract the shape changes caused by 5‐hydroxytryptamine (5‐HT) and adenosine 3′, 5′‐diphosphate, also antagonized those induced by NGF and SP. Neither heparin nor methysergide, an antagonist of 5‐HT‐receptors, influenced the shape change induced by NGF or SP. The action of NGF was also antagonized by a specific antibody to NGF. Thymopoietin, like the basic polypeptide polyornithine (mol. wt. 40,000), was not antagonized by PGE1 and butanol. Heparin, which counteracted the effect of polyornithine, did not influence that of thymopoietin. In conclusion, different modes of action are involved in the shape change of blood platelets induced by polypeptides and proteins. SP and NGF may act by stimulating specific membrane receptors.

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The initial uptake of 3H‐5‐hydroxytryptamine (3H‐5‐HT) showed linearity for short time intervals in normal and reserpinized blood platelets of guinea‐pigs, but was lower in reserpinized platelets. The Km values for the 3H‐5‐HT uptake were virtually identical in normal and reserpinized platelets, whereas Vmax was lower in the latter. Imipramine and chlorpromazine caused the same percentage inhibition of 3H‐5‐HT uptake in normal and reserpinized platelets; the reserpine‐like compound Ro 4–1284 inhibited the uptake of 3H‐5‐HT in the normal, but not markedly in the reserpinized platelets. Haloperidol, prenylamine and Ro 4–9040 were more potent inhibitors in normal than in reserpinized platelets. It is concluded that (a) the Km of the initial uptake of 5‐HT by platelets is probably determined by the mechanism at the plasma membrane, whereas Vmax may be codetermined by the intracellular storage capacity, (b) platelets are models for differentiating the site of action (plasma membrane or storage organelles) of drugs interfering with 5‐HT uptake, and (c) neuroleptics‐ and reserpine‐like compounds may either act selectively on the plasma membrane or on the intracellular storage organelles, or affect both of these subcellular sites.