The action of (*)-propranolol and (+)-propranolol on the electrical stimulation of adrenergic nerves to smooth muscle has been studied in the isolated ear artery from rabbits and the isolated vas deferens preparation from rats. Both drugs exhibited an adrenergic neuron blocking action at a pre-junctional site at concentrations ranging from 4.6 to 14pg/ml. At lower concentrations the effects were variable and more often potentiation of the responses was observed. The responses to added noradrenaline were uniformly potentiated. The effect was related to local anaesthetic activity and not considered to be a specific adrenergic neuron blocking effect as occurs with guanethidine or bretylium.

SummaryCollagen-induced platelet aggregation in mouse citrated platelet-rich plasma (PRP) was associated with 5-hydroxytryptamine (5-HT) release and degranulation. Adenosine 5’-diphosphate (ADP) induced monophasic and reversible aggregation with no degranulation. Mouse platelets gave no response to adrenaline but changed shape and sometimes aggregated in response to 5-HT. Both amines potentiated the effect of ADP. The respective potencies of prostaglandin E1, papaverine, VK 774, BL 3459 and adenosine as inhibitors of ADP-induced aggregation were similar in mouse and human PRP. Although ticlopidine had similar activity in the two species, aspirin and flurbiprofen were considerably less potent in mouse than human PRP as inhibitors of collagen-induced aggregation. It is suggested that collagen-induced aggregation of mouse platelets in vitro occurs by a mechanism largely independent of arachidonic acid metabolites.

A series of substituted 1,2-benzisothiazol-3-ones was synthesized, and the compounds were tested for ability to inhibit platelet aggregation induced by adenosine diphosphate and collagen in rats and guinea pigs ex vivo. Alkyl substituents at the 2-position bearing a basic group were necessary for ex vivo activity. Several of the compounds were potent inhibitors of adenosine diphosphate induced first-phase aggregation, but adverse toxicological findings terminated their further development. Preliminary studies suggested that inhibition of aggregation was not attributable to inhibition of prostanoid synthesis or to raised levels of cyclic 3',5'-adenosine monophosphate.

The effect of nabumetone (BRL 14777) on human platelet reactivity ex vivo was compared with that of naproxen at equitherapeutic doses in the same six subjects. Nabumetone had only a weak and equivocal effect on collagen-induced and second phase aggregation in response to adenosine diphosphate and adrenaline. After nabumetone, platelets fully aggregated in response to sodium arachidonate, though approximately twice as much was needed as on control occasions. Sodium arachidonate was unable to elicit a full aggregation response after naproxen. These results suggest that nabumetone may cause less interference with haemostasis than other non-steroidal anti-inflammatory drugs.

SummaryTwo hybrid plasminogen activators, plasmin A-chair/t-PA Bchain and plasmin A-chain/u-PA B-chain have been synthestzed and purified in sufficient yield to permit measurement of clearance in small laboratory animals. Each hybrid enzyme was reversibly acylated at the active centre to allow the pharmacokinetic profile to be followed using an activity-based method without interference from plasma inhibitors. The acylated plasmin/u-PA hybrid had a clearance half-life (t½) in guinea pigs of approximately 80 min, whereas acyl u-PA had a t½ of 3 min. The pharmacokinetic profile of the acylated plasmin/t-PA hybrid was measured in guinea pigs, rats and rabbits; the half-lives in all three species were 60–80 min compared to half-lives of acylated, native t-PA that were in the range 0.5–1.0 min. Thus, plasmin A-chaincontaining, acylated hybrid enzymes are cleared some 30- to 100-fold more slowly than the acylated parent activators.