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Since the synthesis of aspirin in 1897, aspirin-like or nonsteroidal antiinflammatory drugs (NSAIDs) have been the mainstay of therapy for rheumatoid arthritis. Although of diverse chemical structure, these drugs not only exhibit the same antipyretic, analgesic and antiinflammatory therapeutic actions, but they also manifest identical toxic actions on the gastric mucosa and the kidney. This indicated that a single pharmacological effect was responsible for the properties of NSAIDs, a theory that was confirmed by the epochal discovery by Vane in 1971, that inhibition of the enzyme-producing prostanoids (cyclooxygenase [COX]) produced both the therapeutic and side effects of aspirin-like drugs. However, at equivalent antiinflammatory doses, different NSAIDs exhibited different degrees of toxicity. The reason for this was resolved by the discovery that prostaglandins at sites of tissue damage were synthesized by an inducible COX (COX-2) formed by a gene distinct from that producing the constitutive enzyme (COX-1), responsible for the formation of prostaglandins that serve an essential physiological function. Modification of the structure of drugs showing a moderately selective effect on COX-2, and the elucidation of the crystal structure of both enzymes, has paved the way for the synthesis of NSAIDs that are highly selective for the inducible enzyme and which are, therefore, antiinflammatory without the typical side effects of the classical NSAIDs. The focus on COX-2 has also expanded our knowledge of the pathophysiological significance of prostanoids and raised the possibility of new uses for selective COX-2 inhibitors, for example, in colon cancer, premature labor and possibly Alzheimer's disease. However, the clinical effects of chronic administration of potent, selective COX-2 inhibitors must await the results of ongoing clinical trials.

Intravascular aggregation of platelets was evaluated in relation to the fibrinolytic system in order to assess the possibility of a "cause-effect" relationship. The spontaneous fibrinolytic activities of the plasma of male rats and of female rats at the various stages of the oestrous cycle were determined. Male rats had higher euglobulin clot lysis time (54.5 +/- 5.3 vs 29.2 +/- 3.1 min; P less than 0.05), higher fibrinogen levels (330.0 +/- 15.8 vs 231.0 +/- 31.1 mg/dl; P less than 0.025) and higher plasminogen activity (8.1 +/- 1.2 vs 6.1 +/- 1.6 plasmin units/ml; P less than 0.05) than female rats. Female rats had higher fibrinolytic index (8.8 +/- 0.8 vs 6.3 +/- 0.3 mg/dl; P less than 0.05) and plasminogen activator activity (99.1 +/- 6.0 vs 76.5 +/- 7.7 Plough units/ml; P less than 0.05) than male rats. The antiplasmin activities were the same in both sexes. During the oestrous cycle in female rats, euglobulin clot lysis time was not significantly different though it was highest during met-oestrous (34.2 +/- 3.6 min). However, pro-oestrous rats had lower fibrinogen (122.9 +/- 5.3 mg/dl; P less than 0.005), higher fibrinolytic index (10.6 +/- 0.8 mg/dl/min; P less than 0.001) and higher plasminogen activator activity (109.4 +/- 7.8 Plough units/ml; P less than 0.05) than rats from the other stages of the oestrous cycle. There were no significant differences in plasminogen content and antiplasmin activity. Using native rats, aggregatory responses to submaximal doses of adenosine diphosphate (20 micrograms/kg) were determined and correlated with the fibrinolytic data in age- and weight-matched rats (of both sexes). Aggregatory responses in all the groups of rats used correlated positively with fibrinogen levels (r = 0.8316; P less than 0.001) and negatively with plasminogen activator activity (r = -0.7839; P less than 0.05). Streptokinase (250-1000 Plough units/kg/hr) and urokinase (1000-4000 Plough units/kg/hr) produced dose-related reductions in intravascular aggregation induced by adenosine diphosphate. The streptokinase effect (but not urokinase effect) was reversed by epsilon-aminocaproic acid. Following the cessation of infusion of streptokinase and urokinase, there was a recovery of the platelets to aggregate to adenosine diphosphate. These observations suggest fibrinolytic pathway-specific effects. However, on its own, epsilon-amino-caproic acid did not affect the aggregatory responses of platelets from pro-oestrous rats. These results suggest that changes in fibrinolytic mechanisms may account for differences observed in intravascular aggregation of platelets of male and female rats and of female rats during the oestrous cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Study Objective: The aim was to determine the receptors involved in the antiaggregatory effects of adrenaline in the rat., Design: The 111indium oxine technique was used to evaluate ADP induced pulmonary accumulation of 111In labelled platelets in adrenalectomised rats (ie, no endogenous adrenaline) in the absence of anticoagulants. Adrenaline was infused (10, 20 and 40 micrograms.kg-1.h-1) and ADP aggregation measured. Adrenoceptor agonists, isoprenaline, methoxamine, and BHT 933, were given to evaluate whether they mimic the adrenaline effects. Adrenoceptor antagonists, yohimbine, propranolol, prazosin, and WY 26392, were given to assess whether they block the adrenaline effects., Measurements and Main Results: In all cases, pulmonary accumulation of platelets was measured in response to ADP. Adrenaline dose dependently inhibited platelet aggregation. BHT 933 (1.5 micrograms.kg-1.min-1) mimicked, while phentolamine (1 mg.kg-1), yohimbine (2.5 mg.kg-1), and WY 26392 (0.1, 1.0, 5.0 mg.kg-1) blocked, the adrenaline effects. Methoxamine (3.3 micrograms.kg-1.min-1) produced a relatively weak non-specific inhibition of ADP aggregation. Isoprenaline (33 ng.kg-1.min-1) did not mimic the effects of adrenaline, neither did propranolol (1 mg.kg-1) affect the adrenaline inhibition of the aggregatory responses to ADP. Indomethacin (3 mg.kg-1) blocked the inhibitory effects of adrenaline., Conclusions: Adrenaline stimulates alpha receptors on platelets but inhibits platelet aggregation. There is no evidence to suggest that beta receptors participated in the effects produced by adrenaline. There is a role for cyclo-oxygenase products in the inhibitory effects of adrenaline on aggregation.

Physiological levels of oestradiol and adrenaline inhibit intravascular aggregation of platelets, and effect dependent on the presence of an adrenal gland secretion (possibly adrenaline) and oestrogens, respectively. This infers a "mutual dependence" phenomenon. Acute adrenalectomy had a biphasic effect on intravascular aggregation: enhancing platelet aggregation when levels of oestradiol are high, e.g. in pro-oestrous rat, and reducing platelet aggregation when levels of oestradiol are nil or very low, i.e., in ovariectomized or di-oestrous rats, respectively. Ovariectomy also had a biphasic effect on platelet aggregation reducing aggregation in the absence of adrenaline and enhancing aggregation in its presence. Removal of endogenous oestradiol (by ovariectomy) and its replacement fully corroborates the "mutual dependence" hypothesis, whereas the removal of endogenous adrenaline (by acute adrenalectomy) and its replacement only partially supports it. It is concluded that, though both oestradiol and adrenaline have inhibitory effects on intravascular aggregation at physiological doses, each seems to need the full compliment of the other to achieve the effect.

Intravascular platelet aggregation to adenosine diphosphate (ADP) was measured in anesthetized rats using 111indium-labelled platelets. Acute adrenalectomy increased the aggregatory effect of ADP in vivo, whereas infusions of low concentrations of adrenaline into adrenalectomized rats suppressed ADP-induced platelet aggregation. Similar antiaggregatory effects were seen with the alpha 2 agonist B-HT 933 and the alpha 1 agonist methoxamine, but not with isoprenaline. The effect of adrenaline was inhibited by phentolamine, yohimbine, the selective alpha 2 adrenoceptor antagonist WY 26392 and by indomethacin, but not by propranolol or prazosin. Adrenaline thus inhibits ADP-induced aggregation in vivo by a mechanism that may involve stimulation of an alpha 2 adrenoreceptor and may be dependent on activation of cyclooxygenase enzyme.