Tsuneo Fujita

Tissue-type plasminogen activator and streptokinase induce platelet hyperaggregability in the rabbit

The ex vivo aggregability of rabbit platelets was assessed after rabbits were treated in vivo with thrombolytic doses of tissue plasminogen activator (t-PA) or streptokinase (SK). t-PA was evaluated at 2 doses; an effective thrombolytic dose of 10 micrograms/kg/min, i.v. and a higher dose of 30 micrograms/kg/min, i.v.. At both concentrations, ex vivo platelet hyperaggregability was observed when collagen, arachidonic acid or ADP were employed as the aggregating agonists. Significant falls in circulating platelet counts were observed after t-PA infusion. Infusion of SK also resulted in ex vivo platelet hyperaggregation. These data reveal that thrombolytic therapy may result in hyperaggregable platelets which may play a role in reocclusion of successfully recanalized blood vessels.

Effect of thromboxane synthase inhibition on the thrombolytic action of tissue-type plasminogen activator in a rabbit model of peripheral arterial thrombosis

The thrombolytic efficacy of recombinant tissue-type plasminogen activator (tPA) in the presence and absence of a thromboxane synthase inhibitor was studied in a model of femoral artery thrombosis in the anesthetized rabbit. The thrombus was formed by injection of thrombin and whole blood into an isolated segment of the femoral artery. After 30 min of stable thrombotic occlusion of the femoral artery, sodium heparin (300 U/kg, i.v.) was administered and tPA was infused locally to the site of the thrombus for 30 min at 0.01, 0.10 or 1.0 microgram/kg/min. In other experiments, CGS 13080, a selective thromboxane synthase inhibitor, was administered at a dose of 2 mg/kg i.v., 5 min before tPA was infused and at the end of the 30 min tPA infusion. Pretreatment with CGS 13080 resulted in a shorter time to tPA-induced reperfusion, greater incidence of reperfusion and increased the magnitude of femoral artery blood flow achieved after effective thrombolysis. Furthermore, pretreatment with CGS 13080 resulted in a greater than 10-fold enhancement in the effective dose of tPA. These data indicate that thromboxane synthase inhibition may be beneficial as an adjunct to thrombolytic therapy with tPA.

Mechanisms underlying reserpine-induced ptosis and blepharospasm: Evidence that reserpine decreases central sympathetic outflow in rats

Abstract Reserpine-induced blepharospasm in rats is a central action mediated through the temporal and zygomatic branches of the facial nerve. Reserpine-induced ptosis, on the other hand, occurs as a consequence of reduced sympathetic outflow. Evidence is presented that this reduction in sympathetic outflow occurs as a consequence of peripheral depletion of norepinephrine from postganglionic sympathetic nerve endings as well as via a central or preganglionic reduction in sympathetic outflow. The degree of central as opposed to peripheral effect is apparently dependent on pretreatment time as well as on the dose of reserpine administered.

Technic to record arterial blood pressure of unanesthetized rats

Abstract An uncomplicated and facile technic is described for the direct recording of blood pressure of unanesthetized rats. Essentially the procedure involves cannulation of the caudal artery of the rat under ether anesthesia. Approximately sixteen to twenty-four hours following the surgery the animals are ready for recording of systolic, mean and diastolic blood pressures. This technic is useful only for short term experiments, i.e., over one or two days time.

Interaction of Dopamine, (±)-Dobutamine and the (−)-Enantiomer of Dobutamine with α- and β-Adrenoceptors in the Pulmonary Circulation of the Dog

The effects of dopamine, (±)-dobutamine (racemic mixture) and (–)-dobutamine on α-adrenoceptor-mediated vasoconstriction were evaluated in the pulmonary circulation of the anesthetized dog. The drugs were studied in the absence and presence of pro-pranolol (1 mg/kg, i.v.) in order to assess β-adrenoceptor-mediated effects in the pulmonary circulation. Intra-arterial administration of dopamine, (±)-dobutamine and (–)-dobutamine elicited dose-dependent increases in pulmonary perfusion pressure, reflecting increases in pulmonary vascular resistance. In control animals, dopamine elicited the largest increases in pulmonary perfusion pressure (45% above resting pulmonary pressure) followed by (–)-dobutamine (30% increase) and (±)-dobutamine (15% increase). The pressor effects of dopamine in the pulmonary circulation were mediated by both postjunctional vascular α1-and α2-adrenoceptors, since prazosin, (100 μg/kg, i.v.), a selective α1-adrenoceptor antagonist, and rauwolscine (100 μg/kg, i.v.), a selective α1-adrenoceptor antagonist, both inhibited the vasopressor response elicited by dopamine to roughly equivalent degrees. Pulmonary vasoconstriction produced by (±)-dobutamine and (–)-dobutamine was mediated primarily by postsynaptic vascular α1-adrenoceptors, although α2-adrenoceptor-mediated vasoconstriction was observed. In propranolol-pretreated animals, the increase in pulmonary perfusion pressure elicited by dopamine and (–)-dobutamine was qualitatively and quantitatively similar to that observed in control animals, suggesting that these agents have little activity on vascular β2-adrenoceptors in the pulmonary circulation. In marked contrast, the maximum pulmonary vasopressor response obtained with (±)-dobutamine were greater in propranolol-pretreated animals, indicating that (±)-dobutamine also has the capacity to stimulate pulmonary vascular β2-adrenoceptors which mediate pulmonary vasodilation that, in part, mask α-adrenoceptor-mediated pulmonary vasoconstriction. Since the (–)-enantiomer of dobutamine has little or no β2-adrenoceptor agonist activity, the β2-adrenoceptor-mediated effect of (±)-dobutamine must result from the (+)-enantiomer as has been previously proposed. The results of the present study indicate that dopamine has a greater propensity for increasing pulmonary vascular resistance, and therefore pulmonary arterial blood pressure, relative to (±)-dobutamine. This results, at least in part, from the relatively weaker activity of dopamine in stimulating pulmonary vascular β2-adrenoceptors which mediate vasodilation. This, in turn, shifts the balance of activity for dopamine in favor of activating pulmonary vascular α1 and α2-adrenoceptors to produce vasoconstriction. The results are consistent with, and may even account for, the clinical observation that dopamine is far more likely to increase pulmonary capillary wedge pressure and pulmonary vascular resistance in patients with congestive heart failure than is (±)-dobutamine, and that the β2-adrenoceptor agonist activity of (±)-dobutamine may be critical for the beneficial effects of this drug in the pulmonary circulation.

EFFECT OF SELECTIVE ENDOPEROXIDE/THROMBOXANE A2 RECEPTOR ANTAGONISM WITH SULOTROBAN ON tPA‐INDUCED THROMBOLYSIS IN A RABBIT MODEL OF FEMORAL ARTERIAL THROMBOSIS

Summary— The thrombolytic efficacy of recombinant tissue‐type plasminogen activator (tPA) in the presence and absence of the selective endoperoxide/thromboxane A2 (TXA2) receptor antagonist, sulotroban (BM 13.177, SK&F 95587) was studied in a model of femoral artery thrombosis in the anesthetized rabbit. The thrombus was formed by injection of thrombin, CaCl2 and whole blood into an isolated segment of the femoral artery. After 30 min of stable thrombotic occlusion of the femoral artery, tPA was infused IV for 90 min at doses of 5.0, 7.5 and 10.0 μg/kg/min. In other experiments, sulotroban was administered as a bolus dose of 1 mg/kg/IV, followed by a constant infusion of 1 mg/kg/hr concurrent with tPA infusion. Sulotroban had no effect on the incidence of tPA‐induced reperfusion at any dose studied or on residual clot weight.