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Vascular fibrinolysis in aging: enhanced response to adrenergic stimulation
Vol. 70, Suppl. 1
ABSTRACTS OF 12TH NATIONAL CONGRESS
c 149 ADRENERGIC STIMULATION OF TISSUE-TYPE PLASMINOGEN ACTIVATOR RELEASE’IN A MODEL OF VASCULAR PERFUSION IN RATS. Licia Iacoviello, Amalia De Curtis, Maria Cristina D’Adamo, Wlodzimierz Buczko e Maria Benedetta Donati. Laboratory for thrombosis pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud - 66030 Santa Maria Imbaro (Italy). t-PA release by vascular endothelium plays a pivotal role in the activation of the fibrinolytic system. The ability of catecholamines to stimulate t-PA secretion is well known. Recently, we reported an enhancement of t-PA activity in perfusate samples after epinepbrine infusion in the perfused rat hiidleg model. We aimed to study the mechanisms of adrenergic stimulation that modulate the vascular tibrinolytic response in rats. Epinephrine infusion (O.Ol-25pM) induced a dose-depended release of t-PA activity, and, at the same time. an increase in the perfusion pressure. S-receptor blockade (propanolol,5OpM, lOmin), totally inhibited the effect of epinephrine (6.25@vI. Smin) on t-PA release, but only partially the effect on the perfusion pressure (from 184k7.2 to 114&13 mmHg, mearrhse, n=6). On the contrary, a selective alblocker (prazosine.O.l@vI, 10min)was able to totally inhibit both t-PA and perfusion pressure increase ofter epinephrine infusion. Finallyg selective a2blocker (yohimbine,lOpM. 1Omin) was ineffective on t-PA release while it inhibited of 62% the increase in perfusion pressure (from 184f72 to 52k1.7 mmHg). Phenilephrine(l0 pM. 5 min), a al receptor agonist,was also able to increase t-PA release (from O.tiO.01 to 0.32fO.O8UI/ml) and perfusion pressure (horn 27i0.8 to 94f5mmHg in our system). Both effects were totally blocked by prazosin (O.lpM, 1Omin) while propanolol totally inhibited t-PA release , but only partiahy the perfusion pressure increase.In conclusion, the t-PA release induced by epinephrine could be mediated by both a and 8 receptors, is not dependent by the pressure increase and probably involves central and peripheral mechanisms.
c 150 VASCULAR FIBRINOLYSIS IN AGING: ENHANCED RESPONSE TO ADRENERGIC STIMULATION. Licia Iacoviello, Amalia De Curtis, Maria Cristina D’Adamo and Maria Benedetta Donati. Laboratory of Thrombosis Pharmacology. Istituto di Ricerche Farmacologiche Mario Negri Consorzio Mario Negri Sud. 66030 Santa Maria Imbaro (Italy). Adrenergic stimulation induces an acute fibrinolytic response in the vascular wall and can play an important role in limiting thrombus growthAs many adrenergic functions are affected during aging, we decided to study the vascular fibrinolytic response to epinephrine in a model of “in vivo” vascular perfusion in young(3+ 1 month) and aged (l&3 month) rats. The basal levels of fibrinolytic activity were higher in aged than in young rats (0.2tiO.02 vs 0.13+_0.01 IU/ml; pcO.01). Epinephrine infusion (5 min) induced a dose-dependent increase in fibrinolytic activity in both groups of animals: the maximal response, however, was higher in aged rats (0.78+0.06 vs 0.4M0.07 IU/ml; ~~0.01). In this group of animals, there was also a delay in tbe fibrinolytic response, more evident at the higher doses of epinephrine studied. On the contrary, the perfusion pressure, increased less in aged than in young animals. To evaluate whether the change in vascular response was specific for the adrenergic stimulation, we infused, in the same model, PAF, another agonist of the librinolytic system. In young rats PAF (0.01-5 nM) induced a dose-dependent increase in t-PA release, up to the concentration of 1.25 nM. The t-PA activity increased from 0.04*0.008 to 0.84f0.13 Ill/ml, during PAF (0.75 nM, 5 min) infusion and was back to basal values at the end of infusion. In aged rats we observed a comparable increase in t-PA activity at each dose of PAF evaluated. In conclusion, the fibrinolytic response to epinephrine infusion is enhanced by aging and this effect is specific for the adrenergic stimulation. In particular, such change in fibrinolytic response could be an adaptative mechanism to the thrombotic tendency developing during aging.
s77
ABSTRACTS OF 12TH NATIONAL CONGRESS
c 149 ADRENERGIC STIMULATION OF TISSUE-TYPE PLASMINOGEN ACTIVATOR RELEASE’IN A MODEL OF VASCULAR PERFUSION IN RATS. Licia Iacoviello, Amalia De Curtis, Maria Cristina D’Adamo, Wlodzimierz Buczko e Maria Benedetta Donati. Laboratory for thrombosis pharmacology, Istituto di Ricerche Farmacologiche Mario Negri, Consorzio Mario Negri Sud - 66030 Santa Maria Imbaro (Italy). t-PA release by vascular endothelium plays a pivotal role in the activation of the fibrinolytic system. The ability of catecholamines to stimulate t-PA secretion is well known. Recently, we reported an enhancement of t-PA activity in perfusate samples after epinepbrine infusion in the perfused rat hiidleg model. We aimed to study the mechanisms of adrenergic stimulation that modulate the vascular tibrinolytic response in rats. Epinephrine infusion (O.Ol-25pM) induced a dose-depended release of t-PA activity, and, at the same time. an increase in the perfusion pressure. S-receptor blockade (propanolol,5OpM, lOmin), totally inhibited the effect of epinephrine (6.25@vI. Smin) on t-PA release, but only partially the effect on the perfusion pressure (from 184k7.2 to 114&13 mmHg, mearrhse, n=6). On the contrary, a selective alblocker (prazosine.O.l@vI, 10min)was able to totally inhibit both t-PA and perfusion pressure increase ofter epinephrine infusion. Finallyg selective a2blocker (yohimbine,lOpM. 1Omin) was ineffective on t-PA release while it inhibited of 62% the increase in perfusion pressure (from 184f72 to 52k1.7 mmHg). Phenilephrine(l0 pM. 5 min), a al receptor agonist,was also able to increase t-PA release (from O.tiO.01 to 0.32fO.O8UI/ml) and perfusion pressure (horn 27i0.8 to 94f5mmHg in our system). Both effects were totally blocked by prazosin (O.lpM, 1Omin) while propanolol totally inhibited t-PA release , but only partiahy the perfusion pressure increase.In conclusion, the t-PA release induced by epinephrine could be mediated by both a and 8 receptors, is not dependent by the pressure increase and probably involves central and peripheral mechanisms.
c 150 VASCULAR FIBRINOLYSIS IN AGING: ENHANCED RESPONSE TO ADRENERGIC STIMULATION. Licia Iacoviello, Amalia De Curtis, Maria Cristina D’Adamo and Maria Benedetta Donati. Laboratory of Thrombosis Pharmacology. Istituto di Ricerche Farmacologiche Mario Negri Consorzio Mario Negri Sud. 66030 Santa Maria Imbaro (Italy). Adrenergic stimulation induces an acute fibrinolytic response in the vascular wall and can play an important role in limiting thrombus growthAs many adrenergic functions are affected during aging, we decided to study the vascular fibrinolytic response to epinephrine in a model of “in vivo” vascular perfusion in young(3+ 1 month) and aged (l&3 month) rats. The basal levels of fibrinolytic activity were higher in aged than in young rats (0.2tiO.02 vs 0.13+_0.01 IU/ml; pcO.01). Epinephrine infusion (5 min) induced a dose-dependent increase in fibrinolytic activity in both groups of animals: the maximal response, however, was higher in aged rats (0.78+0.06 vs 0.4M0.07 IU/ml; ~~0.01). In this group of animals, there was also a delay in tbe fibrinolytic response, more evident at the higher doses of epinephrine studied. On the contrary, the perfusion pressure, increased less in aged than in young animals. To evaluate whether the change in vascular response was specific for the adrenergic stimulation, we infused, in the same model, PAF, another agonist of the librinolytic system. In young rats PAF (0.01-5 nM) induced a dose-dependent increase in t-PA release, up to the concentration of 1.25 nM. The t-PA activity increased from 0.04*0.008 to 0.84f0.13 Ill/ml, during PAF (0.75 nM, 5 min) infusion and was back to basal values at the end of infusion. In aged rats we observed a comparable increase in t-PA activity at each dose of PAF evaluated. In conclusion, the fibrinolytic response to epinephrine infusion is enhanced by aging and this effect is specific for the adrenergic stimulation. In particular, such change in fibrinolytic response could be an adaptative mechanism to the thrombotic tendency developing during aging.
s77