Dexamethasone affects platelet aggregation and fibrinolytic activity in rats at different doses which is reflected by their effect on arterial thrombosis.

The effect of oral administration of dexamethasone to rats on the haemostatic system was investigated. Dexamethasone was given once daily for 5 consecutive days. Plasma PAI-1 antigen levels were increased dose dependently (up to 210 +/- 29% of control values at a dose of 3 mg/kg) whereas no significant effects on plasma t-PA antigen levels were observed (131 +/- 6% compared with control values). In addition, treatment with 1 mg/kg dexamethasone decreased t-PA activity in tissue extracts of the aorta, heart and liver (65%, 28% and 58%, respectively) whereas tissue u-PA activity was not influenced. In vivo fibrinolytic activity was significantly decreased after dexamethasone treatment at a dose of 3 mg/kg but not at a dose of 1 mg/kg. The effect of dexamethasone on in vivo platelet aggregation was studied in an arterial thrombosis model. Dexamethasone treatment resulted in a two-fold decrease in arterial thrombosis at a dose of 0.1 mg/kg. At a dose of 1 mg/kg a less pronounced but significant decrease was observed. We conclude that in haemostasis the primary effect of dexamethasone treatment is an inhibition of arterial thrombosis by inhibition of platelet aggregation which is neutralized at higher doses by a decreased fibrinolytic activity.

Systemic and regional hemodynamic effects of the 5-hydroxytryptamine1A receptor agonists flesinoxan and 8-hydroxy-2(di-N-propylamino)tetralin in the conscious rat.

The systemic and regional hemodynamic effects of the centrally acting 5-Hydroxytryptamine1A (5-HT1A) receptor agonist flesinoxan (0.5 and 2.5 mg kg-1, intraarterially, i.a.) were investigated in conscious freely moving spontaneously hypertensive rats (SHR) and compared with those of 8-hydroxy-2(di-N-propylamino)tetralin (8-OH-DPAT) (0.1 and 0.5 mg kg-1, i.a.). In one group of animals, cardiac output (CO) was measured with a precalibrated electromagnetic flow probe around the ascending aorta. In another group, regional vascular conductances were measured using radioactive microspheres. Flesinoxan and 8-OH-DPAT dose dependently decreased blood pressure (BP) (22 +/- 5 and 13 +/- 4%, respectively, at the highest dose) mainly resulting from an increase in total peripheral vascular conductance (TPC) (34 +/- 12 and 16 +/- 3%, respectively) since there was no effect on CO. Both drugs reduced heart rate (HR) (17 +/- 4 and 20 +/- 4% for flesinoxan and 8-OH-DPAT, respectively, at the highest dose). Flesinoxan and 8-OH-DPAT showed a qualitatively similar pattern with regard to their effects on vascular conductances, causing increases in vascular conductances in the heart and skeletal muscles in contrast to results in a saline-treated group. Vascular conductances in the lungs were markedly increased by both flesinoxan and 8-OH-DPAT, which may indicate that the conductance in the arteriovenous shunt vessels was enhanced. These results demonstrate that flesinoxan and 8-OH-DPAT elicit a qualitatively similar systemic and regional hemodynamic profile in conscious SHR. Furthermore, the increase in TPC appears to be due mainly to vasodilatation in the skeletal muscles.

Pressor effects following microinjection of 5-HT1A receptor agonists into the raphe obscurus of the anaesthetized rat.

1. The effects of electrical stimulation and microinjections (90 nl) of the 5-HT1A receptor agonists, flesinoxan and 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), and glutamate into the raphe obscurus on blood pressure, heart rate and phrenic nerve activity (central inspiratory drive) were investigated in rats anaesthetized with alpha-chloralose. 2. Electrical stimulation of the raphe obscurus caused a rise in blood pressure which was associated with bradycardia, while glutamate (2.7 nmol) caused only a rise in blood pressure. 3. Flesinoxan (1.3 nmol) and 8-OH-DPAT (0.7 nmol) increased blood pressure by 9 +/- 1 and 14 +/- 2 mmHg, respectively and did not affect heart rate. For both agonists the effect on blood pressure was shown to be dose-dependent; again no effect on the heart rate was observed over the dose-ranges chosen. 4. Microinjections of the non-selective 5-HT1A receptor antagonists, (+/-)-pindolol (2.7 nmol) or methiothepin (5.2 nmol), into the raphe obscurus prevented the increase in blood pressure caused by microinjection of flesinoxan. However, (+/-)-pindolol caused a sustained rise in blood pressure of 15 +/- 1 mmHg while methiothepin caused a transient rise in blood pressure. Neither drugs affected heart rate. The ability of methiothepin to attenuate the pressor effect of flesinoxan was found to be partially reversed after 30 min. 5. It is suggested that activation of 5-HT1A receptors within the raphe obscurus can cause sympatho-excitation.

Comparison of the cardiovascular effects of the 5-HT1A receptor agonist flesinoxan with that of 8-OH-DPAT in the rat.

The cardiovascular response to flesinoxan and 8-OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin), 5-HT1A receptor agonists, has been investigated in anaesthetized Wistar rats and spontaneously hypertensive rats (SHR) and in conscious SHR. Flesinoxan and 8-OH-DPAT potently lowered blood pressure and heart rate in these models. In conscious SHR, atropine reversed the bradycardia induced by flesinoxan partially and that induced by 8-OH-DPAT completely. In pithed rats with vasopressin-raised blood pressure, neither flesinoxan nor 8-OH-DPAT lowered blood pressure or heart rate. Intracisternal administration of either flesinoxan or 8-OH-DPAT was less efficacious than intravenous administration. The cardiovascular responses to flesinoxan and 8-OH-DPAT in the anaesthetized Wistar were inhibited by the putative 5-HT1A antagonists methiothepin, buspirone, spiroxatrine and 8-MeO-C1EPAT (8-methoxy-2-(N-2-cholroethyl-N-n-propylamino)tetralin). 8-MeO-C1EPAT appeared to be the most suitable antagonist in this model. The 5-HT1C, antagonist ritanserin or the 5-HT3 antagonist GR 38032F had no effect on the responses to flesinoxan or 8-OH-DPAT. In conscious SHR however, 8-MeO-C1EPAT did not antagonize these cardiovascular responses. This study confirms the involvement of central 5-HT1A receptors in the cardiovascular effects of flesinoxan and 8-OH-DPAT.

Systemic and regional hemodynamic effects of the putative 5-HT1A receptor agonist flesinoxan in the cat.

The systemic and regional hemodynamic effects of the centrally acting putative 5-HT1A receptor agonist flesinoxan (3, 10, 30, and 100 micrograms/kg) were investigated in the anesthetized cat and compared with those of 8-hydroxy-2(di-n-prophylamino) tetralin (8-OH-DPAT 3, 10, 30, and 100 micrograms/kg) and clonidine (0.3, 1, 3, and 10 micrograms/kg). Cardiac output (CO) was measured with a precalibrated electromagnetic flow probe placed on the ascending aorta, and regional blood flows and conductances were measured with radioactive microspheres. Flesinoxan and 8-OH-DPAT caused a decrease in blood pressure (BP 44 and 37%, respectively, at 100 micrograms/kg) mainly resulting from an increased peripheral vascular conductance; in the case of 8-OH-DPAT, however, a reduction in CO (34%) also contributed. Clonidine decreased BP (12% at 10 micrograms/kg) by reducing CO (31%). All three drugs decreased heart rate (HR). Flesinoxan and 8-OH-DPAT decreased tissue perfusion in the heart, lungs, gastrointestinal tract, eyes, and skin, but both renal and cerebral blood flows were preserved as a result of increased vascular conductances. These two drugs also redistributed intrarenal blood flow from the outer cortex toward the inner cortex and medulla. Low doses of clonidine tended to increase but higher doses decreased organ blood flows, especially to the heart, lungs, liver, and eyes. Clonidine did not redistribute intrarenal blood flows. These results establish that the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT elicited a systemic and regional hemodynamic profile that differs from that of the alpha 2-adrenoceptor agonist clonidine.

Sympathoadrenal influence on glucose, FFA, and insulin levels in exercising rats.

The effects of sympathoadrenal manipulations on the exercise-induced alterations in blood glucose, plasma free fatty acids (FFA), and insulin were investigated in intact and adrenodemedullated rats. Exercise consisted of strenuous swimming against a countercurrent for 15 min. Before, during, and after swimming, blood samples were taken through a permanent heart catheter. Adrenodemedullation (Adm) markedly reduced the exercise-induced increase in both glucose and FFA. This effect was counteracted by intravenous infusion of epinephrine (E, 20 ng/min). Intravenous infusion of 50 ng E/min into Adm rats caused an exaggerated increase in glucose. In two additional experiments 1) specific adrenoceptor agonists and antagonists were administered to exercising intact and Adm rats, and 2) E or norepinephrine (NE; 20 ng/min) was infused into intact resting rats. The results suggest that E from the adrenal medulla directly affects glucose and insulin but not FFA concentrations in the blood. NE released from peripheral sympathetic nerve endings probably acts in two different ways: as neurotransmitter on liver and pancreas and as a hormone on adipose tissue.

Experience affects exercise-induced changes in catecholamines, glucose, and FFA.

The interference of the experimental conditions on the exercise-induced alterations in plasma catecholamines, plasma free fatty acids, and glucose and insulin concentrations was investigated in rats. Exercise consisted of strenuous swimming against a countercurrent (0.22 m/s) for 15 min in a pool with water of 33 degrees C. Before, during, and after swimming, blood samples were taken through a permanent heart catheter. The blood component levels in rats that were confronted with exercise for the very first time were compared with the levels in rats that were well accustomed to the exercise conditions. The very first time rats swam caused an enhanced release of epinephrine from the adrenal medulla and a reduced output of norepinephrine from the sympathetic nerve endings. Furthermore, in the first time swim group, blood glucose levels were higher and plasma free fatty acid concentrations were lower compared with the well-accustomed animals. There were no differences in plasma insulin concentrations. It is concluded that the experimental conditions may interfere considerably with the hormonal and metabolic response to exercise. Furthermore the results reinforce the idea that the two parts of the sympathoadrenal system are functionally and metabolically dissociated.

Adrenal and sympathetic catecholamines in exercising rats.

The effects of adrenodemedullation and/or adrenoceptor agonists and antagonists on plasma epinephrine (E) and norepinephrine (NE) concentrations during exercise were investigated in rats. Exercise consisted of strenuous swimming against a countercurrent for 15 min in a pool with water of 33 degrees C. Before, during, and after swimming, blood samples were taken through a permanent heart catheter. E was not detectable in plasma of adrenodemedullated (Adm) rats. A marked reduction in the normal exercise-induced increase in plasma NE concentrations occurred in both Adm rats as well as in intact rats injected with the beta 2-selective adrenoceptor antagonist ICI 118551. Intravenous infusion of either E or the beta 2-selective agonist fenoterol restored the increase in plasma NE in Adm rats. Injection of the alpha 2-selective antagonist yohimbine in combination with infusion of the beta 2-selective agonist fenoterol into Adm rats caused an enormous increase in plasma NE. It is concluded that all NE in plasma as released during exercise originates from the peripheral nerve endings of the sympathetic nervous system. Adrenal E influences the release of NE via activation of presynaptic beta 2-adrenoceptors.