pituitrin and furegrelate

1. In the present study, we aimed to determine the involvement of brain thromboxane A2 (TXA2) in blood pressure decreases evoked by acute and/or graded haemorrhage in rats. 2. Sprague-Dawley rats were used throughout the study. Acute haemorrhage was achieved by withdrawing a total volume of 2.1 and 2.5 mL blood/100 g bodyweight over a period of 10 min. A microdialysis study was performed in a hypothalamic area to measure extracellular TXA2 levels. Graded haemorrhage was conducted successively by withdrawing carotid arterial blood (0.55 mL/100 g bodyweight) over a 10 s period four times (S1-S4) at 5 min intervals. Furegrelate (125, 250 and 500 microg), a TXA2 synthase inhibitor, was injected intracerebroventricularly (i.c.v.) 60 min before acute or graded haemorrhage was initiated. U-46619 (0.5, 1 and 2 microg, i.c.v.), a synthetic TXA2 analogue, was administered 5 min before acute haemorrhage (2.1 mL/100 g bodyweight). 3. Acute haemorrhage produced a severe and long-lasting decrease in blood pressure and had a tendency to increase heart rate. Both haemorrhage protocols (2.1 or 2.5 mL/100 g) generated similar approximate twofold increases in extracellular hypothalamic TXA2 levels. Intracerebroventricular furegrelate (250 microg) pretreatment completely blocked the TXA2 increases induced by acute haemorrhage. Furegrelate administration (100, 250 and 500 microg, i.c.v.) attenuated the fall in arterial pressure evoked by acute haemorrhage and caused significant increases in heart rate at all doses injected. 4. Graded haemorrhage progressively lowered arterial pressure and increased plasma vasopressin and adrenaline levels in the last period. Furegrelate-injected rats were greatly resistant to the hypotensive effect of haemorrhage for all degrees of blood removed. Plasma adrenaline and vasopressin levels were significantly elevated in furegrelate-pretreated rats compared with the saline-treated group during S2-S3 and S4, respectively. U-46619 administration caused small but statistically significant decreases in arterial pressure induced by haemorrhage. 4. The results show that acute hypotensive haemorrhage increases extracellular hypothalamic TXA2 levels. The increase in brain endogenous TXA2 levels involves a decrease in blood pressure evoked by haemorrhage because the blockade of TXA2 synthesis by furegrelate pretreatment attenuated the haemorrhagic hypotension. Increases in plasma adrenaline and vasopressin levels may mediate this effect.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Benzofurans; Blood Pressure; Disease Models, Animal; Epinephrine; Heart Rate; Hemorrhage; Hypotension; Hypothalamus; Injections, Intraventricular; Male; Rats; Rats, Sprague-Dawley; Thromboxane A2; Thromboxane-A Synthase; Time Factors; Vasoconstrictor Agents; Vasopressins

Plasma noradrenaline reflects the release from adrenal medulla and sympathetic nerves; however, the exact mechanisms of adrenal noradrenaline release remain to be elucidated. The present study was designed to characterize the source of plasma noradrenaline induced by centrally administered vasopressin and corticotropin-releasing hormone (CRH) in urethane-anesthetized rats. Intracerebroventricularly administered vasopressin (0.2 nmol/animal) and CRH (1.5 nmol/animal) elevated plasma levels of noradrenaline and adrenaline. Intracerebroventricularly administered indomethacin [1.2 micromol (500 microg)/animal] (an inhibitor of cyclooxygenase) abolished the elevations of both noradrenaline and adrenaline induced by vasopressin and CRH. Intracerebroventricularly administered furegrelate [1.8 micromol (500 microg)/animal] (an inhibitor of thromboxane A(2) synthase) abolished the elevations of both noradrenaline and adrenaline induced by vasopressin, while the reagent only attenuated the elevation of plasma adrenaline evoked by CRH. Acute bilateral adrenalectomy abolished the elevation of both noradrenaline and adrenaline induced by vasopressin, while the procedure reduced only the elevation of adrenaline induced by CRH. These results suggest that the release of noradrenaline from adrenal medulla and sympathetic nerves is mediated by different central mechanisms. The vasopressin-induced noradrenaline release from adrenal medulla is mediated by brain thromboxane A(2)-mediated mechanisms, while the CRH-induced noradrenaline release from sympathetic nerves is mediated by brain prostanoid (other than thromboxane A(2))-mediated mechanisms. The vasopressin- and CRH-induced adrenaline release from adrenal medulla is also mediated by brain thromboxane A(2)-mediated mechanisms in rats.

Topics: Adrenal Medulla; Adrenalectomy; Animals; Arachidonic Acid; Benzofurans; Brain; Corticotropin-Releasing Hormone; Epinephrine; Injections, Intraventricular; Male; Norepinephrine; Rats; Rats, Wistar; Thromboxane A2; Vasopressins