Crocetin reduces activation of hepatic apoptotic pathways and improves survival in experimental hemorrhagic shock.

BACKGROUND: Hemorrhagic shock results in cellular damage and cell death. A primary mechanism is cellular apoptosis from mitochondrial damage. This study demonstrated that administration of crocetin to experimental animals during resuscitation from shock significantly improved postshock survival and reduced apoptosis. Crocetin is a component of saffron and has long been used in traditional medicine in Asia. METHODS: Male Sprague-Dawley rats (350 ± 30 g) were randomly assigned to 1 of 4 groups of 8 animals. Hemorrhagic shock was induced by withdrawing blood until the mean arterial pressure was 35-40 mm Hg, and blood pressure was maintained at that level for 60 minutes with further withdrawals as needed. Resuscitation was carried out by administration of 21 mL/kg lactated Ringer's solution and return of shed blood, with or without concurrent administration of crocetin (2 mg/kg). Control animals were sham-treated with surgical preparation, without shock or resuscitation, and with and without crocetin. Rats were sacrificed 24 hours after completion of resuscitation. The extent of activation of hepatic apoptosis was established by measuring levels of hepatic cytosolic cytochrome c, caspase-3, and bcl-2. A separate group of 53 animals treated identically was used to assess survival. RESULTS: Crocetin administration during resuscitation resulted in less extensive activation of hepatic apoptosis and significantly increased survival relative to controls. CONCLUSIONS: Crocetin administration to experimental animals during resuscitation post hemorrhage increased survival, at least in part by protecting the liver from activation of apoptotic cell death. This agent continues to show promise as a potential treatment strategy for hemorrhagic shock.

Genetic predisposition to hypertension sensitizes borderline hypertensive rats to the hypertensive effects of prenatal glucocorticoid exposure.

An adverse intrauterine environment can increase the incidence of hypertension and other cardiovascular disease risk factors. However, in clinical and experimental studies the magnitude of the effect is variable. Possibly, the relative influence of the prenatal environment on cardiovascular disease is determined in part by genetic factors that predispose individuals to the development of environmentally induced hypertension. We tested this hypothesis by comparing the effects of prenatal dexamethasone treatment (Dex, 300 microg kg(-1) i.p. on days 15 and 16 of gestation) in borderline hypertensive rats (BHR) and control Wistar-Kyoto (WKY) rats. Blood pressure, heart rate and plasma corticosterone values were measured at rest during the middle of the day, and during 1 h of restraint stress in the adult offspring using indwelling arterial catheters implanted at least 4 days prior to data collection. Compared with the saline (vehicle) control treatment, prenatal dexamethasone significantly (P < 0.05) increased baseline mean arterial pressure in male (123 +/- 2 versus 131 +/- 3 mmHg, saline versus Dex) and female (121 +/- 2 versus 130 +/- 2 mmHg, saline versus Dex) BHR, but not in male (108 +/- 3 versus 113 +/- 2 mmHg, saline versus Dex) or female (112 +/- 2 versus 110 +/- 2 mmHg, saline versus Dex) WKY rats. Relative to saline treatment, prenatal Dex also significantly increased baseline heart rate (328 +/- 6 versus 356 +/- 5 beats min(-1), saline versus Dex) and plasma corticosterone (5 +/- 2 versus 24 +/- 4 microg dl(-1), saline versus Dex), and prolonged the corticosterone response to acute stress, selectively in female BHR. However, prenatal Dex significantly enhanced the arterial pressure response to acute stress only in female WKY, while Dex augmented the elevation in heart rate during stress only in male rats. We conclude that prenatal dexamethasone increased baseline arterial pressure selectively in BHR, and plasma corticosterone only in female BHR. In contrast, prenatal Dex enhanced cardiovascular reactivity to stress in both BHR and WKY rats.

Chronic activation of dorsal hindbrain corticosteroid receptors augments the arterial pressure response to acute stress.

Augmented cardiovascular responses to acute stress can predict cardiovascular disease in humans. Chronic systemic increases in glucocorticoids produce enhanced cardiovascular responses to psychological stress; however, the site of action is unknown. Recent evidence indicates that glucocorticoids can act within the dorsal hindbrain to modulate cardiovascular function. Therefore, we tested the hypothesis that the endogenous glucocorticoid corticosterone can act in the dorsal hindbrain to enhance cardiovascular responses to restraint stress in conscious rats. Adrenal-intact animals with indwelling arterial catheters were treated for 4 or 6 days with 3- to 4-mg pellets of corticosterone or silastic (sham pellets) implanted on the dorsal hindbrain surface. Corticosterone pellets were also implanted either on the surface of the dura or subcutaneously to control for the systemic effects of corticosterone (systemic corticosterone). The integrated increase in arterial pressure during 1 hour of restraint stress was significantly (P<0.05) greater in dorsal hindbrain corticosterone (912+/-98 mm Hg per 60 minutes) relative to dorsal hindbrain sham (589+/-57 mm Hg per 60 minutes) or systemic corticosterone (592+/-122 mm Hg per 60 minutes) rats. The plasma glucose response after 10 minutes of stress was also significantly higher in dorsal hindbrain corticosterone-treated rats relative to both other groups. There were no significant between-group differences in the heart rate or corticosterone responses to stress. There were no differences in baseline values for any measured parameters. We conclude that corticosterone can act selectively in the dorsal hindbrain in rats with normal plasma corticosterone levels to augment the arterial pressure response to restraint stress.