Vascular adaptive responses to physical exercise and to stress are affected differently by nandrolone administration

Androgenic anabolic steroid, physical exercise and stress induce cardiovascular adaptations including increased endothelial function. The present study investigated the effects of these conditions alone and in combination on the vascular responses of male Wistar rats. Exercise was started at 8 weeks of life (60-min swimming sessions 5 days per week for 8 weeks, while carrying a 5 percent body-weight load). One group received nandrolone (5 mg/kg, twice per week for 8 weeks, im). Acute immobilization stress (2 h) was induced immediately before the experimental protocol. Curves for noradrenaline were obtained for thoracic aorta, with and without endothelium from sedentary and trained rats, submitted or not to stress, treated or not with nandrolone. None of the procedures altered the vascular reactivity to noradrenaline in denuded aorta. In intact aorta, stress and exercise produced vascular adaptive responses characterized by endothelium-dependent hyporeactivity to noradrenaline. These conditions in combination did not potentiate the vascular adaptive response. Exercise-induced vascular adaptive response was abolished by nandrolone. In contrast, the aortal reactivity to noradrenaline of sedentary rats and the vascular adaptive response to stress of sedentary and trained rats were not affected by nandrolone. Maximum response for 7-10 rats/group (g): sedentary 3.8 ± 0.2 vs trained 3.0 ± 0.2*; sedentary/stress 2.7 ± 0.2 vs trained/stress 3.1 ± 0.1*; sedentary/nandrolone 3.6 ± 0.1 vs trained/nandrolone 3.8 ± 0.1; sedentary/stress/nandrolone 3.2 ± 0.1 vs trained/stress/nandrolone 2.5 ± 0.1*; *P < 0.05 compared to its respective control. Stress and physical exercise determine similar vascular adaptive response involving distinct mechanisms as indicated by the observation that only the physical exercise-induced adaptive response was abolished by nandrolone.

Vascular adaptive responses to physical exercise and to stress are affected differently by nandrolone administration.

Androgenic anabolic steroid, physical exercise and stress induce cardiovascular adaptations including increased endothelial function. The present study investigated the effects of these conditions alone and in combination on the vascular responses of male Wistar rats. Exercise was started at 8 weeks of life (60-min swimming sessions 5 days per week for 8 weeks, while carrying a 5% body-weight load). One group received nandrolone (5 mg/kg, twice per week for 8 weeks, im). Acute immobilization stress (2 h) was induced immediately before the experimental protocol. Curves for noradrenaline were obtained for thoracic aorta, with and without endothelium from sedentary and trained rats, submitted or not to stress, treated or not with nandrolone. None of the procedures altered the vascular reactivity to noradrenaline in denuded aorta. In intact aorta, stress and exercise produced vascular adaptive responses characterized by endothelium-dependent hyporeactivity to noradrenaline. These conditions in combination did not potentiate the vascular adaptive response. Exercise-induced vascular adaptive response was abolished by nandrolone. In contrast, the aortal reactivity to noradrenaline of sedentary rats and the vascular adaptive response to stress of sedentary and trained rats were not affected by nandrolone. Maximum response for 7-10 rats/group (g): sedentary 3.8 ± 0.2 vs trained 3.0 ± 0.2*; sedentary/stress 2.7 ± 0.2 vs trained/stress 3.1 ± 0.1*; sedentary/nandrolone 3.6 ± 0.1 vs trained/nandrolone 3.8 ± 0.1; sedentary/stress/nandrolone 3.2 ± 0.1 vs trained/stress/nandrolone 2.5 ± 0.1*; *P < 0.05 compared to its respective control. Stress and physical exercise determine similar vascular adaptive response involving distinct mechanisms as indicated by the observation that only the physical exercise-induced adaptive response was abolished by nandrolone.

Effect of L-arginine, dimercaptosuccinic acid (DMSA) and the association of L-arginine and DMSA on tissue lead mobilization and blood pressure level in plumbism.

Lead (Pb)-induced hypertension is characterized by an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO). In the present study we evaluated the effect of L-arginine (NO precursor), dimercaptosuccinic acid (DMSA, a chelating agent and ROS scavenger), and the association of L-arginine/DMSA on tissue Pb mobilization and blood pressure levels in plumbism. Tissue Pb levels and blood pressure evolution were evaluated in rats exposed to: 1) Pb (750 ppm, in drinking water, for 70 days), 2) Pb plus water for 30 more days, 3) Pb plus DMSA (50 mg kg(-1) day(-1), p.o.), L-arginine (0.6%, in drinking water), and the combination of L-arginine/DMSA for 30 more days, and 4) their respective matching controls. Pb exposure increased Pb levels in the blood, liver, femur, kidney and aorta. Pb levels in tissues decreased after cessation of Pb administration, except in the aorta. These levels did not reach those observed in nonintoxicated rats. All treatments mobilized Pb from the kidney, femur and liver. Pb mobilization from the aorta was only effective with the L-arginine/DMSA treatment. Blood Pb concentrations in Pb-treated groups were not different from those of the Pb/water group. Pb increased blood pressure starting from the 5th week. L-arginine and DMSA treatments (4th week) and the combination of L-arginine/DMSA (3rd and 4th weeks) decreased blood pressure levels of intoxicated rats. These levels did not reach those of nonintoxicated rats. Treatment with L-arginine/DMSA was more effective than the isolated treatments in mobilizing Pb from tissues and in reducing the blood pressure of intoxicated rats.

Effect of L-arginine, dimercaptosuccinic acid (DMSA) and the association of L-arginine and DMSA on tissue lead mobilization and blood pressure level in plumbism

Lead (Pb)-induced hypertension is characterized by an increase in reactive oxygen species (ROS) and a decrease in nitric oxide (NO). In the present study we evaluated the effect of L-arginine (NO precursor), dimercaptosuccinic acid (DMSA, a chelating agent and ROS scavenger), and the association of L-arginine/DMSA on tissue Pb mobilization and blood pressure levels in plumbism. Tissue Pb levels and blood pressure evolution were evaluated in rats exposed to: 1) Pb (750 ppm, in drinking water, for 70 days), 2) Pb plus water for 30 more days, 3) Pb plus DMSA (50 mg kg-1 day-1, po), L-arginine (0.6 percent, in drinking water), and the combination of L-arginine/DMSA for 30 more days, and 4) their respective matching controls. Pb exposure increased Pb levels in the blood, liver, femur, kidney and aorta. Pb levels in tissues decreased after cessation of Pb administration, except in the aorta. These levels did not reach those observed in nonintoxicated rats. All treatments mobilized Pb from the kidney, femur and liver. Pb mobilization from the aorta was only effective with the L-arginine/DMSA treatment. Blood Pb concentrations in Pb-treated groups were not different from those of the Pb/water group. Pb increased blood pressure starting from the 5th week. L-arginine and DMSA treatments (4th week) and the combination of L-arginine/DMSA (3rd and 4th weeks) decreased blood pressure levels of intoxicated rats. These levels did not reach those of nonintoxicated rats. Treatment with L-arginine/DMSA was more effective than the isolated treatments in mobilizing Pb from tissues and in reducing the blood pressure of intoxicated rats

The sympathetic adrenomedullary system, but not the hypothalamic-pituitary-adrenal axis, participates in aorta adaptive response to stress: nitric oxide involvement.

Stress induced a decrease in the reactivity of the aorta to noradrenaline (NA), as a consequence of an endothelial nitric oxide (NO) system hyperactivity. The main characteristic of the stress response is activation of the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic adrenomedullary (SA) system. The participation of the HPA axis and SA system in the decreased reactivity to NA in the aorta of rats exposed to 4-h immobilization was investigated. Concentration-response relationships for NA were obtained in the aorta, with and without endothelium, isolated from normal and stressed rats, following these procedures: (1) in the absence and presence of L-NAME; (2) after adrenalectomy (ADX) or not, in the absence or presence of L-NAME; (3) ADX rats treated or not with corticosterone; (4) ADX associated with stress; and (5) treated or not with reserpine. The reactivity of aorta without endothelium was unaffected by the procedures. The reactivity of aorta with endothelium was decreased by either stress or ADX. This effect was reversed by both L-NAME and corticosterone. ADX did not potentiate the decrease in the aorta reactivity induced by stress. Reserpine did not change the reactivity of aorta with endothelium from normal rats, but prevented the decrease in reactivity induced by stress. It is concluded that the HPA axis participates in endothelium-dependent modulation of aorta reactivity in normal conditions and that the SA system participates in hyperactivity of the endothelial NO-system induced by stress, which is responsible for the decreased aorta reactivity to NA.

Endothelial dysfunction in DOCA-salt hypertension: possible involvement of prostaglandin endoperoxides.

The effects of the arachidonic acid metabolism inhibitors on the acetylcholine responses of aortae from control (CR) and deoxycorticosterone acetate (DOCA)-salt hypertensive (HR) rats were investigated. The acetylcholine decreased response observed in HR [relaxation (%): CR 95.5+/-2.7, n = 4; HR 52.0+/-6.3, n = 5, p < 0.05] was restored by the cyclooxygenase inhibitor piroxicam [relaxation (%): CR 99.8+/-0.2, n = 4; HR 86.0+/-4.0, n = 5] and by the thromboxane synthetase inhibitor and the thromboxane A2/prostaglandin H2 receptor antagonist ridogrel [relaxation (%): CR 92.1+/-4.4, n = 7; HR 93.1+/-2.0, n = 7] but not by the inhibitors of thromboxane synthetase, prostacyclin synthetase, cytochrome P-450 monooxygenase, and lipoxygenase. So, endoperoxide intermediates seem to be involved in the decreased endothelium-dependent relaxation to acetylcholine in DOCA-salt hypertension.

Denervation supersensitivity to phenylephrine in guinea-pig vas deferens in vivo and in vitro: functional studies on alpha1-adrenoceptors.

The objective was to estimate alterations in adrenergic receptor sites of guinea pig vas deferens, in vivo and in vitro, induced by chronic denervation. The denervation process induced an increased sensitivity (3-fold at the EC50 level) without alteration in the maximum response to phenylephrine in vitro. The sensitivity alteration was characterized by the decrease in the dissociation constant of phenylephrine for alpha-adrenoceptor [K(A): normal tissue 3.50 (0.75-16.21) x 10(-5) and denervated tissue 0.43 (0.11-1.67) x 10(-5) M, p < 0.05] without changing the dissociation constant of prazosin. A decrease in pD'2 value for phenylephrine-phenoxybenzamine, probably due to a qualitative rather than a quantitative alteration in the alpha-adrenoceptor, was also shown in vitro [pD'2: normal tissue (8.2776+/-0.0402) and denervated tissue (8.0051+/-0.0442), p < 0.05]. No change in sensitivity and maximum response to phenylephrine was observed in vivo after denervation, although an increased resistance of vas deferens to phenoxybenzamine blockade has been evidenced in this condition.

Decreased endothelium-dependent vasoconstriction to noradrenaline in acute-stressed rats is potentiated by previous chronic stress: nitric oxide involvement.

1. The objective was to determine whether nitric oxide participates in stress adaptive responses. Acute stress (AS) decreased endothelium-dependent vasoconstriction to noradrenaline (NA) in rat aorta [control rat (CR) 3.90 +/- 0.18, n = 22; AS 2.76 +/- 0.20, n = 13; P < 0.05]. 2. Chronic stress exposure previous to AS (CS) potentiated this effect [CS 1.93 +/- 0.19; n = 9; P < 0.05 related to CR, P < 0.05 related to AS]. 3. Methylene blue and NG-monomethyl-L-arginine, but not indomethacin, restored the decreased aorta reactivity to NA. 4. No reactivity alteration was observed in aorta without endothelium either in both stress conditions or in the presence of inhibitors. These data show that the nitric oxide participates in stress responses.

Indirect evidence for an endothelium-derived contracting factor release in aorta of deoxycorticosterone acetate-salt hypertensive rats.

In order to investigate the involvement of endothelium-derived vasoactive substances in deoxycorticosterone acetate (DOCA)-salt hypertension, the responses to noradrenaline, acetylcholine, sodium nitroprusside and papaverine were studied in the absence and presence of indomethacin. Noradrenaline was equally effective in evoking a constrictor response of aorta, with or without endothelium, isolated from DOCA-salt hypertensive rats, while in controls, noradrenaline induced higher submaximal responses in rubbed than in unrubbed preparations. A decreased response to acetylcholine, an endothelium-dependent vasodilator, was observed in aorta with endothelium which had been precontracted with noradrenaline isolated from hypertensive rats. The relaxant response was lost after removal of the endothelium in both control and DOCA-salt hypertensive groups. The response to sodium nitroprusside, an endothelium-independent agent, in aorta isolated from hypertensive rats as well as the response to papaverine, an agent partially dependent on the endothelium, was not altered. Indomethacin treatment altered the response to noradrenaline only in unrubbed aorta of hypertensive rats. In these preparations, a biphasic response to noradrenaline was observed. At lower concentrations noradrenaline induced the characteristic constrictor response, while at higher concentrations a relaxant response was obtained that was abolished by methylene blue, a guanylate cyclase inhibitor. This could indicate that noradrenaline induced the release of endothelium-derived relaxing factor (EDRF) in aorta of hypertensive rats. Furthermore, indomethacin treatment restored the decreased response to acetylcholine in aorta isolated from DOCA-salt hypertensive rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Reactivity of macro- and microvessels of DOCA-salt hypertensive rats: role of the endothelial cell.

The responses to noradrenaline (NA) and acetylcholine (ACh) of aortae and microvessels were compared in control and DOCA-salt hypertensive rats. Macro- and microvessels from hypertensive rats showed an increased response to NA and a decreased response to ACh (an endothelium-dependent vasodilator). Unlike ACh, sodium nitroprusside (an endothelium-independent agent), was equally effective in evoking a vasodilator response from aortae and microvessels of hypertensive rats. These data suggest that the impaired response to ACh and the increased response to NA in DOCA-salt hypertension may result from an alteration of endothelial cell function.

Reactivity of macro-and microvessels of doca-salt hypertensive rats: role of the endothelial cell

The responses to noradrenaline (NA) and acetylcholine (ACh) of aortae and microvessels were cocmpared in control and DOCA-salt hypertensive rats. Macro - and microvessels from hypertensive rats showed an increased response to NA and a decreased response to ACh (an endothelium-dependent vasodilator). Unlike ACh, sodium nitroprusside (an endothelium-independent agent), was equally effective in evoking a vasodilator response from aortae and microvessels of hypertensive rats. These data suggest that the impaired response to ACh and the increased response to NA in DOCA-salt hypertension may result from an alteration of endothelial cell function

Reactivity of aorta and mesenteric microvessels to drugs in spontaneously hypertensive rats: role of the endothelium.

The response to vasoactive agents of microvessels in situ and aortae in vitro was studied in normal and spontaneously hypertensive rats (SHR). Noradrenaline (NA) was equally effective in evoking a constrictor response of mesenteric microvessels in normal rats and SHR. The vasodilator response to acetylcholine (ACH), as endothelium-dependent relaxing agent, was lower in SHR microvessels whereas isoproterenol, papaverine, agents which are partially dependent on endothelium, and sodium nitroprusside, an endothelium-independent vasodilator, induced similar responses in control rats and SHR. Median effective concentrations and maximal responses to NA obtained in isolated SHR aortae, with or without endothelium, were similar to those obtained in their respective controls. NA-precontracted aortae with intact endothelium were less responsive to ACH in SHR than in controls. The relaxant response of the preparations was lost after endothelial cell removal in both groups. Sodium nitroprusside evoked similar relaxing effect in SHR and control NA-precontracted aortae. Isoproterenol-induced responses were potentiated in SHR-precontracted aortae, with or without endothelium. Removal of the endothelium diminished isoproterenol-induced relaxation, both in controls and SHR. With submaximal concentration of papaverine there was no difference between SHR aortae with or without endothelium and control aortae with endothelium. Control aortae without endothelium relaxed less than control aortae with endothelium and SHR aortae with or without endothelium. The rate of relaxation after papaverine was altered in aortae without endothelium isolated from SHR or control rats. These results indicate that the endothelium of SHR is altered. This could explain its decreased response to ACH. It is suggested that smooth muscle cells develop a compensatory mechanism that increases the response of agents that mobilize cAMP, such as papaverine and isoproterenol.

The vas deferens as a suitable preparation for the study of alpha-adrenoreceptor molecular mechanisms.

The responses of the isolated guinea pig vas deferens to phenylephrine in the absence or presence of phenoxybenzamine were studied. The occurrence of a homogenous receptor population was suggested by the finding that the dissociation constant (KA) values for the agonist did not change following varying degrees of receptor inactivation by different concentrations of phenoxybenzamine in the organ bath. In addition, constant pD'2 values were obtained for the antagonistic effect of phenoxybenzamine in these circumstances. Different values for KA and median effective concentration indicated a full agonistic effect for phenylephrine. The presence of spare receptors was revealed by comparing theoretical curves for receptor occupancy and concentration-effect curves for phenylephrine. It is suggested that the isolated guinea pig vas deferens may be a suitable preparation for the study of alpha-adrenergic mechanisms and their regulation.