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Hemodynamic effects of hypertonic saline infusions in hemorragic and intact rats
IMPROVEMENT OF M A C R O C | R C U L A T O R Y FLOW RESPONSIVENESS BY THE NEUROPROTECTIVE ACTION OF THE ACTH,vgANALOGUE ORG 2766 IN DIABETIC RATS T. v..___anBuren, C.M. Kasbergen, W.H. Gispen and D.J. de Wildt Rudolf Magnus Institute for Neurosciences, Medical Faculty, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
HEMODYNAMIC EFFECTS OF HYPERTONIC SALINE INFUSIONS IN HEMORRAGIC AND INTACT RATS V. Veljkovid, M, Jerkid, J: Varagid, D. Jovovid and J. Vueovid Institute for Medical Research, Dr. Suboti~a 4, POBox 721, 11001 Belgrade, Yugoslavia
Autonomic neuropathy in diabetes mellitus (DM) is associated with damage to the sympathetic nervous system (SNS) and microcirculafion, thereby affecting the control of blood pressure and regional blood flow 1. The purpose of this study was to determine the effect of treatment with Org 2766 on DM-induced autonomic neuropathy in streptozotocin (STZ)-diabetic rats on the adrenergic reactivity of femoral blood flow (FF), which represent the macrocirculatory supply to the sciatic nerve blood flow (NBF). The microcirculatory sciatic NBF and FF, measured by laser-Doppler and ultrasonic-Doppler flowmetry, resp., were reduced by 48% and 42%, resp., after 12 weeks of DM. Mean arterial pressure (MAP) (control: 108 + 7, diabetic: 105 _+7 mmHg) and heart rate (control: 380 + 19, diabetic: 366 + 17 bpm) were not significantly different in control and diabetic rats. Treatment with Org 2766, beginning 6 weeks after the induction of DM, had no influence on these haemodynamic variables. To determine whether sympathetic denervation occurred in diabetic rats, the response of the femoral artery to tyramine (TYR) and phenylephrine (PHE) was determined. There was no difference in the increase in MAP following administration of TYR, whereas diabetic rats were hyporesponsive to PHE (p<0.05). The FF of diabetic rats showed a smaller response to TYR (p<0.05) and PHE (p<0.05) than that of control rats. A strong local vasoconstrictor action of higher doses of PHE counteracted the flow-increasing effect of PHE in the control rats. Org 2766 increased the FF response to TYR and PHE to that of the control rats. In conclusion, the decrease in basal FF might be responsible for the lowered sciatic NBF. Org 2766 is capable of improving the adrenergic responsiveness of the macrocirculation in the STZ-diabetic rats, possibly by neuroprotective effects within the SNS. 1 Kappelle AC, Biessels G, Buren van T, Erkelens DW, Wildt de DJ, Gispen WH (1993) Eur J Pharmacol 250:43-49
Although hypertonic saline infusions have been used in treatment of hemorrhagic shock for at least 60 years, the mechanisms by which beneficial hemodynamic effects were produced remain unknown. In the present study we investigated whether hemodynamic effects were different between anesthetized hemorrhagic and intact rats after intravenous infusion of hypertonic saline solution. Wistar male rats were divided in two groups. In the first group bleeding was performed at a rate adjusted to reduce mean arterial pressure to 50 mmHg, while the second group consisted of normotensive normovolemic rats. Both groups of rats were given 4 ml/kg intravenous infusion of 4.5% saline solution (HSS). Hemodynamic analysis in the hemorrhagic animals showed that immediately after infusion of HSS mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR) were restored to the control level, until heart rate (HR) was slightly deminished. These values did not vary during the course of the experiment, In intact rats infusion of HSS produced an increase of MAP, CO and HR, but TPR was reduced. However, these changes were transient. These data indicated that the possible mechanism for fast effects of HSS probably involved the reflex activation. However, the differences in hemodynamic parameters between groups might be caused by unequal conditions in which animals reestablished cardiovascular homeostasis.
REDUCED BLOOD SUPPLY TO THE RAT BRAIN IN LIVE ESCHERICHIA COLI SEPTIC SHOCK PREVENTED BY INTRAVENOUS CIPROFLOXACIN W.Vleeming1 C van den Berg 1, C.M.Kasbergen 2, J.D te Biesebeek and D.J. de Wildt1'2. 1) National Institute of Public Health and Environmental Protection, PO Box 1, 3720 BA Bilthoven, The Netherlands. 2) Rudolf Magnus Institute for Neurosciences, Medical Faculty, Utrecht University, Utrecht, The Netherlands.
INTERFERENCE OF INCREASING PERCENTAGES OF GLYCOSYLATED HUMAN HEMOGLOBIN ON ENDOTHELIUM-DEPENDENT RELAXATIONS. Am,ulo J. R0drfguez-Mafias L, Marfn J, R0drfguez-Martfnez M A, Barrfis M T, Peir6 C and S~inchez-Ferrer C F. Departament0 de Farmacol0gfa y Terapedtica, Facultad de Medicina, Uidversidad Aut6noma de Madrid and *Hospital Uhiversitario de Getafe. Spain
In the course of the septic shock syndrome cerebral hypoperfusion may lead to ischemia and to increased risk of development of an altered mental status and neurological disorders. Antibiotic therapy is an important therapeutical approach to treat sepsis. Therefore, the present study was focused on the effect of ciprofloxacin on cerebral blood flow (CBF) during sepsis in rat. In anesthetized non-septic control rats, after administration of phenylephrine and sodium nitroprusside, within the mean arterial pressure (MAP) window of 34 mm Hg to 118 mm Hg, the CBF was constant. So, autoregulation of CBF in anaesthetized rats was intact. In septic rats, starting at one hour after administration of live E.coli, both CBF and MAP declined with a similar time course. Ciprofloxacin injections ( 12 m g / k g / i v at t= -5 min and 2, 4, 8 h) 1) prevented reduction of CBF, 2) maintained intracerebral carotid blood flow partly through redistribution of flow from extra- to intracerebral vascular beds, 3) prevented systemic hypotension 4) prevented metabolic acidosis, and 4) enhanced 10 h survival rafe from 17 up to 100 %. These results might indicate a 0loss of autoregulatory control of CBF in sepsis and emphasize the importance of early administration of antibiotics in the therapeutic approach of sepsis.
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Endothelium-dependent vasodilation is reduced in diabetes. High glycosylated human hemoglobin (GHHb) impairs nitric oxidemediated responses, but the percentage of glycosylation from which this effect is observed and the mechanisms involved are unknown. Therefore, the effects of increasing percentages Of GHHb (7.3%; 8%; 9%; 10%; 12%; 14%) were tested on the endothelium-dependent relaxations induced by acetylcholine in rat aorta segments. Human hemoglobin (1-10 nmol/L) inhibited endothelium-dependentresponses when glycated at a percentage of 9% or higher. To elucidate the mechanism(s) involved, the effect of 14% GHHb on acetylcholineevoked responses was evaluated in vessels preincubated with the scavenger of superoxide anions superoxide dismutase (SOD; 100 U/mL), the cyelooxygenase inhibitor indomethacin (10 gmol/L), the thromboxane synthase inhibitor dazoxiben (100 gmol/L), the thromboxane A2/prostaglandin H2 antagonist SQ 30741 (1 gmol/L) or the endothelin antagonist BQ 123 (1 ~tmol/L). SOD, but not any of the other substances, abolished the effect of 14% GHHb. SOD also abolished the effect of 14 % GHHb on exogenous nitric oxideinduced vasodflations in deendothelialized vessels. We conclude that GHHb exerts its inhibitory effect on endothelium-dependent relaxations from a percentage of glycosylation of 9%. This effect is mediated by the interference with nitric oxide by means of superoxide anions production. 'Ibis work was supported by grants from FIS (94/0162; 93/0916E) and DGICYT (FAR 91-0205) integrated in the BIOMED Project (PL93-1375).
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HEMODYNAMIC EFFECTS OF HYPERTONIC SALINE INFUSIONS IN HEMORRAGIC AND INTACT RATS V. Veljkovid, M, Jerkid, J: Varagid, D. Jovovid and J. Vueovid Institute for Medical Research, Dr. Suboti~a 4, POBox 721, 11001 Belgrade, Yugoslavia
Autonomic neuropathy in diabetes mellitus (DM) is associated with damage to the sympathetic nervous system (SNS) and microcirculafion, thereby affecting the control of blood pressure and regional blood flow 1. The purpose of this study was to determine the effect of treatment with Org 2766 on DM-induced autonomic neuropathy in streptozotocin (STZ)-diabetic rats on the adrenergic reactivity of femoral blood flow (FF), which represent the macrocirculatory supply to the sciatic nerve blood flow (NBF). The microcirculatory sciatic NBF and FF, measured by laser-Doppler and ultrasonic-Doppler flowmetry, resp., were reduced by 48% and 42%, resp., after 12 weeks of DM. Mean arterial pressure (MAP) (control: 108 + 7, diabetic: 105 _+7 mmHg) and heart rate (control: 380 + 19, diabetic: 366 + 17 bpm) were not significantly different in control and diabetic rats. Treatment with Org 2766, beginning 6 weeks after the induction of DM, had no influence on these haemodynamic variables. To determine whether sympathetic denervation occurred in diabetic rats, the response of the femoral artery to tyramine (TYR) and phenylephrine (PHE) was determined. There was no difference in the increase in MAP following administration of TYR, whereas diabetic rats were hyporesponsive to PHE (p<0.05). The FF of diabetic rats showed a smaller response to TYR (p<0.05) and PHE (p<0.05) than that of control rats. A strong local vasoconstrictor action of higher doses of PHE counteracted the flow-increasing effect of PHE in the control rats. Org 2766 increased the FF response to TYR and PHE to that of the control rats. In conclusion, the decrease in basal FF might be responsible for the lowered sciatic NBF. Org 2766 is capable of improving the adrenergic responsiveness of the macrocirculation in the STZ-diabetic rats, possibly by neuroprotective effects within the SNS. 1 Kappelle AC, Biessels G, Buren van T, Erkelens DW, Wildt de DJ, Gispen WH (1993) Eur J Pharmacol 250:43-49
Although hypertonic saline infusions have been used in treatment of hemorrhagic shock for at least 60 years, the mechanisms by which beneficial hemodynamic effects were produced remain unknown. In the present study we investigated whether hemodynamic effects were different between anesthetized hemorrhagic and intact rats after intravenous infusion of hypertonic saline solution. Wistar male rats were divided in two groups. In the first group bleeding was performed at a rate adjusted to reduce mean arterial pressure to 50 mmHg, while the second group consisted of normotensive normovolemic rats. Both groups of rats were given 4 ml/kg intravenous infusion of 4.5% saline solution (HSS). Hemodynamic analysis in the hemorrhagic animals showed that immediately after infusion of HSS mean arterial pressure (MAP), cardiac output (CO) and total peripheral resistance (TPR) were restored to the control level, until heart rate (HR) was slightly deminished. These values did not vary during the course of the experiment, In intact rats infusion of HSS produced an increase of MAP, CO and HR, but TPR was reduced. However, these changes were transient. These data indicated that the possible mechanism for fast effects of HSS probably involved the reflex activation. However, the differences in hemodynamic parameters between groups might be caused by unequal conditions in which animals reestablished cardiovascular homeostasis.
REDUCED BLOOD SUPPLY TO THE RAT BRAIN IN LIVE ESCHERICHIA COLI SEPTIC SHOCK PREVENTED BY INTRAVENOUS CIPROFLOXACIN W.Vleeming1 C van den Berg 1, C.M.Kasbergen 2, J.D te Biesebeek and D.J. de Wildt1'2. 1) National Institute of Public Health and Environmental Protection, PO Box 1, 3720 BA Bilthoven, The Netherlands. 2) Rudolf Magnus Institute for Neurosciences, Medical Faculty, Utrecht University, Utrecht, The Netherlands.
INTERFERENCE OF INCREASING PERCENTAGES OF GLYCOSYLATED HUMAN HEMOGLOBIN ON ENDOTHELIUM-DEPENDENT RELAXATIONS. Am,ulo J. R0drfguez-Mafias L, Marfn J, R0drfguez-Martfnez M A, Barrfis M T, Peir6 C and S~inchez-Ferrer C F. Departament0 de Farmacol0gfa y Terapedtica, Facultad de Medicina, Uidversidad Aut6noma de Madrid and *Hospital Uhiversitario de Getafe. Spain
In the course of the septic shock syndrome cerebral hypoperfusion may lead to ischemia and to increased risk of development of an altered mental status and neurological disorders. Antibiotic therapy is an important therapeutical approach to treat sepsis. Therefore, the present study was focused on the effect of ciprofloxacin on cerebral blood flow (CBF) during sepsis in rat. In anesthetized non-septic control rats, after administration of phenylephrine and sodium nitroprusside, within the mean arterial pressure (MAP) window of 34 mm Hg to 118 mm Hg, the CBF was constant. So, autoregulation of CBF in anaesthetized rats was intact. In septic rats, starting at one hour after administration of live E.coli, both CBF and MAP declined with a similar time course. Ciprofloxacin injections ( 12 m g / k g / i v at t= -5 min and 2, 4, 8 h) 1) prevented reduction of CBF, 2) maintained intracerebral carotid blood flow partly through redistribution of flow from extra- to intracerebral vascular beds, 3) prevented systemic hypotension 4) prevented metabolic acidosis, and 4) enhanced 10 h survival rafe from 17 up to 100 %. These results might indicate a 0loss of autoregulatory control of CBF in sepsis and emphasize the importance of early administration of antibiotics in the therapeutic approach of sepsis.
--239
Endothelium-dependent vasodilation is reduced in diabetes. High glycosylated human hemoglobin (GHHb) impairs nitric oxidemediated responses, but the percentage of glycosylation from which this effect is observed and the mechanisms involved are unknown. Therefore, the effects of increasing percentages Of GHHb (7.3%; 8%; 9%; 10%; 12%; 14%) were tested on the endothelium-dependent relaxations induced by acetylcholine in rat aorta segments. Human hemoglobin (1-10 nmol/L) inhibited endothelium-dependentresponses when glycated at a percentage of 9% or higher. To elucidate the mechanism(s) involved, the effect of 14% GHHb on acetylcholineevoked responses was evaluated in vessels preincubated with the scavenger of superoxide anions superoxide dismutase (SOD; 100 U/mL), the cyelooxygenase inhibitor indomethacin (10 gmol/L), the thromboxane synthase inhibitor dazoxiben (100 gmol/L), the thromboxane A2/prostaglandin H2 antagonist SQ 30741 (1 gmol/L) or the endothelin antagonist BQ 123 (1 ~tmol/L). SOD, but not any of the other substances, abolished the effect of 14% GHHb. SOD also abolished the effect of 14 % GHHb on exogenous nitric oxideinduced vasodflations in deendothelialized vessels. We conclude that GHHb exerts its inhibitory effect on endothelium-dependent relaxations from a percentage of glycosylation of 9%. This effect is mediated by the interference with nitric oxide by means of superoxide anions production. 'Ibis work was supported by grants from FIS (94/0162; 93/0916E) and DGICYT (FAR 91-0205) integrated in the BIOMED Project (PL93-1375).
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