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Changes in cerebral blood flow in two rat models of vascular ageing
867
vagal component of baroreflex (assessed by the influence of methylatropine or bilateral vagotomy on BRS), or the result from frequency analysis of the spontaneous cerebral cortex EEG. BRS during the reperfusion period of 60 to 210 min following 5-n-h ischemia was about SO% of the pre-ischemic value under pentobarbital-anesthesia, while it was about 80% under halothane-anesthesia; the difference in the extent of decrease in BRS was statistically significant. In another group of halothane-anesthetized dogs, halothane was withdrawn and substituted with thiopental just before ischemia, and then BRS during the reperfusion period was measured under halothane anesthesia after the animals recovered from thiopental-anesthesia. In this case, a marked decrease in BRS was observed during reperfusion period. These results suggest that barbiturates may be unexpectedly more deleterious than halothane during cerebral ischemia at least for baroreflex system.
References Kurihara. J.. H. Nishimura, N. Oda and H. Kate, 1989a, Japan. J. Pharmacol.. 49, 255. Kurihara, J.. T. Sahara and H. Kato, 198% Japan. J. Pharmacol.. 51,493. Smith, A.L., J.T. Hoff, S.L. Nielsen and C.P. Larson, 1974, Stroke, 5, 1.
1P.tu.198
1
ow in tworat models Lartaud, I., Janian, P., Bray, L., Atkinson, Laboratoire de Pharmacologic,
of
vascular agei
J., Hicks *, P.E. and Capdeville, C.
Fccul16 de Pharmacie. 5 rue Albert Lebrun, 54000 Nancy and * D&artement Recherche Syntex France, 913OC Mont/h&y,
de Pharmacologic,
France
As vascular ageing in man is characterized by arterial calcium overload (Fleckenstein et al., 1987) and a decrease in cerebral blood flow (CBF) (Davis et al., 1983) we have measured calcium levels and CBF in 2 rat models (i) 22 month old Fischer F 344, and (ii) 2 month old Wistar treated with vitamin D3 (3OtMMKlIU/kg, im) followed by 2 days’ treatment with nicotine (25 mg/kg, po, twice daily). The latter group was tested 15 days later (Vit Da + nit); Fleckenstein et al. (1987) proposed a similar treatment as a modei of vascular ageing. CBF was measured by hydrogen clearance and mean arterial pressure via an aortic caranula in the awake rat. The lower limit of CBF autoregulation was determined by measuring CBF during the rise in pressure following hypotensive haemorrhage. Calcium levels were measured by atomic absorption. In the Wistar Vit Dj + nit model, as in ageing in man, pronounced calcium overload and a fall in basal CBF were observed. The lower limit of CBF autoregulation was at a lower systemic pressure. Ageing in the Fischer rat was not associated with changes in CBF and calcium overloading was less pronounced. Calcium levels, arterial pressure and the lower limit of autoregulation of CBF were higher in Fischer F 344. Wistar Vit Ds + nit appears to be the better model of vascular ageing in man. Table 1 Mean arterial pressure (mm Hg), basal CBF (ml/100 g/mm), lower limit CBF autoregulation (mm Hg) and calcium ievh (Pmol/g) in Fischer F 344 and Wistar rats treated with vitamin D, plus nicotine. N
N Body weight (g) Aorticcalcium Myocardial calcium Arterial pressure Basal CBF Limit CBF
2 month old Wistar rats
Fischer F 344 rats
control
Vit D, + nit
2 month
22 month
7 230 f 7 9.2 f 0.4 4.2i0.4 100 *3 88 *3 70
11 221 f 7 320.1 f 77.3 * 32.7f 6.6 * 101 * 3 69 f4* 50 *
7 242 f3 22.0 f 3.3 5.8 + 0.6 114 *4+ 98 f3 90 *
5 403 f18* 49.5 f 6.1 8.9* 1.3 97 + 2 93 * 4 90 *
+ P < 0.05 versus Wistar control group
I-I. Ackerman, J.A. Correia, N.M. Alpert, J. Chang, F. Buonnnno. R.E: Rosner and J.M. Taveras. 1983. Neurology 33. 391. ein A., M. Frey. J. Zijm and 6. Fleckenstein-Griln. 1987. TiPS 8. 4%.
ir
e, c8
tes
Trouvk, R., Nahas, G., Manger, W.M. and Kypson, A. INSERiU, H@ital Femand Widal, Paris, France and Columbia University, New York 10032. U.S.A. In the awake Sprague Dawlay rat, fitted with an intraarterial caudal catheter, selected calcium antagonists (nitrendipine, nicardipine, diltiazem, flunarixine) will act as antidotes to a lethal dose of cocaine (60 mg/kg 1-P.). This dose will produce in control animals behavioral and cardiovascular anomalies as well as convulsions and death within an average time of 10 min. Antidotes are administered 5 minutes after the lethal dose of cocaine. Besides selected calcium antagatists, a converting enzyme inhibitor enalaprilat, associated with diazepam is also an antidote to lethal cocaine intoxication. In the present study, the effects of a lethal dose of cocaine on plasma catecholamine concentration was investigated in the rats untreated or treated with either nitrendipine or enalaprilat associated with diazepam. Twenty four fasting rats (295 f 28 g) are fitted under pentobarbital anesthesia with a catheter in the caudal and carotid arteries. The caudal catheter is connected to a constant microinfusion pump and to a recorder for on line recording of blood pressure which is processed by microcomputer for on line display of heart rate and pulse pressure. Four groups of 6 animals are studied. Group I (control) is administered saline I.P. and 5’ later saline intraarterially(1.A). Group II, III and IV are administered 60 mg/kg cocaine I.P.. Five minutes after, group II is administered I.A. saline; group III nitrendipine I.A. (7.2 c(g loading dose and 1.2 pg/kg/min); group IV diazepam (0.7 mg/kg) and enalaprilat I.A. (0.3 mg/kg). Two 0.8 ml samples of blood are withdrawn from the carotid artery in all groups: one (A), 4’ after saline or cocaine administration and the second(B) 5’ after treatment with saline or antidotes. Volume of blood removed is replaced with dextran. easurements of catechols are performed by the radio-enzymatic method of Peuler and Johnson. Results are summarized in following table. Catechol @icomoles/mI)
Group I Saline control
Group II Cocaine + saline
Group III Cocaine + nitrendipine
Group IV Cocaine + enalaprilat + diazepam
(A) Dopamine (B) Dopamine (A) Epinephrine (B) Epinephrine (A) Norepinephrine (B) Norepinephrine
91f 30 lOO+ 42 154f 83 1368 f 753 * 323 f 195 704f201 **
95f 22 223* 82 * s79*255 2430+649 * * 603&121 1538*702 ***
185&129 188* 58 775 f 778 1318*636 673 f 380 1223*551
226 f 222 239*114 572f419 1264*883 776 f 508 1475 f 700
Sipnificance of paired t-test
*p c 0.015 +“pco.O02
*p<0.006 ‘*p
***p
Catecholamine concentrations were compared between groups (unpaired t-test). These concentrations especially of epinephrine were significantly higher in group II as compared to group I (p < 0.003) indicating that cocaine releases catechols from the adrenal gland. Four minutes after cocaine intoxication, epinephrine concentration (A) was not significantly different in group II, III and IV. Following treatment (B) either with nitrendipine (III) or with enalaprilat and diazepam (IV) epinephrine was significantly lower (p < 0.02) than in the untreated rat (II) and similar to control (I). Cardiovascular and toxic effects of cocaine appear to be mediated in great part through its stimulating effects on the sympathoadreual and renin angiotensin systems.
vagal component of baroreflex (assessed by the influence of methylatropine or bilateral vagotomy on BRS), or the result from frequency analysis of the spontaneous cerebral cortex EEG. BRS during the reperfusion period of 60 to 210 min following 5-n-h ischemia was about SO% of the pre-ischemic value under pentobarbital-anesthesia, while it was about 80% under halothane-anesthesia; the difference in the extent of decrease in BRS was statistically significant. In another group of halothane-anesthetized dogs, halothane was withdrawn and substituted with thiopental just before ischemia, and then BRS during the reperfusion period was measured under halothane anesthesia after the animals recovered from thiopental-anesthesia. In this case, a marked decrease in BRS was observed during reperfusion period. These results suggest that barbiturates may be unexpectedly more deleterious than halothane during cerebral ischemia at least for baroreflex system.
References Kurihara. J.. H. Nishimura, N. Oda and H. Kate, 1989a, Japan. J. Pharmacol.. 49, 255. Kurihara, J.. T. Sahara and H. Kato, 198% Japan. J. Pharmacol.. 51,493. Smith, A.L., J.T. Hoff, S.L. Nielsen and C.P. Larson, 1974, Stroke, 5, 1.
1P.tu.198
1
ow in tworat models Lartaud, I., Janian, P., Bray, L., Atkinson, Laboratoire de Pharmacologic,
of
vascular agei
J., Hicks *, P.E. and Capdeville, C.
Fccul16 de Pharmacie. 5 rue Albert Lebrun, 54000 Nancy and * D&artement Recherche Syntex France, 913OC Mont/h&y,
de Pharmacologic,
France
As vascular ageing in man is characterized by arterial calcium overload (Fleckenstein et al., 1987) and a decrease in cerebral blood flow (CBF) (Davis et al., 1983) we have measured calcium levels and CBF in 2 rat models (i) 22 month old Fischer F 344, and (ii) 2 month old Wistar treated with vitamin D3 (3OtMMKlIU/kg, im) followed by 2 days’ treatment with nicotine (25 mg/kg, po, twice daily). The latter group was tested 15 days later (Vit Da + nit); Fleckenstein et al. (1987) proposed a similar treatment as a modei of vascular ageing. CBF was measured by hydrogen clearance and mean arterial pressure via an aortic caranula in the awake rat. The lower limit of CBF autoregulation was determined by measuring CBF during the rise in pressure following hypotensive haemorrhage. Calcium levels were measured by atomic absorption. In the Wistar Vit Dj + nit model, as in ageing in man, pronounced calcium overload and a fall in basal CBF were observed. The lower limit of CBF autoregulation was at a lower systemic pressure. Ageing in the Fischer rat was not associated with changes in CBF and calcium overloading was less pronounced. Calcium levels, arterial pressure and the lower limit of autoregulation of CBF were higher in Fischer F 344. Wistar Vit Ds + nit appears to be the better model of vascular ageing in man. Table 1 Mean arterial pressure (mm Hg), basal CBF (ml/100 g/mm), lower limit CBF autoregulation (mm Hg) and calcium ievh (Pmol/g) in Fischer F 344 and Wistar rats treated with vitamin D, plus nicotine. N
N Body weight (g) Aorticcalcium Myocardial calcium Arterial pressure Basal CBF Limit CBF
2 month old Wistar rats
Fischer F 344 rats
control
Vit D, + nit
2 month
22 month
7 230 f 7 9.2 f 0.4 4.2i0.4 100 *3 88 *3 70
11 221 f 7 320.1 f 77.3 * 32.7f 6.6 * 101 * 3 69 f4* 50 *
7 242 f3 22.0 f 3.3 5.8 + 0.6 114 *4+ 98 f3 90 *
5 403 f18* 49.5 f 6.1 8.9* 1.3 97 + 2 93 * 4 90 *
+ P < 0.05 versus Wistar control group
I-I. Ackerman, J.A. Correia, N.M. Alpert, J. Chang, F. Buonnnno. R.E: Rosner and J.M. Taveras. 1983. Neurology 33. 391. ein A., M. Frey. J. Zijm and 6. Fleckenstein-Griln. 1987. TiPS 8. 4%.
ir
e, c8
tes
Trouvk, R., Nahas, G., Manger, W.M. and Kypson, A. INSERiU, H@ital Femand Widal, Paris, France and Columbia University, New York 10032. U.S.A. In the awake Sprague Dawlay rat, fitted with an intraarterial caudal catheter, selected calcium antagonists (nitrendipine, nicardipine, diltiazem, flunarixine) will act as antidotes to a lethal dose of cocaine (60 mg/kg 1-P.). This dose will produce in control animals behavioral and cardiovascular anomalies as well as convulsions and death within an average time of 10 min. Antidotes are administered 5 minutes after the lethal dose of cocaine. Besides selected calcium antagatists, a converting enzyme inhibitor enalaprilat, associated with diazepam is also an antidote to lethal cocaine intoxication. In the present study, the effects of a lethal dose of cocaine on plasma catecholamine concentration was investigated in the rats untreated or treated with either nitrendipine or enalaprilat associated with diazepam. Twenty four fasting rats (295 f 28 g) are fitted under pentobarbital anesthesia with a catheter in the caudal and carotid arteries. The caudal catheter is connected to a constant microinfusion pump and to a recorder for on line recording of blood pressure which is processed by microcomputer for on line display of heart rate and pulse pressure. Four groups of 6 animals are studied. Group I (control) is administered saline I.P. and 5’ later saline intraarterially(1.A). Group II, III and IV are administered 60 mg/kg cocaine I.P.. Five minutes after, group II is administered I.A. saline; group III nitrendipine I.A. (7.2 c(g loading dose and 1.2 pg/kg/min); group IV diazepam (0.7 mg/kg) and enalaprilat I.A. (0.3 mg/kg). Two 0.8 ml samples of blood are withdrawn from the carotid artery in all groups: one (A), 4’ after saline or cocaine administration and the second(B) 5’ after treatment with saline or antidotes. Volume of blood removed is replaced with dextran. easurements of catechols are performed by the radio-enzymatic method of Peuler and Johnson. Results are summarized in following table. Catechol @icomoles/mI)
Group I Saline control
Group II Cocaine + saline
Group III Cocaine + nitrendipine
Group IV Cocaine + enalaprilat + diazepam
(A) Dopamine (B) Dopamine (A) Epinephrine (B) Epinephrine (A) Norepinephrine (B) Norepinephrine
91f 30 lOO+ 42 154f 83 1368 f 753 * 323 f 195 704f201 **
95f 22 223* 82 * s79*255 2430+649 * * 603&121 1538*702 ***
185&129 188* 58 775 f 778 1318*636 673 f 380 1223*551
226 f 222 239*114 572f419 1264*883 776 f 508 1475 f 700
Sipnificance of paired t-test
*p c 0.015 +“pco.O02
*p<0.006 ‘*p
***p
Catecholamine concentrations were compared between groups (unpaired t-test). These concentrations especially of epinephrine were significantly higher in group II as compared to group I (p < 0.003) indicating that cocaine releases catechols from the adrenal gland. Four minutes after cocaine intoxication, epinephrine concentration (A) was not significantly different in group II, III and IV. Following treatment (B) either with nitrendipine (III) or with enalaprilat and diazepam (IV) epinephrine was significantly lower (p < 0.02) than in the untreated rat (II) and similar to control (I). Cardiovascular and toxic effects of cocaine appear to be mediated in great part through its stimulating effects on the sympathoadreual and renin angiotensin systems.