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Histamine desensitization in rat isolated perfused mesenteric bed
Pharmacological Research, Vol. 31, No. 2,1995
KA+L-NAME than in that of animals given only the neurotoxin. It is evident that the complete inhibition of NO synthesis is very likely detrimental under certain conditions. In fact, NO is implicated in various physiological functions; in KA-injected rats L-NAME could interfere with vasogenic and/or neurogenic control of cerebral blood flow and microvessel functionality. In, conclusion, our results seem to exclude the view that L-NAME may be used for limiting possible NO toxic effects associated to KA-induced seizures.
ENDOTHELIN-1 IN RAT CENTRAL GRAY INDUCES HYPERTENSION VIA GLUTAMATERGIC RECEPTORS M. D’amico, L. Berrino, S. Maione, A. Filippelli, A. Pizzirusso, S. Vitagliano and F. Rossi Institute of Pharmacology and Toxicology, Faculty of Medicine and Surgery,II University of Naples, via Costantinopoli 16, 80138 Naples, Italy Endothelin- 1 (ET- 1) is a vasoconstrictor peptide which induces pressor effects [I]. The aim of this study was to investigate the possible relationship between endothelin-1 and the glutamatergic system in cardiovascular function control in the dorsolateral periaqueductal gray area. ET-1 was injected into the dorsolateral periaqueductal gray (PAG) area of freely moving rats at doses ranging from 0.1 to 1 pmol. ET-l increased (from 751.6 to 55+ 4.1 mmHg) in a dose-dependent manner the arterial blood pressure and induced characteristic behavioural changes such as longitudinal rolling of the body (barrel-rolling). The DL-2-amino-5 phosphonovaleric acid (2-APV), a selective Nmethyl-D-aspartate excitatory amino acid receptor antagonist, administered in the same area 10 min before ET-l at dose of 5 nmol per rat, significantly (P
147
AGEINGAND HYPERTENSION-INDUCED CHANGES IN THE MECHANISMS INVOLVED IN THE VASORELAXANT EFFECT OF ACETYLCHOLINE: ROLES OF EDHF AND EDRF L. Mantelli, S. Amerini and F. Ledda Department of Pharmacology, University of Florence, Viale G.B. Morgagni 65, 50134 Florence, Italy Acetylcholine (Ach) produced an endotheliumdependent vasorelaxation of a similar degree in mesenteric vascular bed preparations obtained from 2-month-old normotensive Wistar Kyoto (WKY) rats and age-matched spontaneously hypertensive rats (SHR). The response to Ach declined in vessels from l&month-old animals. In preparations from young WKY rats, the effect of Ach was slightly reduced by 500~~ L-NAME and was consistently antagonized by the unspecific K’-channel blocker tetraethylammonium (TEA, 2.5-10 mM). The pattern of the response to the two inhibitors was different in preparations obtained from aged WKY animals, as well as in those from young and aged SHR animals. In these preparations the Ach-induced vasodilation was significantly and concentration-dependently reduced by 100 and 500 PM L-NAME. On the other hand the effect of TEA was lesser than that observed in young normotensive animals. These results confirm that the vasodilating response to Ach declines with age and hypertension, and suggest that the effect of Ach in vessels from young normotensive animals is mainly due to the release of a substance able to activate K+-channels (EDHF), whereas in preparations from old normotensive, as well as in those from young and old hypertensive animals Ach chiefly relaxes through EDRF release.
HISTAMINE DESENSITIZATION IN RAT ISOLATED PERFUSED MESENTERIC BED G. Ignesti, R. Pino, G. Banchelli, L. Raimondi and R. Pirisino Dipartimento di Farmacologia Preclinica e Clinica “M. Aiazzi-Mancini”, University of Florence, Italy The noradrenaline (NA) vasoconstriction in rat isolated perfused mesenteric bed (MB) is antagonized, in an endothelium-dependent way, by histamine. The histamine effect in MB of rats weighing 250-300 g undergoes desensitization either by repeating the administration of single doses or by continuous perfusion of the amine. The histaminedesensitized MB is fully responsive to carbachol relaxation. In old rats (450-500 g) the response to histamine in MB decreases {as already observed by Moritoki et al. [l] in mesenteric aorta rings (MA))
Pharmacological Research, Vol. 31, No. 2,1995
148
and a faster desensitization is also observed. In streptozotocin-diabetic rats the MB shows the same response to histamine as in age-matched controls while the EDs0 of NA increases in diabetic rats. The response of MB to NA or histamine shows some diversity in respect to MA: (a) the response to NA does not increase in MB of older control rats, while it increases in MA [l], (b) the response to histamine in MB of diabetic rats does not change, while it increases in MA [2]. The different responsiveness of microvessels in respect to the artery [3] might account for different pressure response of the two preparations. REFERENCES 1. Moritoki H, Hosoki 1986; 126: 61. 2. Withe RE, Carrier
E, Ishida OG.
Y. Eur
J
Pharmacology
Pharmacol
1986; 33:
34. 3. Fortes ZB., Scivoletto Pharmac 1989: 20: 615.
R,
Garcia-Leme.
J
Gen
REACTIVITY TO ENDOTHELIN-1 OF FROM TRANSGENIC STRIPS AORTIC HYPERTENSIVE RATS TGR (mRen 2) 27 S. Bova, G. P. Rossi*, A. C. Pessina*, P. Debetto, S. Luciani, D. Gantent, J. Peters? and G. Cargnelli Dipartimenti di Farmacologia e “Medicina Clinica, Universith di Padova-Italy, 1_MDC, Berlin-Germany Ageing decreases aortic strip responsiveness to endothelin-1 (ET-l) in SHR and does not in WKY rats. In heterozygous female transgenic hypertensive blood pressure increases from rats (TGR), normotensive to hypertensive level at about 5 weeks of age. Thus, we wish to compare isometric contractile response to ET-l (l-100 nM> of endothelium-deprived aortae from 5, 11 and 35 week-old TGR rats with sex- and age-matched, normotensive Sprague-Dawley rats (SD), genetically similar except for transgenic. Dose-response curves to ET-l of SD rats of all ages are biphasic and the to the highest ET-l concentrations response (20-100 nM) increases with ageing. Dose-response curve to ET-l of TGR rats is biphasic only in 35 week-old animals and the response to the highest ET-l concentrations (20-100 nM) decreases with ageing. The biphasic pattern of dose-response curves to ET-l suggests the presence of low- and high-affinity binding sites. Ageing decreases responsiveness to ET-l in TGR rats as does in SHR, indicating a relationship with the hypertensive state. However, in SHR this phenomenon is specific for ET-l, whereas in TGR rats appears to be nonspecific since the responsiveness to noradrenaline is also decreased.
ROLE OF BRAIN DOPAMINE SYSTEMS IN ACTH-INDUCED REVERSAL OF THE HAEMORRHAGIC SHOCK S. Guarini, C. Bazzani and A. Bertolini Department of Biomedical Sciences, Section of Pharmacology, University of Modena (Italy) (MSH-ACTH) neuropeptides, Melanocortin intravenously (i.v.) injected in experimental or clinical conditions of haemorrhagic shock, induce a prompt and sustained improvement of cardiovascular and respiratory functions, with restoration of tissue perfusion and with an impressive increase in the survival time and in time-limit for blood reinfusion to be effective [ 1;3]. Since there is a remarkable coincidence of ACTH-MSH-containing fibers and catecholamine (especially dopamine) -containing projections in the brain, and since several data indicate that ACTH-MSH neuropeptides may induce extrahormonal effects by modulating their catecholamine-and particularly dopamine-systems in the brain, we have investigated the possible influence of dopamine receptor blockade on the ACTH-induced reversal of haemorrhagic shock. Pretreatment with either haloperidol, 300 ,ug kg-’ i.v. (antagonist at dopamine Dr and DP receptors), or SCH 23390, 50 ,ug kg-’ intraperitoneally or 0.1 pg per rat intracerebroventricularly (selective antagonist at dopamine D1 receptors) significantly inhibited the effect of ACTH-(1-24). On the other hand, i.v. pretreatment with I-sulpiride, 25 mg kg-’ (selective antagonist at dopamine DZ receptors), had only a negligible effect. The present results indicate that dopamine systems play an important role in the complex mechanism of the melanocortin-induced reversal of haemorrhagic shock, brain Dr receptors being especially involved. REFERENCES Bertolini A, Guarini S, Rompianesi E, Ferrari W. aACTH fragments and other improve MSH cardiovascular function and survival in experimental haemorrhagic shock. Eur J Phurmucol 1986; 130:
19-26. Bertolini A, Guarini S, Ferrari W, Noera G, Massini C, Di Tizio S. ACTH-(1-24) restores blood pressure in acute hypovolaemia and haemorrhagic shock in humans. Eur J Clin Pharmucol 1987; 32: 537-8. Guarini S, Tagliavini S, Bazzani C, Ferrari W, Berolini A. Early treatment with ACTH-(1-24) in a rat model of haemorrhagic shock prolongs survival and extends the time-limit for blood reinfusion to be effective. Crit Care Med 1990; 18: 862-S.
KA+L-NAME than in that of animals given only the neurotoxin. It is evident that the complete inhibition of NO synthesis is very likely detrimental under certain conditions. In fact, NO is implicated in various physiological functions; in KA-injected rats L-NAME could interfere with vasogenic and/or neurogenic control of cerebral blood flow and microvessel functionality. In, conclusion, our results seem to exclude the view that L-NAME may be used for limiting possible NO toxic effects associated to KA-induced seizures.
ENDOTHELIN-1 IN RAT CENTRAL GRAY INDUCES HYPERTENSION VIA GLUTAMATERGIC RECEPTORS M. D’amico, L. Berrino, S. Maione, A. Filippelli, A. Pizzirusso, S. Vitagliano and F. Rossi Institute of Pharmacology and Toxicology, Faculty of Medicine and Surgery,II University of Naples, via Costantinopoli 16, 80138 Naples, Italy Endothelin- 1 (ET- 1) is a vasoconstrictor peptide which induces pressor effects [I]. The aim of this study was to investigate the possible relationship between endothelin-1 and the glutamatergic system in cardiovascular function control in the dorsolateral periaqueductal gray area. ET-1 was injected into the dorsolateral periaqueductal gray (PAG) area of freely moving rats at doses ranging from 0.1 to 1 pmol. ET-l increased (from 751.6 to 55+ 4.1 mmHg) in a dose-dependent manner the arterial blood pressure and induced characteristic behavioural changes such as longitudinal rolling of the body (barrel-rolling). The DL-2-amino-5 phosphonovaleric acid (2-APV), a selective Nmethyl-D-aspartate excitatory amino acid receptor antagonist, administered in the same area 10 min before ET-l at dose of 5 nmol per rat, significantly (P
147
AGEINGAND HYPERTENSION-INDUCED CHANGES IN THE MECHANISMS INVOLVED IN THE VASORELAXANT EFFECT OF ACETYLCHOLINE: ROLES OF EDHF AND EDRF L. Mantelli, S. Amerini and F. Ledda Department of Pharmacology, University of Florence, Viale G.B. Morgagni 65, 50134 Florence, Italy Acetylcholine (Ach) produced an endotheliumdependent vasorelaxation of a similar degree in mesenteric vascular bed preparations obtained from 2-month-old normotensive Wistar Kyoto (WKY) rats and age-matched spontaneously hypertensive rats (SHR). The response to Ach declined in vessels from l&month-old animals. In preparations from young WKY rats, the effect of Ach was slightly reduced by 500~~ L-NAME and was consistently antagonized by the unspecific K’-channel blocker tetraethylammonium (TEA, 2.5-10 mM). The pattern of the response to the two inhibitors was different in preparations obtained from aged WKY animals, as well as in those from young and aged SHR animals. In these preparations the Ach-induced vasodilation was significantly and concentration-dependently reduced by 100 and 500 PM L-NAME. On the other hand the effect of TEA was lesser than that observed in young normotensive animals. These results confirm that the vasodilating response to Ach declines with age and hypertension, and suggest that the effect of Ach in vessels from young normotensive animals is mainly due to the release of a substance able to activate K+-channels (EDHF), whereas in preparations from old normotensive, as well as in those from young and old hypertensive animals Ach chiefly relaxes through EDRF release.
HISTAMINE DESENSITIZATION IN RAT ISOLATED PERFUSED MESENTERIC BED G. Ignesti, R. Pino, G. Banchelli, L. Raimondi and R. Pirisino Dipartimento di Farmacologia Preclinica e Clinica “M. Aiazzi-Mancini”, University of Florence, Italy The noradrenaline (NA) vasoconstriction in rat isolated perfused mesenteric bed (MB) is antagonized, in an endothelium-dependent way, by histamine. The histamine effect in MB of rats weighing 250-300 g undergoes desensitization either by repeating the administration of single doses or by continuous perfusion of the amine. The histaminedesensitized MB is fully responsive to carbachol relaxation. In old rats (450-500 g) the response to histamine in MB decreases {as already observed by Moritoki et al. [l] in mesenteric aorta rings (MA))
Pharmacological Research, Vol. 31, No. 2,1995
148
and a faster desensitization is also observed. In streptozotocin-diabetic rats the MB shows the same response to histamine as in age-matched controls while the EDs0 of NA increases in diabetic rats. The response of MB to NA or histamine shows some diversity in respect to MA: (a) the response to NA does not increase in MB of older control rats, while it increases in MA [l], (b) the response to histamine in MB of diabetic rats does not change, while it increases in MA [2]. The different responsiveness of microvessels in respect to the artery [3] might account for different pressure response of the two preparations. REFERENCES 1. Moritoki H, Hosoki 1986; 126: 61. 2. Withe RE, Carrier
E, Ishida OG.
Y. Eur
J
Pharmacology
Pharmacol
1986; 33:
34. 3. Fortes ZB., Scivoletto Pharmac 1989: 20: 615.
R,
Garcia-Leme.
J
Gen
REACTIVITY TO ENDOTHELIN-1 OF FROM TRANSGENIC STRIPS AORTIC HYPERTENSIVE RATS TGR (mRen 2) 27 S. Bova, G. P. Rossi*, A. C. Pessina*, P. Debetto, S. Luciani, D. Gantent, J. Peters? and G. Cargnelli Dipartimenti di Farmacologia e “Medicina Clinica, Universith di Padova-Italy, 1_MDC, Berlin-Germany Ageing decreases aortic strip responsiveness to endothelin-1 (ET-l) in SHR and does not in WKY rats. In heterozygous female transgenic hypertensive blood pressure increases from rats (TGR), normotensive to hypertensive level at about 5 weeks of age. Thus, we wish to compare isometric contractile response to ET-l (l-100 nM> of endothelium-deprived aortae from 5, 11 and 35 week-old TGR rats with sex- and age-matched, normotensive Sprague-Dawley rats (SD), genetically similar except for transgenic. Dose-response curves to ET-l of SD rats of all ages are biphasic and the to the highest ET-l concentrations response (20-100 nM) increases with ageing. Dose-response curve to ET-l of TGR rats is biphasic only in 35 week-old animals and the response to the highest ET-l concentrations (20-100 nM) decreases with ageing. The biphasic pattern of dose-response curves to ET-l suggests the presence of low- and high-affinity binding sites. Ageing decreases responsiveness to ET-l in TGR rats as does in SHR, indicating a relationship with the hypertensive state. However, in SHR this phenomenon is specific for ET-l, whereas in TGR rats appears to be nonspecific since the responsiveness to noradrenaline is also decreased.
ROLE OF BRAIN DOPAMINE SYSTEMS IN ACTH-INDUCED REVERSAL OF THE HAEMORRHAGIC SHOCK S. Guarini, C. Bazzani and A. Bertolini Department of Biomedical Sciences, Section of Pharmacology, University of Modena (Italy) (MSH-ACTH) neuropeptides, Melanocortin intravenously (i.v.) injected in experimental or clinical conditions of haemorrhagic shock, induce a prompt and sustained improvement of cardiovascular and respiratory functions, with restoration of tissue perfusion and with an impressive increase in the survival time and in time-limit for blood reinfusion to be effective [ 1;3]. Since there is a remarkable coincidence of ACTH-MSH-containing fibers and catecholamine (especially dopamine) -containing projections in the brain, and since several data indicate that ACTH-MSH neuropeptides may induce extrahormonal effects by modulating their catecholamine-and particularly dopamine-systems in the brain, we have investigated the possible influence of dopamine receptor blockade on the ACTH-induced reversal of haemorrhagic shock. Pretreatment with either haloperidol, 300 ,ug kg-’ i.v. (antagonist at dopamine Dr and DP receptors), or SCH 23390, 50 ,ug kg-’ intraperitoneally or 0.1 pg per rat intracerebroventricularly (selective antagonist at dopamine D1 receptors) significantly inhibited the effect of ACTH-(1-24). On the other hand, i.v. pretreatment with I-sulpiride, 25 mg kg-’ (selective antagonist at dopamine DZ receptors), had only a negligible effect. The present results indicate that dopamine systems play an important role in the complex mechanism of the melanocortin-induced reversal of haemorrhagic shock, brain Dr receptors being especially involved. REFERENCES Bertolini A, Guarini S, Rompianesi E, Ferrari W. aACTH fragments and other improve MSH cardiovascular function and survival in experimental haemorrhagic shock. Eur J Phurmucol 1986; 130:
19-26. Bertolini A, Guarini S, Ferrari W, Noera G, Massini C, Di Tizio S. ACTH-(1-24) restores blood pressure in acute hypovolaemia and haemorrhagic shock in humans. Eur J Clin Pharmucol 1987; 32: 537-8. Guarini S, Tagliavini S, Bazzani C, Ferrari W, Berolini A. Early treatment with ACTH-(1-24) in a rat model of haemorrhagic shock prolongs survival and extends the time-limit for blood reinfusion to be effective. Crit Care Med 1990; 18: 862-S.