RESUMEN
Losartan, an AT1 angiotensin II (ANG II) receptor non-peptide antagonist, induces an increase in mean arterial pressure (MAP) when injected intracerebroventricularly (icv) into rats. The present study investigated possible effector mechanisms of the increase in MAP induced by icv losartan in unanesthetized rats. Male Holtzman rats (280-300 g, N = 6/group) with a cannula implanted into the anterior ventral third ventricle received an icv injection of losartan (90 micro g/2 micro l) that induced a typical peak pressor response within 5 min. In one group of animals, this response to icv losartan was completely reduced from 18 +/- 1 to 4 +/- 2 mmHg by intravenous (iv) injection of losartan (2.5-10 mg/kg), and in another group, it was partially reduced from 18 +/- 3 to 11 +/- 2 mmHg by iv prazosin (0.1-1.0 mg/kg), an alpha1-adrenergic antagonist (P<0.05). Captopril (10 mg/kg), a converting enzyme inhibitor, injected iv in a third group inhibited the pressor response to icv losartan from 24 +/- 3 to 7 +/- 2 mmHg (P<0.05). Propranolol (10 mg/kg), a beta-adrenoceptor antagonist, injected iv in a fourth group did not alter the pressor response to icv losartan. Plasma renin activity and serum angiotensin-converting enzyme activity were not altered by icv losartan in other animals. The results suggest that the pressor effect of icv losartan depends on angiotensinergic and alpha1-adrenoceptor activation, but not on increased circulating ANG II.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Antagonistas de Receptores de Angiotensina , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antihipertensivos/farmacología , Hipertensión/sangre , Losartán/farmacología , Peptidil-Dipeptidasa A/sangre , Renina/sangre , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/antagonistas & inhibidores , Presión Sanguínea/efectos de los fármacos , Hipertensión/inducido químicamente , Inyecciones Intraventriculares , Losartán/administración & dosificación , Losartán/antagonistas & inhibidores , Masculino , Radioinmunoensayo , Ratas , Ratas Sprague-DawleyRESUMEN
Losartan, an AT1 angiotensin II (ANG II) receptor non-peptide antagonist, induces an increase in mean arterial pressure (MAP) when injected intracerebroventricularly (icv) into rats. The present study investigated possible effector mechanisms of the increase in MAP induced by icv losartan in unanesthetized rats. Male Holtzman rats (280-300 g, N = 6/group) with a cannula implanted into the anterior ventral third ventricle received an icv injection of losartan (90 æg/2 æl) that induced a typical peak pressor response within 5 min. In one group of animals, this response to icv losartan was completely reduced from 18 ± 1 to 4 ± 2 mmHg by intravenous (iv) injection of losartan (2.5-10 mg/kg), and in another group, it was partially reduced from 18 ± 3 to 11 ± 2 mmHg by iv prazosin (0.1-1.0 mg/kg), an alpha1-adrenergic antagonist (P<0.05). Captopril (10 mg/kg), a converting enzyme inhibitor, injected iv in a third group inhibited the pressor response to icv losartan from 24 ± 3 to 7 ± 2 mmHg (P<0.05). Propranolol (10 mg/kg), a ß-adrenoceptor antagonist, injected iv in a fourth group did not alter the pressor response to icv losartan. Plasma renin activity and serum angiotensin-converting enzyme activity were not altered by icv losartan in other animals. The results suggest that the pressor effect of icv losartan depends on angiotensinergic and alpha1-adrenoceptor activation, but not on increased circulating ANG II
Asunto(s)
Animales , Masculino , Ratas , Agonistas alfa-Adrenérgicos , Inhibidores de la Enzima Convertidora de Angiotensina , Hipertensión , Losartán , Peptidil-Dipeptidasa A , Receptores de Angiotensina , Renina , Captopril , Inyecciones Intraventriculares , Losartán , Prazosina , Propranolol , Radioinmunoensayo , Ratas Sprague-DawleyRESUMEN
Non-adrenergic ligands that bind to imidazoline receptors (I-R), a selective ligand that binds to alpha2-adrenoceptors (alpha2-AR) and mixed ligands that bind to both receptors were tested for their action on water intake behavior of 24-h water-deprived rats. All drugs were injected into the third cerebral ventricle. Except for agmatine (80 nmol), mixed ligands binding to I-R/alpha2-AR such as guanabenz (40 nmol) and UK 14304 (20 nmol) inhibited water intake by 65 percent and up to 95 percent, respectively. The selective non-imidazoline alpha2-AR agonist, alpha-methylnoradrenaline, produced inhibition of water intake similar to that obtained with guanabenz, but at higher doses (80 nmol). The non-adrenergic I-R ligands histamine (160 nmol, mixed histaminergic and imidazoline ligand) and imidazole-4-acetic acid (80 nmol, imidazoline ligand) did not alter water intake. The results show that selective, non-imidazoline alpha2-AR activation suppresses water intake, and suggest that the action on imidazoline sites by non-adrenergic ligands is not sufficient to inhibit water intake
Asunto(s)
Animales , Masculino , Ratas , Ingestión de Líquidos/efectos de los fármacos , Guanidinas/farmacología , Imidazoles/farmacología , Nordefrin/farmacología , Quinoxalinas/farmacología , Receptores Adrenérgicos alfa 2/fisiología , Imidazoles/agonistas , Inyecciones Intraventriculares , Ligandos , Ratas Sprague-Dawley , Vasoconstrictores/farmacología , Privación de AguaRESUMEN
Non-adrenergic ligands that bind to imidazoline receptors (I-R), a selective ligand that binds to alpha2-adrenoceptors (alpha2-AR) and mixed ligands that bind to both receptors were tested for their action on water intake behavior of 24-h water-deprived rats. All drugs were injected into the third cerebral ventricle. Except for agmatine (80 nmol), mixed ligands binding to I-R/alpha2-AR such as guanabenz (40 nmol) and UK 14304 (20 nmol) inhibited water intake by 65% and up to 95%, respectively. The selective non-imidazoline alpha2-AR agonist, alpha-methylnoradrenaline, produced inhibition of water intake similar to that obtained with guanabenz, but at higher doses (80 nmol). The non-adrenergic I-R ligands histamine (160 nmol, mixed histaminergic and imidazoline ligand) and imidazole-4-acetic acid (80 nmol, imidazoline ligand) did not alter water intake. The results show that selective, non-imidazoline alpha2-AR activation suppresses water intake, and suggest that the action on imidazoline sites by non-adrenergic ligands is not sufficient to inhibit water intake.
Asunto(s)
Ingestión de Líquidos/efectos de los fármacos , Guanidinas/farmacología , Imidazoles/farmacología , Nordefrin/farmacología , Quinoxalinas/farmacología , Receptores Adrenérgicos alfa 2/fisiología , Agonistas de Receptores Adrenérgicos alfa 2 , Animales , Tartrato de Brimonidina , Imidazoles/agonistas , Inyecciones Intraventriculares , Ligandos , Masculino , Ratas , Ratas Sprague-Dawley , Vasoconstrictores/farmacología , Privación de AguaRESUMEN
1. Angiotensin (Ang)II is involved in responses to hypovolaemia, such as sodium appetite and increase in blood pressure. Target areas subserving these responses for AngII include the cardiovascular system in the periphery and the circumventricular organs in the brain. 2. Conflicting data have been reported for the role of systemic versus brain AngII in the mediation of sodium appetite. 3. The role for systemic AngII and systemic AngII receptors in the control of blood pressure in hypovolaemia is well established. In contrast with systemic injections, i.c.v injections of AngII non-peptide AT1 and AT2 receptor antagonists, such as losartan and PD123319, do not reduce arterial pressure in sodium-depleted (furosemide injection plus removal of ambient sodium for 24 h) rats. Thus, brain AngII receptors are likely not important for cardiovascular responses to hypovolaemia induced by sodium depletion. 4. Intracerebroventricular injections of losartan or PD123319 increase arterial pressure when injected at relatively high doses. This hypertensive effect is unlikely to be an agonist effect on brain AngII receptors. Increases in arterial pressure produced by i.c.v. losartan are attenuated by lesions of the tissue surrounding the anterior third ventricle (AV3V). The hypertensive effect of i.c.v. AngII is abolished by lesions of the AV3V. 5. Hypertension induced by AngII receptor antagonists is consistent with hypotension induced by AngII acting in the brain. However, the full physiological significance of this hypotensive effect mediated by brain AngII receptors remains to be determined.
Asunto(s)
Angiotensina II/fisiología , Presión Sanguínea/fisiología , Hipovolemia/fisiopatología , Receptores de Angiotensina/fisiología , Angiotensina II/farmacología , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Química Encefálica , Humanos , Imidazoles/farmacología , Losartán/farmacología , Piridinas/farmacología , Ratas , Receptor de Angiotensina Tipo 1 , Receptor de Angiotensina Tipo 2 , Receptores de Angiotensina/efectos de los fármacos , Solución Salina Hipertónica , Vasoconstrictores/farmacologíaRESUMEN
The effect of noradrenaline, and mixed ligands to alpha 2-adrenoceptors (alpha 2-AR) and imidazoline receptors (IR), injected intracerebroventricularly (i.c.v.), on sodium intake of sodium depleted rats, was tested against idazoxan, a mixed antagonist ligand to alpha 2-AR and IR. The inhibition of sodium intake induced by noradrenaline (80 nmol) was completely reversed by idazoxan (160 and 320 nmol) injected i.c.v. The inhibition of sodium intake induced by mixed ligands to alpha 2-AR and IR, UK14,304, guanabenz and moxonidine, was antagonized from 50 to 60% by idazoxan i.c.v. The results demonstrate that noradrenaline, a non-ligand for IR, acts on alpha 2-AR inhibiting sodium intake. The possibility that either alpha 2-AR or IR mediate the effect of mixed agonists on sodium intake remains an open question.
Asunto(s)
Agonistas alfa-Adrenérgicos/farmacología , Norepinefrina/farmacología , Receptores Adrenérgicos alfa 2/fisiología , Receptores de Droga/fisiología , Sodio en la Dieta/farmacología , Antagonistas Adrenérgicos alfa/farmacología , Animales , Antihipertensivos/farmacología , Apetito/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Tartrato de Brimonidina , Deshidratación/fisiopatología , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Privación de Alimentos , Guanabenzo/farmacología , Idazoxan/farmacología , Imidazoles/farmacología , Receptores de Imidazolina , Inyecciones Intraventriculares , Ligandos , Masculino , Quinoxalinas/farmacología , Ratas , Ratas Sprague-Dawley , Saciedad/efectos de los fármacos , Sodio en la Dieta/metabolismoRESUMEN
The alpha2-adrenergic agonist clonidine and the neuropeptide oxytocin, inhibit sodium intake when injected intracerebroventricularly (i.c.v.). The present work investigates whether (1) vasopressin also inhibits sodium intake when injected i.c.v., and (2) the effect of oxytocin and of vasopressin on sodium intake is affected by i.c.v. injection of idazoxan, an alpha2-adrenergic antagonist. Clonidine (30 nmol), oxytocin (40, 80 nmol) and vasopressin (40, 80 nmol) were injected i.c.v. 20 min prior to a 1.5% NaCl appetite test, in rats depleted of sodium for 24 h by a combination of a single s.c. injection of furosemide (10 mg/rat) and removal of ambient sodium. Every dose of clonidine, oxytocin and vasopressin inhibited the 1.5% NaCl intake. Seizures were observed with the higher dose of vasopressin, but not with either dose of oxytocin. The effect of i.c.v. injection of clonidine (30 nmol), oxytocin (80 nmol) or vasopressin (40 nmol) was partially inhibited by prior i.c.v. injection of idazoxan (160, 320 nmol). The results suggest that the inhibition of 1.5% NaCl intake induced by i.c.v. injection of neuropeptides in sodium-depleted rats depends, in part, on the activation of central alpha2-adrenoceptors.
Asunto(s)
Antagonistas Adrenérgicos alfa/administración & dosificación , Arginina Vasopresina/administración & dosificación , Idazoxan/administración & dosificación , Oxitocina/administración & dosificación , Sodio en la Dieta/administración & dosificación , Sodio/deficiencia , Agonistas alfa-Adrenérgicos/administración & dosificación , Animales , Conducta Animal/efectos de los fármacos , Clonidina/administración & dosificación , Inyecciones Intraventriculares , Masculino , Ratas , Receptores Adrenérgicos alfa 2/efectos de los fármacos , Receptores Adrenérgicos alfa 2/fisiologíaRESUMEN
Angiotensin II (Ang II) non-peptide antagonists were injected i.c.v. (6.25-200 nmol, n = 5-8 rats/group). In sodium replete rats, losartan (AT1 receptor antagonist) induced an increase in mean arterial pressure (MAP) and in heart rate (HR) by 3rd ventricular (3rdV) injection, and an weaker pressor response and bradycardia by 4th ventricular (4thV) injection. PD123319 (AT2 receptor antagonist) induced an increase in MAP and in HR by 3rdV injection, and an increase in MAP and no alteration in HR by 4thV injection. In sodium deplete (furosemide plus removal of ambient sodium for 24 h) rats, losartan induced an increase in MAP and no alteration in HR by 3rdV injection, and no alteration in MAP and bradycardia by 4thV injection. PD123319 induced an increase in MAP and in HR by 3rdV injection, and an increase in MAP and bradycardia by 4thV injection. Thus, there were no fall in MAP by central injections of Ang II antagonists. Intravenous injection of losartan, but not of PD123319, induced a fall in MAP in both sodium replete and sodium deplete animals. Therefore, losartan and PD123319 can have similar effects on MAP and HR when injected intracerebroventricularly, although some differences are also present. The bradycardia is consistent with an withdrawal of Ang II inhibitory action on baroreflex.