RESUMEN
Sepsis is a severe disorder characterized by systemic inflammatory responses in the presence of an infection and may progress to multiple organ dysfunction and death. Alterations in cerebral microcirculation fulfill a crucial role in the pathogenesis of severe sepsis, and include a decrease in capillary density and disturbances in leukocyte movement along capillaries. Nevertheless, the mechanisms involved in sepsis-associated cerebral microcirculatory alterations have so far not been defined. We investigated the effect of the peroxisome proliferator-activated receptor gamma (PPARγ) selective agonist rosiglitazone on leukocyte/endothelial cell interaction and functional capillary density in the brain in the cecal ligation and puncture (CLP) model of sepsis. Anti-inflammatory effects of rosiglitazone on the cerebral microcirculation were marked. Functional capillary density increased and leukocyte rolling and adhesion were decreased in animals submitted to CLP and treated with rosiglitazone. Our data provide evidence for involvement of PPARγ activation in leukocyte-endothelium interactions and alterations in capillary density. Improved cerebral perfusion in animals treated with rosiglitazone, suggests that PPARγ activation is protective against cerebral microvascular dysfunction in sepsis.
Asunto(s)
Antiinflamatorios/farmacología , Encéfalo/irrigación sanguínea , Circulación Cerebrovascular/efectos de los fármacos , Trastornos Cerebrovasculares/prevención & control , Microcirculación/efectos de los fármacos , Microvasos/efectos de los fármacos , PPAR gamma/agonistas , Sepsis/tratamiento farmacológico , Tiazolidinedionas/farmacología , Animales , Ciego/cirugía , Trastornos Cerebrovasculares/inmunología , Trastornos Cerebrovasculares/metabolismo , Trastornos Cerebrovasculares/fisiopatología , Citoprotección , Modelos Animales de Enfermedad , Rodamiento de Leucocito/efectos de los fármacos , Ligadura , Masculino , Ratones , Microvasos/inmunología , Microvasos/metabolismo , Microvasos/fisiopatología , Infiltración Neutrófila/efectos de los fármacos , PPAR gamma/metabolismo , Punciones , Rosiglitazona , Sepsis/inmunología , Sepsis/metabolismo , Sepsis/fisiopatologíaRESUMEN
We investigated the acute effects of centrally acting antihypertensive drugs on the microcirculation of pentobarbital-anesthetized spontaneously hypertensive rats (SHR). The effects of the sympatho-inhibitory agents clonidine and rilmenidine, known to activate both alpha2-adrenoceptors and nonadrenergic I1-imidazoline binding sites (I1BS) in the central nervous system, were compared to those of dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H -pyrrol-2-yl)-amine hydrochloride (LNP 509), which selectively binds to the I1BS. Terminal mesenteric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 µg, ic) induced marked vasoconstriction of the mesenteric microcirculation (27 ± 3 percent; N = 6, P < 0.05). In contrast, the marked hypotensive and bradycardic effects elicited by intracisternal injection of clonidine (1 µg), rilmenidine (7 µg) and LNP 509 (60 µg) were accompanied by significant increases in arteriolar diameter (12 ± 1, 25 ± 10 and 21 ± 4 percent, respectively; N = 6, P < 0.05). The vasodilating effects of rilmenidine and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic inhibition elicited by baclofen (1 µg, ic), a GABA B receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine) or exclusively (LNP 509) upon I1BS than with those presenting important alpha2-adrenergic activity (clonidine).
Asunto(s)
Animales , Ratas , Antihipertensivos , Clonidina , Microcirculación , Circulación Esplácnica , Ratas Endogámicas SHR , Sistema Nervioso Simpático , VasodilataciónRESUMEN
We investigated the acute effects of centrally acting antihypertensive drugs on the microcirculation of pentobarbital-anesthetized spontaneously hypertensive rats (SHR). The effects of the sympatho-inhibitory agents clonidine and rilmenidine, known to activate both alpha2-adrenoceptors and nonadrenergic I1-imidazoline binding sites (I1BS) in the central nervous system, were compared to those of dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H-pyrrol-2-yl)-amine hydrochloride (LNP 509), which selectively binds to the I1BS. Terminal mesenteric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 microg, ic) induced marked vasoconstriction of the mesenteric microcirculation (27 +/- 3%; N = 6, P < 0.05). In contrast, the marked hypotensive and bradycardic effects elicited by intracisternal injection of clonidine (1 microg), rilmenidine (7 microg) and LNP 509 (60 microg) were accompanied by significant increases in arteriolar diameter (12 +/- 1, 25 +/- 10 and 21 +/- 4%, respectively; N = 6, P < 0.05). The vasodilating effects of rilmenidine and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic inhibition elicited by baclofen (1 microg, ic), a GABA B receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine) or exclusively (LNP 509) upon I1BS than with those presenting important alpha2-adrenergic activity (clonidine).
Asunto(s)
Antihipertensivos/farmacología , Microcirculación/efectos de los fármacos , Circulación Esplácnica/efectos de los fármacos , Animales , Antihipertensivos/administración & dosificación , Clonidina/administración & dosificación , Clonidina/farmacología , Ciclopropanos/administración & dosificación , Ciclopropanos/farmacología , Receptores de Imidazolina , Oxazoles/administración & dosificación , Oxazoles/farmacología , Pirroles/administración & dosificación , Pirroles/farmacología , Ratas , Ratas Endogámicas SHR , Receptores de Droga/efectos de los fármacos , Rilmenidina , Sistema Nervioso Simpático/efectos de los fármacos , Vasodilatación/efectos de los fármacosRESUMEN
The haemodynamic alterations induced by the central and peripheral administration of the armed spider (Phoneutria nigriventer) venom (PNV) were investigated in anaesthetised rabbits. The intracerebroventricular injection of increasing doses of PNV (30 and 100 microg/kg) elicited a biphasic cardiovascular response characterised by a brief hypotension (1-3 min) followed by a marked and sustained (more than 30 min) increase in mean arterial pressure (61 +/- 5 and 61 +/- 10%, respectively) and in systemic vascular resistance (135 +/- 21 and 161 +/- 37%) accompanied by mild increases in cardiac contractility. Systemic alterations such as salivation and muscular fasciculation were also observed. At the opposite, the dose of 100 microg/kg of PNV injected intravenously produced only a hypotensive effect (29 +/- 4% decrease in mean arterial pressure) and a decrease in vascular resistance (38 +/- 5%). Nevertheless, a much higher dose of PNV (1 mg/kg) injected intravenously produced a hypertensive response analogous to the one observed upon central administration. The central hypertensive response induced by PNV was not affected by preteating the animals with selective antagonists of receptors of different neurotransmitters or endogenous mediators such as: acethylcoline muscarinic, bradykinin B2, angiotensin II AT1 receptors and also antagonists of the excitatory amino acid receptors of the central nervous system. Nevertheless, the intravenous pretreatment with the selective alpha1-adrenergic receptor antagonist prazosin significantly blunted the excitatory cardiovascular response evoked by the central injection of PNV. It is concluded that PNV can induce central as well as peripheral haemodynamic effects. The central component seems to be mediated by the activation of cardiovascular centres which in turn lead to an increase in the sympathetic outflow to the periphery, whereas the peripheral component can be accounted for either by direct activation of the vascular alpha1-adrenergic receptors or by catecholamine release from the sympathetic nerve endings.
Asunto(s)
Hemodinámica/efectos de los fármacos , Venenos de Araña/toxicidad , Antagonistas Adrenérgicos alfa/administración & dosificación , Antagonistas de Receptores de Angiotensina , Animales , Antihipertensivos/administración & dosificación , Antagonistas de los Receptores de Bradiquinina , Sistema Cardiovascular/efectos de los fármacos , Antagonistas Colinérgicos/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Inyecciones Intravenosas , Masculino , Prazosina/administración & dosificación , Conejos , Venenos de Araña/administración & dosificación , Venenos de Araña/antagonistas & inhibidoresRESUMEN
The purpose of the present study was to investigate the involvement of nitric oxide (NO) in the modulatory role of platelet-activating factor (PAF, 1-O-hexadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine), a vasoactive phospholipid mediator synthesized by endothelial cells, on the vascular tone and arterial blood pressure. In pentobarbitone-anaesthetized rabbits, unloading of the carotid sinus baroreceptors by a bilateral carotid artery occlusion elicited a reflex rise in systemic vascular resistance, which was markedly potentiated by pretreating the animals with the PAF receptor antagonist WEB 2086 ([3-4-(2-chlorphenyl-)-9-methyl-6H-thieno-3,2-f-1,2,4-triazolo-4,3 -alpha-1,4 -diazepin-2-yl-(4-morpholinyl)-1-propanone]; 5 mg/kg, i.v.). In contrast, the inhibition of the biosynthesis of NO via NO synthase using N omega-nitro-L-arginine methyl ester (L-NAME) neither affected the systemic vasoconstriction induced by carotid artery occlusion nor modified the potentiating effect of WEB 2086. The haemodynamic alterations induced by L-NAME administration were corrected by continuous infusions of the directly-acting vasodilators sodium nitroprusside or diazoxide. The results of the present study confirm previous studies from our group suggesting the involvement of PAF in a negative feedback mechanism effective in the local regulation of vasomotor tone in anaesthetized rabbits, but exclude the participation of NO in this process.
Asunto(s)
Presión Sanguínea/fisiología , Estenosis Carotídea/fisiopatología , Factor de Activación Plaquetaria/fisiología , Receptores de Superficie Celular , Receptores Acoplados a Proteínas G , Resistencia Vascular/fisiología , Animales , Azepinas/farmacología , Gasto Cardíaco/efectos de los fármacos , Arterias Carótidas/fisiología , Inhibidores Enzimáticos/farmacología , Retroalimentación , Femenino , Masculino , NG-Nitroarginina Metil Éster/farmacología , Óxido Nítrico/fisiología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Glicoproteínas de Membrana Plaquetaria/antagonistas & inhibidores , Presorreceptores/fisiología , Conejos , Transducción de Señal , Triazoles/farmacología , Vasoconstricción/efectos de los fármacosRESUMEN
The purpose of the present study was to investigate the role of platelet-activating factor (PAF, 1-O-hexadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine), a phospholipid mediator synthesized by endothelial and smooth muscle cells, in the modulation of vascular tone and blood pressure. In pentobarbitone-anaesthetised rabbits, unloading of the carotid sinus baroreceptors by a bilateral carotid artery occlusion elicited a reflex rise in arterial pressure which was markedly potentiated by pretreating the animals with the PAF receptor antagonists WEB 2086 [3-4-(2-chlorphenyl)-9-methyl-6H-thieno-3,2f-1,2,4-triazolo-4, 3 a-1,4-diazepin-2-yl-(4-morpholinyl)-I-propanone; 2, 5 or 10 mg kg-1, i.v.] or BN 52021 (ginkgolide B; 0.1, 0.3 or 1.0 mg kg-1, i.v.). The increases in systemic vascular resistance induced by noradrenaline (30 micrograms kg-1, i.v.) or by the central activation of the sympathetic nervous system with glutamate (1 mg kg-1, intracerebroventricular) were also significantly potentiated in animals pretreated with WEB 2086 (5 mg kg-1, i.v.). In contrast, pretreatment with the cyclooxygenase inhibitor indomethacin (3 mg kg-1, i.v.) did not affect the haemodynamic actions of noradrenaline, thus excluding the possibility that prostacyclin may modulate the potentiating effect. To further confirm that PAF is released during systemic vasoconstriction, the cardiovascular PAF receptors were desensitized by the daily administration of PAF (3 micrograms kg-1, i.v.) for seven days. This procedure significantly reduced the intensity and duration of the hypotensive response to a subsequent PAF injection (3 micrograms kg-1, i.v.). In desensitized animals, the hypertensive response to bilateral carotid artery occlusion was potentiated to the same extent as in the animals treated with PAF receptor antagonists. Inhibition of PAF biosynthesis by pretreatment of the animals with the phospholipase A2 inhibitor mepacrine (5 mg kg-1, i.v.) also enhanced the increase in blood pressure elicited by carotid artery occlusion. We conclude that PAF is involved in the acute but not basal modulation of vasomotor tone and, hence, arterial pressure, probably by a negative feedback mechanism triggered by important increases in the vascular tone.