RESUMEN
Recently, we showed that renal afferent neurons exhibit a unique firing pattern, i.e., predominantly sustained firing, upon stimulation. Pathological conditions such as renal inflammation likely alter excitability of renal afferent neurons. Here, we tested whether the proinflammatory chemokine CXCL1 alters the firing pattern of renal afferent neurons. Rat dorsal root ganglion neurons (Th11-L2), retrogradely labeled with dicarbocyanine dye, were incubated with CXCL1 (20 h) or vehicle before patch-clamp recording. The firing pattern of neurons was characterized as tonic, i.e., sustained action potential (AP) firing, or phasic, i.e., <5 APs following current injection. Of the labeled renal afferents treated with vehicle, 58.9% exhibited a tonic firing pattern vs. 7.8%, in unlabeled, nonrenal neurons (P < 0.05). However, after exposure to CXCL1, significantly more phasic neurons were found among labeled renal neurons; hence the occurrence of tonic neurons with sustained firing upon electrical stimulation decreased (35.6 vs. 58.9%, P < 0.05). The firing frequency among tonic neurons was not statistically different between control and CXCL1-treated neurons. However, the lower firing frequency of phasic neurons was even further decreased with CXCL1 exposure [control: 1 AP/600 ms (1-2) vs. CXCL1: 1 AP/600 ms (1-1); P < 0.05; median (25th-75th percentile)]. Hence, CXCL1 shifted the firing pattern of renal afferents from a predominantly tonic to a more phasic firing pattern, suggesting that CXCL1 reduced the sensitivity of renal afferent units upon stimulation.
Asunto(s)
Quimiocina CXCL1/farmacología , Ganglios Espinales/efectos de los fármacos , Riñón/inervación , Neuronas/efectos de los fármacos , Potenciales de Acción , Vías Aferentes/efectos de los fármacos , Vías Aferentes/fisiología , Animales , Células Cultivadas , Ganglios Espinales/fisiología , Cinética , Masculino , Neuronas/fisiología , Ratas Sprague-DawleyRESUMEN
The role of serotonin in the hemodynamic response to blood loss remains controversial. Caudal raphe serotonin neurons are activated during hypotensive hemorrhage, and their destruction attenuates sympathetic increases following blood loss in unanesthetized rats. Caudal raphe neurons provide serotonin-positive projections to the nucleus tractus solitarii (NTS), and disruption of serotonin-positive nerve terminals in the NTS attenuates sympathetic recovery following hemorrhage. Administration of 5-HT1A-receptor agonists following hemorrhage augments sympathetic-mediated increases in venous tone and tissue hypoxia. These findings led us to hypothesize that severe blood loss promotes activation of 5-HT1A receptors in the NTS, which facilitates sympathetic recovery and peripheral tissue perfusion. Here, we developed an adeno-associated viral vector encoding an efficacious small hairpin RNA sequence targeting the rat 5-HT1A receptor. Unanesthetized rats subjected to NTS injection of the anti-rat 5-HT1A small hairpin RNA-encoding vector 4 wk prior showed normal blood pressure recovery, but an attenuated recovery of renal sympathetic nerve activity (-6.4 ± 12.9 vs. 42.6 ± 15.6% baseline, P < 0.05) 50 min after 21% estimated blood volume withdrawal. The same rats developed increased tissue hypoxia after hemorrhage, as indicated by prolonged elevations in lactate (2.77 ± 0.5 vs. 1.34 ± 0.2 mmol/l, 60 min after start of hemorrhage, P < 0.05). 5-HT1A mRNA levels in the commissural NTS were directly correlated with renal sympathetic nerve activity (P < 0.01) and inversely correlated with lactate (P < 0.05) 60 min after start of hemorrhage. The data suggest that 5-HT1A receptors in the commissural NTS facilitate tissue perfusion after blood loss likely by increasing sympathetic-mediated venous return.
Asunto(s)
Barorreflejo , Hemorragia/metabolismo , Hipotensión/metabolismo , Riñón/inervación , Receptor de Serotonina 5-HT1A/metabolismo , Neuronas Serotoninérgicas/metabolismo , Núcleo Solitario/metabolismo , Sistema Nervioso Simpático/metabolismo , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea , Volumen Sanguíneo , Modelos Animales de Enfermedad , Hemorragia/genética , Hemorragia/fisiopatología , Hipotensión/genética , Hipotensión/fisiopatología , Ácido Láctico/metabolismo , Masculino , Interferencia de ARN , ARN Mensajero/metabolismo , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/efectos de los fármacos , Receptor de Serotonina 5-HT1A/genética , Recuperación de la Función , Neuronas Serotoninérgicas/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Transducción de Señal , Núcleo Solitario/efectos de los fármacos , Núcleo Solitario/fisiopatología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Factores de TiempoRESUMEN
Sympathetic efferent and peptidergic afferent renal nerves likely influence hypertensive and inflammatory kidney disease. Our recent investigation with confocal microscopy revealed that in the kidney sympathetic nerve endings are colocalized with afferent nerve fibers (Ditting T, Tiegs G, Rodionova K, Reeh PW, Neuhuber W, Freisinger W, Veelken R. Am J Physiol Renal Physiol 297: F1427-F1434, 2009; Veelken R, Vogel EM, Hilgers K, Amman K, Hartner A, Sass G, Neuhuber W, Tiegs G. J Am Soc Nephrol 19: 1371-1378, 2008). However, it is not known whether renal afferent nerves are influenced by sympathetic nerve activity. We tested the hypothesis that norepinephrine (NE) influences voltage-gated Ca(2+) channel currents in cultured renal dorsal root ganglion (DRG) neurons, i.e., the first-order neuron of the renal afferent pathway. DRG neurons (T11-L2) retrogradely labeled from the kidney and subsequently cultured, were investigated by whole-cell patch clamp. Voltage-gated calcium channels (VGCC) were investigated by voltage ramps (-100 to +80 mV, 300 ms, every 20 s). NE and appropriate adrenergic receptor antagonists were administered by microperfusion. NE (20 µM) reduced VGCC-mediated currents by 10.4 ± 3.0% (P < 0.01). This reduction was abolished by the α-adrenoreceptor inhibitor phentolamine and the α(2)-adrenoceptor antagonist yohimbine. The ß-adrenoreceptor antagonist propranolol and the α(1)-adrenoceptor antagonist prazosin had no effect. The inhibitory effect of NE was abolished when N-type currents were blocked by ω-conotoxin GVIA, but was unaffected by other specific Ca(2+) channel inhibitors (ω-agatoxin IVA; nimodipine). Confocal microscopy revealed sympathetic innervation of DRGs and confirmed colocalization of afferent and efferent fibers within in the kidney. Hence NE released from intrarenal sympathetic nerve endings, or sympathetic fibers within the DRGs, or even circulating catecholamines, may influence the activity of peptidergic afferent nerve fibers through N-type Ca(2+) channels via an α(2)-adrenoceptor-dependent mechanism. However, the exact site and the functional role of this interaction remains to be elucidated.
Asunto(s)
Canales de Calcio/fisiología , Riñón/inervación , Neuronas Aferentes/fisiología , Norepinefrina/farmacología , omega-Conotoxinas/farmacología , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Animales , Bloqueadores de los Canales de Calcio/farmacología , Células Cultivadas , Interacciones Farmacológicas , Ganglios Espinales/citología , Ganglios Espinales/fisiología , Masculino , Neuronas Aferentes/citología , Neuronas Aferentes/efectos de los fármacos , Técnicas de Cultivo de Órganos , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos alfa 2/fisiología , Fibras Simpáticas Posganglionares/efectos de los fármacos , Fibras Simpáticas Posganglionares/fisiología , Yohimbina/farmacologíaRESUMEN
Administration of the 5-HT(1A) receptor agonist, 8-OH-DPAT, improves cardiovascular hemodynamics and tissue oxygenation in conscious rats subjected to hypovolemic shock. This effect is mediated by sympathetic-dependent increases in venous tone. To determine the role of splanchnic nerves in this response, effects of 8-OH-DPAT (30 nmol/kg iv) were measured following fixed-arterial blood pressure hemorrhagic shock (i.e., maintenance of 50 mmHg arterial pressure for 25 min) in rats subjected to bilateral splanchnic nerve denervation (SD). Splanchnic denervation decreased baseline venous tone as measured by mean circulatory filling pressure (MCFP) and accelerated the onset of hypotension during blood loss. Splanchnic denervation did not affect the immediate pressor effect of 8-OH-DPAT but did reverse the drug's lasting pressor effect, as well as its ability to increase MCFP and improve metabolic acidosis. Like SD, adrenal demedullation (ADMX) lowered baseline MCFP and accelerated the hypotensive response to blood withdrawal but also reduced the volume of blood withdrawal required to maintain arterial blood pressure at 50 mmHg. 8-OH-DPAT raised MCFP early after administration in ADMX rats, but the response did not persist throughout the posthemorrhage period. In a fixed-volume hemorrhage model, 8-OH-DPAT continued to raise blood pressure in ADMX rats. However, it produced only a transient and variable rise in MCFP compared with sham-operated animals. The data indicate that 8-OH-DPAT increases venoconstriction and improves acid-base balance in hypovolemic rats through activation of splanchnic nerves. This effect is due, in part, to activation of the adrenal medulla.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Hemodinámica/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Choque Hemorrágico/fisiopatología , Nervios Esplácnicos/fisiología , Sistema Nervioso Simpático/fisiología , Equilibrio Ácido-Base/efectos de los fármacos , Equilibrio Ácido-Base/fisiología , Médula Suprarrenal/inervación , Médula Suprarrenal/fisiología , Médula Suprarrenal/cirugía , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Hemodinámica/fisiología , Masculino , Modelos Animales , Ratas , Ratas Sprague-Dawley , Nervios Esplácnicos/cirugía , Simpatectomía , Sistema Nervioso Simpático/cirugía , Vasoconstricción/efectos de los fármacos , Vasoconstricción/fisiologíaRESUMEN
Serotonin (5-hydroxytryptamine; 5-HT) delivered over 1 week results in a sustained fall in blood pressure in the sham and deoxycorticosterone acetate (DOCA)-salt rat. We hypothesized 5-HT lowers blood pressure through direct receptor-mediated vascular relaxation. In vivo, 5-HT reduced mean arterial pressure (MAP), increased heart rate, stroke volume, cardiac index, and reduced total peripheral resistance during a 1 week infusion of 5-HT (25 µg/kg/min) in the normotensive Sprague Dawley rat. The mesenteric vasculature was chosen as an ideal candidate for the site of 5-HT receptor mediated vascular relaxation given the high percentage of cardiac output the site receives. Real-time RT-PCR demonstrated that mRNA transcripts for the 5-HT2B, 5-HT1B, and 5-HT7 receptors are present in sham and DOCA-salt superior mesenteric arteries. Immunohistochemistry and Western blot validated the presence of the 5-HT2B, 5- HT1B and 5-HT7 receptor protein in sham and DOCA-salt superior mesenteric artery. Isometric contractile force was measured in endothelium-intact superior mesenteric artery and mesenteric resistance arteries in which the contractile 5- HT2A receptor was antagonized. Maximum concentrations of BW-723C86 (5- HT2B agonist), CP 93129 (5-HT1B agonist) or LP-44 (5-HT7 agonist) did not relax the superior mesenteric artery from DOCA-salt rats vs. vehicle. Additionally, 5-HT (10-9 M to 10-5 M) did not cause relaxation in either contracted mesenteric resistance arteries or superior mesenteric arteries from normotensive Sprague- Dawley rats. Thus, although 5-HT receptors known to mediate vascular relaxation are present in the superior mesenteric artery, they are not functional, and are therefore not likely involved in a 5-HT-induced fall in total peripheral resistance and MAP.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Arterias Mesentéricas/efectos de los fármacos , Receptores de Serotonina/fisiología , Serotonina/farmacología , Resistencia Vascular/efectos de los fármacos , Animales , Desoxicorticosterona , Técnicas In Vitro , Contracción Isométrica/efectos de los fármacos , Masculino , Arterias Mesentéricas/fisiología , Mineralocorticoides , Ratas , Ratas Sprague-Dawley , Agonistas de Receptores de Serotonina/farmacología , VasodilataciónRESUMEN
Serotonin neurons of the caudal raphe facilitate ventilatory and sympathetic responses that develop following blood loss in conscious rats. Here, we tested whether serotonin projections to the caudal portion of the dorsomedial brain stem (including regions of the nucleus tractus solitarius that receive cardiovascular and chemosensory afferents) contribute to cardiorespiratory compensation following hemorrhage. Injections of the serotonin neurotoxin 5,7-dihydroxytryptamine produced >90% depletion of serotonin nerve terminals in the region of injection. Withdrawal of â¼21% of blood volume over 10 min produced a characteristic three-phase response that included 1) a normotensive compensatory phase, 2) rapid sympathetic withdrawal and hypotension, and 3) rapid blood pressure recovery accompanied by slower recovery of heart rate and sympathetic activity. A gradual tachypnea developed throughout hemorrhage, which quickly reversed with the advent of sympathetic withdrawal. Subsequently, breathing frequency and neural minute volume (determined by diaphragmatic electromyography) declined below baseline following termination of hemorrhage but gradually recovered over time. Lesioned rats showed attenuated sympathetic and ventilatory responses during early compensation and later recovery from hemorrhage. Both ventilatory and sympathetic responses to chemoreceptor activation with potassium cyanide injection were attenuated by the lesion. In contrast, the gain of sympathetic and heart rate baroreflex responses was greater, and low-frequency oscillations in blood pressure were reduced after lesion. Together, the data are consistent with the view that serotonin innervation of the caudal dorsomedial brain stem contributes to sympathetic compensation during hypovolemia, possibly through facilitation of peripheral chemoreflex responses.
Asunto(s)
Barorreflejo , Células Quimiorreceptoras/metabolismo , Hemorragia/metabolismo , Bulbo Raquídeo/metabolismo , Terminales Presinápticos/metabolismo , Ventilación Pulmonar , Neuronas Serotoninérgicas/metabolismo , Sistema Nervioso Simpático/metabolismo , 5,7-Dihidroxitriptamina/administración & dosificación , Adaptación Fisiológica , Animales , Presión Sanguínea , Células Quimiorreceptoras/efectos de los fármacos , Modelos Animales de Enfermedad , Frecuencia Cardíaca , Hemorragia/patología , Hemorragia/fisiopatología , Hipotensión/metabolismo , Hipotensión/fisiopatología , Hipovolemia/metabolismo , Hipovolemia/fisiopatología , Inyecciones , Riñón/inervación , Masculino , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/patología , Bulbo Raquídeo/fisiopatología , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiopatología , Cianuro de Potasio/administración & dosificación , Terminales Presinápticos/efectos de los fármacos , Terminales Presinápticos/patología , Ventilación Pulmonar/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Neuronas Serotoninérgicas/efectos de los fármacos , Neuronas Serotoninérgicas/patología , Serotoninérgicos/administración & dosificación , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , Factores de TiempoRESUMEN
Serotonin is thought to contribute to the syncopal-like response that develops during severe blood loss by inhibiting presympathetic neurons of the rostroventrolateral medulla (RVLM). Here, we tested whether serotonin cells activated during hypotensive hemorrhage, i.e., express the protein product of the immediate early gene c-Fos, are critical for the normal sympathetic response to blood loss in unanesthetized rats. Serotonin-immunoreactive cells of the raphe obscurus and raphe magnus, parapyramidal cells of the B3 region, subependymal cells of the ventral parapyramidal region, and cells of the ventrolateral periaqueductal gray region were activated by hypotensive hemorrhage, but not by hypotension alone. In contrast to findings in anesthetized animals, lesion of hindbrain serotonergic cells sufficient to produce >80% loss of serotonin nerve terminal immunoreactivity in the RVLM accelerated the sympatholytic response to blood loss, attenuated recovery of sympathetic activity after termination of hemorrhage, and exaggerated metabolic acidosis. Hindbrain serotonin lesion also attenuated ventilatory and sympathetic responses to stimulation of central chemoreceptors but increased spontaneous arterial baroreflex sensitivity and decreased blood pressure variability. A more global neurotoxic lesion that also eliminated tryptophan hydroxylase-immunoreactive cells of the ventrolateral periaqueductal gray region had no further effect on the sympatholytic response to blood loss. Together, the data indicate that serotonin cells of the caudal hindbrain contribute to compensatory responses following blood loss that help maintain oxygenation of peripheral tissue in the unanesthetized rat. This effect may be related to facilitation of chemoreflex responses to acidosis.
Asunto(s)
Hemorragia Cerebral/fisiopatología , Neuronas/fisiología , Núcleos del Rafe/fisiología , Serotonina/fisiología , Sistema Nervioso Simpático/fisiología , Animales , Barorreflejo/fisiología , Presión Sanguínea , Frecuencia Cardíaca , Hipotensión/complicaciones , Masculino , Bulbo Raquídeo/fisiología , Neurotoxinas/toxicidad , Células Piramidales/fisiología , Ratas , Ratas Sprague-Dawley , Triptófano Hidroxilasa/metabolismoRESUMEN
Pressor effects of the vasoconstrictor hormone arginine vasopressin (AVP), observed when systemic AVP concentrations are less than 100 pM, are important for the physiological maintenance of blood pressure, and they are also the basis for therapeutic use of vasopressin to restore blood pressure in hypotensive patients. However, the mechanisms by which circulating AVP induces arterial constriction are unclear. We examined the novel hypothesis that KCNQ potassium channels mediate the physiological vasoconstrictor actions of AVP. Reverse transcriptase polymerase chain reaction revealed expression of KCNQ1, KCNQ4, and KCNQ5 in rat mesenteric artery smooth muscle cells (MASMCs). Whole-cell perforated patch recordings of voltage-sensitive K+ (Kv) currents in freshly isolated MASMCs revealed 1,3-dihydro-1-phenyl-3,3-bis(4-pyridinylmethyl)-2H-indol-2-one (linopirdine)- and 10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone (XE-991)-sensitive KCNQ currents that were electrophysiologically and pharmacologically distinct from other Kv currents. Suppression of KCNQ currents by AVP (100 pM) was associated with significant membrane depolarization, and it was abolished by the protein kinase C (PKC) inhibitor calphostin C (250 nM). The KCNQ channel blocker linopirdine (10 microM) inhibited KCNQ currents in MASMCs, and it induced constriction of isolated rat mesenteric arteries. The vasoconstrictor responses were not additive when combined with 30 pM AVP, and they were prevented by the L-type Ca2+ channel blocker verapamil. Ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl] carbamic acid (flupirtine) significantly enhanced KCNQ currents, and it reversed constrictor responses to 30 pM AVP. In vivo, i.v. administration of linopirdine induced a dose-dependent increase in mesenteric artery resistance and blood pressure, whereas flupirtine had the opposite effects. We conclude that physiological concentrations of AVP induce mesenteric artery constriction via PKC-dependent suppression of KCNQ currents and L-type Ca2+ channel activation in MASMCs.
Asunto(s)
Canales de Potasio KCNQ/fisiología , Arterias Mesentéricas/efectos de los fármacos , Células Musculares/efectos de los fármacos , Proteína Quinasa C/fisiología , Vasoconstrictores/farmacología , Vasopresinas/farmacología , Aminopiridinas/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Canales de Calcio Tipo L/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Indoles/farmacología , Canales de Potasio KCNQ/agonistas , Canales de Potasio KCNQ/antagonistas & inhibidores , Masculino , Arterias Mesentéricas/citología , Arterias Mesentéricas/fisiología , Células Musculares/fisiología , Bloqueadores de los Canales de Potasio/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Resistencia Vascular/efectos de los fármacosRESUMEN
The 5-HT(1A) receptor agonist, 8- OH-DPAT, increases whole body venous tone (mean circulatory filling pressure; MCFP), and attenuates metabolic acidosis in a rat model of unresuscitated hemorrhagic shock. To determine whether improved acid-base balance was associated with sympathetic activation and venous constriction, MCFP, sympathetic activity (SA), and blood gases were compared in hemorrhaged rats following administration of 5-HT(1A) receptor agonist 8-OH-DPAT, the arterial vasoconstrictor arginine vasopressin (AVP), or saline. To further determine whether protection of acid-base balance was dependent on splenic contraction and blood mobilization, central venous pressure (CVP), MCFP, and blood gases were determined during hemorrhage and subsequent 8-OH-DPAT-administration in rats subjected to real or sham splenectomy. Subjects were hemorrhaged to an arterial pressure of 50 mmHg for 25 min and subsequently were treated with 8-OH-DPAT (30 nmol/kg iv), AVP titrated to match the pressor effect of 8-OH-DPAT (approximately 2 ng/min iv), or infusion of normal saline. 8-OH-DPAT increased MAP, CVP, MCFP, and SA, and decreased lactate accumulation. AVP did not affect CVP or SA, but raised MCFP slightly to a level intermediate between 8-OH-DPAT- and saline-treated rats. Infusion of AVP also produced a modest protection against metabolic acidosis. Splenectomy prevented the rise in CVP, MCFP, and protection against metabolic acidosis produced by 8-OH-DPAT but had no effect on the immediate pressor response to the drug. Together, the data indicate that 8-OH-DPAT produces a pattern of cardiovascular responses consistent with a sympathetic-mediated venoconstriction that is, in part, responsible for the drug's beneficial effect on acid-base balance. Moreover, blood mobilization stimulated by the spleen is required for the beneficial effects of 8-OH-DPAT.
Asunto(s)
Circulación Sanguínea/fisiología , Presión Sanguínea/fisiología , Receptor de Serotonina 5-HT1A/fisiología , Agonistas del Receptor de Serotonina 5-HT1 , Choque Hemorrágico/fisiopatología , Bazo/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Equilibrio Ácido-Base/efectos de los fármacos , Animales , Arginina Vasopresina/farmacología , Circulación Sanguínea/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Masculino , Modelos Animales , Ratas , Ratas Sprague-Dawley , Serotoninérgicos/farmacología , Esplenectomía , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Vasoconstrictores/farmacologíaRESUMEN
OBJECTIVE: To describe a woman with a previously unrecognized pheochromocytoma who died after ingesting over-the-counter pseudoephedrine-containing medications. METHODS: We present a case report including laboratory, radiographic, and pathologic findings in a patient with a previously unrecognized pheochromocytoma. RESULTS: A 31-year-old woman had symptoms consistent with intermittent, excessive release of catecholamines since childhood. She developed an upper-respiratory infection and used over-the-counter medications containing pseudoephedrine. Subsequently, she developed a hypertensive crisis with congestive heart failure and died of a cardiac arrhythmia and shock. Findings from postmortem examination included a right adrenal pheochromocytoma, congestive heart failure, and catecholamine cardiomyopathy. CONCLUSION: This patient death may be linked to the use of pseudoephedrine hydrochloride. Physicians and pharmacists should warn patients with known pheochromocytoma or those at risk for having pheochromocytoma on the basis of family history or genetic testing that pseudoephedrine use may be harmful. Over-the-counter packaging should include such warning.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/complicaciones , Cardiomiopatías/inducido químicamente , Catecolaminas/efectos adversos , Muerte , Hipertensión/diagnóstico , Hipertensión/etiología , Feocromocitoma/complicaciones , Seudoefedrina/efectos adversos , Neoplasias de las Glándulas Suprarrenales/diagnóstico , Adulto , Resultado Fatal , Femenino , Humanos , Hallazgos Incidentales , Medicamentos sin Prescripción/efectos adversos , Feocromocitoma/diagnóstico , AutocuidadoRESUMEN
The 5-hydroxytryptamine(1A) receptor agonist, (+)-8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), raises blood pressure (BP) and venous tone in rats subjected to hemorrhagic shock. Here, BP, ascending aortic blood flow [i.e., estimate of cardiac output (CO)] and venous blood gases were measured to determine the hemodynamic effects of 8-OH-DPAT (30 nmol/kg i.v., n = 10), saline (n = 10), or an equipressor infusion of epinephrine (n = 10) in unanesthetized rats subjected to hemorrhagic shock (25 min of hypotensive hemorrhage, approximately 50 mm Hg). Renal and iliac blood flow were measured in separate groups of similarly hemorrhaged rats given the same dose of 8-OH-DPAT (n = 7) or saline (n = 6). Compared with saline treatment, 8-OH-DPAT produced a sustained rise in BP (+32 +/- 4 versus +9 +/- 2 mm Hg, 15 min after injection, P < 0.01) and CO (+27 +/- 5 versus +4 +/- 6 ml/min/kg, P < 0.01) but did not affect total peripheral resistance (TPR). Infusion of epinephrine reduced CO (-12 +/- 6 ml/min/kg, P < 0.01) and dramatically increased TPR [+0.37 +/- 0.11 versus +0.05 +/- 0.05 log (mm Hg/ml/min/kg), P < 0.01]. 8-OH-DPAT increased renal conductance (+7 +/- 1 versus +4 +/- 1 microl/min/mm Hg, P < 0.01) but did not significantly affect iliac conductance. 8-OH-DPAT attenuated further development of acidosis compared with either saline or epinephrine (-5.6 +/- 1.6 versus -13.0 +/- 2.0 versus -11.3 +/- 2.6 mmol/liter base excess 45 min after start of hemorrhage, both P < 0.01 versus 8-OH-DPAT). These data demonstrate that 8-OH-DPAT improves hemodynamics during circulatory shock, in part, through renal vasodilation and mobilizing of blood stores.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Gasto Cardíaco/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , Choque/fisiopatología , Animales , Presión Sanguínea/efectos de los fármacos , Dióxido de Carbono/sangre , Epinefrina/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Ilion/irrigación sanguínea , Ilion/efectos de los fármacos , Masculino , Norepinefrina/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Baroreflex control of heart rate (HR) is impaired after chronic intermittent hypoxia (CIH). However, the location and nature of this response remain unclear. We examined baroreceptor afferent, vagal efferent, and central components of the baroreflex circuitry. Fischer 344 (F344) rats were exposed to room air (RA) or CIH for 35-50 days and were then anesthetized with isoflurane, ventilated, and catheterized for measurement of mean arterial blood pressure (MAP) and HR. Baroreceptor function was characterized by measuring percent changes of integrated aortic depressor nerve (ADN) activity (Int ADNA) relative to the baseline value in response to sodium nitroprusside- and phenylephrine-induced changes in MAP. Data were fitted to a sigmoid logistic function curve. HR responses to electrical stimulation of the left ADN and the right vagus nerve were assessed under ketamine-acepromazine anesthesia. Compared with RA controls, CIH significantly increased maximum baroreceptor gain or maximum slope, maximum Int ADNA, and Int ADNA range (maximum - minimum Int ADNA), whereas other parameters of the logistic function were unchanged. In addition, CIH increased the maximum amplitude of bradycardic response to vagal efferent stimulation and decreased the time from stimulus onset to peak response. In contrast, CIH significantly reduced the maximum amplitude of bradycardic response to left ADN stimulation and increased the time from stimulus onset to peak response. Therefore, CIH decreased central mediation of the baroreflex but augmented baroreceptor afferent function and vagal efferent control of HR.
Asunto(s)
Barorreflejo , Presión Sanguínea , Frecuencia Cardíaca , Corazón/inervación , Corazón/fisiopatología , Hipoxia/fisiopatología , Sistema Nervioso Parasimpático/fisiopatología , Animales , Enfermedad Crónica , Ratas , Ratas Endogámicas F344RESUMEN
Adjuvant treatment of hypovolemic shock with vasoconstrictors is controversial due to their propensity to raise arterial resistance and exacerbate ischemia. A more advantageous therapeutic approach would use agents that also promote venoconstriction to augment perfusion pressure through increased venous return. Recent studies indicate that 5-hydroxytryptophan (5-HT)(1A) receptor agonists increase blood pressure by stimulating sympathetic drive when administered after acute hypotensive hemorrhage. Given that venous tone is highly dependent upon sympathetic activation of alpha(2)-adrenergic receptors, we hypothesized that the 5-HT(1A) receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), would increase venous tone in rats subject to hypovolemic shock through sympathetic activation of alpha(2)-adrenergic receptors. Systemic administration of 8-OH-DPAT produced a sustained rise in blood pressure (+44 +/- 3 mm Hg 35 min after injection, P < 0.01 versus saline) and mean circulatory filling pressure (+4.2 +/- 0.7 mm Hg, P < 0.01 versus saline) in conscious rats subjected to hypovolemic shock. An equipressor infusion of epinephrine failed to influence mean circulatory filling pressure (MCFP). Ganglionic blockade, alpha(1)-, or peripheral alpha(2)-adrenergic receptor blockade prevented the rise in MCFP observed with 8-OH-DPAT, but only alpha(1)-adrenergic receptor blockade diminished the pressor effect of the drug (P < 0.01). 8-OH-DPAT raises blood pressure in rats in hypovolemic shock through both direct vascular activation and sympathetic activation of alpha(1)-adrenergic receptors. The sympathoexcitatory effect of 8-OH-DPAT contributes to elevated venous tone through concurrent activation of both alpha(1)- and alpha(2)-adrenergic receptors. The data suggest that 5-HT(1A) receptor agonists may provide an advantageous alternative to currently therapeutic interventions used to raise perfusion pressure in hypovolemic shock.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Presión Venosa Central/efectos de los fármacos , Agonistas de Receptores de Serotonina/farmacología , Choque/tratamiento farmacológico , Sistema Nervioso Simpático/efectos de los fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralin/uso terapéutico , Animales , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Prazosina/farmacología , Quinolizinas/farmacología , Ratas , Ratas Sprague-Dawley , Choque/fisiopatología , Sistema Nervioso Simpático/fisiologíaRESUMEN
Neuroendocrine responses to administration of serotonin releasing agents or 5-hydroxytryptamine (5-HT) 1A receptor agonists have been used as an index of serotonin receptor function in patients with depression and other mood disorders. However, the receptor population that mediates these responses has not been clearly identified. We tested the hypothesis that 5-HT1A receptors in the paraventricular nucleus of the hypothalamus (PVN) mediate the release of adrenocorticotropin hormone (ACTH) and oxytocin after administration of a selective 5-HT1A agonist in conscious rats. Low-dose infusion (1 nmol/100 nl/side) of the selective 5-HT1A antagonist, WAY100635 (WAY; [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl) ethyl)-N-(2-pyridinyl)cyclohexanecarboxamidetrihydrochloride), into the PVN blocked the rise in ACTH and oxytocin stimulated by low-dose (30 nmol/kg) i.v. administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 274 +/- 53 versus 70 +/- 20 pg/ml, P < 0.01 for ACTH and 10.7 +/- 3.4 versus 4.6 +/- 0.7 pg/ml, P < 0.05 for oxytocin after saline or WAY pretreatment, respectively). WAY did not influence the bradycardic effect of 8-OH-DPAT (-56 +/- 7 versus -54 +/- 6 beats per minute after saline or WAY). 8-OH-DPAT treatment also elicited locomotor activation followed by hind limb abduction and flat body posture. Surprisingly, WAY attenuated some aspects of locomotor activation and reduced the duration of hind limb abduction elicited by the agonist (5.1 +/- 0.9 versus 0.3 +/- 0.3 min for saline- or WAY-treated rats). These data indicate that 5-HT1A receptor stimulation in the PVN mediates the characteristic neuroendocrine response to serotonin agonist challenge. Moreover, they provide the first evidence that aspects of the behavioral serotonin syndrome are mediated by forebrain hypothalamic receptors.
Asunto(s)
Hormona Adrenocorticotrópica/metabolismo , Conducta Animal/efectos de los fármacos , Oxitocina/metabolismo , Núcleo Hipotalámico Paraventricular/fisiología , Receptor de Serotonina 5-HT1A/fisiología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Frecuencia Cardíaca/efectos de los fármacos , Masculino , Piperazinas/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Left ventricular (LV) end-diastolic pressure (LVEDP) increase due to volume expansion (VExp) enhances mechanosensitive vagal cardiac afferent C-fiber activity (CNFA), thus decreasing renal sympathetic nerve activity (RSNA). Hypotensive hemorrhage (hHem) attenuates RSNA despite decreased LVEDP. We hypothesized that CNFA increases with any change in LVEDP. Coronary perfusion pressure (CPP), supposedly affected in both conditions, might also be a stimulus of CNFA. VExp and hHem were performed in anesthetized male Sprague-Dawley rats while blood pressure, heart rate, and RSNA were measured. Cervical vagotomy abolished RSNA response in both reflex responses. Single-unit CNFA was recorded while LVEDP was changed. Rapid changes (+/- 4, +/-6, +/-8 mmHg) were obtained by graded occlusion of the caval vein and descending aorta. Prolonged changes were obtained by VExp and hHem. Furthermore, CNFA was recorded in a modified Langendorff heart while CPP was changed (70, 100, 40 mmHg). Rapid LVEDP changes increased CNFA [caval vein occlusion: +16 +/- 3 Hz (approximately +602%); aortic occlusion: +15 +/- 3 Hz (approximately +553%); 70 units; P < 0.05]. VExp and hHem (n = 6) increased CNFA [VExp: +10 +/- 4 Hz (approximately +1,033%); hHem: +10 +/- 2 Hz (approximately +1,225%); P < 0.05]. An increase in CPP increased CNFA [+2 +/- 1 Hz (approximately +225%); P < 0.05], whereas a decrease in CPP decreased CNFA [-0.8 +/- 0.4 Hz (approximately -50%); P < 0.05]. All C fibers recorded originated from the LV. CNFA increased with any LVEDP change but changed equidirectionally with CPP. Thus neither LVEDP nor CPP fully accounts directly for afferent C-fiber and reflex sympathetic responses. The intrinsic afferent stimuli and receptive fields accounting for reflex sympathoinhibition still remain cryptic.
Asunto(s)
Corazón/fisiología , Hemorragia/fisiopatología , Mecanorreceptores/fisiología , Fibras Nerviosas Amielínicas/fisiología , Función Ventricular Izquierda/fisiología , Vías Aferentes/fisiología , Animales , Aorta , Presión Sanguínea/fisiología , Volumen Cardíaco/fisiología , Cateterismo , Circulación Coronaria/fisiología , Corazón/inervación , Riñón/inervación , Riñón/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/fisiología , Nervio Vago/fisiologíaRESUMEN
Central administration of serotonergic 5-HT1A receptor agonists delays the reflex sympatholytic response to severe hemorrhage in conscious rats. To determine the region where 5-HT1A receptor agonists act to mediate this response, recovery of mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) was compared in hemorrhaged rats after injection of the selective 5-HT1A agonist, (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), in various regions of the cerebroventricular system or the systemic circulation. Three minutes after injection of 8-OH-DPAT (48 nmol/kg), MAP and RSNA were higher in hemorrhaged rats given drug in the fourth ventricle (94 +/- 5 mmHg, 82 +/- 18% of baseline) or the systemic circulation (90 +/- 4 mmHg, 113 +/- 15% of baseline) than in rats given drug in the Aqueduct of Sylvius (63 +/- 4 mmHg, 27 +/- 11% of baseline), the lateral ventricle (42 +/- 3 mmHg, -8 +/- 18% of baseline), or in rats given saline in various brain regions (47 +/- 5 mmHg, -42 +/- 10% of baseline). A lower-dose injection of 8-OH-DPAT (10 nmol/kg) also accelerated the recovery of MAP and RSNA in hemorrhaged rats when given in the fourth ventricle (94 +/- 26 mmHg, 72 +/- 33% of baseline 3 min after injection) but not the systemic circulation (46 +/- 4 mmHg, -25 +/- 30% of baseline). These data indicate that 8-OH-DPAT acts on receptors in the hindbrain to reverse the sympatholytic response to hemorrhage in conscious rats.
Asunto(s)
8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Hemorragia/fisiopatología , Receptores de Serotonina/efectos de los fármacos , Rombencéfalo/efectos de los fármacos , Rombencéfalo/fisiología , Agonistas de Receptores de Serotonina/farmacología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiopatología , 8-Hidroxi-2-(di-n-propilamino)tetralin/administración & dosificación , Animales , Presión Sanguínea/efectos de los fármacos , Acueducto del Mesencéfalo , Relación Dosis-Respuesta a Droga , Cuarto Ventrículo , Frecuencia Cardíaca/efectos de los fármacos , Inyecciones Intraventriculares , Riñón/inervación , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/administración & dosificación , Índice de Severidad de la EnfermedadRESUMEN
5-Hydroxytryptamine 1A (5-HT1A) receptor agonists reverse the hypotensive and sympathoinhibitory responses to severe hemorrhage in rats. To determine whether 5-HT1A receptor-mediated pressor responses in hypovolemic animals are due to sympathoexcitation and/or direct vasoconstriction, blood pressure (BP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to the partial 5-HT1A receptor agonist buspirone or the more selective, full 5-HT1A receptor agonist (+)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) were compared in intact and ganglionic blocked, hemorrhaged Sprague-Dawley rats. Buspirone produced dose-dependent increases in BP (110 +/- 4(**), 86 +/- 4(**), 65 +/- 7 mm Hg), HR [369 +/- 10(**), 337 +/- 14, 277 +/- 16 beats per minute (bpm)], and RSNA (114 +/- 36(**), 34 +/- 21, -23 +/- 25% baseline for 0.2, 0.1, and 0 mg/kg; (**)p < 0.01 versus 0 mg/kg, 3 min after injection). Ganglionic blockade with hexamethonium chloride blocked the pressor effect of 9.9 microg/kg 8-OH-DPAT and attenuated, but did not block, the pressor response to 0.2 mg/kg buspirone (85 +/- 7 versus 46 +/- 6 mm Hg for buspirone + ganglionic blockade versus saline + ganglionic blockade; p < 0.01). In subsequent tests, rats treated with the selective alpha1-adrenergic receptor antagonist prazosin (25 microg/kg) continued to show extensive tachycardic (+73 +/- 26 bpm) and sympathoexcitatory (128 +/- 55% baseline) responses to 0.2 mg/kg buspirone. Ganglionic blockade combined with prazosin completely blocked all responses to buspirone. Buspirone (0.2 mg/kg) produced significant bradycardic (-89 +/- 12 bpm; p < 0.01) and sympathoinhibitory (-72 +/- 7% baseline; p < 0.01) responses in euvolemic rats 3 min after injection. It is concluded that the pressor effect of buspirone is unique to hypovolemic animals and is mediated by sympathetic activation as well as direct activation of vascular alpha1-adrenergic receptors.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Buspirona/farmacología , Hemorragia/fisiopatología , Receptores Adrenérgicos alfa 1/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Modelos Animales de Enfermedad , Masculino , Presorreceptores/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Agonistas del Receptor de Serotonina 5-HT1 , Agonistas de Receptores de Serotonina/farmacología , Sistema Nervioso Simpático/fisiologíaRESUMEN
Acute increases in osmolality suppress renal sympathetic nerve activity (RSNA). However, it is not known whether prolonged physiological increases in plasma osmolality chronically inhibit RSNA. To address this hypothesis, mean arterial blood pressure (MAP), heart rate (HR), and RSNA were measured during acute normalization of plasma osmolality in conscious rats made hyperosmotic by 48 h of water deprivation. Water deprivation significantly elevated MAP (120 +/- 1 vs. 114 +/- 3 mmHg, P < 0.05) and plasma osmolality (306 +/- 1 vs. 293 +/- 1 mosmol/kgH2O, P < 0.01). When plasma osmolality was subsequently lowered to normal (-17 +/- 1 mosmol/kgH2O) with a 2-h (0.12 ml/min) infusion of 5% dextrose in water (5DW), MAP decreased (-11 +/- 1 mmHg), and RSNA increased (25 +/- 10% baseline). To assess the role of circulating vasopressin in these changes, rats were pretreated with a V1-vasopressin receptor antagonist before infusion of 5DW. The antagonist lowered MAP (-4 +/- 1 mmHg) and raised RSNA (31 +/- 3% baseline) and HR (25 +/- 5 beats/min) in water-deprived rats (all changes P < 0.05). However, V1-vasopressin receptor blockade did not increase RSNA or HR independently of baroreflex responses to decreases in arterial pressure. After V1 blockade, infusion of 5DW lowered blood pressure (-8 +/- 1 mmHg) but did not further affect HR or RSNA. An isotonic saline infusion that produced the same volume expansion as 5DW lowered MAP (-5 +/- 2 mmHg) and HR (-68 +/- 2 beats/min) but had no effect on osmolality or RSNA in water-deprived rats. Finally, 5DW infusion had negligible effects in water-replete animals. In conclusion, these results fail to support the hypothesis that sustained increases in plasma osmolality, either directly or via increased vasopressin, tonically suppress RSNA.