RESUMEN
We have shown that an antibody to dopamine-ß-hydroxylase conjugated with saporin (anti-DBH-SAP) damages catecholamine neurons in the nucleus tractus solitarii (NTS) of rat, attenuates arterial baroreflexes, and leads to lability of arterial blood pressure, damage to cardiac myocytes, and, in some animals, sudden death. However, others have shown that injection of 6-hydroxydopamine (6-OHDA), a toxin devoid of saporin, also damaged NTS catecholamine neurons but did not lead to these cardiovascular changes. We found similar cardiovascular changes after injecting a different SAP conjugate to target NTS neurons with neurokinin (NK1) receptors. Because ribosome-inactivating proteins may be toxic to glia, we hypothesized that SAP, a ribosome-inactivating protein, might target glia whose loss could account for physiological changes. We tested this hypothesis by assessing effects on select neurons and on glia in the NTS after exposure to SAP, targeted SAP conjugates, or 6-OHDA. SAP and all SAP conjugates led to loss of immunoreactivity for glial fibrillary acidic protein, a marker for astrocytes, in the NTS while 6-OHDA did not. As reported previously, anti-DBH-SAP selectively killed noradrenergic neurons in the NTS while SAP conjugated to stabilized substance P (SSP-SAP) selectively killed neurons with NK1 receptors. In contrast, SAP produced no demonstrable neuronal damage. All injections led to activation of microglia in the NTS; however, only SAP and its conjugates attenuated cardiovascular reflexes while also producing lability of arterial pressure, damage to cardiac myocytes, and in some animals, sudden death. Thus, NTS astrocytes may play a role in mediating cardiovascular reflex transmission through the NTS.
Asunto(s)
Astrocitos/fisiología , Barorreflejo/fisiología , Presión Sanguínea/fisiología , Núcleo Solitario/citología , Adrenérgicos/farmacología , Animales , Astrocitos/efectos de los fármacos , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunotoxinas/farmacología , Masculino , Microinyecciones , Miocardio/patología , Proteínas del Tejido Nervioso/metabolismo , Oxidopamina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-1/metabolismo , Proteínas Inactivadoras de Ribosomas Tipo 1/farmacología , Saporinas , Núcleo Solitario/efectos de los fármacosAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Comorbilidad , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/mortalidad , Rituximab/administración & dosificación , Resultado del TratamientoRESUMEN
Lesions that remove neurons expressing neurokinin-1 (NK1) receptors from the nucleus tractus solitarii (NTS) without removing catecholaminergic neurons lead to loss of baroreflexes, labile arterial pressure, myocardial lesions, and sudden death. Because destruction of NTS catecholaminergic neurons expressing tyrosine hydroxylase (TH) may also cause lability of arterial pressure and loss of baroreflexes, we sought to test the hypothesis that cardiac lesions associated with lability are not dependent on damage to neurons with NK1 receptors but would also occur when TH neurons in NTS are targeted. To rid the NTS of TH neurons we microinjected anti-dopamine ß-hydroxylase conjugated to saporin (anti-DBH-SAP, 42 ng/200 nl) into the NTS. After injection of the toxin unilaterally, immunofluorescent staining confirmed that anti-DBH-SAP decreased the number of neurons and fibers that contain TH and DBH in the injected side of the NTS while sparing neuronal elements expressing NK1 receptors. Bilateral injections in eight rats led to significant lability of arterial pressure. For example, on day 8 standard deviation of mean arterial pressure was 16.8 ± 2.5 mmHg when compared with a standard deviation of 7.83 ± 0.33 mmHg in six rats in which phosphate buffered saline (PBS) had been injected bilaterally. Two rats died suddenly at 5 and 8 days after anti-DBH-SAP injection. Seven-treated animals demonstrated microscopic myocardial necrosis as reported in animals with lesions of NTS neurons expressing NK1 receptors. Thus, cardiac and cardiovascular effects of lesions directed toward catecholamine neurons of the NTS are similar to those following damage directed toward NK1 receptor-containing neurons.
Asunto(s)
Catecolaminas/metabolismo , Muerte Súbita Cardíaca/patología , Miocardio/metabolismo , Miocardio/patología , Núcleo Solitario/patología , Animales , Muerte Súbita Cardíaca/etiología , Masculino , Neuronas/metabolismo , Neuronas/patología , Ratas , Ratas Sprague-Dawley , Receptores de Neuroquinina-1/biosíntesis , Núcleo Solitario/metabolismoRESUMEN
Increasing renal pelvic pressure results in PGE2-mediated release of substance P, leading to increases in afferent renal nerve activity (ARNA) and natriuresis, that is, a renorenal reflex response. The renorenal reflexes are impaired in congestive heart failure (CHF). Impairment of the renorenal reflexes may contribute to the increased renal sympathetic nerve activity and sodium retention in CHF. Endothelin (ET)-1 contributes to the pathological changes in cardiac and renal function in CHF. Therefore, we examined whether the ETA receptor antagonist BQ123 altered the responsiveness of renal mechanosensory nerves in CHF. The ARNA responses to increasing renal pelvic pressure were suppressed in CHF but not in sham-CHF rats. In CHF, increasing renal pelvic pressure by 7.5 mm Hg before and during renal pelvic perfusion with BQ123 increased ARNA 12% +/- 3% and 21% +/- 3% (p < 0.05 vs. vehicle). In isolated renal pelvises from CHF rats, PGE2 increased substance P release from 5 +/- 0 to 7 +/- 1 pg/min without BQ123 and from 4 +/- 1 to 9 +/- 1 pg/min with BQ123 in the bath (p < 0.01 vs. vehicle). BQ123 had no effect on the ARNA responses or substance P release in sham-CHF. In conclusion, activation of ETA receptors contributes to the impaired responsiveness of renal mechanosensory nerves in CHF rats by a mechanism(s) at the renal sensory nerve endings.
Asunto(s)
Insuficiencia Cardíaca/fisiopatología , Riñón/inervación , Riñón/fisiopatología , Mecanorreceptores/fisiología , Receptor de Endotelina A/metabolismo , Vías Aferentes/fisiopatología , Animales , Antihipertensivos/farmacología , Dinoprostona/farmacología , Modelos Animales de Enfermedad , Antagonistas de los Receptores de la Endotelina A , Insuficiencia Cardíaca/patología , Presión Hidrostática , Riñón/efectos de los fármacos , Riñón/metabolismo , Pelvis Renal/efectos de los fármacos , Pelvis Renal/inervación , Pelvis Renal/metabolismo , Pelvis Renal/fisiopatología , Masculino , Miocardio/patología , Tamaño de los Órganos , Péptidos Cíclicos/administración & dosificación , Péptidos Cíclicos/farmacología , Perfusión , Ratas , Ratas Sprague-Dawley , Sodio/orina , Sustancia P/metabolismo , Disfunción Ventricular Izquierda/patología , Disfunción Ventricular Izquierda/fisiopatologíaRESUMEN
OBJECTIVE: To study effects of endogenous angiotensin II on responses to standardized stimulation of afferent neural input into the central portion of the arterial and cardiac baroreflexes. DESIGN: Different dietary sodium intakes were used to physiologically alter endogenous angiotensin II activity. Candesartan, an angiotensin II type 1 receptor antagonist, was used to assess dependency of observed effects on angiotensin II stimulation of angiotensin II type 1 receptors. Electrical stimulation of arterial and cardiac baroreflex afferent nerves was used to provide a standardized input to the central portion of the arterial and cardiac baroreflexes. METHODS: In anesthetized rats in balance on low, normal and high dietary sodium intake, arterial pressure, heart rate and renal sympathetic nerve activity responses to electrical stimulation of vagus and aortic depressor nerves were determined. Compared with plasma renin activity values in normal dietary sodium intake rats, those from low dietary sodium intake rats were higher and those from high dietary sodium intake rats were lower. During vagus nerve stimulation, the heart rate, arterial pressure and renal sympathetic nerve activity responses were similar in all three dietary sodium intake groups. During aortic depressor nerve stimulation, the heart rate and arterial pressure responses were similar in all three dietary sodium intake groups. However, the renal sympathetic nerve activity response was significantly greater in the low sodium group than in the normal and high sodium group at 4, 8 and 16 Hz. Candesartan administered to low dietary sodium intake rats had no effect on the heart rate and arterial pressure responses to either vagus or aortic depressor nerve stimulation but increased the magnitude of the renal sympathoinhibitory responses. CONCLUSIONS: Increased endogenous angiotensin II in rats on a low dietary sodium intake attenuates the renal sympathoinhibitory response to activation of the cardiac and sinoaortic baroreflexes by standardized vagus and aortic depressor nerve stimulation, respectively.
Asunto(s)
Angiotensina II/metabolismo , Neuronas Aferentes/fisiología , Presorreceptores/metabolismo , Sistema Nervioso Simpático/fisiología , Animales , Antihipertensivos/farmacología , Aorta/inervación , Barorreflejo/fisiología , Bencimidazoles/farmacología , Compuestos de Bifenilo , Dieta Hiposódica , Estimulación Eléctrica , Masculino , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio Dietético/farmacología , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/efectos de los fármacos , Tetrazoles/farmacología , Nervio Vago/fisiologíaRESUMEN
The role of central angiotensinergic pathways in the cardiovascular regulation has been examined using the microinjection of angiotensin peptides and angiotensin receptor antagonists. However, in such studies, neither the overall nor the local level of activity of the renin-angiotensin system is generally known. Herein, physiological changes in the endogenous level of activity of the renin-angiotensin system were produced by alterations in the dietary sodium intake. Microinjection of the angiotensin II AT1 receptor antagonists losartan or candesartan into the rostral ventrolateral medulla produced the bradycardic, depressor and renal sympathoinhibitory responses which were greater in low sodium diet rats with stimulated activity of the renin-angiotensin system than in high sodium diet rats with suppressed activity of the renin-angiotensin system activity. The renal sympathoexcitatory responses to activation of the paraventricular nucleus by microinjection of bicuculline, known to be dependent on the excitatory synaptic inputs to the rostral ventrolateral medulla mediated by AT1 receptors, were greater in low sodium diet rats than in high sodium rats. These observations support the view that physiologically regulated angiotensin peptides of the brain origin exert a local paracrine or autocrine action on sites that influence the renal sympathetic nerve activity.
Asunto(s)
Angiotensinas/metabolismo , Encéfalo/metabolismo , Dieta Hiposódica , Antagonistas de Receptores de Angiotensina , Animales , Antihipertensivos/farmacología , Bencimidazoles/farmacología , Bicuculina/farmacología , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Riñón/inervación , Losartán/farmacología , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/fisiología , Microinyecciones , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Núcleo Hipotalámico Paraventricular/fisiología , Ratas , Receptor de Angiotensina Tipo 1 , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/fisiología , Tetrazoles/farmacologíaRESUMEN
Increasing efferent renal sympathetic nerve activity (ERSNA) increases afferent renal nerve activity (ARNA), which decreases ERSNA to prevent sodium retention. High-sodium diet enhances ARNA, suggesting an important role for ARNA in suppressing ERSNA during excess sodium intake. Mean arterial pressure (MAP) is elevated in afferent renal denervated by dorsal rhizotomy (DRX) rats fed high-sodium diet. We examined whether the increased MAP in DRX is due to impaired arterial baroreflex function. In DRX and sham DRX rats fed high-sodium diet, arterial baroreflex function was determined in conscious rats by intravenous nitroprusside and phenylephrine or calculation of transfer function gain from arterial pressure to ERSNA (spontaneous baroreflex sensitivity). Increasing MAP did not suppress ERSNA to the same extent in DRX as in sham DRX, -60 +/- 4 vs. -77 +/- 6%. Maximum gain, -4.22 +/- 0.45 vs. -6.04 +/- 0.90% DeltaERSNA/mmHg, and the maximum value of instantaneous gain, -4.19 +/- 0.45 vs. -6.04 +/- 0.81% DeltaERSNA/mmHg, were less in DRX than in sham DRX. Likewise, transfer function gain was lower in DRX than in sham DRX, 3.9 +/- 0.2 vs. 6.1 +/- 0.5 NU/mmHg. Air jet stress produced greater increases in ERSNA in DRX than in sham DRX, 35,000 +/- 4,900 vs. 20,900 +/- 3,410%.s (area under the curve). Likewise, the ERSNA responses to thermal cutaneous stimulation were greater in DRX than in sham DRX. These studies suggest impaired arterial baroreflex suppression of ERSNA in DRX fed high-sodium diet. There were no differences in arterial baroreflex function in DRX and sham DRX fed normal-sodium diet. Impaired arterial baroreflex function contributes to increased ERSNA, which would eventually lead to sodium retention and increased MAP in DRX rats fed high-sodium diet.
Asunto(s)
Barorreflejo , Presión Sanguínea , Riñón/inervación , Neuronas Aferentes/fisiología , Neuronas Eferentes/fisiología , Rizotomía , Sistema Nervioso Simpático/fisiología , Presión del Aire , Animales , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Calor , Masculino , Modelos Cardiovasculares , Neuronas Aferentes/efectos de los fármacos , Neuronas Eferentes/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Cloruro de Sodio Dietético/administración & dosificación , Estrés Fisiológico , Sistema Nervioso Simpático/efectos de los fármacos , Vasoconstrictores/farmacología , Vasodilatadores/farmacologíaRESUMEN
Low dietary sodium intake increases central nervous system angiotensin activity, which increases basal renal sympathetic nerve activity and shifts its arterial baroreflex control to a higher level of arterial pressure. This results in a higher level of renal sympathetic nerve activity for a given level of arterial pressure during low dietary sodium intake than during either normal or high dietary sodium intake, in which there is less central angiotensin activity. Peripheral thermal receptor stimulation overrides arterial baroreflex control and produces a pressor response, tachycardia, increased renal sympathetic nerve activity, and renal vasoconstriction. To test the hypothesis that increased central angiotensin activity would enhance the responses to peripheral thermal receptor stimulation, anesthetized normal rats in balance on low, normal, and high dietary sodium intake were subjected to acute peripheral thermal receptor stimulation. Low sodium rats had greater increases in renal sympathetic nerve activity, greater decreases in RBF, and greater increases in renal vascular resistance than high sodium rats. Responses of normal sodium rats were between those of low and high sodium rats. Arterial pressure and heart rate responses were not different among dietary groups. Spontaneously hypertensive rats, known to have increased central nervous system angiotensin activity, also had greater renal sympathoexcitatory and vasoconstrictor responses than normotensive Wistar-Kyoto rats. These results support the view that increased central nervous system angiotensin activity alters arterial baroreflex control of renal sympathetic nerve activity such that the renal sympathoexcitatory and vasoconstrictor responses to peripheral thermoreceptor stimulation are enhanced.