ABSTRACT
Hypertension is the largest risk factor for cardiovascular disease, the leading cause of mortality worldwide. As blood pressure regulation is influenced by multiple physiological systems, hypertension cannot be attributed to a single identifiable etiology. Three decades of research into Mendelian forms of hypertension implicated alterations in the renal tubular sodium handling, particularly the distal convoluted tubule (DCT)-native, thiazide-sensitive Na-Cl cotransporter (NCC). Altered functions of the NCC have shown to have profound effects on blood pressure regulation as illustrated by the over activation and inactivation of the NCC in Gordon's and Gitelman syndromes respectively. Substantial progress has uncovered multiple factors that affect the expression and activity of the NCC. In particular, NCC activity is controlled by phosphorylation/dephosphorylation, and NCC expression is facilitated by glycosylation and negatively regulated by ubiquitination. Studies have even found parvalbumin to be an unexpected regulator of the NCC. In recent years, there have been considerable advances in our understanding of NCC control mechanisms, particularly
ABSTRACT
Hypertension is a clinical syndrome characterized by elevated systemic arterial blood pressure, which may be accompanied by functional or organic damage of heart, brain, kidney and other organs. The pathogenesis and development of hypertension are affected by genetic, environmental, epigenetic, intestinal microbiota and other factors. They are the result of multiple factors that promote the change of blood pressure level and vascular resistance. G protein coupled receptors(GPCRs) are the largest and most diverse superfamily of transmembrane receptors that transmit signals across cell membranes and mediate a large number of cellular responses required by human physiology. A variety of GPCRs are involved in the control of blood pressure and the maintenance of normal function of cardiovascular system. Hypertension contributes to the damages of heart, brain, kidney, intestine and other organs. Many GPCRs are expressed in various organs to regulate blood pressure. Although many GPCRs have been used as therapeutic targets for hypertension, their efficacy has not been fully studied. The purpose of this paper is to elucidate the role of GPCRs in blood pressure regulation and its distribution in target organs. The relationship between GPCRs related to intestinal microorganisms and blood pressure is emphasized. It is proposed that traditional Chinese medicine may be a new way to treat hypertension by regulating the related GPCRs via intestinal microbial metabolites.
Subject(s)
Humans , Blood Pressure , GTP-Binding Proteins , Gastrointestinal Microbiome , Hypertension/genetics , Receptors, G-Protein-Coupled/metabolismABSTRACT
Fenofibrate, an agonist for peroxisome proliferator-activated receptor alpha (PPAR-α), lowers blood pressure, but whether this action is mediated via baroreflex afferents has not been elucidated. In this study, the distribution of PPAR-α and PPAR-γ was assessed in the nodose ganglion (NG) and the nucleus of the solitary tract (NTS). Hypertension induced by drinking high fructose (HFD) was reduced, along with complete restoration of impaired baroreceptor sensitivity, by chronic treatment with fenofibrate. The molecular data also showed that both PPAR-α and PPAR-γ were dramatically up-regulated in the NG and NTS of the HFD group. Expression of the downstream signaling molecule of PPAR-α, the mitochondrial uncoupling protein 2 (UCP2), was up-regulated in the baroreflex afferent pathway under similar experimental conditions, along with amelioration of reduced superoxide dismutase activity and increased superoxide in HFD rats. These results suggest that chronic treatment with fenofibrate plays a crucial role in the neural control of blood pressure by improving baroreflex afferent function due at least partially to PPAR-mediated up-regulation of UCP2 expression and reduction of oxidative stress.
Subject(s)
Animals , Male , Afferent Pathways , Antihypertensive Agents , Pharmacology , Baroreflex , Blood Pressure , Fenofibrate , Pharmacology , Oxidative Stress , PPAR gamma , Metabolism , Rats, Sprague-Dawley , Signal Transduction , Transcriptional Activation , Uncoupling Protein 2 , Metabolism , Up-RegulationABSTRACT
La región anteroventral del tercer ventrículo (AV3V) es capaz de detectar la concentración sanguínea de NaCl y ajustar la función cardiovascular y renal en respuesta a la composición hidroelectrolítica del líquido extracelular. La microinyección de NaCl hipertónico en esta área cerebral induce un incremento de la actividad simpática que aumenta de la presión arterial; la frecuencia cardíaca y la función renal. Estos cambios pueden ser modulados por la administración central de antagonistas de receptores 5HT2 de serotonina y bloqueadores de los receptores AT1 de angiotensina o por la administración periférica de antagonistas alfa y beta de los receptores adrenérgicos. El papel de las endotelinas cerebrales y del factor natriurético auricular (FNA) en esta región cerebral no ha sido estudiado. Se evaluó la participación de los receptores para endotelinas cerebrales y del FNA en la respuesta cardiovascular al NaCl hipertónico 1,5 M (2myL) administrado en la región AV3V de ratas anestesiadas. La microinyección de NaCl 1,5 M en la región AV3V de ratas normotensas produjo un incremento de la presión arterial media en un máximo de 17,9 ± 2,2 mm de Hg (p<0,01). La microinyección previa de FNA a una dosis 5myg/2myL no alteró la presión arterial media (PAM) ni el efecto en la PAM inducidos por la microinyección de NaCl 1,5 M en AV3V. La administración previa del antagonista no selectivo de los receptores de endotelinas PD-142893 (3myg/2myL) no alteró la PAM basal pero redujo en 8,52 ± 1,20 mm de Hg (47,6%) el incremento de la presión arterial media inducido por el NaCl 1,5 M (p<0,01). Los resultados indican un papel modulador de las endotelinas en la respuesta cardiovascular al NaCl 1,5 M administrado en la región AV3V y ausencia de la participación del FNA en la respuesta cardiovascular simpática evocada por el NaCl.
Third ventricle anteroventral area (AV3V) is sensitive to changes in NaCl concentration and able to modify blood pressure and renal function in response to NaCl concentration. Hypertonic NaCl microinjections in AV3V induce a sympathetic cardiovascular response which increases blood pressure and heart rate; these changes can be modulated by central administration of 5HT2 and AT1 receptor blockers, and also by peripheral administration of alpha and beta adrenergic receptor antagonists. Influence of endothelin receptors (ETR) and atrial natriuretic factor (ANF) on sensitivity to NaCl has not been explored. Hypertonic 1,5 M NaCl (2 muL volume) microinjections in AV3V of normotensive anesthetized rats increased mean arterial blood pressure by 17,9 ± 2.2 mm Hg (p<0.01). ANF microinjections (5mug/2muL) in AV3V neither changed mean arterial blood pressure nor altered the hypertensive response to NaCl 1,5 M microinjection. Microinjection of PD 142893 into AV3V a non selective endothelin antagonist (3mug/2muL) did not modify basal blood pressure but reduced by 47,6% (p<0,01) the hypertensive response to 1,5 M NaCl injection. These results indicates a possible modulator effect of endothelin receptors in the NaCl centrally- evocated cardiovascular response to hypertonic NaCl injections in AV3V. Acute microinjection of ANF in this brain area seems not to be involved in the NaCl-evoked sympathetic cardiovascular response.