apelin-13-peptide and Hypertension

Numerous studies suggest that apelin plays a significant role in cardiovascular regulation and in the pathogenesis of hypertension. The purpose of the present study was to determine whether apelin-13 (AP-13) is involved in the regulation of cardiovascular responses to acute stress in spontaneous hypertension.. The effects of intracerebroventricular (ICV) administration of AP-13 on changes in mean arterial blood pressure (MABP) and heart rate evoked by an alarming stress (air jet stress) were compared in awake normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The rats were divided into four groups: Groups 1 (WKY) and 3 (SHR) received ICV infusion of 0.9% sodium chloride (vehicle), whereas Groups 2 (WKY) and 4 (SHR) were ICV infused with AP-13. All animals were exposed to the alarming stress.. During the ICV administration of the vehicle, the pressor response to stress was significantly greater in SHR than in WKY. The ICV infusion of AP-13 reduced the pressor response evoked by the application of the stressor in SHR but not in WKY. It also abolished the difference in stress-induced MABP increases between WKY and SHR.. The results show that centrally acting apelin may play an essential role in the regulation of blood pressure responses to an alarming stress in SHR rats.

Topics: Animals; Arterial Pressure; Cardiovascular System; Heart Rate; Hypertension; Infusions, Intraventricular; Intercellular Signaling Peptides and Proteins; Male; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Stress, Physiological

It is known that apelin has definite protective effects on various cardiovascular diseases; however, the mechanism through which hypertension with heart failure (H-HF) is affected by pyroglutamylated apelin-13 (Pyr-AP13) remain unclear. Thus, in the present study, we investigated the effects of apelin on the cardiac hemodynamics in rats with hypertension and heart failure. In our study, cardiac function, dimensions and histological determination of the fibrosis of rats with two-kidney, one-clip induced hypertension and sham-operated rats were assessed using an echocardiography system and Masson's trichrome. The infusion of either 5% glucose injection (GS) alone or 5% GS containing Pyr-AP13 as a dose, time-matched design on the cardiac hemodynamics in H-HF rats and sham-operated rats was recorded. For the determination of the effects of potential related proteins on cardiac hemodynamics in the H-HF rats, the animals were divided into 5 groups: i) the sham-operated group (n=8); ii) H-HF (n=8); iii) H-HF with infusion of 0.1 µg dose of Pyr-AP13 (n=8) or 5% glucose (GS) (n=8); iv) H-HF with infusion of 1 µg dose of Pyr-AP13 (n=8) or 5% GS (n=8); and v) H-HF with infusion of 10 µg dose of Pyr-AP13 (n=8) or 5% GS (n=8). The concentration of cyclic adenosine 3',5'-monophosphate (cAMP) was determined by ELISA. The expression of membrane and cytosolic proteins was evaluated by western blot analysis. Significant cardiac and perivascular fibrosis was observed in the H-HF rats. Following the infusion of Pyr-AP13, the systolic and diastolic function was significantly improved in the cardiac hemodynamic parameters in the H-HF rats treated with Pyr-AP13. The apelin receptor (APJ), which was activated by the exogenous infusion of Pyr-AP13, was partially recycled from the cytoplasm back to the plasma membrane; however, membrane APJ was eventually downregulated in the H-HF rats treated with Pyr-AP13 compared with the sham-operated group rats. Our findings suggested that a complex was formed after Pyr-AP13 combined with cellular membrane APJ receptor. However, the endogenous downregulation of the APJ receptor results in benefits from the exogenous administration of apelin.

Topics: Animals; Apelin Receptors; Cardiotonic Agents; Cell Separation; Cyclic AMP; Extracellular Signal-Regulated MAP Kinases; Fibrosis; Heart; Heart Failure; Hemodynamics; Hypertension; Intercellular Signaling Peptides and Proteins; Male; Myocytes, Cardiac; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Time Factors; Ultrasonography; Ventricular Function, Left

Apelin is a specific endogenous ligand of orphan G protein-coupled receptor APJ. This study was designed to determine the roles and mechanisms of apelin-13 and APJ in paraventricular nucleus (PVN) in renal sympathetic nerve activity (RSNA), arginine vasopressin (AVP) release and mean arterial pressure (MAP) in spontaneously hypertensive rats (SHR).. Acute experiment was carried out in 13-week-old male SHR and Wistar-Kyoto rats (WKY) under anaesthesia. RSNA and MAP responses to the PVN microinjection were determined. Apelin and APJ expressions were examined with quantitative real-time PCR and Western blot. AVP and noradrenaline were determined with ELISA. Osmotic minipumps were used for chronic PVN infusion in conscious WKY.. Apelin and APJ in the PVN were up-regulated in SHR. The PVN microinjection of apelin-13 increased, but APJ antagonist F13A decreased the RSNA, MAP, plasma noradrenaline and AVP levels in SHR. N-methyl-D-aspartate receptor (NMDAR) antagonist plus non-NMDAR antagonist abolished the apelin-13-induced sympathetic activation rather than AVP release. NMDAR antagonist or non-NMDAR antagonist alone attenuated the apelin-13-induced sympathetic activation. Chronic infusion of apelin-13 into the PVN in normotensive rats induced hypertension, increased plasma noradrenaline and AVP levels and promoted myocardial atrial natriuretic peptide and beta-myosin heavy chain mRNA expressions, two indicative markers of cardiac hypertrophy.. Apelin-13 and APJ in the PVN contribute to hypertension via sympathetic activation and AVP release in SHR. The sympatho-excitatory effect of apeline-13 is mediated by both NMDAR and non-NMDAR in the PVN. Persistent activation of APJ in the PVN induces hypertension.

Topics: Animals; Apelin Receptors; Arginine Vasopressin; Blotting, Western; Electrophysiology; Hypertension; Intercellular Signaling Peptides and Proteins; Male; Paraventricular Hypothalamic Nucleus; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptors, G-Protein-Coupled; Reverse Transcriptase Polymerase Chain Reaction; Sympathetic Nervous System

Apelin is the endogenous ligand of APJ, which belongs to the family of G protein‑coupled receptors. Apelin and APJ are highly expressed in various cardiovascular tissues, including the heart, kidney and vascular endothelial and smooth muscle cells. Although apelin exerts hypotensive effects via activation of endothelial nitric oxide synthase (eNOS), the ability of apelin to regulate blood pressure under pathological conditions is poorly understood. In the current study, NG‑nitro‑L‑arginine methyl ester (L‑NAME), a potent NOS inhibitor, was administered chronically, to induce peripheral vascular damage in mice. L‑NAME‑treated mice exhibited hypertension, increased vascular cell adhesion molecule‑1 and plasminogen activator inhibitor‑1 mRNA levels in the aorta and impaired vasodilatation associated with decreased aortic eNOS expression, consistent with endothelial damage. Three days following withdrawal of L‑NAME treatment, the blood pressure response to apelin stimulation was assessed. Although apelin reduced blood pressure in non‑treated mice, it was found to transiently elevate blood pressure in L‑NAME‑treated mice. These results indicate that apelin functions as a vasopressor peptide under pathological conditions, including vascular endothelial dysfunction in mice.

Topics: Animals; Aorta; Blood Pressure; Body Weight; Endothelium, Vascular; Gene Expression Regulation; Hypertension; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred ICR; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Systole; Vasoconstrictor Agents; Vasodilation

Asymmetric dimethylarginine (ADMA) is a risk factor for endothelial dysfunction. The polypeptide apelin has biphasic effects on blood vessels in vivo and in vitro. We investigated the effect of apelin-13 on ADMA-damaged vessels. Rats were divided among ADMA-treated and control groups, which were treated with ADMA (10 mg·(kg body mass)(-1)·day(-1)) or saline, respectively, for 4 weeks. Systolic blood pressure (SBP) was measured before and after the injection of apelin-13. The ultrastructure of endothelial cells in caudal arteries was examined using transmission electron microscopy. The reactivities of isolated caudal artery rings were observed after exposure to apelin-13, and myosin light chain (MLC) phosphorylation was assessed by immunohistochemistry in rings treated with or without apelin-13. ADMA induced hypertension and endothelial dysfunction. After injection of apelin-13, SBP declined in the control group but was elevated in the ADMA-treated group. In vitro, apelin-13 caused relaxation in rings in the control group, but it contracted rings in the ADMA-treated group. Apelin-13 promoted MLC phosphorylation in vascular smooth muscle cells (VSMCs) in the ADMA group. These results indicate that apelin-13 might pass through ADMA-damaged endothelium and act on VSMCs to increase MLC phosphorylation, thus contributing to vasoconstriction and exacerbating hypertension.

Topics: Animals; Arginine; Blood Pressure; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Hypertension; Injections, Intravenous; Intercellular Signaling Peptides and Proteins; Male; Myosin Light Chains; Nitric Oxide; Phosphorylation; Rats; Rats, Sprague-Dawley; Time Factors; Vasoconstriction; Vasodilation; von Willebrand Factor

The peripheral apelin system plays a significant role in cardiovascular homeostasis and in the pathophysiology of cardiovascular diseases. However, the central effect of this neurohormonal system in neural control of cardiovascular function remains poorly understood. Thus, this study was undertaken to evaluate the effect of apelin in the rostral ventrolateral medulla (RVLM) on blood pressure, cardiac function, and sympathetic nerve activity. Apelin mRNA and protein levels were detected with real-time RT-PCR and Western blots, respectively. Expression of apelin was significantly enhanced in the RVLM of spontaneously hypertensive rat (SHR) compared with normotensive Wistar-Kyoto (WKY) rats. To study the functional consequence of upregulated apelin expression, apelin was overexpressed by bilateral microinjection of the AAV2-apelin viral vector into the RVLM of WKY rats. Immunofluorescence staining and Western blots demonstrated that microinjection of AAV2-apelin into the RVLM resulted in a significant increase in apelin expression, which was associated with a chronic elevation in blood pressure and cardiac hypertrophy. In addition, direct microinjection of exogenous apelin-13 (200 pmol in 50 nL) into the RVLM caused a 20 mm Hg elevation in blood pressure and a 24% increase in sympathetic nerve activity. The present study is the first to show that apelin expression is enhanced in the RVLM of SHR versus WKY rats and that overexpression of this gene in the RVLM results in chronic blood pressure elevation and cardiac hypertrophy in normotensive rats. Thus, the apelin system in the RVLM may play a very important role in central blood pressure regulation and in the pathogenesis of hypertension.

Topics: Animals; Apelin; Blood Pressure; Cardiomegaly; Carrier Proteins; Dependovirus; Gene Expression; Humans; Hypertension; Intercellular Signaling Peptides and Proteins; Myocardium; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Sympathetic Nervous System; Transduction, Genetic