Renal ?-adrenergic receptors and genetic hypertension

Jackson, Christopher R.; Insel, Paul A.

doi:10.1007/bf01213373

Cited by 13 publications

(4 citation statements)

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“…It has been shown that CQ acts on venous α2B adrenergic receptors to produce constriction and increase venous blood return to the heart and also stimulates central α2A adrenergic receptors to produce a decrease in systemic vascular resistance (SVR) ( Gulati et al, 2020 ; Gulati et al, 2020 ) and thus it helps in increasing the cardiac output. Kidney tissues have abundant α-adrenergic receptors and their localization is primarily in renal arterioles, glomeruli and tubules of the renal cortex and medulla ( Jackson and Insel, 1993 ). They are involved in the regulation of renal blood flow, glomerular filtration rate, renin release and sodium re-absorption ( de Leeuw and Birkenhager, 1988 ).…”

Section: Discussionmentioning

confidence: 99%

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

et al. 2021

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Background: Centhaquine (CQ) (Lyfaquin®) is in late stage clinical development as a safe and effective first-in-class resuscitative agent for hemorrhagic shock patients (NCT02408731, NCT04056065, and NCT04045327). Acute kidney injury (AKI) is known to be associated with hemorrhagic shock. Hence, effect of CQ on protection of kidneys from damage due to hemorrhagic shock was investigated.Methods: To assess effect of CQ on AKI in shock, we created a rat model with hemorrhagic shock and AKI. Renal arteries were clamped and de-clamped to induce AKI like ischemia/reperfusion model and hemorrhage was carried out by withdrawing blood for 30 min. Rats were resuscitated with CQ (0.02 mg/kg) for 10 min. MAP, heart rate (HR), and renal blood flow (RBF) were monitored for 120 min.Results: CQ produced a significant improvement in RBF compared to vehicle (p< 0.003) even though MAP and HR was similar in CQ and vehicle groups. Blood lactate level was lower (p = 0.0064) in CQ than vehicle at 120 min post-resuscitation. Histopathological analysis of tissues indicated greater renal damage in vehicle than CQ. Western blots showed higher HIF-1α (p = 0.0152) and lower NGAL (p = 0.01626) levels in CQ vs vehicle. Immunofluorescence in the kidney cortex and medulla showed significantly higher (p< 0.045) expression of HIF-1α and lower expression of Bax (p< 0.044) in CQ. Expression of PHD 3 (p< 0.0001) was higher, while the expression of Cytochrome C (p = 0.01429) was lower in the cortex of CQ than vehicle.Conclusion: Results show CQ (Lyfaquin®) increased renal blood flow, augmented hypoxia response, decreased tissue damage and apoptosis following hemorrhagic shock induced AKI, and may be explored to prevent/treat AKI.Translational Statement: Centhaquine (CQ) is safe for human use and currently in late stage clinical development as a first-in-class resuscitative agent to treat hemorrhagic shock. In the current study, we have explored a novel role of CQ in protection from hemorrhagic shock induced AKI, indicating its potential to treat/prevent AKI.

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Section: Discussionmentioning

confidence: 99%

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

et al. 2021

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“…1,2 Despite the great amount of research on the subject, the specific events that lead to the development of high blood pressure (BP) are not known. However, at the vascular level, 2 factors seem to be involved in the pathogenesis of this condition: (1) structural changes in blood vessel walls and (2) hypersensitivity of blood vessels to vasoconstrictor stimuli.…”

mentioning

confidence: 99%

Role of the α _1D - Adrenegric Receptor in the Development of Salt-Induced Hypertension

et al. 2002

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Abstract-In an attempt to elucidate whether there is a specific ␣ 1 -adrenergic receptor (␣ 1 -AR) subtype involved in the genesis or maintenance of hypertension, the ␣ 1D -AR subtype was evaluated in a model of salt-induced hypertension. The ␣ 1D -AR-deficient (␣ 1D Ϫ/Ϫ ) and control (␣ 1D ϩ/ϩ ) mice (nϭ8 to 14 in each group) were submitted to subtotal nephrectomy and given 1% saline as drinking water for 35 days. Blood pressure (BP) was monitored by tail-cuff readings and confirmed at the end point by direct intraarterial BP recording. The ␣ 1D Ϫ/Ϫ mice had a significantly (Pϭ0.0004) attenuated increase in BP response in this protocol (baseline 94.6Ϯ2.8 versus end point 107.4Ϯ4.5 mm Hg) compared with that of their wild-type counterparts (␣ 1D ϩ/ϩ ), from a baseline 97.4Ϯ2.9 to an end point 139.4Ϯ4.5 mm Hg. Seven of 15 ␣ 1D ϩ/ϩ mice died with edema, probably owing to renal failure, whereas 14 of 15 ␣ 1D Ϫ/Ϫ mice were maintained for 35 days. Body weight, renal remnant weight, and residual renal function were similar in the 2 groups, whereas the values of plasma catecholamines (epinephrine, norepinephrine, and dopamine) were higher in ␣ 1D ϩ/ϩ than in the ␣ 1D Ϫ/Ϫ mice. These data suggest that ␣ 1D -AR plays an important role in developing a high BP in response to dietary salt-loading, and that agents having selective ␣ 1D -AR antagonism could have significant therapeutic potential in the treatment of hypertension. (Hypertension. 2002;40:101-106.)

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“…5,6 The ARs in the kidney are expressed in arterial smooth muscles, tubule epithelial cells, and juxtaglomerular renin cells, where they reduce renal blood flow, increase reabsorption, and stimulate renin secretion, respectively. Although in vivo and in vitro pharmacological studies have revealed diverse effects of ARs in the kidney 5,[7][8][9][10][11][12] and the vasculature and nephron segments have different types of ARs, [13][14][15][16] the positional relationship of ARs to sympathetic nerve terminals and the pathways through which NE stimulates them remains unknown.…”

Section: Introductionmentioning

confidence: 99%

Morphology of Schwann Cell Processes Supports Renal Sympathetic Nerve Terminals With Local Distribution of Adrenoceptors

Maeda¹,

Minato²,

Kuwahara-Otani³

et al. 2022

J Histochem Cytochem.

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Nerves in the renal parenchyma comprise sympathetic nerves that act on renal arteries and tubules to decrease blood flow and increase primary urine reabsorption, respectively. Synaptic vesicles release neurotransmitters that activate their effector tissues. However, the mechanisms by which neurotransmitters exert individual responses to renal effector cells remain unknown. Here, we investigated the spatial and molecular compositional associations of renal Schwann cells (SC) supporting the nerve terminals in male rats. The nerve terminals of vascular smooth muscle cells (SMCs) enclosed by renal SC processes were exposed through windows facing the effectors with presynaptic specializations. We found that the adrenergic receptors (ARs) α2A, α2C, and β2 were localized in the SMC and the basal side of the tubules, where the nerve terminals were attached, whereas the other subtypes of ARs were distributed in the glomerular and luminal side, where the norepinephrine released from nerve endings may have indirect access to ARs. In addition, integrins α4 and β1 were coexpressed in the nerve terminals. Thus, renal nerve terminals could contact their effectors via integrins and may have a structure, covered by SC processes, suitable for intensive and directional release of neurotransmitters into the blood, rather than specialized structures in the postsynaptic region.

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Renal ?-adrenergic receptors and genetic hypertension

Cited by 13 publications

References 65 publications

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

Role of the α _1D - Adrenegric Receptor in the Development of Salt-Induced Hypertension

Morphology of Schwann Cell Processes Supports Renal Sympathetic Nerve Terminals With Local Distribution of Adrenoceptors

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Renal ?-adrenergic receptors and genetic hypertension

Cited by 13 publications

References 65 publications

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

Centhaquine Restores Renal Blood Flow and Protects Tissue Damage After Hemorrhagic Shock and Renal Ischemia

Role of the α 1D - Adrenegric Receptor in the Development of Salt-Induced Hypertension

Morphology of Schwann Cell Processes Supports Renal Sympathetic Nerve Terminals With Local Distribution of Adrenoceptors

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Role of the α _1D - Adrenegric Receptor in the Development of Salt-Induced Hypertension