Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The defining characteristic of G protein-coupled receptor homologous desensitization is that the receptor must be occupied by an agonist or in an activated conformation that mimics an agonist-induced state. In most instances, the mechanistic basis for this characteristic is the high selectivity of G protein-coupled receptor kinases for the activated receptor. In this issue, Rankin et al. (p. 759) demonstrate that under some conditions, at least, the G protein-coupled receptor kinase GRK4 does not display a preference for the agonist-occupied D1 dopamine receptor. Coexpression of GRK4 and the D1 receptor in a heterologous system induces phosphorylation of the receptor in the absence of agonist, causing constitutive desensitization and internalization of the receptor. Lacking the normal rapid feedback mechanisms associated with homologous desensitization, a system incorporating constitutively active GRK4 will be prone to dysregulation, perhaps explaining the generally low expression of GRK4. Indeed, considerable evidence suggests that just such dysregulation resulting from mutationally activated GRK4 contributes to the heritable component of human essential hypertension (Physiol Genomics 19:223-246, 2004).
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PMID:Novel features of G protein-coupled receptor kinase 4. 1633 88

In humans, the endothelins (ETs) comprise a family of three 21-amino-acid peptides, ET-1, ET-2 and ET-3. ET-1 is synthesised from a biologically inactive precursor, Big ET-1, by an unusual hydrolysis of the Trp21 -Val22 bond by the endothelin converting enzyme (ECE-1). In humans, there are four isoforms (ECE-1a-d) derived from a single gene by the action of alternative promoters. Structurally, they differ only in the amino acid sequence of the extreme N-terminus. A second enzyme, ECE-2, also exists as four isoforms and differs from ECE-1 in requiring an acidic pH for optimal activity. Human chymase can also cleave Big ET-1 to ET-1, which is cleaved, in turn, to the mature peptide as an alternative pathway. ET-1 is the principal isoform in the human cardiovascular system and remains one of the most potent constrictors of human vessels discovered. ET-1 is unusual in being released from a dual secretory pathway. The peptide is continuously released from vascular endothelial cells by the constitutive pathway, producing intense constriction of the underlying smooth muscle and contributing to the maintenance of endogenous vascular tone. ET-1 is also released from endothelial cell-specific storage granules (Weibel-Palade bodies) in response to external stimuli. ETs mediate their action by activating two G protein-coupled receptor sub-types, ETA and ET(B). Two therapeutic strategies have emerged to oppose the actions of ET-1, namely inhibition of the synthetic enzyme by combined ECE/neutral endopeptidase inhibitors such as SLV306, and receptor antagonists such as bosentan. The ET system is up-regulated in atherosclerosis, and ET antagonists may be of benefit in reducing blood pressure in essential hypertension. Bosentan, the first ET antagonist approved for clinical use, represents a significant new therapeutic strategy in the treatment of pulmonary arterial hypertension (PAH).
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PMID:Endothelin. 1699 23

Hypertension and salt sensitivity of blood pressure are two conditions the etiologies of which are still elusive because of the complex influences of genes, environment, and behavior. Recent understanding of the molecular mechanisms that govern sodium homeostasis is shedding new light on how genes, their protein products, and interacting metabolic pathways contribute to disease. Sodium transport is increased in the proximal tubule and thick ascending limb of Henle of the kidney in human essential hypertension. This Review focuses on the counter-regulation between the dopaminergic and renin-angiotensin systems in the renal proximal tubule, which is the site of about 70% of total renal sodium reabsorption. The inhibitory effect of dopamine is most evident under conditions of moderate sodium excess, whereas the stimulatory effect of angiotensin II is most evident under conditions of sodium deficit. Dopamine and angiotensin II exert their actions via G protein-coupled receptors, which are in turn regulated by G protein-coupled receptor kinases (GRKs). Polymorphisms that lead to aberrant action of GRKs cause a number of conditions, including hypertension and salt sensitivity. Polymorphisms in one particular member of this family-GRK4-have been shown to cause hyperphosphorylation, desensitization and internalization of a member of the dopamine receptor family, the dopamine 1 receptor, while increasing the expression of a key receptor of the renin-angiotensin system, the angiotensin II type 1 receptor. Novel diagnostic and therapeutic approaches for identifying at-risk subjects, followed by selective treatment of hypertension and salt sensitivity, might center on restoring normal receptor function through blocking the effects of GRK4 polymorphisms.
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PMID:Mechanisms of disease: the role of GRK4 in the etiology of essential hypertension and salt sensitivity. 1706 56

G protein-coupled receptor (GPCR) kinases (GRKs) regulate the sensitivity of GPCRs, including dopamine receptors. The GRK4 locus is linked to, and some of its polymorphisms are associated with, human essential hypertension. Transgenic mice overexpressing human (h) GRK4gamma A142V on a mixed genetic background (C57BL/6J and SJL/J) have impaired renal D(1)-dopamine receptor (D(1)R) function and increased blood pressure. We now report that hGRK4gamma A142V transgenic mice, in C57BL/6J background, are hypertensive and have higher blood pressures than hGRK4gamma wild-type transgenic and nontransgenic mice. The hypertensive phenotype is stable because blood pressures in transgenic founders and F6 offspring are similarly increased. To determine whether the hypertension is associated with increased production of reactive oxygen species (ROS), we measured renal NADPH oxidase (Nox2 and Nox4) and heme oxygenase (HO-1 and HO-2) protein expressions and urinary excretion of 8-isoprostane and compared the effect of Tempol on blood pressure in hGRK4gamma A142V transgenic mice and D(5)R knockout (D(5)(-/-)) mice in which hypertension is mediated by increased ROS. The expressions of Nox isoforms and HO-2 and the urinary excretion of 8-isoprostane were similar in hGRK4gamma A142V transgenic mice and their controls. HO-1 expression was increased in hGRK4gamma A142V relative to hGRK4gamma wild-type transgenic mice. In contrast with the hypotensive effect of Tempol in D(5)(-/-) mice, it had no effect in hGRK4gamma A142V transgenic mice. We conclude that the elevated blood pressure of hGRK4gamma A142V transgenic mice is due mainly to the effect of hGRK4gamma A142V transgene acting via D(1)R and increased ROS production is not a contributor.
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PMID:The elevated blood pressure of human GRK4gamma A142V transgenic mice is not associated with increased ROS production. 1725 40

For many years, modulators of the renin angiotensin system (RAS) have been trusted by clinicians for the control of essential hypertension. It was recently demonstrated that these modulators have other pleiotropic properties independent of their hypotensive effects, such as enhancement of cognition. Within the brain, different components of the RAS have been extensively studied in the context of neuroprotection and cognition. Interestingly, a crosstalk between the RAS and other systems such as cholinergic, dopaminergic and adrenergic systems have been demonstrated. In this review, the preclinical and clinical evidence for the impact of RAS modulators on cognitive impairment of multiple etiologies will be discussed. In addition, the expression and function of different receptor subtypes within the RAS such as: Angiotensin II type I receptor (AT1R), Angiotensin II type II receptor (AT2R), Angiotensin IV receptor (AT4R), Mas receptor (MasR), and Mas-related-G protein-coupled receptor (MrgD), on different cell types within the brain will be presented. We aim to direct the attention of the scientific community to the plethora of evidence on the importance of the RAS on cognition and to the different disease conditions in which these agents can be beneficial.
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PMID:Within the Brain: The Renin Angiotensin System. 2954 76

Ca2+-sensing receptor (CaSR), a member of G protein-coupled receptor family, is widely expressed in the vascular system, including perivascular neurons, vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). When stimulated, CaSR can further increase the cytosolic Ca2+ concentration ([Ca2+]cyt) in two ways: intracellular Ca2+ release from endo/sarcoplasmic reticulum (ER/SR) and extracellular Ca2+ entry through Ca2+-permeable cation channels. In endothelium, increased Ca2+ subsequently activate nitric oxide synthase (NOS) and intermediate conductance Ca2+-activated K+ channels (IKCa), resulting in vasodilation through NOS-mediated NO release or membrane hyperpolarization. In VSMCs, CaSR-induced intracellular Ca2+ increase causes blood vessel constriction. CaSR activation predominantly induces vasorelaxation of whole vascular tissues through VECs-dependent mechanisms; however, CaSR-induced Ca2+ signaling in VSMCs may play a braking role in CaSR-mediated vasorelaxation. Emerging evidence reveals the importance of CaSR in the regulation of vascular tone and blood pressure. Here, we summarized recent advances in CaSR-mediated vascular reaction and the underlying mechanisms in different species, including humans. In addition, several studies have demonstrated that CaSR dysfunction may be associated with some fatal vascular diseases, such as pulmonary arterial hypertension, primary hypertension, diabetes, acute myocardial infarction and vascular calcification. With the advance of studies on CaSR in vascular health and disease, it is expected positive modulators or negative modulators of CaSR used for the treatment of specific diseases may be promising therapeutic options for the prevention and/or treatment of vascular diseases.
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PMID:Important roles of the Ca2+-sensing receptor in vascular health and disease. 3009 42