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Genetic Basis of Blood Pressure and Hypertension
Published in Giuseppe Mancia, Guido Grassi, Konstantinos P. Tsioufis, Anna F. Dominiczak, Enrico Agabiti Rosei, Manual of Hypertension of the European Society of Hypertension, 2019
Sandosh Padmanabhan, Alisha Aman, Anna F. Dominiczak
Advances in genomics have accelerated over the last decade, leading to an unparalleled leap in our understanding of the genetic architecture of BP and HTN (40). While the technological and analytic aspects of genomics have been very successful in discovering DNA sequence variants associated with BP and HTN, the functional and biological significance of the vast number of these variants in the human genome are unknown. The UMOD locus from GWAS is now the basis of a clinical trial (clinicaltrials.gov NCT03354897) to reposition a loop diuretic in the HTN care pathway. Other GWAS loci encoding MARK3, PDGFC, TRHR, ADORA1, GABRA2, VEGFA and PDE3A within systems that have existing drugs not currently linked to a known antihypertensive mechanism and may offer repurposing opportunities. Moving from single-locus dissection, newer analytic methods will test the molecular network hypothesis on a genome-wide scale to fully understand the networks of pathways that govern the genotype—BP causality relationship. Another emerging hypothesis for contributions from the genome to complex traits is that alterations in nuclear organization of DNA resulting in higher order structures, such as folds of DNA within chromatin, confer differential susceptibility. Other ‘omics’ technologies such as metabolomics and metagenomics are potentially powerful tools to identify molecular pathways, involvement of the microbiome and environmental factors in influencing the BP phenotype. Thus the future of BP genomics is set to move into the realms of further discovery using novel platforms, functional dissection and validation of pathways in molecular and clinical studies.
Human mass balance, pharmacokinetics and metabolism of rovatirelin and identification of its metabolic enzymes in vitro
Published in Xenobiotica, 2019
Kaoru Kobayshi, Yoshikazu Abe, Asuka Kawai, Takao Furihata, Hiroshi Harada, Takuro Endo, Hiroo Takeda
Thyrotropin-releasing hormone (TRH) was originally isolated from the hypothalamus (Guillemin, 1978; Schally, 1978), and TRH is distributed throughout the central nervous system (Morley, 1979). TRH binds to the G protein-coupled TRH receptor (TRHR) (Yamada et al., 1993). The endocrine functions of TRH include controlling the levels of thyrotropin, thyroid-stimulating hormone (TSH) and prolactin. In addition to these endocrine functions, TRH also possesses neuropharmacological functions, including cerebral nerve activation (stimulation of motor function), effects on spinal function (stimulation of spinal motor neurons) and effects on the central nervous system (antidepressant activity) (Daimon et al., 2013; Khomane et al., 2011). Spinocerebellar degeneration (SCD) is a degenerative disease caused by the slow degeneration of the brainstem and cerebellum, and its major symptom is ataxia. TRH has been clinically investigated for the treatment of SCD (Sobue et al., 1983), and TRH agents, such as protirelin (synthetic TRH) and taltirelin (TRH analogue), are currently prescribed to patients with SCD in Japan. However, protirelin is administered via intravenous or intramuscular injection because of its short plasma half-life (4–5 min), poor metabolic stability and low bioavailability (Bassiri & Utiger, 1973; Griffiths, 1976; Khomane et al., 2011; Kinoshita et al., 1998). These disadvantages are not as severe for taltirelin, and the drug is approved for twice-daily oral administration (Kinoshita et al., 1998).
GRK2 and GRK5 as therapeutic targets and their role in maladaptive and pathological cardiac hypertrophy
Published in Expert Opinion on Therapeutic Targets, 2019
Paroxetine is a selective serotonin reuptake inhibitor (SSRI) class of antidepressants. Paroxetine was found to have selective GRK2 inhibition through disrupting its active site in a way that ATP can no longer bind [77]. Paroxetine was able to prevent GRK2-mediated phosphorylation of light-sensitive rhodopsin at a pIC50 of 4.7 ± 0.04 nM, phosphorylation of tubulin at a pIC50 of 5.6 ± 0.07 nM, and phosphorylation of thyrotropin-releasing hormone receptor at a IC50 of ~30 μM [77]. GRK2’s thermostability was also increased with paroxetine. Early experiments using paroxetine in vitro, showed paroxetine increasing βAR-mediated myocardial contractility after isoproterenol. Currently, paroxetine has not been used in vivo in a pressure-overload maladaptive hypertrophy model. However, it has been used in an MI model of HF where GRK2 is also involved in the pathophysiology [78,79]. Chronic paroxetine treatment (5 mg/kg/day) after 2 weeks post-MI in mice not only improved cardiac function, but limited adverse ventricular remodeling [78]. HW/TL and heart length/TL were significantly blunted at the end of 4 weeks of paroxetine treatment after MI.
Non-clinical pharmacokinetic profiles of rovatirelin, an orally available thyrotropin-releasing hormone analogue
Published in Xenobiotica, 2019
Kaoru Kobayashi, Yoshikazu Abe, Hiroshi Harada, Emiko Oota, Takuro Endo, Hiroo Takeda
Thyrotropin-releasing hormone (TRH) was originally isolated from the hypothalamus (Guillemin, 1978; Schally, 1978), and TRH is distributed throughout the central nervous system (Morley, 1979). TRH binds the G-protein-coupled thyrotropin-releasing hormone receptor (TRHR) (Yamada et al., 1993). The endocrine functions of TRH include controlling the level of thyrotropin, thyroid-stimulating hormone (TSH), and prolactin. Besides these endocrine functions, TRH also possesses neuropharmacological functions, including cerebral nerve activation (stimulation of motor function), effects on spinal function (stimulation of spinal motor neurons), and effects on the central nervous system (antidepressant activity) (Daimon et al., 2013; Khomane et al., 2011). Spinocerebellar degeneration (SCD) is a degenerative disease caused by the slow degeneration of the brainstem and cerebellum and whose major symptom is ataxia. TRH has been clinically investigated for the treatment of SCD (Sobue et al., 1983) and TRH agents, such as protirelin (synthetic TRH) and taltirelin (a TRH analogue), are currently prescribed to SCD patients in Japan. However, protirelin is administered via intravenous or intramuscular injection due to short plasma half-life (4–5 min), poor metabolic stability, and low bioavailability (Bassiri & Utiger, 1973; Griffiths, 1976; Khomane et al., 2011; Kinoshita et al., 1998). These disadvantages are not as severe with taltirelin and the drug is approved for oral administration twice daily (Kinoshita et al., 1998).