KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST)

Beitelshees, Amber L.; Gong, Yan; Wang, Daqing; Schork, Nicholas J.; Cooper‐DeHoff, Rhonda M.; Langaee, Taimour; Shriver, Mark D.; Sadée, Wolfgang; Knot, Harm J.; Pepine, Carl J.

doi:10.1097/fpc.0b013e32810f2e3c

Cited by 68 publications

(60 citation statements)

References 22 publications

(35 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…10,11 Alternatively, the E65K mutant b1-subunit may directly influence the BP response to b-blocker drugs through the physical interaction of the BK channel with the b-adrenergic receptor. 12 Because our results are consistent with earlier studies, 4,5,8 we consider a false positive association to be less likely. Limited effect and sample sizes may have restricted our power to detect a genotypephenotype association, especially in African-American Heart SCORE subjects whose K-allele frequency was lower and sample size smaller.…”

supporting

confidence: 82%

“…8 We identified a trend towards lower pressures among all classes of medication, but statistical significance was reached solely in the b-blockade subgroup. We consider two molecular mechanisms by which E65K would have a selective effect on BP in the setting of hypertension and b-blockade therapy.…”

mentioning

confidence: 94%

“…To examine the role of hypertension in the association of E65K with BP, we tested our a priori hypothesis that E65K interacts with anti-hypertensive therapy, age and gender. 5,8 There was no interaction between E65K and age in Heart SCORE, and tests for interaction with gender were nonsignificant in both cohorts. By comparison, in Heart SCORE, the test for interaction between genotype status and anti-hypertensive medication use was significant (P ¼ 0.003, DBP model).…”

mentioning

confidence: 99%

See 2 more Smart Citations

The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with β-blockade

et al. 2008

View full text Add to dashboard Cite

supporting

confidence: 82%

mentioning

confidence: 94%

mentioning

confidence: 99%

See 1 more Smart Citation

The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with β-blockade

et al. 2008

View full text Add to dashboard Cite

“…Studies also illustrate that singlenucleotide polymorphisms within the ␣-or ␤ 1 -subunit can confer a gain or loss of function (8,19). It follows that "gain-of-function" alternative splice variants of the ␣-and ␤ 1 -subunits could be activated during hypoxic stress, thereby conferring an increase in Ca 2ϩ sensitivity and vasorelaxation.…”

Section: Discussionmentioning

confidence: 99%

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

Blum-Johnston

Thorpe

Wee

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

-Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of largeconductance Ca 2ϩ -activated K ϩ (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca 2ϩ . Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca 2ϩ signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (ϳ140 days gestation) and newborn, 10-to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for Ͼ100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca 2ϩ responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 M nitro-L-arginine methyl ester or 10 M 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel ␣1-subunit expression but increased ␤1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. potassium channels; sheep; pulmonary artery; contractility; maturation; hypoxia REGULATION OF SMOOTH MUSCLE tone in pulmonary arteries during development is a delicate balance of vasoconstrictive and vasorelaxant pathways. Endothelial cells play a crucial role in determining the overall level of vasorelaxation (39, 67), and endothelium-dependent relaxation is partially mediated through bradykinin stimulation (31). Bradykinin is a potent vasodilator that is important in the fetal pulmonary circulation, as well as during inflammation, and its relationship to pulmonary hypertension has been explored (5, 31, 83).Endothelial bradykinin receptor activation induces vasorelaxation through modulation of several different intracellular signaling pathways that are largely dependent on a rise of endothelial intracellular Ca 2ϩ ([Ca 2ϩ ] i ) (67). The most widely studied pathway is bradykinin-induced activation of endothelial nitric oxide (NO) synthase (eNOS), an enzyme that generates NO (64). NO acts on nearby smooth muscle cells to cause downstream stimulation of soluble guanylate cyclase (sGC) pathways that leads to vasorelaxation (3,45). Previous studies have shown that regulatio...

show abstract

“…Single-nucleotide polymorphisms (SNPs) that promote either "gain-of-function" or "loss-of-function" have been identified in both the α and β1 subunits. [215][216][217] AE65K polymorphism in the β1 subunit diminishes the prevalence of severe hypertension as well as myocardial infarction. 204,218 BK channels and diabetes In diabetes mellitus there are several metabolic changes, some of which are reflected in BK channel function.…”

Section: Bk Channels and Diseases Pathophysiological And Genetic Invmentioning

confidence: 99%

A BK (Slo1) channel journey from molecule to physiology

et al. 2013

View full text Add to dashboard Cite

KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/Trandolapril STudy (INVEST)

Cited by 68 publications

References 22 publications

The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with β-blockade

The protective effect of KCNMB1 E65K against hypertension is restricted to blood pressure treatment with β-blockade

Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth

A BK (Slo1) channel journey from molecule to physiology

Contact Info

Product

Resources

About