scholarly journals Contribution of Kv7.4/Kv7.5 Heteromers to Intrinsic and Calcitonin Gene-Related Peptide–Induced Cerebral Reactivity

2014 ◽  
Vol 34 (4) ◽  
pp. 887-893 ◽  
Author(s):  
Preet S. Chadha ◽  
Thomas A. Jepps ◽  
Georgina Carr ◽  
Jennifer B. Stott ◽  
Hei-Lei Zhu ◽  
...  
Keyword(s):  
Cerebral Arteries ◽  
Calcitonin Gene Related Peptide ◽  
Isometric Tension ◽  
Proximity Ligation Assay ◽  
Kv7 Channels ◽  
Proximity Ligation ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Systemic Arteries ◽  
First Time

Objective— Middle cerebral artery (MCA) diameter is regulated by inherent myogenic activity and the effect of potent vasodilators such as calcitonin gene-related peptide (CGRP). Previous studies showed that MCAs express KCNQ1, 4, and 5 potassium channel genes, and the expression products (Kv7 channels) participate in the myogenic control of MCA diameter. The present study investigated the contribution of Kv7.4 and Kv7.5 isoforms to myogenic and CGRP regulation of MCA diameter and determined whether they were affected in hypertensive animals. Approach and Results— Isometric tension recordings performed on MCA from normotensive rats produced CGRP vasodilations that were inhibited by the pan-Kv7 channel blocker linopirdine ( P <0.01) and after transfection of arteries with siRNA against KCNQ4 ( P <0.01) but not KCNQ5. However, isobaric myography revealed that myogenic constriction in response to increases in intravascular pressure (20–80 mm Hg) was affected by both KCNQ4 and KCNQ5 siRNA. Proximity ligation assay signals were equally abundant for Kv7.4/Kv7.4 or Kv7.4/Kv7.5 antibody combinations but minimal for Kv7.5/Kv7.5 antibodies or Kv7.4/7.1 combinations. In contrast to systemic arteries, Kv7 function and Kv7.4 abundance in MCA were not altered in hypertensive rats. Conclusions— This study reveals, for the first time to our knowledge, that in cerebral arteries, Kv7.4 and Kv7.5 proteins exist predominantly as a functional heterotetramer, which regulates intrinsic myogenicity and vasodilation attributed to CGRP. Surprisingly, unlike systemic arteries, Kv7 activity in MCAs is not affected by the development of hypertension, and CGRP-mediated vasodilation is well maintained. As such, cerebrovascular Kv7 channels could be amenable for therapeutic targeting in conditions such as cerebral vasospasm.

scholarly journals Acetaminophen (Paracetamol) Metabolites Induce Vasodilation and Hypotension by Activating Kv7 Potassium Channels Directly and Indirectly

2020 ◽  
Vol 40 (5) ◽  
pp. 1207-1219 ◽  
Author(s):  
Jennifer van der Horst ◽  
Rian W. Manville ◽  
Katie Hayes ◽  
Morten B. Thomsen ◽  
Geoffrey W. Abbott ◽  
...  
Keyword(s):  
Preventive Intervention ◽  
Ex Vivo ◽  
Calcitonin Gene Related Peptide ◽  
Mesenteric Arteries ◽  
Benzoquinone Imine ◽  
Kv7 Channels ◽  
Related Peptide ◽  
Calcitonin Gene ◽  
Perivascular Nerves ◽  
Life Threatening

Objective: Intravenous acetaminophen/paracetamol (APAP) is well documented to cause hypotension. Since the patients receiving intravenous APAP are usually critically ill, any severe hemodynamic changes, as with those associated with APAP, can be life-threatening. The mechanism underlying this dangerous iatrogenic effect of APAP was unknown. Approach and Results: Here, we show that intravenous APAP caused transient hypotension in rats, which was attenuated by the Kv7 channel blocker, linopirdine. APAP metabolite N-acetyl-p-benzoquinone imine caused vasodilatation of rat mesenteric arteries ex vivo. This vasodilatation was sensitive to linopirdine and also the calcitonin gene-related peptide antagonist, BIBN 4096. Further investigation revealed N-acetyl-p-benzoquinone imine stimulates calcitonin gene-related peptide release from perivascular nerves, causing a cAMP-dependent activation of Kv7 channels. We also show that N-acetyl-p-benzoquinone imine enhances Kv7.4 and Kv7.5 channels overexpressed in oocytes, suggesting that it can activate Kv7.4 and Kv7.5 channels directly, to elicit vasodilatation. Conclusions: Direct and indirect activation of Kv7 channels by the APAP metabolite N-acetyl-p-benzoquinone imine decreases arterial tone, which can lead to a drop in blood pressure. Our findings provide a molecular mechanism and potential preventive intervention for the clinical phenomenon of intravenous APAP-dependent transient hypotension.

scholarly journals ANTIDROMIC EFFECT OF CALCITONIN GENE-RELATED PEPTIDE CONTAINING NERVES ON CEREBRAL ARTERIES IN RATS

2001 ◽  
Vol 47 (2) ◽  
pp. 75-84 ◽  
Author(s):  
JUN ASARI ◽  
KYOICHI SUZUKI ◽  
MASATO MATSUMOTO ◽  
TATSUYA SASAKI ◽  
NAMIO KODAMA
Keyword(s):  
Cerebral Arteries ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene

Gene transfer of calcitonin gene-related peptide to cerebral arteries

2000 ◽  
Vol 278 (2) ◽  
pp. H586-H594 ◽  
Author(s):  
Kazunori Toyoda ◽  
Frank M. Faraci ◽  
Andrew F. Russo ◽  
Beverly L. Davidson ◽  
Donald D. Heistad
Keyword(s):  
Cerebrospinal Fluid ◽  
Gene Transfer ◽  
Basilar Artery ◽  
Cultured Cells ◽  
Cerebral Arteries ◽  
Calcitonin Gene Related Peptide ◽  
Related Peptide ◽  
Calcitonin Gene

Overexpression of calcitonin gene-related peptide (CGRP), an extremely potent vasodilator, to blood vessels is a possible strategy for prevention of vasospasm. We constructed an adenoviral vector that encodes prepro-CGRP (Adprepro-CGRP) and examined the effects of gene transfer on cultured cells and cerebral arteries. Transfection of Adprepro-CGRP to Cos-7 and NIH-3T3 cells increased CGRP-like immunoreactivity in media and produced an increase in cAMP in recipient cells. Five days after injection of Adprepro-CGRP into the cisterna magna of rabbits, the concentration of CGRP-like immunoreactivity increased by 93-fold in cerebrospinal fluid. In basilar artery, cAMP increased by 2.3-fold after Adprepro-CGRP compared with a control adenovirus. After transfection of Adprepro-CGRP, contraction of basilar artery in vitro to histamine and serotonin was attenuated, and relaxation to an inhibitor of cyclic nucleotide phosphodiesterase 3-isobutyl-1-methylxanthine was augmented compared with nontransduced arteries or arteries transfected with a control gene. Altered vascular responses were restored to normal by pretreatment with a CGRP1 receptor antagonist CGRP-(8–37). Thus gene transfer of prepro-CGRP in vivo overexpresses CGRP in cerebrospinal fluid and perivascular tissues and modulates vascular tone. We speculate that this approach may be useful in prevention of vasospasm after subarachnoid hemorrhage.

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