Activation of particulate guanylate cyclase by adrenomedullin in cultured SV-40 transformed cat iris sphincter smooth muscle (SV-CISM-2) cells

2000 ◽  
Vol 12 (7) ◽  
pp. 491-498 ◽  
Author(s):  
Nawab Ali ◽  
Sardar Y.K. Yousufzai ◽  
Ata A. Abdel-Latif
Keyword(s):  
Smooth Muscle ◽  
Guanylate Cyclase ◽  
Iris Sphincter

Abstract 107: Cytochrome B5 Reductase 3 Sensitizes Soluble Guanylate Cyclase to Nitric Oxide in Vascular Smooth Muscle

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Adam C Straub ◽  
Anh T Nguyen ◽  
Mizanur Rahaman ◽  
Stephanie M Mutchler ◽  
Megan Miller ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Cytochrome B5 ◽  
Heme Iron ◽  
Cytochrome B5 Reductase ◽  
Arterial Blood

The inability nitric oxide (NO) to stimulate soluble guanylate cyclase (sGC) has been linked to numerous cardiovascular diseases (CVD) including hypertension. While several studies have defined the importance of sGC expression in the cardiovascular system, the basic mechanisms that regulate sGC activity remain incompletely understood. Here, we report for the first time that sGC heme iron redox state, which is essential for NO-induced sGC activation, is regulated by cytochrome B5 reductase 3 (CyB5R3). Genetic knockdown and pharmacological inhibition of CyB5R3 in primary rat vascular smooth muscle cells resulted in a 60% loss in cGMP production. Conversely, the sGC activator Bay 58-2667, which activates oxidized or heme free sGC, reversed these effects. Consistent with our cell culture work, purified protein studies demonstrate that CyB5R3 can directly reduce oxidized sGC heme iron and sensitize sGC to NO. To test the functional importance of Cyb5R3 activity, we cultured mouse thoracodorsal arteries with a pharmacological inhibitor of Cyb5R3 (ZINC 747) and performed vascular reactivity studies using pressure myography. Arteries treated with ZINC 747 showed decreased responsiveness the NO donor DETA-NONOate but increase sensitivity to Bay 58-2667. We then treated mice with 10mg/kg/day of ZINC 747 using osmotic mini pumps, which caused an increase in mean arterial blood pressure (107.5±3.4 vs 131±13.16) measured via radio telemetry. Lastly, translational studies reveal that the CyB5R3 T116S polymorphism with allele frequency 0.23 only in African Americans is unable to reduce sGC and correlates with increased blood pressure. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to NO therapies and new classes of sGC activator medications, we anticipate that these studies may significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (T117S SNP based drug selection).

scholarly journals Soluble guanylate cyclase modulators blunt hyperoxia effects on calcium responses of developing human airway smooth muscle

2015 ◽  
Vol 309 (6) ◽  
pp. L537-L542 ◽  
Author(s):  
Rodney D. Britt ◽  
Michael A. Thompson ◽  
Ine Kuipers ◽  
Alecia Stewart ◽  
Elizabeth R. Vogel ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Guanylate Cyclase ◽  
Therapeutic Strategy ◽  
Soluble Guanylate Cyclase ◽  
Novel Drugs ◽  
Intracellular Ca ◽  
Recurrent Wheeze ◽  
Airway Tone ◽  
Sgc Stimulators

Exposure to moderate hyperoxia in prematurity contributes to subsequent airway dysfunction and increases the risk of developing recurrent wheeze and asthma. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic GMP (cGMP) axis modulates airway tone by regulating airway smooth muscle (ASM) intracellular Ca2+ ([Ca2+]i) and contractility. However, the effects of hyperoxia on this axis in the context of Ca2+/contractility are not known. In developing human ASM, we explored the effects of novel drugs that activate sGC independent of NO on alleviating hyperoxia (50% oxygen)-induced enhancement of Ca2+ responses to bronchoconstrictor agonists. Treatment with BAY 41–2272 (sGC stimulator) and BAY 60-2770 (sGC activator) increased cGMP levels during exposure to 50% O2. Although 50% O2 did not alter sGCα1 or sGCβ1 expression, BAY 60-2770 did increase sGCβ1 expression. BAY 41-2272 and BAY 60-2770 blunted Ca2+ responses to histamine in cells exposed to 50% O2. The effects of BAY 41-2272 and BAY 60-2770 were reversed by protein kinase G inhibition. These novel data demonstrate that BAY 41-2272 and BAY 60-2770 stimulate production of cGMP and blunt hyperoxia-induced increases in Ca2+ responses in developing ASM. Accordingly, sGC stimulators/activators may be a useful therapeutic strategy in improving bronchodilation in preterm infants.

Role of K+Channels in Augmented Relaxations to Sodium Nitroprusside Induced by Mexiletine in Rat Aortas

2000 ◽  
Vol 92 (3) ◽  
pp. 813-820 ◽  
Author(s):  
Hiroyuki Kinoshita ◽  
Toshizo Ishikawa ◽  
Yoshio Hatano
Keyword(s):  
Nitric Oxide ◽  
Smooth Muscle ◽  
Sodium Nitroprusside ◽  
Guanylate Cyclase ◽  
Nitric Oxide Donor ◽  
Nitric Oxide Donors ◽  
K Channels ◽  
Vasodilator Effect ◽  
Isolated Rat

Background A class Ib antiarrhythmic drug, mexiletine, augments relaxations produced by adenosine triphosphate (ATP) sensitive K+ channel openers in isolated rat aortas, suggesting that it produces changes in the vasodilation mediated by ATP-sensitive K+ channels. Nitric oxide can induce its vasodilator effect via K+ channels, including ATP-sensitive K+ channels, in smooth muscle cells. Effects of mexiletine on arterial relaxations to nitric oxide donors, have not been studied. Therefore, the current study in isolated rat aortas was designed to (1) evaluate whether mexiletine augments relaxation in response to nitric oxide donors, including sodium nitroprusside, and (2) determine the role of K+ channels in mediating effects of mexiletine on such nitric oxide-mediated relaxation. Methods Rings of rat aortas without endothelia were suspended for isometric force recording. Concentration-response curves of sodium nitroprusside (10(-10) to 10(-5) M) and 1-hydroxy-2-oxo-3-(N-methyl-3-aminopropyl)-3-methyl-1-triazene (NOC-7; 10(-9) to 10(-5) M) were obtained in the absence and in the presence of mexiletine, in combination with a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo [4,3,-a]quinoxaline-1-one (ODQ), or inhibitors for ATP-sensitive K+ channels (glibenclamide), inward rectifier K+ channels (BaCl2), delayed rectifier K+ channels (4-aminopyridine), large conductance Ca2+-dependent K+ channels (iberiotoxin), or small conductance Ca2+-dependent K+ channels (apamin). Results Mexiletine (10(-5) or 3 x 10(-5) M) augmented relaxations to sodium nitroprusside and NOC-7. In arteries treated with glibenclamide (10(-5) M), mexiletine (3 x 10(-5) M) did not affect relaxations to nitric oxide donors, whereas mexiletine augmented relaxations to sodium nitroprusside despite the presence of BaCl2 (10(-5) M), 4-aminopyridine (10(-3) M), iberiotoxin (5 x 10(-8) M) and apamin (5 x 10(-8) M). Relaxations to sodium nitroprusside were abolished by ODQ (5 x 10(-6) M), whereas these relaxations were augmented by mexiletine (3 x 10(-5) M) in arteries treated with ODQ (5 x 10(-6) M). Conclusions These results suggest that ATP-sensitive K+ channels in vascular smooth muscle, contribute to the augmented vasodilator effect of a nitric oxide donor, sodium nitroprusside induced by mexiletine, and that the vasodilator effect is produced, at least in part, via the guanylate cyclase-independent mechanism.

Immortalization of cat iris sphincter smooth muscle cells by SV40 virus: Growth, morphological, biochemical and pharmacological characteristics

1995 ◽  
Vol 61 (5) ◽  
pp. 535-545 ◽  
Author(s):  
Anette Ocklind ◽  
Sardar Y.K. Yousufzai ◽  
Sikha Ghosh ◽  
Miguel Coca-Prados ◽  
Johan St Jernschantz ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Virus Growth ◽  
Sv40 Virus ◽  
Iris Sphincter
Sign in / Sign up

Export Citation Format

Share Document