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1.
Int J Radiat Biol ; 83(3): 161-9, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17378524

ABSTRACT

PURPOSE: The goal of this study was to evaluate the influence of ionizing irradiation on large conductance Ca2+-dependent potassium (BKCa) channels in rat coronary endothelial cells. MATERIALS AND METHODS: Rats were exposed to a 6 Gy dose from a cobalt60 source. Experimental design of this study comprised recording of contractile force using isolated rat aortic rings and whole-cell patch clamp techniques to study whole-cell potassium currents in isolated rat coronary artery endothelial cells. RESULTS: It has been shown that outward potassium currents in endothelial cells 9 days after irradiation appear to be suppressed or even totally abolished. The reversal potential for these currents in irradiated cells was shifted to more positive values. Paxilline (500 nM), an inhibitor of BKCa channels, had no or only a negligible effect on irradiated cells. The experiments using isolated aortic rings demonstrated that both paxilline and irradiation significantly shifted the acetylcholine dependent concentration-relaxation response curve to the right. Irradiated tissues were insensitive to paxilline. CONCLUSION: The results suggest that non-fatal, whole-body gamma-irradiation suppresses large conductance, calcium-activated potassium channels, which control the driving force for Ca2+ entry and therefore Ca2+ dependent nitric oxide (NO) synthesis in endothelial cells. This may contribute, in part, to radiation-induced endothelium dysfunction and an increase in arterial blood pressure.


Subject(s)
Coronary Vessels/radiation effects , Endothelial Cells/radiation effects , Potassium Channels, Calcium-Activated/physiology , Acetylcholine/pharmacology , Animals , Aorta, Thoracic/cytology , Aorta, Thoracic/drug effects , Aorta, Thoracic/radiation effects , Coronary Vessels/cytology , Coronary Vessels/drug effects , Dose-Response Relationship, Drug , Endothelial Cells/drug effects , Endothelial Cells/physiology , Gamma Rays , Male , Membrane Potentials/drug effects , Membrane Potentials/radiation effects , Patch-Clamp Techniques , Paxillin/pharmacology , Potassium Channels, Calcium-Activated/antagonists & inhibitors , Rats , Rats, Wistar , Vasodilation/drug effects , Vasodilation/radiation effects , Vasodilator Agents/pharmacology , Whole-Body Irradiation
2.
Am J Physiol Regul Integr Comp Physiol ; 289(3): R755-62, 2005 Sep.
Article in English | MEDLINE | ID: mdl-15890787

ABSTRACT

Radiation exposure increases vascular responsiveness, and this change involves endothelial damage, as well as direct effects on vascular smooth muscle. In this study, we tested the hypothesis that myofilament Ca(2+) sensitivity in vascular smooth muscle is increased from single whole body gamma irradiation (6 Gy). We measured contractile responses from intact and permeabilized rat thoracic aortic rings combined with cytosolic Ca(2+) ([Ca(2+)](i)) measurements. The sensitivity to KCl and phenylephrine increased significantly in tissues from animals on the 9th and 30th days postirradiation compared with control. Irradiation also significantly increased Ca(2+) sensitivity in beta-escin permeabilized smooth muscle on the 9th and 30th days postirradiation. Inhibitors of protein kinase C, chelerythrine, and staurosporine, had no effect on the pCa-tension curves in control permeabilized tissues but significantly decreased Ca(2+) sensitivity in permeabilized tissues on the 9th and 30th days postirradiation. Phorbol dibutyrate (PDBu, 10(-7) M) increased Ca(2+) sensitivity in control skinned smooth muscle but was without effect in irradiated vascular rings. Simultaneous measurement of contractile force and [Ca(2+)](i) showed that myofilament Ca(2+) sensitivity defined as the ratio of force change to [Ca(2+)](i) significantly increased following gamma-irradiation. PDBu (10(-6) M) stimulation of intact aorta produced a sustained contraction, while the increase in [Ca(2+)](i) was transient. In irradiated tissues, PDBu-induced contractions were greater than those seen in control tissues but there was no elevation in [Ca(2+)](i). Taken together, these data strongly support the hypothesis that irradiation increases the sensitivity of vascular smooth muscle myofilaments to Ca(2+) and this effect is dependent on activation of protein kinase C.


Subject(s)
Actin Cytoskeleton/physiology , Actin Cytoskeleton/radiation effects , Calcium/physiology , Muscle, Smooth, Vascular/physiology , Muscle, Smooth, Vascular/radiation effects , Protein Kinase C/physiology , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiology , Aorta, Thoracic/radiation effects , Calcium/metabolism , Capillary Permeability , In Vitro Techniques , Intracellular Membranes/metabolism , Osmolar Concentration , Potassium Chloride/pharmacology , Rats , Rats, Inbred WKY , Vasoconstriction/physiology
3.
Br J Pharmacol ; 138(5): 837-44, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12642385

ABSTRACT

(1) Gamma radiation impairs vascular function, leading to the depression of endothelium-dependent vasodilatation. Loss of the nitric oxide (NO) pathway has been implicated, but little is known about radiation effects on other endothelial mediators. (2) This study investigated the mechanisms of endothelial dysfunction in rabbits subjected to whole-body irradiation from a cobalt(60) source. (3) The endothelium-dependent relaxation of rabbit aorta evoked by acetylcholine (ACh) or A23187 was impaired in a dose-dependent manner by irradiation at 2 Gy or above. Inhibition was evident 9 days post-irradiation and persisted over the 30 day experimental period. (4) Endothelium-independent responses to glyceryl trinitrate (GTN), sodium nitroprusside (SNP) and 3-morpholino-sydnonimine (SIN-1) were suppressed over a similar dose range at 7-9 days post-irradiation, but recovered fully by 30 days post-irradiation. (5) In healthy vessels, ACh-induced relaxation was inhibited by L-N(omega)-nitroarginine (L-NA; 3 x 10(-4) M) and charybdotoxin (10(-8) M) plus apamin (10(-6) M) but resistant to indomethacin, indicating the involvement of NO and endothelium-derived hyperpolarizing factor (EDHF). Supporting this, ACh caused smooth muscle hyperpolarization that was reduced by L-NA and charybdotoxin plus apamin. (6) In irradiated vessels, responses to ACh were insensitive to L-NA but abolished by charybdotoxin plus apamin, indicating selective loss of NO-mediated relaxation. (7) In animals treated shortly after irradiation with the antioxidant, alpha-tocopherol acetate, the NO-dependent relaxation was restored without effect on the EDHF-dependent component. (8) The results imply that radiation selectively impairs the NO pathway as a consequence of oxidative stress, while EDHF is able to maintain endothelium-dependent relaxation at a reduced level.


Subject(s)
Endothelium, Vascular/radiation effects , Nitric Oxide/radiation effects , Vasodilation/radiation effects , Animals , Aorta, Thoracic/drug effects , Aorta, Thoracic/physiology , Aorta, Thoracic/radiation effects , Dose-Response Relationship, Drug , Dose-Response Relationship, Radiation , Endothelium, Vascular/drug effects , Endothelium, Vascular/physiology , In Vitro Techniques , Male , Nitric Oxide/physiology , Rabbits , Radiation, Ionizing , Vasodilation/drug effects , Vasodilation/physiology
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