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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Ionizing radiation alters myofilament calcium sensitivity in vascular smooth muscle: potential role of protein kinase C

¹Institute of Pharmacology and Toxicology, Academy of Medical Sciences, Kiev, Ukraine; and ²Drexel University College of Medicine, Department of Pharmacology and Physiology, Philadelphia, Pennsylvania

Submitted 3 November 2004 ; accepted in final form 6 May 2005

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 Ca²⁺ 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 Ca²⁺ ([Ca²⁺]_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 Ca²⁺ sensitivity in -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 Ca²⁺ sensitivity in permeabilized tissues on the 9th and 30th days postirradiation. Phorbol dibutyrate (PDBu, 10^–7 M) increased Ca²⁺ sensitivity in control skinned smooth muscle but was without effect in irradiated vascular rings. Simultaneous measurement of contractile force and [Ca²⁺]_i showed that myofilament Ca²⁺ sensitivity defined as the ratio of force change to [Ca²⁺]_i significantly increased following -irradiation. PDBu (10^–6 M) stimulation of intact aorta produced a sustained contraction, while the increase in [Ca²⁺]_i was transient. In irradiated tissues, PDBu-induced contractions were greater than those seen in control tissues but there was no elevation in [Ca²⁺]_i. Taken together, these data strongly support the hypothesis that irradiation increases the sensitivity of vascular smooth muscle myofilaments to Ca²⁺ and this effect is dependent on activation of protein kinase C.

ionized irradiation; chelerythrine; fura-2; staurosporine; phorbol dibutyrate