This project will examine the effects of acute myocardial ischemia, produced by ligation of either the right or left coronary arteries and subsequent reperfusion on the activity and reflex properties of cardiopulmonary vagal and sympathetic afferents in rats. Production of free oxygen radicals in ischemia and reperfusion may play an important role in the mechanism of these effects. While studies have made progress in understanding the role of free-radical oxidation in ischemia/reperfusion damage of the heart and in the onset of arrhythmias, there have been no studies, to date, to examine the effect of free-radical oxidation on cardiac sensory receptors. Furthermore, there have been no studies to date to assess the effect of right ventricular ischemia and reperfusion on the afferent and reflex properties of cardiac afferent fibers. The investigators will measure impulse activity form single, afferent fibers in the vagus and thoracic sympathetic trunk that arise form mechano-and chemosensitive endings in the heart (afferent studies) and from efferent fibers in a branch of the renal sympathetic nerve (RSN, reflex studies). The investigators will determine whether free-radical oxidation (by topical administration of chemical activators of free-radical formation (xanthine/xanthine oxidase, hydroperoxides)) activate vagal and sympathetic afferents and RSN reflexes from the heart and other vascular regions; and to determine whether the effects can be reversed by enzymatic and nonenzymatic antioxidants (superoxide dismutase (SOD), catalase, deferoxamine, allopurinol, dimethylthiourea). The investigators will also determine whether free-radical oxidation contributes to the activation of cardiac afferents and RSN reflexes in response to acute right or left main coronary occlusion and subsequent reperfusion. The investigators will limit free-radical formation during ischemia and reperfusion by systemic administration of enzymatic and nonenzymatic antioxidants as described above. Possible interactions of free radicals with cyclooxygenase production of prostaglandins and their effects on cardiac afferents and RSN reflexes also will be investigated. An elucidation of the effects of free radicals on cardiac afferents and RSN reflexes will provide further insights into the role of oxygen free radicals in regulatory disturbances during ischemia and reperfusion of both the right and left ventricles.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052190-04
Application #
2750411
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Project Start
1995-08-01
Project End
2001-07-31
Budget Start
1998-08-01
Budget End
2001-07-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Nebraska Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
City
Omaha
State
NE
Country
United States
Zip Code
68198
Schultz, H D (2001) Cardiac vagal chemosensory afferents. Function in pathophysiological states. Ann N Y Acad Sci 940:59-73
Sun, S Y; Wang, W; Schultz, H D (2001) Activation of cardiac afferents by arachidonic acid: relative contributions of metabolic pathways. Am J Physiol Heart Circ Physiol 281:H93-H104
Ustinova, E E; Barrett, C J; Sun, S Y et al. (2000) Oxidative stress impairs cardiac chemoreflexes in diabetic rats. Am J Physiol Heart Circ Physiol 279:H2176-87
Sun, S Y; Wang, W; Zucker, I H et al. (1999) Enhanced activity of carotid body chemoreceptors in rabbits with heart failure: role of nitric oxide. J Appl Physiol 86:1273-82
Barrett, C J; Schultz, H D (1999) Sympathoinhibitory effects of atrial natriuretic peptide in rats with heart failure. J Card Fail 5:316-23
Sun, S Y; Wang, W; Zucker, I H et al. (1999) Enhanced peripheral chemoreflex function in conscious rabbits with pacing-induced heart failure. J Appl Physiol 86:1264-72
Schultz, H D; Ustinova, E E (1998) Capsaicin receptors mediate free radical-induced activation of cardiac afferent endings. Cardiovasc Res 38:348-55
Schultz, H D; Ustinova, E E (1996) Cardiac vagal afferent stimulation by free radicals during ischaemia and reperfusion. Clin Exp Pharmacol Physiol 23:700-8