Abstract

The clinical consequences of hypoxic cerebrovascular insults in the neonate, can be severe. It would therefore be valuable to understand the mechanisms of hypoxia-induced cerebrovasodilation. These studies were done in ovine middle cerebral and common carotid arteries to help elucidate the mechanisms through which calcium handling is involved in hypoxic cerebral vasodilation, comparing newborns and adults. The present studies demonstrate that calcium sensitivity (measured by the pD2) and the maximum contractile response to calcium increased with maturation. In addition, hypoxia depressed the maximum response to calcium and this effect was greater in adult than in newborn arteries. These results suggest that calcium sensitivity is less in newborn than in adult arteries, that intracellular calcium concentration and calcium conductance is greater in newborn than adult arteries and that hypoxia decreases both calcium sensitivity and calcium conductance. To isolate age-related vascular differences in calcium conductance only, we measured 45Ca uptakes under both receptor-dependent (100 µM serotonin) and receptor-independent (122 mM K+) mechanisms of contraction. Under both conditions, calcium uptakes were uniformly greater in newborn than adult arteries, and were greater in the middle cerebral than common carotid segments of the same age. In addition, for equivalent contractile tensions, newborn arteries required greater calcium uptakes than corresponding adult arteries. Therefore, it appears that calcium conductance does decrease with age and may be associated with age-related variations in the activation of calcium entry through voltage-sensitive and receptor-operated membrane calcium channels. To address how changes in calcium handling may play a role in age-related cerebrovascular contractile differences in response to hypoxia, we manipulated the extracellular calcium concentration to determine if hypoxia is acting to alter calcium influx. Our findings suggest that hypoxia relaxes newborn arteries more than adult arteries, that endothelial contributions to hypoxic relaxation increase with age and that both hypo- and hypercalcemic conditions enhance hypoxic relaxation and attenuate endothelial effects during hypoxia, independent of age. Clearly calcium-mediated mechanisms other than inhibition of calcium uptake are also involved in hypoxic vasorelaxation. This observation was verified when direct 45Ca uptakes were measured. Contractile tensions and 45Ca uptakes were measured under both normoxia and hypoxia during stimulation by both receptor-dependent and receptorindependent mechanisms of contraction in endothelial denuded newborn and adult common carotid and middle cerebral arteries. Again newborn middle cerebral arteries had higher uptake values than adult arteries but hypoxia did not affect 45Ca uptake in either age group or artery type. Based on both contractile and 45Ca uptake values to the different agonists under hypoxia, the membrane potential and changes in calcium sequestration, efflux and/or sensitivity for the contractile apparatus appear to play an important role in elucidating possible age-related vascular differences in response to hypoxia.

LLU Discipline

Pharmacology

Department

Pharmacology

School

Graduate School

First Advisor

William J. Pearce

Second Advisor

Sue Piper Duckles

Third Advisor

Charles A. Ducsay

Fourth Advisor

Marvin Peters

Fifth Advisor

Lubo Zhang

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

1995

Date (Title Page)

6-1995

Language

English

Library of Congress/MESH Subject Headings

Calmodulin; Anoxia; Muscle, Smooth, Vascular

Type

Dissertation

Page Count

2; x; 158

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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