Date of Award

1988

Degree Type

Thesis

Degree Name

Master of Science in Pharmacology and Toxicology

Department

Pharmacology and Toxicology

First Advisor

Robert L. Rodgers

Abstract

Hypertension is associated with elevated rates of collagen synthesis and deposition in the arterial wall. Whether the increased synthesis and accumulation of vascular collagen is a cause or an effect of the elevated blood pressure in animal models of hypertension is still unresolved. Previous studies in this laboratory have indicated that chronic streptozotocin (STZ)-induced diabetes (8 weeks) reduces systolic arterial pressure (SAP) and vascular collagen synthesis in the spontaneously hypertensive rat (SHR) without affecting either measurement in the normotensive Wistar-Kyoto (WKY) strain. It was not apparent from those studies whether the reductions in SAP and vascular collagen synthesis in the diabetic SHR were causally or coincidentally related. Others have shown that diabetes does not affect SAP in the Goldblatt renovascular hypertensive (RVH) rat. Its effects on vascular collagen synthesis in the RVH model of hypertension has not been investigated. Aortic collagen synthesis was measured in diabetic and non-diabetic RVH and WKY rats in order to determine whether diabetes affects vascular collagen synthesis indirectly through changes in SAP, or whether diabetes affects vascular smooth muscle (VSM) collagen synthesis by a different mechanism. Vascular collagen synthesis was quantified by measuring the incorporation of [14c]-proline into collagen-bound [ 14c]-hydroxyproline in rat aortic minces in vitro. Aortic prolyl hydoxylase (PH; a collagen biosynthetic enzyme) activity was also measured as an index of collagen biosynthesis. Compared to vehicle-injected controls, rats injected with STZ exhibited the weight-loss, elevated serum glucose, and reduced serum insulin and thyroid hormone levels characteristic of the diabetic state. Renovascular hypertension caused an increase in vascular PH activity and collagen synthesis, presumably through an increase in arterial wall tension. Diabetes significantly reduced vascular collagen biosynthesis and PH activity in the RVH and WKY rat without affecting SAP of either group. Diabetes and hypertension had no significant effects on aortic collagen concentration. These results suggest that experimental diabetes inhibits vascular collagen synthesis by a mechanism independent of a reduction in arterial pressure. The mechanism by which diabetes reduces VSM collagen synthesis in the rat is unknown, but may involve hypoinsulinemia, hypothyroidism, or autonomic neuropathy.

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