Date of Award

2001

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Veterinary Medical Sciences - Pathobiological Sciences

First Advisor

Rustin M. Moore

Abstract

Clinically healthy horses were instrumented to measure hemodynamic, metabolic, hematologic, and serum biochemical variables and monitor clinical signs during and after IV infusion of ATP-MgCl2. Conscious horses were administered ATP-MgCl2 (0.05 mg ATP/kg body weight/min; 0.05 mg/kg/min increments; maximum rate-1.0 mg/kg/min), which caused a rate-dependent increase in cardiac output, decrease in systemic vascular resistance, and mild pulmonary hypertension. The maximal safe infusion rate was 0.3 mg ATP/kg body weight/min. Anesthetized horses administered ATP-MgCl2 (0.1 to 1 mg/kg/min; 0.1 mg/kg/min increments) developed a rate-dependent decrease in systemic and colonic vascular resistance via vasodilatation. In conscious horses administered lowdose endotoxin, ATP-MgCl2 (dose-100 mumole/kg ATP and 100 mumole/kg MgCl 2; rate 0.3 mg/kg/min) failed to attenuate the clinical, hemodynamic, metabolic, and hematologic alterations that occur secondary to endotoxin exposure; ATP-MgCl2 infusion appeared to potentiate pulmonary hypertension, leukopenia, and neutropenia observed with endotoxin. Based on the results of the in vivo studies, the effects of ATP on vasomotor tone of isolated equine colonic arterial and venous rings were studied. Non-cumulative dose response curves of vessel rings from normal horses to ATP (10 -8 to 10-3 M) were generated in the presence and absence of endothelium and in the presence of a non-specific nitric oxide synthase inhibitor, L-NAME (10-4 M). ATP caused a biphasic response at high doses (10-4 and 10-3 M) in both vessel types, an initial transient contraction followed by a slow, substantial and sustained relaxation, which was attenuated with endothelium removal. The endothelium-dependent relaxation component was mediated by a mechanism other than nitric oxide. A method to quantify adenine nucleotides in equine colonic mucosa was validated. Adenine nucleotides were stable in lyophilized tissue stored at -70 C for at least 54 days. Effects of an electron transport inhibitor (antimycin A) on mucosal nucleotides was determined in a whole tissue model. In the presence of glucose and oxygen, ATP was stable for up to 4 hrs, but ADP and AMP decreased. In the absence of glucose, ATP remained stable for only 3 hrs. Antimycin A (50 muM) caused a time-dependent, irreversible decrease in adenine nucleotides.

ISBN

9780493272962

Pages

256

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