Sodium homeostasis, pH regulation, and high energy phosphate metabolism in hypertrophied hearts during ischemia

Author

Arrie Lynelle Golden

Date of Award

5-1992

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Life Sciences

Major Professor

James E. Lawler

Committee Members

Jan Bright, Martin Pike, Bill Jacobs, George Kabalka

Abstract

Hearts with hypertrophy associated with pressure overload have an increased susceptibility to ischemic dysfunction and damage. There is evidence that hypertrophied hearts have altered Na⁺ and Ca⁺² homeostasis, and a greater dependence on anaerobic glycolysis that may promote increased ischemic damage and dysfunction via mechanisms involving disruption of cation gradients. The primary objectives of the studies described in the following chapters were to evaluate the role of an increase in intracellular Na⁺ in promoting ischemic dysfunction and damage in hypertrophied hearts, and to relate the increase in intracellular Na⁺ to changes in high energy phosphates and pH.

The gradual occurrence of hypertension in the Borderline Hypertensive Rat (BHR) fed a high salt diet suggested that this model might be useful in understanding early myocardial changes in hypertension. The objectives of the preliminary study described in Chapter 2 were to characterize the development of myocardial hypertrophy, and associated changes in creatine kinase (CK) isozyme expression in the BHR heart. The results indicated that BHR fed a high salt diet develop significant, but minimal, hypertrophy that does not increase in severity with age. In addition, the BHR did not develop changes in CK expression that are characteristic of models of more severe pressure overload hypertrophy such as the Spontaneously Hypertensive Rat (SHR).

The objective of the studies described in Chapter 3 was to develop an ischemic protocol to relate diastolic dysfunction with increased intracellular Na⁺. Interleaved ²³Na and ³¹P NMR spectra were acquired in perfused hearts to assess changes in diastolic function, intracellular Na⁺ pH and high energy phosphates in BHR hearts during demand ischemia. The results indicated that induction of diastolic dysfunction during demand ischemia required a perfusate free [Ca⁺²] above 1mM, but a higher [Ca⁺²] was not compatible with the ²³Na shift reagent TmDOTP^-5. In addition, the increase in intracellular Na⁺ was not greater in the hypertrophied BHR compared with control BHR. Thus, more severe ischemia, and SHR with greater hypertrophy were used in later experiments.

The objectives of the studies described in Chapter 4 were to determine if the increase in intracellular Na⁺ was greater in hypertrophied SHR hearts compared with Wistar-Kyoto (YvKY) controls during low flow ischemia, and to determine whether the accumulation of Na⁺ in these hearts was associated with ischemic dysfunction and damage. In addition, the increase in Na⁺ was related to decreases in high energy phosphates and pH. Interleaved ³¹P and ²³Na (with the NMR shift reagent TmDOTP^-5) spectra were acquired in perfused hearts from 8-10 month old SHR during low flow ischemia and reperfusion. Left ventricular pressures were monitored continuously.

The ischemic protocol distinguished two groups of hypertrophied SHR. The SHR group that exhibited contractile failure during ischemia will be referred to as the SHF, and the second group of SHR that sustained contractile function during ischemia will be referred to as the SHS. The SHS represented the majority of the SHR studied, and did not exhibit either a greater increase in intracellular Na⁺ during ischemia, or greater ischemic dysfunction and damage compared with the WKY. In contrast, the SHF did exhibit a greater increase in intracellular Na+ during ischemia compared with the WKY. Furthermore, the greater accumulation of Na⁺ in the SHF hearts was associated with greater systolic and diastolic dysfunction during ischemia, and poorer recovery following reperfusion. Therefore, impaired Na⁺ handling may indeed contribute to the greater sensitivity of hypertrophied hearts to ischemic dysfunction and damage. However, since not all hypertrophied hearts were affected, the impaired Na⁺ handling was not associated with hypertrophy per se. We propose that impaired Na⁺ handling may be indicative of' a subtle transition towards a less compensated stage of hypertrophy that may precede the development of congestive heart failure, and be manifest as an increased sensitivity to ischemia.

Recommended Citation

Golden, Arrie Lynelle, "Sodium homeostasis, pH regulation, and high energy phosphate metabolism in hypertrophied hearts during ischemia. " PhD diss., University of Tennessee, 1992.
https://trace.tennessee.edu/utk_graddiss/10892