Captopril is an orally active antihypertensive agent, proposed to act primarily, if not solely, by inhibition of angiotensin I converting enzyme. Often though, a low-sodium (Na) diet and/or diuretic must be employed along with captopril in order to completely normalize blood pressure. In addition to lowering pressure, captopril attenuates vascular responses to Alpha-adrenergic agonists and this attenuation is prevented by excess Na-intake. This attenuation of vascular Alpha-adrenergic responsiveness may be an important antihypertensive action of captopril which is often masked by excess dietary Na; therefore, the proposed project is designed to test the hypothesis that Na interacts with captopril on vascular Alpha-adrenergic responses. The effects of both elevtions and reductions in Na concentration on the captopril-induced attenuation of vascular Alpha-adrenergic responsiveness will be tested in rats both acutely, as changes in the intra- and extracellular Na concentration of vascular smooth muscle in vitro, and chronically, as changes in the dietary Na concentration during captopril-treatment for 5-wk. For both studies, Alpha-adrenergic responsiveness will be evaluated as the in vitro responses of rings of both thoracic aorta and caudal artery from rats to the Alpha-adrenergic agonist, phenylephrine. Additional chronic studies will investigate separately the effects of both returning to normal dietary Na and administration of a diuretic to rats fed a high-Na diet on the captopril-induced attentuation of Alpha-adrenergic responses. For this study, Alpha-adrenergic responsiveness will be evaluated as the in vivo pressor responses of unanesthetized, unrestrained rats to phenylephrine and will be measured both prior to (while on high-Na diet) and following return to normal dietary Na or administration of the diuretic for 2 wk. Effects of chronic alterations in dietary Na could be due to either direct effects of the Na itself at the level of vascular smooth muscle or to indirect effects mediated by a variety of possible Na-induced changes, including changes in the plasma levels of a humoral Na-pump inhibitor. The effects of these chronic alterations on vascular Na-pump activity will be evaluated. Results of the acute study should indicate whether Na itself can interact with captopril at the level of vasculr smooth muscle. The proposed studies should provide further insight into how dietary Na and/or diuretics may interact with the antihypertensive action(s) of captopril and help define future studies aimed at investigating the mechanism(s) for this Na/captopril interaction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R23)
Project #
1R23HL033416-01A1
Application #
3448750
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1985-09-01
Project End
1988-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Graduate Hospital (Philadelphia)
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19146