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The Renal (Diuretic) and Extra Renal (Non-Diuretic) Actions of Hydrochlorothiazide

Alshahrani, Saeed

Abstract Details

2017, PhD, University of Cincinnati, Medicine: Molecular, Cellular and Biochemical Pharmacology.
Thiazide and thiazide-like diuretic agents, including hydrochlorothiazide (HCTZ), are specific inhibitors of the Na+_Cl- Co-transporter (NCC) in the kidney distal tubules, and the most commonly used diuretic agents for the treatment of mild to moderate hypertension. Despite the recognized hypotensive effects of HCTZ, the mechanism by which it reduces the blood pressure remains uncertain. There are two proposed mechanisms of the antihypertensive action of HCTZ: 1) HCTZ reduces the blood pressure by inhibition of NCC in the kidney, which causes an increase in urine and salt excretion and reduces the plasma volume, and thereby lowers the blood pressure 2) HCTZ has vasorelaxant effects causing vasodilation via activation of the large conductance Ca2+ activated K+ channels (BK channels). In addition to the uncertainty of the actual mechanism of action, the circumstances under which the renal (diuretic) or extra renal (non-diuretic, vasorelaxation) mechanism predominates remain unknown. Therefore, the purpose of this dissertation is to elucidate the renal and extra renal mechanisms of HCTZ and to better understand the triggers of each mechanism. It is well documented that NCC and Cl-/HCO3- exchanger, pendrin, are expressed in the distal nephron and mediate salt absorption, with pendrin working in tandem with the epithelial sodium channel (ENaC) and NCC working by itself. To understand the interaction between NCC and pendrin in response to HCTZ, two genetically modified mice were used, NCC and Pendrin KO mice, and treated with HCTZ. This work demonstrates that the diuretic effects of HCTZ are pendrin dependent, and deletion of pendrin enhances the salt and water excretion subsequent to treatment with HCTZ. To address the vasorelaxation effects of HCTZ, blood pressure was measured in response to HCTZ in mice lacking the NCC; i.e. the renal target of HCTZ. These studies demonstrated that HCTZ significantly reduced the blood pressure only when mice are volume-depleted, induced by salt restriction or salt wasting such as pendrin/NCC dKO mice. The reduction in blood pressure in volume-depleted mice by HCTZ occurs in the absence of enhanced salt excretion, and is not associated with any changes in echocardiography monitored cardiac output. To further test whether BK channels are mediating these hypotensive effects, BK channels blocker (paxilline) and BK channels KO mice were used. The results demonstrate that blocking or deleting BK channels did not prevent the effects of HCTZ, indicating there are other mechanisms involved. To further test the direct action of HCTZ on the blood vessels, aorta ring contractions were performed. The vasoreactivity studies revealed that HCTZ has minimal effects on the aorta of NCC KO mice on low salt compared to control diet. In conclusion, this dissertation demonstrates that pendrin blunts the diuretic effects of HCTZ, and thus pendrin inactivation significantly augments the diuresis by HCTZ. In addition, our results indicate that HCTZ causes significant reduction in the blood pressure independent of its diuretic action only in volume depletion conditions caused by either salt restriction or salt wasting. The blood pressure reduction is not mediated by BK channel activation. These studies suggest that HCTZ may reduce the blood pressure through reversal of a feedback system that is activated in response to volume depletion and functions to maintain vascular resistance.
Manoocher Soleimani, M.D. (Committee Chair)
John Lorenz, Ph.D. (Committee Member)
Robert Rapoport, Ph.D. (Committee Member)
Jack Rubinstein, M.D. (Committee Member)
162 p.

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Citations

  • Alshahrani, S. (2017). The Renal (Diuretic) and Extra Renal (Non-Diuretic) Actions of Hydrochlorothiazide [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505124710040326

    APA Style (7th edition)

  • Alshahrani, Saeed. The Renal (Diuretic) and Extra Renal (Non-Diuretic) Actions of Hydrochlorothiazide. 2017. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505124710040326.

    MLA Style (8th edition)

  • Alshahrani, Saeed. "The Renal (Diuretic) and Extra Renal (Non-Diuretic) Actions of Hydrochlorothiazide." Doctoral dissertation, University of Cincinnati, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1505124710040326

    Chicago Manual of Style (17th edition)