Abstract
The chronic reduction of arterial blood pressure by thiazide diuretics (TZD) in hypertensive patients is mediated through an extra-renal mechanism. It is widely held that this extra-renal mechanism is a direct TZD inhibition of vasoconstriction. This study tested whether the TZD, hydrochlorothiazide (HCTZ), inhibited agonist constriction of mesenteric arterioles ex vivo. Mice deficient in the kidney distal convoluted tubule Na+/Cl− cotransporter (NCC), i.e., the target of thiazide inhibition–mediated diuresis, and wild type (WT), were subjected to Na+-restricted diet. Mesenteric arterioles from NCC knockout and WT mice were then isolated, placed under constant pressure, and the inhibitory effects of HCTZ (100 μM) on phenylephrine constriction determined. HCTZ did not inhibit phenylephrine constriction of arterioles from NCC knockout and wild type (WT) mice subjected to Na+-restricted diet. This study suggests that future investigations to identify the extra-renal site of chronic TZD treatment should (1) focus on indirect inhibition of vascular constriction and (2) be determined under clinically relevant conditions. These conditions include chronic TZD at relevant concentrations in hypertensive animals.
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References
Abrahams Z, Tan LL, Pang MY, Abrahams B, Tan MM, Wright JM (1996) Demonstration of an in vitro direct vascular relaxant effect of diuretics in the presence of plasma. J Hypertens 14:381–388
Abrahams Z, Pang MY, Lam EK, Wright JM (1998) What is the plasma cofactor required by diuretics for direct vascular relaxant effect in vitro? J Hypertens 16:801–809
Alshahrani S, Rapoport RM, Zahedi K, Jiang M, Nieman M, Barone S, Meredith AL, Lorenz JN, Rubinstein J, Soleimani M (2017) The non-diuretic hypotensive effects of thiazides are enhanced during volume depletion states. PLoS One 12:e0181376
Calder JA, Schachter M, Sever PS (1992) Direct vascular actions of hydrochlorothiazide and indapamide in isolated small vessels. Eur J Pharmacol 220:19–26
Calder JA, Schachter M, Sever PS (1993) Ion channel involvement in the acute vascular effects of thiazide diuretics and related compounds. J Pharmacol Exp Ther 265:1175–1180
Calder JA, Schachter M, Sever PS (1994) Potassium channel opening properties of thiazide diuretics in isolated guinea pig resistance arteries. J Cardiovasc Pharmacol 24:158–164
Colas B, Slama M, Collin T, Safar M, Andrejak M (2000a) Mechanisms of methyclothiazide-induced inhibition of contractile responses in rat aorta. Eur J Pharmacol 408:63–67
Colas B, Slama M, Masson H, Colas JL, Collin T, Arnould ML, Hary L, Safar M, Andrejak M (2000b) Direct vascular actions of methyclothiazide and indapamide in aorta of spontaneously hypertensive rats. Fundam Clin Pharmacol 14:363–368
Colas B, Colas JL, Masson H, Slama M, Collin T, Andrejak M (2000c) Effect of methyclothiazide on the entry of calcium into vascular smooth muscle cells. Arch Mal Coeur Vaiss 93:901–904
Colas B, Collin T, Safraou F, Chatelain D, Cordonnier C, Henry X, Safar M, Andrejak M, Slama M (2001) Direct vascular actions of methyclothiazide in remodeled mesenteric arteries from hypertensive patients. Am J Hypertens 14:989–994
Daniel EE, Nash CW (1965) The effects of diuretic and non-diuretic benzothiadiazine and of structurally related diuretic drugs on active ion transport and contractility in smooth muscles. Arch Int Pharmacodyn Ther 158:139–154
Duarte JD, Cooper-DeHoff RM (2010) Mechanisms for blood pressure lowering and metabolic effects of thiazide and thiazide-like diuretics. Expert Rev Cardiovasc Ther 8:793–802
Dunn WR, Wellman GC, Bevan JA (1994) Enhanced resistance artery sensitivity to agonists under isobaric compared with isometric conditions. Am J Phys 266(1 Pt 2):H147–H155
Ellison DH, Loffing J (2009) Thiazide effects and adverse effects: insights from molecular genetics. Hypertension 54:196–202
Hughes AD (2004) How do thiazide and thiazide-like diuretics lower blood pressure? J Renin-Angiotensin-Aldosterone Syst 5:155–160
Mironneau J, Savineau JP, Mironneau C (1981) Compared effects of indapamide, hydrochlorothiazide and chlorthalidone on electrical and mechanical activities in vascular smooth muscle. Eur J Pharmacol 75:109–113
Nevitt C, McKenzie G, Christian K, Austin J, Hencke S, Hoying J, LeBlanc A (2016) Physiological levels of thrombospondin-1 decrease NO-dependent vasodilation in coronary microvessels from aged rats. Am J Physiol Heart 310:H1842–H1850
Pickkers P, Hughes AD (1995) Relaxation and decrease in [Ca2+]i by hydrochlorothiazide in guinea-pig isolated mesenteric arteries. Br J Pharmacol 114:703–707
Pickkers P, Garcha RS, Schachter M, Smits P, Hughes A (1999) Inhibition of carbonic anhydrase accounts for the direct vascular effects of hydrochlorothiazide. Hypertension 33:1043–1048
Pourafshar N, Alshahrani S, Karimi A, Soleimani M (2018) Thiazide therapy in chronic kidney disease: renal and extra renal targets. Curr Drug Metab 19:1012–1020
Rapoport RM, LeBlanc AJ, Beare JE, Soleimani M (2018) Lack of thiazide diuretic inhibition of agonist constriction of mouse mesenteric arterioles ex vivo. Naunyn Schmiedebergs Arch Pharmacol. https://doi.org/10.1007/s00210-018-1590-5
Shah S, Khatri I, Freis ED (1978) Mechanism of antihypertensive effect of thiazide diuretics. Am Heart J 95:611–618
Shahin MH, Johnson JA (2016) Mechanisms and pharmacogenetic signals underlying thiazide diuretics blood pressure response. Curr Opin Pharmacol 27:31–37
Sigaroudi A, Kinzig M, Wahl O, Stelzer C, Schroeter M, Fuhr U, Holzgrabe U, Sörgel F (2018) Quantification of hydrochlorothiazide and ramipril/ramiprilate in blood serum and cerebrospinal fluid: a pharmacokinetic assessment of central nervous system adverse effects. Pharmacology 102:133–137
Sládková M, Kojsová S, Jendeková L, Pechánová O (2007) Chronic and acute effects of different antihypertensive drugs on femoral artery relaxation of L-NAME hypertensive rats. Physiol Res 56(Suppl 2):S85–S91
Soleimani M, Barone S, Xu J, Shull GE, Siddiqui F, Zahedi K, Amlal H (2012) Double knockout of pendrin and Na-Cl cotransporter (NCC) causes severe salt wasting, volume depletion, and renal failure. Proc Natl Acad Sci U S A 109:13368–13373
Tobian L, Coffee K (1964) Effect of thiazide drugs on renovascular hypertension in contrast to their effect on essential hypertension. Proc Soc Exp Biol Med 115:196–198
Zhu Z, Zhu S, Liu D, Cao T, Wang L, Tepel M (2005) Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase. Hypertension 45:233–239
Acknowledgements
We thank Glenn Doerman (University of Cincinnati) for the figure.
Funding sources
This study was financially supported by Merit Review 5 I01 BX001000-06 award from the Department of Veterans Affairs and funds from the Center on Genetics of Transport and Epithelial Biology at the University of Cincinnati, and US Renal Care Inc. (MS), R01 AG053585 from NIA, Jewish Heritage Fund for Excellence, and the Gheens Foundation (AJL), and a Professional Development Grant from the University of Cincinnati (RMR).
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RMR and MS conceived of the research. RMR, AJL, and JEB designed the research and conducted the experiments. MS contributed the mouse model. RMR, AJL, and JEB analyzed data. RMR wrote the manuscript. All authors read and approved the manuscript.
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Robert M. Rapoport and Amanda J. LeBlanc are co-first authors
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Rapoport, R.M., LeBlanc, A.J., Beare, J.E. et al. Lack of thiazide diuretic inhibition of agonist constriction of mouse mesenteric arterioles ex vivo. Naunyn-Schmiedeberg's Arch Pharmacol 392, 117–121 (2019). https://doi.org/10.1007/s00210-018-1590-5
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DOI: https://doi.org/10.1007/s00210-018-1590-5