Platelet Cyclic GMP Levels Are Reduced in Patients with Primary Aldosteronism

Overview

Journal J Clin Med

Specialty General Medicine

Date 2023 Nov 25

PMID 38002693

Authors

Carla Sala

Marta Rescaldani

Elisa Gherbesi

Gianni Bolla

Cesare Cuspidi

Massimiliano Ruscica

Stefano Carugo

Affiliations

Soon will be listed here.

Abstract

Background And Aim: Nitric oxide inhibits platelet aggregation by increasing the second messenger cyclic guanosine-3',5'-monophosphate (cGMP) through the activation of soluble guanylyl cyclase in target cells. Within this context, the oxidative stress associated with the aldosterone excess impairs the nitric oxide availability. Thus, the aim of the present study was to assess the impact of chronic aldosterone excess on the platelet nitric oxide/cGMP pathway in humans.

Methods: The levels of cGMP were evaluated in platelets of male patients, 12 with primary aldosteronism (PA) and 32 with uncomplicated essential hypertension (EH), matched for age and blood pressure (BP) values.

Results: PA and EH patients were 52.8 ± 3 years old and 51.6 ± 1.6 years old, respectively. Systolic and diastolic BP were 158 ± 5.0 mmHg and 105.9 ± 2.3 mmHg in PA and did not differ compared to EH patients (156.6 ± 2.4 mmHg and 104.7 ± 1.2 mmHg). Mean aldosterone levels were significantly higher in PA (25.5 ± 8.8 ng/dL) compared toEH (8.11 ± 0.73 ng/dL), whereas potassium was significantly lower in PA (3.52 ± 0.18 mEq/L) compared to EH (4.08 ± 0.04 mEq/L). Aldosterone and potassium were inversely related (r = -0.49, = 0.0006) in the whole study population ( = 44). Platelet cGMP was significantly lower in PA (5.1 ± 0.36 pM/10 cells) than in EH (7.1 ± 0.53 pM/10 cells), and in the entire study cohort, it was directly related to plasma potassium (r = 0.43, = 0.0321).

Conclusions: These results show an impairment of nitric oxide/cGMP signaling in platelets of PA patients. This effect is likely related to the potassium-depleting effect of chronic aldosterone excess. Future studies are needed to understand whether the platelet nitric oxide/cGMP system is involved in the atherothrombotic events in these patients.

References

Funder J, Carey R, Mantero F, Murad M, Reincke M, Shibata H . The Management of Primary Aldosteronism: Case Detection, Diagnosis, and Treatment: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016; 101(5):1889-916. DOI: 10.1210/jc.2015-4061. View

Buffolo F, Tetti M, Mulatero P, Monticone S . Aldosterone as a Mediator of Cardiovascular Damage. Hypertension. 2022; 79(9):1899-1911. DOI: 10.1161/HYPERTENSIONAHA.122.17964. View

Moraes L, Paul-Clark M, Rickman A, Flower R, Goulding N, Perretti M . Ligand-specific glucocorticoid receptor activation in human platelets. Blood. 2005; 106(13):4167-75. DOI: 10.1182/blood-2005-04-1723. View

Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Fasolo C . Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation. 1995; 91(7):1981-7. DOI: 10.1161/01.cir.91.7.1981. View

Schiffrin E . Effects of aldosterone on the vasculature. Hypertension. 2006; 47(3):312-8. DOI: 10.1161/01.HYP.0000201443.63240.a7. View

Potter L, Abbey-Hosch S, Dickey D . Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2005; 27(1):47-72. DOI: 10.1210/er.2005-0014. View

DElia L, Barba G, Cappuccio F, Strazzullo P . Potassium intake, stroke, and cardiovascular disease a meta-analysis of prospective studies. J Am Coll Cardiol. 2011; 57(10):1210-9. DOI: 10.1016/j.jacc.2010.09.070. View

Gromotowicz-Poplawska A, Marcinczyk N, Misztal T, Golaszewska A, Aleksiejczuk M, Rusak T . Rapid effects of aldosterone on platelets, coagulation, and fibrinolysis lead to experimental thrombosis augmentation. Vascul Pharmacol. 2019; 122-123:106598. DOI: 10.1016/j.vph.2019.106598. View

Bodary P, Sambaziotis C, Wickenheiser K, Rajagopalan S, Pitt B, Eitzman D . Aldosterone promotes thrombosis formation after arterial injury in mice. Arterioscler Thromb Vasc Biol. 2005; 26(1):233. DOI: 10.1161/01.ATV.0000195782.07637.44. View

10.

Balligand J, Feron O, Dessy C . eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev. 2009; 89(2):481-534. DOI: 10.1152/physrev.00042.2007. View

11.

Funder J . Reconsidering the roles of the mineralocorticoid receptor. Hypertension. 2009; 53(2):286-90. DOI: 10.1161/HYPERTENSIONAHA.108.119966. View

12.

Radomski M, Palmer R, Moncada S . An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci U S A. 1990; 87(13):5193-7. PMC: 54288. DOI: 10.1073/pnas.87.13.5193. View

13.

Mellion B, Ignarro L, Ohlstein E, Pontecorvo E, HYMAN A, Kadowitz P . Evidence for the inhibitory role of guanosine 3', 5'-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood. 1981; 57(5):946-55. View

14.

Nagata D, Takahashi M, Sawai K, Tagami T, Usui T, Shimatsu A . Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. Hypertension. 2006; 48(1):165-71. DOI: 10.1161/01.HYP.0000226054.53527.bb. View

15.

Nishizaka M, Zaman M, Green S, Renfroe K, Calhoun D . Impaired endothelium-dependent flow-mediated vasodilation in hypertensive subjects with hyperaldosteronism. Circulation. 2004; 109(23):2857-61. DOI: 10.1161/01.CIR.0000129307.26791.8E. View

16.

Oberleithner H, Callies C, Kusche-Vihrog K, Schillers H, Shahin V, Riethmuller C . Potassium softens vascular endothelium and increases nitric oxide release. Proc Natl Acad Sci U S A. 2009; 106(8):2829-34. PMC: 2637279. DOI: 10.1073/pnas.0813069106. View

17.

He F, Marciniak M, Carney C, Markandu N, Anand V, Fraser W . Effects of potassium chloride and potassium bicarbonate on endothelial function, cardiovascular risk factors, and bone turnover in mild hypertensives. Hypertension. 2010; 55(3):681-8. DOI: 10.1161/HYPERTENSIONAHA.109.147488. View

18.

Sugimoto T, Tobian L, Ganguli M . High potassium diets protect against dysfunction of endothelial cells in stroke-prone spontaneously hypertensive rats. Hypertension. 1988; 11(6 Pt 2):579-85. DOI: 10.1161/01.hyp.11.6.579. View

19.

Friebe A, Mergia E, Dangel O, Lange A, Koesling D . Fatal gastrointestinal obstruction and hypertension in mice lacking nitric oxide-sensitive guanylyl cyclase. Proc Natl Acad Sci U S A. 2007; 104(18):7699-704. PMC: 1863512. DOI: 10.1073/pnas.0609778104. View

20.

Dangel O, Mergia E, Karlisch K, Groneberg D, Koesling D, Friebe A . Nitric oxide-sensitive guanylyl cyclase is the only nitric oxide receptor mediating platelet inhibition. J Thromb Haemost. 2010; 8(6):1343-52. DOI: 10.1111/j.1538-7836.2010.03806.x. View