Increase in the constrictor effects of Rho-kinase in skeletal muscle and coronary arteries of rats with chronic hypothyroidism

Aim. The deficit of thyroid function is known to be accompanied by an increase in the overall peripheral vascular resistance. This work tested the hypothesis that long-term hypothyroidism leads to an increase in the vasoconstrictor effect of Rho-kinase in skeletal muscle and heart resistance arteries of adult rats.

Materials and methods. Male Wistar rats consumed the antithyroid drug propylthiouracil (PTU) in drinking water (0.025%), starting at 10 weeks of age. The rats of the control group received PTU-free water. After 14 weeks, the contractile responses of the gastrocnemius muscle arteries (to the α1-adrenoceptor agonist methoxamine) and the septal coronary artery (to the thromboxane A2 receptor agonist U46619) were isometrically recorded. The contribution of the Rho-kinase to the arterial contractile responses was assessed using inhibitor Y27632 (3 μM).

Results. The consumption of propylthiouracil was accompanied by a marked decrease of thyroid hormone concentrations and an increase in total cholesterol serum level as well as a decrease in body weight. Maximal contractile responses of studied arteries were also reduced in hypothyroid rats. However, basal tone and reactivity to the moderate concentrations of agonists in arteries of hypothyroid rats were increased compared to control animals. Y27632 significantly weakened the contractile responses of the arteries and negated the differences between the two groups of rats.

Conclusion. Chronic hypothyroidism leads to an increase in the activity of the Rho-kinase signaling pathway in the arteries of the gastrocnemius muscle and heart, which results in the increase of the spontaneous tone of the arteries and their reactivity to agonists.

1. Danzi S., Klein I. Thyroid hormone and the cardiovascular system. Med. Clin. North Am. 2012; 96: 257–268. DOI:10.1016/j.mcna.2012.01.006.

2. Taylor P.N., Albrecht D., Scholz A., Gutierrez-Buey G., Lazarus J.H., Dayan CM, Okosieme O.E. Global epidemiology of hyperthyroidism and hypothyroidism. Nat. Rev. Endocrinol. 2018; 14: 301–316. DOI:10.1038/nrendo.2018.18.

3. Owen P.J.D., Sabit R., Lazarus J.H. Thyroid disease and vascular function. Thyroid. 2007; 17 (6): 519–524. DOI: 10.1089/thy.2007.0051.

4. Vargas F., Moreno J.M., Rodrнguez-Gуmez I., Wangensteen R., Osuna A., Alvarez-Guerra M., Garcнa-Estaс J. Vascular and renal function in experimental thyroid disorders. Eur. J. Endocrinol. 2006; 154 (2): 197–212. DOI: 10.1530/eje.1.02093.

5. Gunasekera R.D., Kuriyama H. The influence of thyroid states upon responses of the rat aorta to catecholamines. Br. J. Pharmacol. 1990; 99 (3): 541–547.

6. Baсos G., Martнnez F., Grimaldo J.I., Franco M. Adenosine participates in regulation of smooth muscle relaxation in aortas from rats with experimental hypothyroidism. Can. J. Physiol. Pharmacol. 2002; 80 (6): 507–514. DOI: 10.1139/Y02-064.

7. Sabio J.M., Rodriguez-Maresca M., Luna J.D., Garcнa del Rнo C., Vargas F. Vascular reactivity to vasoconstrictors in aorta and renal vasculature of hyperthyroid and hypothyroid rats. Pharmacology. 1994; 49 (4): 257–264.

8. Pantos C., Mourouzis C., Katramadou M., Saranteas T., Mourouzis I., Karageorgiou H., Tesseromatis C., Kostopanagiotou G., Asimacopoulos P., Cokkinos D.V. Decreased vascular reactivity to alpha1 adrenergic stimulation in the presence of hypothyroid state: a part of an adaptive response? Int. Angiol. 2006; 25 (2): 216–220.

9. Rahmani M.A., Cheema I.R., Sen S., Peoples B., Riley S.R. The effect of hyperthyroidism and hypothyroidism on alpha 1- and alpha 2-adrenergic responsiveness in rat aortic smooth muscle. Artery. 1987; 14 (6): 362–383.

10. Ishac E.J., Pennefather J.N. The influence of the thyroid state upon responses to noradrenaline and phentolamine in perfused mesenteric arterioles from the rat. J. Pharm. Pharmacol. 1983; 35 (7): 466–468.

11. McAllister R.M., Delp M.D., Thayer K.A., Laughlin M.H. Muscle blood flow during exercise in sedentary and trained hypothyroid rats. Am. J. Physiol. 1995; 269 (6 Pt 2): H1949–1954.

12. Traub-Weidinger T., Graf S., Beheshti M., Ofluoglu S., Zettinig G., Khorsand A., Nekolla S.G., Kletter K., Dudczak R., Pirich C. Coronary vasoreactivity in subjects with thyroid autoimmunity and subclinical hypothyroidism before and after supplementation with thyroxine. Thyroid. 2012; 22 (3): 245–251. DOI: 10.1089/thy.2011.0183.

13. Sara J.D., Zhang M., Gharib H., Lerman L.O., Lerman A. Hypothyroidism is associated with coronary endothelial dysfunction in women. J. Am. Heart Assoc. 2015; 4 (8): e002225. DOI: 10.1161/JAHA.115.002225.

14. McAllister R.M., Albarracin I., Price E.M., Smith T.K., Turk J.R., Wyatt K.D. Thyroid status and nitric oxide in rat arterial vessels. J. Endocrinol. 2005; 185 (1): 111–119. DOI: 10.1677/joe.1.06022.

15. La Vignera S., Condorelli R., Vicari E., Calogero A.E. Endothelial dysfunction and subclinical hypothyroidism: a brief review. J. Endocrinol. Invest. 2012; 35 (1): 96– 103. DOI: 10.3275/8190.

16. Shimokawa H., Sunamura S., Satoh K. RhoA/Rho-kinase in the cardiovascular system. Circ. Res. 2016; 118 (2): 352–366. DOI: 10.1161/CIRCRESAHA.115.306532.

17. Sofronova S.I., Gaynullina D.K., Shvetsova A.A., Borzykh A.A., Selivanova E.K., Sharova A.P., Martyanov A.A., Tarasova O.S. Antenatal/early postnatal hypothyroidism alters arterial tone regulation in 2-week-old rats. J. Endocrinol. 2017; 235 (2): 137–151. DOI: 10.1530/JOE-17-0225.

18. Gaynullina D.K., Sofronova S.I., Shvetsova A.A., Selivanova E.K., Sharova A.P., Martyanov A.A., Tarasova O.S. Antenatal/early postnatal hypothyroidism increases the contribution of Rho-kinase to contractile responses of mesenteric and skeletal muscle arteries in adult rats. Pediatr. Res. 2018. May 23. [Epub ahead of print]. DOI: 10.1038/s41390-018-0029-5.

19. Mulvany M.J., Halpern W. Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ. Res. 1977; 41 (1): 19–26.

20. Manna D., Roy G., Mugesh G. Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action. Acc. Chem. Res. 2013; 46 (11): 2706–2715. DOI: 10.1021/ar4001229.

21. Duntas L.H., Brenta G. The effect of thyroid disorders on lipid levels and metabolism. Med. Clin. North Am. 2012; 96 (2): 269–281. DOI: 10.1016/j.mcna.2012.01.012.

22. Puzdrova V.A., Kudryashova T.V., Gaynullina D.K., Mochalov S.V., Aalkjaer C., Nilsson H., Vorotnikov A.V., Schubert R., Tarasova O.S. Trophic action of sympathetic nerves reduces arterial smooth muscle Ca2+-sensitivity during early post-natal development in rats. Acta Physiol. (Oxf). 2014; 212 (2): 128–141. DOI: 10.1111/apha.12331.

23. Tarasova O.S., Mochalov S.V., Tarasova N.V., Vorotnikov A.V., Schubert R. Rho-kinase is particularly important for vascular smooth muscle contraction in newborn and sympathectomised rats. Acta Physiol. 2010; 199: 27–28.

24. Gaynullina D.K., Sofronova S.I., Selivanova E.K., Shvetsova A.A., Borzykh A.A., Sharova A.P., Kostyunina D.S., Martyanov A.A., Tarasova O.S.. NO-mediated anticontractile effect of the endothelium is abolished in coronary arteries of adult rats with antenatal/early postnatal hypothyroidism. Nitric. Oxide. 2017; 63: 21–28. DOI: 10.1016/j.niox.2016.12.007.

25. Morikage N., Kishi H., Sato M., Guo F., Shirao S., Yano T., Soma M., Hamano K., Esato K., Kobayashi S. Cholesterol primes vascular smooth muscle to induce Ca2+-sensitization mediated by a sphingosylphosphorylcholine-Rho-kinase pathway: possible role for membrane raft. Circ. Res. 2006; 99: 299–306. DOI: 10.1161/01.RES.0000235877.33682.e9.

26. Engin A.B., Sepici-Dincel A., Gonul I.I., Engin A. Oxidative stress-induced endothelial cell damage in thyroidectomized rat. Exp. Toxicol. Pathol. 2012; 64: 481–485. DOI: 10.1016/j.etp.2010.11.002.