Nebivolol, but not Propranolol, Induced Relaxation of the Isolated Bovine Coronary Segments: Role of NO and K+ Channels

Section: Research Paper
Issue
Vol. 21 No. 4 (2024): Volume 21 Issue 4
Published
Dec 1, 2024
Pages
155-161

Abstract

Background and objectives: Beta-blockers are the most used antihypertensive agents due to their blood pressure-lowering effect alongside decreasing heart rate. Nebivolol (NB) seems to provide typical antihypertensive alongside vasorelaxant effects. The present study aimed to elucidate the differential impacts of NB on bovine coronary tone with a specific focus on the involvement of nitric oxide and K+ channels. Using an in vitro isolated bovine coronary segments, vascular reactivity was assessed through tension measurement in response to NB. Methods: Using isolated tissue baths, the impact of NB on bovine coronary artery segments' contractility was assessed. The contractions were induced by KCl, NB was added to check the vasorelaxant effects, and methylene blue was used to examine the role of NO. In addition, the effect on tone was compared with another -blocker, propranolol, to determine the role of adrenoceptor. Results: NB significantly induced relaxation in the coronary bovine artery segments, 49.7 7.84 VS 4.44 6.87. Incubation with methylene blue (30 M) inhibited NB relaxation, 46.08 4.37 vs MB 12.16 4.28, KCl depolarization did not affect on the relaxation induced by NB in comparison to U46619 precontraction KCl 39.52 6.19 vs U46619 58.41 28.92. Propranolol had no effect on the coronary tone when compared to NB, 87.05 7.05 VS Propranolol 34.28 5.71. Conclusions: Our results show that NO but not K+ channel activation is involved in the mechanism of NB induced coronary artery relaxation. These results highlight the necessity of taking these pathways into account when extrapolating the effects of NB in clinical settings.

References

  1. Almallah R AH. Mirabegron-Induced Smooth Muscle Relaxation: Review of the Suggested Mechanisms. Iraqi Journal of Pharmacy 2023;20(Supp-01):195-200.
  2. Almallah R, Almukhtar H. Mirabegron Induced Relaxation of Isolated Bovine Coronary Segments: Role of No and K+ Channel. Georgian Med News 2024(347):87-92.
  3. Almukhtar H, Garle M, Smith P, Roberts RE. Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria. Toxicology and Applied Pharmacology. 2016;305:176-85.
  4. Altwegg LA, d'Uscio LV, Barandier C, Cosentino F, Yang Z, Luscher TF. Nebivolol induces NO-mediated relaxations of rat small mesenteric but not of large elastic arteries. Journal of Cardiovascular Pharmacology 2000;36(3):316-20.
  5. Atwa A, Hegazy R, Mohsen R, Yassin N, Kenawy S. Protective Effects of the Third Generation Vasodilatory Betaeta - Blocker Nebivolol against D-Galactosamine - Induced Hepatorenal Syndrome in Rats. Open Access Macedonian Journal of Medical Sciences 2017;5(7):880-92.
  6. Atwa A, Hegazy R, Shaffie N, Yassin N, Kenawy S. Protective Effects of Vasodilatory Betaeta-Blockers Carvedilol and Nebivolol against Glycerol Model of Rhabdomyolysis-Induced Acute Renal Failure in Rats. Open Access Macedonian Journal of Medical Sciences 2016;4(3):329-36.
  7. Bowman AJ, Chen CP, Ford GA. Nitric oxide mediated venodilator effects of nebivolol. British Journal of Clinical Pharmacology 1994;38(3):199-204.
  8. Coats A, Jain S. Protective effects of nebivolol from oxidative stress to prevent hypertension-related target organ damage. Journal of Human Hypertension 2017;31(6):376-81.
  9. Dawes M, Brett SE, Chowienczyk PJ, Mant TG, Ritter JM. The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension. British Journal of Clinical Pharmacology 1999;48(3):460-3.
  10. Dessy C, Moniotte S, Ghisdal P, Havaux X, Noirhomme P, Balligand JL. Endothelial beta3-adrenoceptors mediate vasorelaxation of human coronary microarteries through nitric oxide and endothelium-dependent hyperpolarization. Circulation 2004;110(8):948-54.
  11. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288(5789):373-6.
  12. Godo S, Takahashi J, Yasuda S, Shimokawa H. Endothelium in Coronary Macrovascular and Microvascular Diseases. Journal of Cardiovascular Pharmacology 2021;78(Suppl 6):S19-S29.
  13. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proceedings of the National Academy of Sciences of the United States of America 1987;84(24):9265-9.
  14. Ignarro LJ, Napoli C, Loscalzo J. Nitric oxide donors and cardiovascular agents modulating the bioactivity of nitric oxide: an overview. Circulation Research 2002;90(1):21-8.
  15. Janssens WJ, Van de Water A, Xhonneux R, Reneman RS, Van Nueten JM, Janssen PA. Nebivolol is devoid of intrinsic sympathomimetic activity. European Journal of Pharmacology 1989;159(1):89-95.
  16. Kamp O, Metra M, Bugatti S, Bettari L, Dei Cas A, Petrini N, et al. Nebivolol: haemodynamic effects and clinical significance of combined beta-blockade and nitric oxide release. Drugs 2010;70(1):41-56.
  17. Kern MJ, Ganz P, Horowitz JD, Gaspar J, Barry WH, Lorell BH, et al. Potentiation of coronary vasoconstriction by beta-adrenergic blockade in patients with coronary artery disease. Circulation 1983;67(6):1178-85.
  18. Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351-7.
  19. Laurens C, Abot A, Delarue A, Knauf C. Central Effects of Beta-Blockers May Be Due to Nitric Oxide and Hydrogen Peroxide Release Independently of Their Ability to Cross the Blood-Brain Barrier. Frontiers in Neuroscience 2019;13:33.
  20. Mayer B, Brunner F, Schmidt K. Inhibition of nitric oxide synthesis by methylene blue. Biochemical Pharmacology 1993;45(2):367-74.
  21. Nurlu Temel E, Savran M, Erzurumlu Y, Hasseyid N, Buyukbayram HI, Okuyucu G, et al. The beta1 Adrenergic Blocker Nebivolol Ameliorates Development of Endotoxic Acute Lung Injury. Journal of Clinical Medicine 2023;12(5).
  22. Okamoto LE, Gamboa A, Shibao CA, Arnold AC, Choi L, Black BK, et al. Nebivolol, but not metoprolol, lowers blood pressure in nitric oxide-sensitive human hypertension. Hypertension 2014;64(6):1241-7.
  23. Priviero FB, Teixeira CE, Claudino MA, De Nucci G, Zanesco A, Antunes E. Vascular effects of long-term propranolol administration after chronic nitric oxide blockade. European Journal of Pharmacology 2007;571(2-3):189-96.
  24. Ratz PH, Berg KM, Urban NH, Miner AS. Regulation of smooth muscle calcium sensitivity: KCl as a calcium-sensitizing stimulus. American Journal of Physiology-Cell Physiology 2005;288(4):C769-83.
  25. Rozec B, Quang TT, Noireaud J, Gauthier C. Mixed beta3-adrenoceptor agonist and alpha1-adrenoceptor antagonist properties of nebivolol in rat thoracic aorta. British Journal of Pharmacology 2006;147(7):699-706.
  26. Saarti M, Almukhtar H, Smith PA, Roberts RE. Effect of mitochondrial complex III inhibitors on the regulation of vascular tone in porcine coronary artery. European Journal of Pharmacology 2021;896:173917.
  27. Severino P, D'Amato A, Pucci M, Infusino F, Birtolo LI, Mariani MV, et al. Ischemic Heart Disease and Heart Failure: Role of Coronary Ion Channels. International Journal of Molecular Sciences 2020;21(9).
  28. Shimizu S, Yamamoto T, Momose K. Inhibition by methylene blue of the L-arginine metabolism to L-citrulline coupled with nitric oxide synthesis in cultured endothelial cells. Research Communications in Chemical Pathology and Pharmacology 1993;82(1):35-48.
  29. Shimokawa H, Yasutake H, Fujii K, Owada MK, Nakaike R, Fukumoto Y, et al. The importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. Journal of Cardiovascular Pharmacology 1996;28(5):703-11.
  30. Sievert H, Frey G, Schrader R, Schmidt T, van der Does R, Kaltenbach M, et al. Influence of carvedilol and propranolol on coronary blood flow. European Journal of Clinical Pharmacology 1990;38 Suppl 2:S122-4.
  31. Toblli JE, DiGennaro F, Giani JF, Dominici FP. Nebivolol: impact on cardiac and endothelial function and clinical utility. Vascular Health and Risk Management 2012;8:151-60.
  32. Vaz-de-Melo RO, Giollo-Junior LT, Martinelli DD, Moreno-Junior H, Mota-Gomes MA, Cipullo JP, et al. Nebivolol reduces central blood pressure in stage I hypertensive patients: experimental single cohort study. So Paulo Medical Journal 2014;132(5):290-6.
  33. Wang Y, Zhang M, Liu Y, Li J, Song E, Niu L, et al. Neither K+ channels nor PI3K/Akt mediates the vasodilative effect of nebivolol on different types of rat arteries. Journal of Cardiovascular Pharmacology and Therapeutics 2009;14(4):332-8.
  34. Watkins RW, Davidson IW. Effect of acetylcholine on phasic and tonic components of vascular smooth muscle contraction. Archives Internationales de Pharmacodynamie et de Thrapie 1980;243(2):217-27.
  35. Zhang Z, Ding L, Jin Z, Gao G, Li H, Zhang L, et al. Nebivolol protects against myocardial infarction injury via stimulation of beta 3-adrenergic receptors and nitric oxide signaling. PLoS One 2014;9(5):e98179.

Authors

Hani Almukhtar

Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq

ORCID
Enas A. Alhafith

Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq

KNV Chenchu Lakshmi
ORCID

Identifiers

Download this PDF file
PDF

Statistics

How to Cite

Almukhtar, H., A. Alhafith, E., & Chenchu Lakshmi, K. (2024). Nebivolol, but not Propranolol, Induced Relaxation of the Isolated Bovine Coronary Segments: Role of NO and K+ Channels. Iraqi Journal of Pharmacy, 21(4), 155–161. Retrieved from https://rjps.uomosul.edu.iq/index.php/iphr/article/view/21612