Abstract
Aim:
To investigate the synergism of low-doses of amlodipine and irbesartan on reduction of blood pressure variability (BPV), amelioration of baroreflex sensitivity (BRS) and organ protection in spontaneously hypertensive rats (SHR).
Methods:
The rats were administered amlodipine (1 mg·kg−1·d−1) alone, irbesartan (10 mg·kg−1·d−1) alone, or the combination of the two drugs for 4 months. The drugs were mixed into the rat chow. Blood pressure (BP) was continuously monitored in conscious animals. After the determination of BRS, the rats were killed for morphological evaluation of organ damages.
Results:
The combination of low-dose irbesartan and amlodipine had statistically significant synergism on reduction of BP and BPV, amelioration of BRS and organ protection in SHR. Multiple regression analysis showed that the decrease in left ventricular hypertrophy was associated with the decrease in systolic BPV (r=0.665, P<0.01); the decrease in aortic hypertrophy was associated with the increase in BRS (r=0.656, P<0.01); and the amelioration in renal lesion was associated with the increase in BRS (r=0.763, P<0.01) and the decrease in systolic BPV (r=0.706, P<0.01).
Conclusion:
Long-term treatment with a combination of low-doses of amlodipine and irbesartan showed significant synergism on reduction of BP and BPV, restoration of BRS and organ protection in SHR. Besides BP reduction, the enhancement of BRS and reduction of BPV might contribute to the organ protection.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Kikuya M, Hozawa A, Ohokubo T, Tsuji I, Michimata M, Matsubara M, et al. Prognostic significance of blood pressure and heart rate variabilities: the Ohasama study. Hypertension 2000; 36: 901–6.
Parati G, Mancia G . Blood pressure variability as a risk factor. Blood Press Monit 2001; 6: 341–7.
Su DF, Miao CY . Reduction of blood pressure variability: a new strategy for the treatment of hypertension. Trends Pharmacol Sci 2005; 26: 388–90.
Su DF, Miao CY . Functional studies of arterial baroreflex function in conscious rats. Acta Pharmacol Sin 2002; 23: 673–9.
Sleight P . The importance of autonomic nervous system in health and disease. Aust N Z J Med 1997; 27: 467–73.
Liu JG, Xu LP, Chu ZX, Miao CY, Su DF . Contribution of blood pressure variability to the effect of nitrendipine on end-organ damage in spontaneously hypertensive rats. J Hypertens 2003; 21: 1961–7.
Gupta AK, Arshad S, Poulter NR . Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension 2010; 55: 399–407.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42: 1206–52.
Xie HH, Miao CY, Liu JG, Su DF . Effects of long-term treatment with candesartan on organ damages in sinoaortic denervated rats. J Cardiovasc Pharmacol 2003; 41: 325–31.
Norman RA Jr, Coleman TG, Dent AC . Continuous monitoring of arterial pressure indicates sinoaortic denervated rats are not hypertensive. Hypertension 1981; 3: 119–25.
Smyth HS, Sleight P, Pickering GW . Reflex regulation of arterial pressure during sleep in man: a quantitative method of assessing baroreflex sensitivity. Circ Res 1969; 24: 109–21.
Su DF, Chen L, Kong XB, Cheng Y . Determination of arterial baroreflex-blood pressure control in conscious rats. Acta Pharmacol Sin 2002; 23: 103–9.
Xie HH, Miao CY, Jiang YY, Su DF . Synergism of atenolol and nitrendipine on hemodynamic amelioration and organ protection in hypertensive rats. J Hypertens 2005; 23: 193–201.
Hayakawa H, Raij L . The link among nitric oxide synthase activity, endothelial function, and aortic and ventricular hypertrophy in hypertension. Hypertension 1997; 29: 235–41.
Miao CY, Tao X, Gong K, Zhang SH, Chu ZX, Su DF . Aterial remodeling in chronic sinoaortic-denervated rats. J Cardiovasc Pharmacol 2001; 37: 6–15.
Kimula K, Tojo A, Matsuoka H, Sugimoto T . Renel arteriolar diameters in spontaneously hypertensive rats: Vascular cast study. Hypertension 1991; 18: 101–10.
Jin ZJ . About the evaluation of drug combination. Acta Pharmacol Sin 2004; 25: 146–7.
Su DF, Xu LP, Miao CY, Xie HH, Shen FM, Jiang YY . Two useful methods for evaluating antihypertensive drugs in conscious freely moving rats. Acta Pharmacol Sin 2004; 25: 148–51.
Waeber B, Ruilope LM . Amlodipine and valsartan as components of a rational and effective fixed-dose combination. Vasc Health Risk Manag 2009; 5: 165–74.
Luft FC, Aronoff GR, Sloan RS, Fineberg NS, Weinberger MH . Calcium channel blockade with nitrendipine. Effects on sodium homeostasis, the renin-angiotensin system, and the sympathetic nervous system in humans. Hypertension 1985; 7: 438–42.
Gennari C, Nami R, Pavese G, Gragnani S, Bianchini C, Buracchi P . Calcium-channel blockade (nitrendipine) in combination with ACE inhibition (captopril) in the treatment of mild to moderate hypertension. Cardiovasc Drugs Ther 1989; 3: 319–25.
Parati G, Pomidossi G, Albini F, Malaspina D, Mancia G . Relationship of 24-hour blood pressure mean and variability to severity of target organ damage in hypertension. J Hypertens 1987; 5: 93–8.
Mancia G, Omboni S, Parati G . The importance of blood pressure variability in hypertension. Blood Press Monit 2000; 5: S9–S15.
Sander D, Kukla C, Klingelhofer J, Winbeck K, Conrad B . Relationship between circadian blood pressure patterns and progression of early carotid atherosclerosis: A 3-year follow-up study. Circulation 2000; 102: 1536–41.
Miao CY, Su DF . The importance of blood pressure variability in rat aortic and left ventricular hypertrophy by sinoaortic denervation. J Hypertens 2002; 20: 1865–72.
Parati G, Lantelme P . Blood pressure variability, target organ damage and cardiovascular events. J Hypertens 2002; 20: 1725–9.
Bristow JD, Honour AJ, Pickering GW, Sleight P, Smyth HS . Diminished baroreflex sensitivity in high blood pressure. Circulation 1969; 39: 48–54.
La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ . Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) Investigators. Lancet 1998; 351: 478–84.
Mortara A, La Rovere MT, Pinna GD, Prpa A, Maestri R, Febo O, et al. Arterial baroreflex modulation of heart rate in chronic heart failure: clinical and hemodynamic correlates and prognostic implications. Circulation 1997; 96: 3450–8.
Cai GJ, Miao CY, Xie HH, Lu LH, Su DF . Arterial baroreflex dysfunction promotes atherosclerosis in rats. Atherosclerosis 2005; 183: 41–7.
Shan ZZ, Dai SM, Su DF . Relationship between baroreceptor reflex function and end-organ damage in spontaneously hypertensive rats. Am J Physiol 1999; 277: H1200–6.
Parmer RJ, Cervenka JH, Stone RA . Baroreflex sensitivity and heredity in essential hypertension. Circulation 1992; 85: 497–503.
Parmer RJ, Cervenka JH, Stone RA, O'Connor DT . Autonomic function in hypertension: Are there racial difference? Circulation 1990; 81: 1305–11.
Brown AM . Receptors under pressure. An update on baroreceptors. Circ Res 1980; 46: 1–10.
Matsumura K, Averill DB, Ferrario CM . Angiotensin II acts at AT1 receptors in the nucleus of the solitary tract to attenuate the baroreceptor reflex. Am J Physiol 1998; 275: R1611–9.
Nishikawa K . Angiotensin AT1 receptor antagonism and protection against cardiovascular end-organ damage. J Human Hypertens 1998; 12: 301–9.
Murayama S, Hirano T, Sakaue T, Okada K, Ikejiri R, Adachi M . Low-dose candesartan cilexetil prevents early kidney damage in type 2 diabetic patients with mildly elevated blood pressure. Hypertens Res 2003; 26: 453–8.
Acknowledgements
This work was supported by the National Science and Technology Major Project (2009ZX09303-002) and the National Natural Science Foundation of China (No 30971158).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Shang, W., Han, P., Yang, Cb. et al. Synergism of irbesartan and amlodipine on hemodynamic amelioration and organ protection in spontaneously hypertensive rats. Acta Pharmacol Sin 32, 1109–1115 (2011). https://doi.org/10.1038/aps.2011.88
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2011.88
