Abstract
ObjectivesThis study investigates the effects on aortic stiffness and vasodilation by arotinolol and the underlying mechanisms in spontaneously hypertensive rats (SHR).MethodsThe vasodilations of rat aortas, renal and mesenteric arteries were evaluated by isometric force recording. Nitric oxide (NO) was measured in human aortic endothelial cells (HAECs) by fluorescent probes. Sixteen-week old SHRs were treated with metoprolol (200 mg·kg-1·d-1), arotinolol (30 mg·kg-1·d-1) for 8 weeks. Central arterial pressure (CAP) and pulse wave velocity (PWV) were evaluated via catheter pressure transducers. Collagen was assessed by immunohistochemistry and biochemistry assay, while endothelial nitric oxide synthase (eNOS) and eNOS phosphorylation (p-eNOS) of HAECs or aortas were analyzed by western blotting.ResultsArotinolol relaxed vascular rings and the relaxations were attenuated by Nω-nitro-L-arginine methyl ester (L-NAME, NO synthase inhibitor) and the absence of endothelium. Furthermore, arotinolol-induced relaxations were attenuated by 4-aminopyridine (4-AP, Kv channels blocker). Arotinolol produced more nitric oxide compared to metoprolol and increased the expression of p-eNOS in HAECs. These results indicated that arotinolol-induced vasodilation involves endothelium-derived NO and Kv channels. The treatement with arotinolol in 8 weeks, but not metoprolol, markedly decreased CAP and PWV. Biochemistry assay and immunohistochemistry showed that aortic collagen depositions in the arotinolol groups were reduced compared with SHRs with metoprolol. Moreover, eNOS phosphorylation was significantly increased in aortinolol-treated SHR compared with SHRs with metoprolol.ConclusionsArotinolol improves arterial stiffness in SHR, which involved in increasing NO and decreasing collagen contents in large arteries.
Highlights
Beta-blockers (b-blockers) are widely prescribed for the treatment of a variety of cardiovascular pathologies including hypertension, heart failure, primary treatment of myocardial infarction, secondary prevention of ischemic cardiac events as well as other non-cardiovascular diseases. [1] The first generation bblockers, for example propranolol, are nonselective and block both b1- and b2-adrenoceptors
Compared with the aortas, the vasodilator response curves in the mesenteric arteries dropped more sharply, indicating that the vasodilatory effects of arotinolol were more obvious in mesenteric arteries than in aortas
Pretreatment of endothelium-intact rings with endothelial nitric oxide synthase (eNOS) inhibitor L-NAME (100 mmol/L) effectively reduced arotinolol-induced relaxations (Fig. 2B). These results indicate that endothelium-derived nitric oxide (NO) was involved in arotinolol-induced vasodilation
Summary
Beta-blockers (b-blockers) are widely prescribed for the treatment of a variety of cardiovascular pathologies including hypertension, heart failure, primary treatment of myocardial infarction, secondary prevention of ischemic cardiac events as well as other non-cardiovascular diseases. [1] The first generation bblockers, for example propranolol, are nonselective and block both b1- and b2-adrenoceptors. [1] The first generation bblockers, for example propranolol, are nonselective and block both b1- and b2-adrenoceptors. The second generation b-blockers, including metoprolol, are cardioselective and selectively block b1adrenoreceptors. There are discrepancies concerning the effect of metoprolol, a secondary generation b-blocker, on blood pressure and arterial stiffness. [2] In contrast, there are studies showing that metoprolol does not have effect on central systolic and diastolic blood pressures, central pulse pressure, as well as left ventricular wall thickness.[3] The third generation vasodilating bblockers, such as nebivolol, are b1-adrenoreceptors specific and have additional ancillary properties including direct vasodilatory effect, and studies show that the vasodilatory effect of nebivolol involves endothelium-derived nitric oxide (NO). Studies show that the third generation of b-blockers have beneficial effect on blood vessels in experimental and human hypertension, [5,6] which are closely related to their vasodilatory effects
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