Effects of chronic treatment with a low dose of nicorandil on the function of the rat aorta during ageing

Autor: Nicole Lavanchy, Barry Starcher, Jean Verdetti, Robert P. Mecham, Paulette Mezin, Gilles Faury, Stéphanie Raveaud
Rok vydání: 2009
Předmět:
Zdroj: Clinical and Experimental Pharmacology and Physiology. 36:988-994
ISSN: 1440-1681
0305-1870
DOI: 10.1111/j.1440-1681.2009.05174.x
Popis: It is known that ATP-sensitive potassium (KATP) channels regulate the membrane potential of smooth muscle cells and vascular tone. Because their activity is altered during ageing, many pharmacological treatments aimed at improving KATP channel and cardiovascular functions have been evaluated. Nicorandil, a KATP channel opener, nitric oxide (NO) donor and anti-oxidant, induces vasodilation, decreases blood pressure and exhibits cardioprotection in ageing, as well as after ischaemia–reperfusion. In the present study, using tension myography and biochemical and histological techniques, we investigated the effects of chronic (2 months) low-dose nicorandil (0.1 mg/kg per day) treatment on the function of rat aorta during ageing (in 4-, 12- and 24-month old rats). The results showed that chronic nicorandil treatment significantly improves mechanical relaxation and noradrenaline-induced vasoconstriction in aged rats. At all ages, the nicorandil-induced vasodilation was primarily mediated by its NO donor group. Nicorandil treatment resulted in an additional 0.5–1 elastic lamella in the aorta and decreased total protein, collagen and elastin content in the aortic wall at all ages. However, in 4-month-old rats, nicorandil significantly increased the elastin : total protein ratio by 19%. In contrast with results of previous studies that used high doses of nicorandil (i.e. 60 mg/kg per day), low-dose nicorandil treatment in the present study did not lead to a progressive desensitization to nicorandil and may be beneficial in improving arterial function in ageing or cardiovascular diseases. Keywords: ageing, arterial mechanics, arteries, ATP-dependent potassium channels, cardiovascular system, collagen, elastic fibres, elastin, nicorandil, vasoactivity INTRODUCTION Ageing large arteries remodel, classically exhibiting accelerated endothelial cell turnover, smooth muscle cell hypertrophy, increased diameter and wall thickness, as well as elastic fibre fragmentation and collagen accumulation. These events progressively lead to wall stiffening and increases in blood pressure.1 Large arteries of aged animals are also more contracted, although less responsive to vasoactive agents/pathways,2 such as noradrenaline/α-adrenoceptors,3–6 acetylcholine (ACh)/nitric oxide (NO)7,8 or membrane K+ channel opening. The latter mechanism blocks voltage-dependent membrane calcium channels and induces vasodilation9 and partly mediates ACh-induced vasodilation.10,11 The ATP-dependent K+ (KATP) channels have the additional role of cell metabolism sensors.12 The function of KATP channels from different cell types is progressively altered because of an age-dependent oxidation of thiol groups from the intracellular portion of the channel.13 This oxidation inhibits both the spontaneous and agonist-triggered activities of the channels,13 leading to age-dependent decreases in arterial reactivity to different vasoregulatory molecules, including catecholamines and ACh.14,15 Because K+ channel dysfunction contributes substantially to the age-dependent arterial dysfunctions described above,14,15 many studies have investigated the relevance of treatments whose purpose was to restore the responsiveness of K+ channels, in particular KATP channels, in ageing or cardiovascular diseases.16–19 Nicorandil (N-(2-hydroxyethyl)-nicotinamide nitrate) is a drug of choice in these treatments because its combined molecular structure and function targets several deleterious mechanisms involved in arterial ageing, namely KATP channel oxidation and dysfunction and NO pathway impairment. Nicorandil is a KATP channel opener molecule combining an organic nitrate and a nicotinamide group, which confer the additional properties of an NO donor and anti-oxidant, respectively.18,20 Acute low doses of nicorandil (range 10 μg/kg to 1 mg/kg) have been shown to lower blood pressure, reduce oxidized KATP channels and restore their activity,21 induce dilation of different types of arteries through NO delivery and KATP channel opening22,23 and improve the global condition of patients with angina pectoris.24 Acute higher doses of nicorandil (25–100 μg/kg) in a cardiac infarction model in rats have been shown to result in decreased formation of microvascular obstruction and a reduction in infarct size.25 In humans with cardiac infarction, acute nicorandil has been shown recently to suppress the infarction-induced increase in plasma levels of matrix metalloproteinase activity and to prevent left ventricular remodelling.26 However, chronic treatment with high doses of nicorandil (60 mg/kg per day) produces opposite effects in the long term (i.e. 2–4 weeks), namely desensitization of KATP channels to agonists and inactivation of the cGMP pathway/vascular smooth muscle cell relaxation.17 Previously, we showed that chronic treatment of rats with a low dose of nicorandil (0.1 mg/kg per day for 2 months) improved cardiac function in ageing, under both physiological and experimentally induced pathological conditions. Heart function (developed pressure, action potential duration, survival rate) was protected during ageing and ischaemia–reperfusion experiments because of a higher activity of KATP channels.27 The aim of the present study was to investigate the effects of chronic treatment with a low dose of nicorandil on arterial structure and function during ageing in rats. The results show that low-dose nicorandil treatment induces aortic remodelling and improves function in aged animals.
Databáze: OpenAIRE
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