| Nitroglycerin (NTG) and other nitrovasodilators have been widely used to treat ischemic heart disease, but its long-term hemodynamic and anti-ischemic efficacy of NTG is rapidly attenuated by the development of tolerance. The mechanisms involved hi the tolerance of NTG are not completely understood yet and probably are multifactorial and multilink. In the past decade, studies have demonstrated that nitroglycerin therapy leads to complex interactions among the vasculature, neurohormones and free oxygen radicals.. There is evidence that nitroglycerin tolerance is associated with an increased bioavailability of superoxide anion (Qj") and the nitric oxide synthase (NOS) uncoupling. The increased 02" takes a bad turn of vascular oxidative stress and reduces the bioavailability of nitroglycerin-derived NO. The NOS uncoupling makes the balance of NO/O2~ to the right, resulting in the net generation of 02". There is also evidence that long-term nitroglycerin therapy leads to the increased production of endthelin-l(ET-l) hi vasculature, decreasing the effects of nitroglycerin because of these changes in the balance of vasomotor tone. Those preventive measures of tolerance can partially restore nitroglycerin response by affecting a piece of mechanisms in the past, however, clinical efficacy is worse. Studies manifested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reduc-tase inhibitors (HCRIs) can not only lower the lipid load of the vessel wall, but also ameliorate vascular endothelial dysfunction. Several explanatory theories that HCRIs leads to increased NO have prevailed, including decreased ability to product 02" and improved oxidative stress in vessel wall, improved eNOS expression by inhibiting the activity of geranylgeranylpyrophosphate, and increased activity of NOS. HCRIs canalso inhibite the expression of pre-pro ET-lmRNA and reduce the levels of immunoreactive ET-1. Abstractly, these agents have a better function for nitroglycerin tolerance. This study was designed to assess the effects of atorvastatin on the development of tolerance during continuous transdermal nitroglycerin therapy and to investigate the mechanism of its action. Method64 health male Sprague-Dawley rats, weighing from 300 to 350 grams, were randomly divided into four groups: group I , group II, groupIII and group IV, 16 rats in every group. In every group, 8 rats were used for vascular rings experiment and measured the contents of ET-1 in vasculature, another 8 were only used for measuring the activity of SOD, the contents of MDA, the contents of NO, the activity of NOS in vessel organization and blood plasma ET-1 contains. The rat models of nitroglycerin tolerance were established by nitroglycerin patches. The animals were handled as follows: (1) group I and group II were administered the same dosage of physiological saline 2~3ml, not or nitroglycerin patches were administered in the last 3 days;(2) groupIII: atorvastatin (5mg-kg-1-d-1) was performed for 4 consecutive weeks, not nitroglycerin patches were administered in the last 3 days; (3) group IV: the administration of atorvastatin was the same as that of groupIII, nitroglycerin patches were administered in the last 3 days. The chest aorta were took out after the animals were, sentenced to death, and parts of the aortas were cut into vascular rings, suspended in a constant temperature organ chamber. The specimens were connected to a force transducer, the organ chamber was aerated with a mixture of 95% O2+5% CO2, equilibrium 45-60 minutes, acceded to noradrenalin (10-6mol-L"1). When the contractions had reached a stable plateau, relaxation responses to nitroglycerin(10"9~ 10-4mol-L-1) were obtained, drawing the density- effect curve, testing the density value of 50% of its own maximal response. The data were processed with SPSS10.0. Results1. The maximal relaxation responses in group II were significantly weakener than that in group I (P<0.01). The maximal relaxation responses in groupIV were significantly stronger than that in group II (P<0.01). There was significant diffe... |
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