State Of ATP-sensitive Potassium Channels And Blood Pressure Variability

INTRODUCTIONBlood pressure (BP) is not constant and there exists a spontaneous variation in BP. This variation is defined as blood pressure variability (BPV). It has been widely reported that BPV is increased in hypertensive human and animals. Furthermore, it was shown that BPV was positively related to the severity of organ damage in hypertensive patients and in SHR. Removal of the carotid sinus and aortic arch baroreceptors results in the inability to buffer moment-to-moment changes in pressure bringing about arterial pressure lability. Lability is the most consistent feature after sinoaortic denervation (SAD) and has been shown to exist in all species in which SAD has been studied. Despite the marked variability of arterial pressure, 24-h mean pressure level is unchanged or only slightly increased in animals without baroreceptor reflexes. It was demonstrated that the increased BPV without the elevation of 24-h BP level after SAD induced organ damage. Jacob et al demonstrated that adenosine reduced BPV in SAD rats. Our previous study found that this effect of adenosine was mediated by adenosine A2A-receptor. ATP-sensitive potassium (KATP) channels play an important role in the cardiovascular system. In the myocardium they are involved in the response to ischemia and ischemic preconditioning. In vascular smooth muscle they regulate vessel tone through responses to a variety of pharmacological vasodilators such as the KATP channels opener pinacidil, and endogenous vasodilators such as adenosine. However there is little information about the effect of KATP channels on the produce of high BPV in SHR and in SAD rat. The objective of the present study was to evaluate the state of KATP channels on BPV in SHR and in SAD rat, and to demonstrate our hypothesis "Sensitized-KATP channels is responsible for the lability of blood pressure in SAD rat". METHODS Male SHR aged from 22-26 weeks, SAD and sham-operated rats (applied four weeks after operation performed in male Sprague-Dawley rats at the age of 10 weeks) were used. With a computerized analysis system of BP, the effects of different adenosine receptor agonists, and KATP channels openers and blockers on BPV in SHR and SAD rats were studied in conscious unrestrained state. Hemodynamic indexes were recorded. SBP, DBP and HP (refer to the time interval between two successive occurrences of SBP) are the average values of these parameters obtained beat by beat during the test period. BPV was defined as the standard deviation of the SBP or DBP and was calculated from each beat during the test periods for each animal. The immunostaining of Kir6.1, Kir6.2 and SUR2B in various arteries was detected by incubation with EnVision complex (horseradish peroxidase labeled) and developed with diaminobenzidine. Following the time-course, for BP and HP paired t-test were used within groups, and analysis of variance followed by Student-Newman-Keuls (SNK) was used between groups.RESULTS1. Activation of KATP channels decreases BPV in SHR, and KATP channels are involved in adenosine-induced reduction of BPV in SHRAdenosine, 5'-N-cyclopropyl-carboxamidoadenosine (CPCA, a selective adenosine A2-receptor agonist) and pinacidil (a nonselective KATP opener) decreased BPV when one of them used alone, whereas N6-cyclopentyladenosine (CPA, a selective adenosine A1-receptor agonist) had no significant effects on BPV. When pretreated with glibenclamide (a nonselective KATP blocker), the inhibitory effects of adenosine and CPCA on BPV were significantly prevented. By itself, however, glibenclamide had no influence on BPV. These results suggest that the effect of adenosine on BPV in spontaneously hypertensive rats is due to activation of KATP mediated by adenosine A2-receptor. 2. Either opening or blocking KATP channels in vascular smooth muscle results in BPV decrease in SAD ratNonselective KATP channels openers, both pinacidil (being capable of activation of Kir6.1/SUR2B and Kir6.2/SUR2B in vascular smooth muscle; and Kir6.2/SUR2A in sarcolemma of cardiac myocytes;...