aprikalim and Hypoxia

Topics: Adenosine Triphosphate; Coronary Vessels; Diabetic Angiopathies; Glyburide; Humans; Hypoxia; Microcirculation; Muscle, Smooth, Vascular; Picolines; Potassium Channels; Pyrans; Vasodilation; Vasodilator Agents

ATP-sensitive K+ channels (K(ATP)) contribute to vasomotor regulation in some species. It is not fully understood the extent to which K(ATP) participate in regulating vasomotor tone under physiological and pathophysiological conditions in the human heart. Arterioles dissected from right atrial appendage were studied with video microscopy, membrane potential recordings, reverse transcription-polymerase chain reaction, and immunohistochemistry. Hypoxia produced endothelium-independent vasodilation and membrane hyperpolarization of vascular smooth muscle cells, both of which were attenuated by glibenclamide. Aprikalim, a selective K(ATP) opener, also induced a potent endothelium-independent and glibenclamide-sensitive vasodilation with membrane hyperpolarization. Reverse transcription-polymerase chain reaction detected mRNA expression for K(ATP) subunits, and immunohistochemistry confirmed the localization of the inwardly rectifying Kir6.1 protein in the vasculature. In patients with type 1 or type 2 diabetes mellitus (DM), vasodilation was reduced to both aprikalim (maximum dilation, DM(+) 90+/-2% versus DM(-) 96+/-1%, P<0.05) and hypoxia (maximum dilation, DM(+) 56+/-8% versus DM(-) 85+/-5%, P<0.01) but was not altered to sodium nitroprusside or bradykinin. Baseline myogenic tone and resting membrane potential were not affected by DM. We conclude that DM impairs human coronary arteriolar dilation to K(ATP) opening, leading to reduced dilation to hypoxia. This reduction in K(ATP) function could contribute to the greater cardiovascular mortality and morbidity in DM.

Topics: Adenosine Triphosphate; Age Factors; Arterioles; Bradykinin; Coronary Vessels; Diabetes Mellitus; Female; Glyburide; Humans; Hypoxia; In Vitro Techniques; Male; Membrane Potentials; Microcirculation; Middle Aged; Muscle, Smooth, Vascular; Nitric Oxide Donors; Picolines; Potassium Channels; Potassium Channels, Inwardly Rectifying; Pyrans; Risk Factors; RNA, Messenger; Sex Factors; Vasodilation; Vasodilator Agents

We tested the hypothesis that relaxation of the carotid artery during hypoxia is mediated by activation of glibenclamide-sensitive potassium channels and that this response is impaired in hyperlipidemic rabbits. In New Zealand White rabbits (plasma cholesterol, 69 +/- 12 mg/dL, mean +/- SEM) and Watanabe heritable hyperlipidemic (WHHL) rabbits (plasma cholesterol, 677 +/- 99 mg/dL), tension of the carotid artery was measured in an organ bath under control conditions and during two levels of hypoxia. In normal rabbits, mild hypoxia produced 21 +/- 2% relaxation in arteries precontracted with phenylephrine. Removal of endothelium or the nitric oxide synthase inhibitor NG-nitro-L-arginine (10(-4) mol/L) almost abolished relaxation in response to mild hypoxia in normal rabbits. Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive potassium channels, attenuated relaxation during mild hypoxia by almost 60%. In WHHL rabbits mild hypoxia relaxed the carotid artery by only 9 +/- 4% (P < .05 versus normal rabbits). Severe hypoxia produced greater relaxation of the carotid artery in normal than in WHHL rabbits (85 +/- 5% versus 52 +/- 8%, respectively, P < .05). Glibenclamide but not endothelial denudation or NG-nitro-L-arginine attenuated relaxation during severe hypoxia in normal and WHHL rabbits. Relaxation of the carotid artery to sodium nitroprusside was similar in normal and WHHL rabbits. These findings suggest that relaxation of the carotid artery in response to mild and severe hypoxia is impaired in WHHL rabbits and is mediated, in large part, by activation of glibenclamide-sensitive potassium channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylcholine; Animals; Carotid Arteries; Hyperlipidemias; Hypoxia; Nitroprusside; Picolines; Pyrans; Rabbits; Vasodilation; Vasodilator Agents

This study investigated the effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction induced in isolated rat lung perfused at constant flow. In order to evaluate the mechanism of the hypoxic vasoconstriction we also studied the effects of an inhibitor of the endothelium-derived relaxing factor (EDRF), NG-nitro-L-arginine methyl ester (100 microM), an inhibitor of the guanylate cyclase, methylene blue (30 microM), two K+ channel blockers, glibenclamide (1 microM) and tetraethylammonium (20 mM). In normoxia, NG-nitro-L-arginine methyl ester, methylene blue, glibenclamide or tetraethylammonium did not enhance significantly the baseline perfusion pressure, suggesting that neither EDRF nor K+ channels are involved in the modulation of the low basal pulmonary vascular tone. In hypoxia, aprikalim and pinacidil (0.03-3 microM) induced a concentration-dependent decrease of pulmonary pressure, exhibiting their spasmolytic effects in acute hypoxia. The hypoxic pressure response was significantly increased by NG-nitro-L-arginine methyl ester, methylene blue and tetraethylammonium, but not by glibenclamide suggesting that EDRF and K+ channels other than ATP-sensitive K+ channels are involved in the modulation of the hypoxic pressure response. The spasmolytic effects of aprikalim and pinacidil (1 microM) were not modified by NG-nitro-L-arginine methyl ester, but were partially reduced by tetraethylammonium and completely abolished by glibenclamide, suggesting that these effects are mainly but not exclusively mediated through ATP-sensitive K+ channel opening.

Topics: Animals; Antihypertensive Agents; Arginine; Guanidines; Hypoxia; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide; Picolines; Pinacidil; Potassium Channels; Pyrans; Rats; Rats, Sprague-Dawley; Vasoconstriction; Vasodilator Agents

The aim was to compare the effects of a potassium channel opener, aprikalim, and of hypoxic and ischaemic preconditioning on extracellular K+ concentration change, metabolism, and ventricular function in isolated globally ischaemic rat hearts.. Isovolumetric rat hearts (37 degrees C) were treated with 1 microM (apri 1) or 30 microM (apri 30) aprikalim, or preconditioned with either 10 min of hypoxia (N2PC) or 5 min of ischaemia followed by 5 min of perfusion (IPC5) or 10 min of ischaemia followed by 3 min of perfusion (IPC10). Control hearts received neither treatment nor preconditioning. All hearts received 30 min of sustained ischaemia followed by 25 min of reperfusion. Extracellular K+ concentration was measured with a potassium sensitive electrode inserted into the extracellular space of the left ventricular wall.. Recovery of left ventricular developed pressure after 25 min of reperfusion was only 19.20(SEM 5.09)% of the preischaemic level in the control group. No recovery was obtained for the apri 1 group. In contrast, a very good recovery was obtained for the apri 30 group [96.69(10.92)%], the N2PC group [104.92(17.40)%], and the IPC10 group [84.96(9.86)%]. The IPC5 group, however, did not have improved recovery of left ventricular pressure [14.15(5.61)%]; this is likely to be related to differences in the stimulation of anaerobic glycolysis. The protection was also markedly attenuated by pretreatment with 50 microM glibenclamide in the apri 30, N2PC, and IPC10 groups [22.76(9.00), 66.06(6.09), and 46.18(7.06)%, respectively]. Hearts treated with aprikalim before inducing ischaemia showed a concentration dependent increase in [K+]e. Hypoxic (N2PC) and ischaemic preconditioning (IPC5 and IPC10) were also associated with an increase in [K+]e over the 5-10 min period preceding the 30 min of sustained ischaemia. During sustained ischaemia all groups showed a nearly triphasic pattern of extracellular K+ changes with an early rising phase, with the exception of the N2PC group for which the early [K+]e rise was barely detectable.. An increase in [K+]e before sustained ischaemia is one of the mechanisms involved in the conditions affording protection. Although important, this is not sufficient, and further protection may be accomplished by decreased stimulation of anaerobic glycolysis during the sustained ischaemia.

Topics: Animals; Antihypertensive Agents; Basal Metabolism; Extracellular Space; Heart; Hypoxia; Lactates; Lactic Acid; Male; Myocardial Ischemia; Myocardial Reperfusion; Perfusion; Picolines; Potassium; Pyrans; Rats; Rats, Wistar

We tested the hypothesis that dilatation of cerebral arterioles during hypoxia is mediated by activation of ATP-sensitive K+ channels. The diameter of pial arterioles was measured through a closed cranial window in anesthetized rabbits. Topical application of aprikalim (10(-6) mol/L), a direct activator of ATP-sensitive K+ channels, dilated pial arterioles by 18 +/- 3% (mean +/- SEM). Glibenclamide (10(-6) mol/L), an inhibitor of ATP-sensitive K+ channels, virtually abolished aprikalim-induced vasodilatation. When arterial PO2 was reduced from 129 +/- 3 to 25 +/- 1 mm Hg, the diameter of cerebral arterioles increased by 66 +/- 9% (P < .05). Glibenclamide inhibited dilatation of pial arterioles during hypoxia by 46 +/- 5% (P < .05). In contrast, vasodilatation in response to sodium nitroprusside was not altered by glibenclamide. Topical application of adenosine (10(-4) mol/L) increased arteriolar diameter by 21 +/- 4%. Glibenclamide did not affect adenosine-induced vasodilatation. These findings suggest that dilatation of cerebral arterioles in response to hypoxia is mediated, in part, by activation of ATP-sensitive K+ channels.

Topics: Adenosine; Adenosine Triphosphate; Animals; Arterioles; Brain; Glyburide; Hypoxia; Male; Picolines; Potassium Channels; Pyrans; Rabbits; Vasodilation