aprikalim and Hypertension

The vasorelaxant actions of adenosine 5'-triphosphate (ATP)-dependent K+ channel openers and sodium nitroprusside in isolated thoracic aorta and pulmonary artery of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats (14-18 weeks old) were investigated. Cumulative addition of sodium nitroprusside and different ATP-dependent K+ channel openers (pinacidil, cromakalim, nicorandil, 2-(2"(1",3"-dioxolone)-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro -2H-1-benzopyren (KR-30450) and aprikalim) to these preparations caused a concentration-dependent relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. The relative order of relaxation potency, estimated by comparing the IC50, was sodium nitroprusside > KR-30450 > aprikalim > or = cromakalim > pinacidil > nicorandil in pulmonary artery and aorta from both strains. At high concentrations (> or =1 microM), cromakalim, aprikalim and KR-30450 produced a greater percentage relaxation in SHR aorta than in WKY aorta. However, there was no apparent difference between SHR and WKY in the relaxation response to all drugs tested on the pulmonary artery. The effects of cromakalim, aprikalim, pinacidil and KR-30450 observed in aorta and pulmonary artery were significantly attenuated by 3 microM glibenclamide. 6-Anilino-5,8-quinolinequinone (LY 83583, 1 microM), a soluble guanylate cyclase inhibitor, abolished the vasorelaxant effects of nicorandil and sodium nitroprusside. In conclusion, sodium nitroprusside and ATP-dependent K+ channel openers cause relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. However, all the drugs tested failed to cause selective relaxation of the pulmonary artery relative to the thoracic aorta.

Topics: Adenosine Triphosphate; Aminoquinolines; Animals; Aorta, Thoracic; Apamin; Benzopyrans; Charybdotoxin; Cromakalim; Dose-Response Relationship, Drug; Glyburide; Hypertension; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nicorandil; Nitroprusside; Norepinephrine; Picolines; Pinacidil; Potassium; Potassium Channels; Pulmonary Artery; Pyrans; Pyrrolidinones; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilator Agents

Cerebral vasodilatation in response to aprikalim, an opener of ATP-sensitive K+ channels, is selectively augmented after subarachnoid hemorrhage (SAH). Vasodilatation in response to activation of ATP-sensitive K+ channels, however, is impaired during chronic hypertension. Hypertension may contribute to a worse outcome after SAH, but the nature of the relationship between hypertension and SAH is uncertain. In the present study we examined responses of the basilar artery to aprikalim after SAH in normotensive Wistar-Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP).. In anesthetized WKY and SHRSP, we measured changes in diameter of the basilar artery in response to aprikalim and papaverine using a cranial window 2 days after injection of 0.3 mL saline or autologous blood into the cistema magna.. Under control conditions, aprikalim (0.1 to 1 mumol/L) and papaverine (10 to 100 mumol/L) produced dilatation of the basilar artery. After SAH, responses to aprikalim were not significantly altered in WKY and were markedly increased in SHRSP compared with saline-injected control rats. In contrast, vasodilator responses to papaverine were not changed by SAH in either WKY or SHRSP, suggesting that augmented vasodilatation in response to aprikalim after SAH was selective.. Responses of the basilar artery to aprikalim were greatly augmented in SHRSP after SAH. Because vasodilator responses to many stimuli are impaired after SAH and cerebral vasodilator responses to several stimuli are impaired by chronic hypertension, augmented responses to activation of K+ channels despite the presence of hypertension are unusual.

Topics: Animals; ATP-Binding Cassette Transporters; Basilar Artery; Hypertension; Ion Channel Gating; KATP Channels; Nerve Tissue Proteins; Papaverine; Picolines; Potassium; Potassium Channels; Potassium Channels, Inwardly Rectifying; Pyrans; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Subarachnoid Hemorrhage; Vasodilation; Vasodilator Agents

We examined the hypothesis that dilatation of the basilar artery in response to activation of ATP-sensitive potassium channels is impaired in stroke-prone spontaneously hypertensive rats (SHRSP). Changes in basilar artery diameter in response to aprikalim, a direct activator of ATP-sensitive potassium channels, were measured in anesthetized SHRSP and normotensive Wistar-Kyoto (WKY) rats through a cranial window. Topical application of aprikalim increased basilar artery diameter in WKY rats. Glibenclamide, a selective inhibitor of ATP-sensitive potassium channels, abolished aprikalim-induced vasodilatation. Thus, ATP-sensitive potassium channels are functional in the basilar artery of WKY rats in vivo. Aprikalim (10(-6) mol/L) dilated the basilar artery by 31 +/- 5% (mean +/- SEM) in WKY rats but only 5 +/- 1% in SHRSP. The concentration-response curve to aprikalim in SHRSP was significantly shifted to the right, but the response to the highest concentration of aprikalim (10(-5.5) mol/L) was similar in SHRSP and WKY rats. Vasodilatation in response to norepinephrine was also impaired in SHRSP. Dilator responses of the basilar artery to forskolin, a direct activator of adenylate cyclase, and nitroprusside, a direct activator of guanylate cyclase, were normal in SHRSP. The findings suggest that dilatation of the basilar artery in response to direct activation of ATP-sensitive potassium channels is impaired in SHRSP compared with WKY rats in vivo.

Topics: Adenosine Triphosphate; Animals; Antihypertensive Agents; Basilar Artery; Cerebrovascular Disorders; Colforsin; Dose-Response Relationship, Drug; Hypertension; In Vitro Techniques; Male; Models, Cardiovascular; Muscle, Smooth, Vascular; Nitroprusside; Norepinephrine; Picolines; Potassium Channels; Pyrans; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Vasodilation