Metabolic syndrome reduces the contribution of K+ channels to ischemic coronary vasodilation

Abstract

This investigation tested the hypothesis that metabolic syndrome decreases the relative contribution of specific K(+) channels to coronary reactive hyperemia. Ca(2+)-activated (BK(Ca)), voltage-activated (K(V)), and ATP-dependent (K(ATP)) K(+) channels were investigated. Studies were conducted in anesthetized miniature Ossabaw swine fed a normal maintenance diet (11% kcal from fat) or an excess calorie atherogenic diet (43% kcal from fat, 2% cholesterol, 20% kcal from fructose) for 20 wk. The latter diet induces metabolic syndrome, increasing body weight, fasting glucose, total cholesterol, and triglyceride levels. Ischemic vasodilation was determined by the coronary flow response to a 15-s occlusion before and after cumulative administration of antagonists for BK(Ca) (penitrem A; 10 microg/kg iv), K(V) (4-aminopyridine; 0.3 mg/kg iv) and K(ATP) (glibenclamide; 1 mg/kg iv) channels. Coronary reactive hyperemia was diminished by metabolic syndrome as the repayment of flow debt was reduced approximately 30% compared with lean swine. Inhibition of BK(Ca) channels had no effect on reactive hyperemia in either lean or metabolic syndrome swine. Subsequent inhibition of K(V) channels significantly reduced the repayment of flow debt ( approximately 25%) in both lean and metabolic syndrome swine. Additional blockade of K(ATP) channels further diminished ( approximately 45%) the repayment of flow debt in lean but not metabolic syndrome swine. These data indicate that the metabolic syndrome impairs coronary vasodilation in response to cardiac ischemia via reductions in the contribution of K(+) channels to reactive hyperemia.

Fig. 1.

Effect of metabolic syndrome (MetS) on coronary reactive hyperemia. A: group average traces of coronary reactive hyperemia in lean (n = 8) and metabolic syndrome (n = 8) swine are shown. Peak hyperemic conductance and the overall volume of repayment were not different between lean and metabolic syndrome swine. However, baseline coronary conductance was significantly elevated by metabolic syndrome; thus, the overall ischemic dilator response in proportion to the incurred oxygen debt (i.e., repayment of flow debt, B) was significantly diminished in metabolic syndrome swine. *P < 0.05 vs. lean.

Fig. 2.

Effect of K⁺ channel inhibition on coronary reactive hyperemia in lean swine. Group average traces of coronary reactive hyperemia in lean swine (n = 8) are shown before and after cumulative administration of K⁺ channel blockers. The Ca²⁺-activated K⁺ (BK_Ca) channel antagonist penitrem A (PenA) had no effect on reactive hyperemia (A and C). Subsequent administration of the voltage-dependent-K⁺ (K_V) channel antagonist 4-aminopyridine (4-AP) and the K_ATP channel antagonist glibenclamide (Glib) significantly reduced the reactive hyperemic response relative to untreated control conditions (B and C). *P < 0.05 vs. lean control.

Fig. 3.

Effect of K⁺ channel inhibition on coronary reactive hyperemia in metabolic syndrome swine. Group average traces of coronary reactive hyperemia in metabolic syndrome swine (n = 8) are shown before and after cumulative administration of K⁺ channel blockers. The BK_Ca channel antagonist penitrem A had no effect on reactive hyperemia (A and C). Subsequent administration of the K_V channel antagonist 4-AP significantly reduced the reactive hyperemic response relative to untreated control conditions (B and C). Further inhibition of K_ATP channels with glibenclamide had no additional effect. *P < 0.05 vs. lean control.

Fig. 4.

Relative contribution of BK_Ca, K_V, and ATP-dependent K⁺ channels to coronary reactive hyperemia in lean and metabolic syndrome swine. Inhibition of BK_Ca channels with penitrem A had no effect on peak coronary conductance (A) or the repayment of coronary flow debt (B). Subsequent administration of the K_V channel antagonist 4-AP significantly reduced the repayment-to-debt ratio in both lean and metabolic syndrome swine. Further inhibition of K_ATP channels with glibenclamide reduced peak conductance and the repayment of flow debt in lean but not metabolic syndrome swine. P < 0.05 vs. untreated control same diet group (*), lean same drug treatment (†), and lean penitrem A + 4-AP (‡).