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J. D. Peuler, G. M. Wahler, J. M. Smith, P-566: Thapsigargin blocks relaxation of arterial smooth muscle by metformin, American Journal of Hypertension, Volume 14, Issue S1, April 2001, Pages 219A–220A, https://doi.org/10.1016/S0895-7061(01)01873-8
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Abstract
The antidiabetic drug metformin (MF) can directly relax adrenergic contractions in arterial smooth muscle, either rapidly at millimolar concentrations of the drug or after a delay of several hours at micromolar levels (≤ 100 μM). Recently, we found that 4-aminopyridine (4AP) greatly attenuates the former and completely blocks the latter (J. Hyper 18: suppl 4, S204, 2000). Thus, MF may relax SM by opening 4AP-inhibitable potassium (K) channels in the cell membrane, permitting increased K efflux and membrane hyperpolarization. However, we have also found that a 4-5 hour exposure to 100 μM MF also relaxes SM contractions induced by high levels of extracellular K, levels high enough to preclude efflux of intracellular K. In addition, 4AP blocks this relaxation, suggesting MF and 4AP interact at some site other than K channels in the cell membrane. 4AP is also known to inhibit K channels in the sarcoplasmic reticulum (SR). Indirectly, this inhibits SR-CaATPase and thus SR Ca sequestration. Thapsigargin (TG) directly inhibits SR-CaATPase, with no effects on cell membrane CaATPase or ion channels at either location. Thus, we examined TG for its ability to block the delayed relaxant effect of 100 μM MF. Vascular contractile rings prepared from ventral tail arteries of rats were incubated with physiological buffer containing 0 and 100 μM MF (n=12 each). TG (< 1 μM) was co-administered with each level of MF in additional preparations. After 4-5 hours, rings were contracted with graded levels of either norepinephrine (NE), arginine vasopressin (AVP), serotonin or high K. In the absence of TG, MF relaxed both maximal and submaximal contractions produced by each substance. The relaxation of maximal contractions was 25 ± 4% for NE, 37 ± 4% for AVP, 29 ± 4% for serotonin and 45 ± 6% for high K (p < 0.05). TG blocked all relaxant effects of MF (p < 0.05). These results were not influenced by removal of either endothelium or adrenergic nerve endings. Thus, the ability of μM levels of MF to relax arterial SM contractions may involve increased CaATPase activity and thus Ca uptake in the SR.
