Musialek P, Lei M, Brown H F, Paterson D J, Casadei B
University Laboratory of Physiology, Oxford, UK.
Circ Res. 1997 Jul;81(1):60-8. doi: 10.1161/01.res.81.1.60.
We investigated the chronotropic effect of increasing concentrations of sodium nitroprusside (SNP, n = 8) or 3-morpholinosydnonimine (SIN-1, n = 6) in isolated guinea pig spontaneously beating sinoatrial node/atrial preparations. Low concentrations of NO donors (nanomolar to micromolar) gradually increased the beating rate, whereas high (millimolar) concentrations decreased it. The increase in rate was (1) enhanced by superoxide dismutase (50 to 100 U/mL, n = 6), (2) prevented by the guanylyl cyclase inhibitors 6-anilino-5,8-quinolinedione (5 mumol/L, n = 6) or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (10 mumol/L, n = 6), and (3) mimicked by 8-bromo-cGMP (n = 6) with no additional positive chronotropic effect of SIN-1 (n = 5). The response to 10 mumol/L SNP (n = 28) or 50 mumol/L SIN-1 (n = 16) was unaffected by IcaL antagonism with nifedipine (0.2 mumol/L) but was abolished after blockade of the hyperpolarization-activated inward current (I(f)) by Cs+ (2 mmol/L) or 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride (1 mumol/L). The effect on I(f) was further evaluated in rabbit isolated patch-clamped sinoatrial node cells (n = 21), where we found that 5 mumol/L SNP or SIN-1 caused a reversible Cs(+)-sensitive increase in this current (+130% at -70 mV and +250% at -100 mV). In conclusion, NO donors can affect pacemaker activity in a concentration-dependent biphasic fashion. Our results indicate that the increase in beating rate is due to stimulation of I(f) via the NO-cGMP pathway. This may contribute to the sinus tachycardia in pathological conditions associated with an increase in myocardial production of NO.
我们研究了在豚鼠离体自发搏动的窦房结/心房标本中，增加硝普钠（SNP，n = 8）或3 - 吗啉代亚磺酰亚胺（SIN - 1，n = 6）浓度时的变时效应。低浓度的一氧化氮供体（纳摩尔至微摩尔）逐渐增加搏动频率，而高浓度（毫摩尔）则使其降低。频率增加是因为：（1）超氧化物歧化酶（50至100 U/mL，n = 6）可增强该作用；（2）鸟苷酸环化酶抑制剂6 - 苯胺基 - 5,8 - 喹啉二酮（5 μmol/L，n = 6）或1H -（1,2,4）恶二唑并（4,3 - a）喹喔啉 - 1 - 酮（10 μmol/L，n = 6）可阻止该作用；（3）8 - 溴 - cGMP（n = 6）可模拟该作用，且SIN - 1（n = 5）无额外的正性变时效应。10 μmol/L SNP（n = 28）或50 μmol/L SIN - 1（n = 16）的反应不受硝苯地平（0.2 μmol/L）对L型钙电流（IcaL）的拮抗作用影响，但在被Cs⁺（2 mmol/L）或4 -（N - 乙基 - N - 苯基氨基）- 1,2 - 二甲基 - 6 -（甲氨基）嘧啶氯化物（1 μmol/L）阻断超极化激活内向电流（I(f)）后被消除。在兔离体膜片钳记录的窦房结细胞（n = 21）中进一步评估了对I(f)的影响，我们发现5 μmol/L SNP或SIN - 1可使该电流产生可逆的Cs⁺敏感增加（在 - 70 mV时增加130%，在 - 100 mV时增加250%）。总之，一氧化氮供体可呈浓度依赖性双相方式影响起搏活动。我们的结果表明，搏动频率增加是由于通过NO - cGMP途径刺激I(f)所致。这可能导致在与心肌一氧化氮生成增加相关的病理状态下出现窦性心动过速。
