NITRIC-OXIDE CAN INCREASE HEART-RATE BY STIMULATING THE HYPERPOLARIZATION-ACTIVATED INWARD CURRENT, I-F

We investigated the chronotropic effect of increasing concentrations o f sodium nitroprusside (SNP, n=8) or 3-morpholinosydnonimine (SIN-1, n =6) in isolated guinea pig spontaneously beating sinoatrial node/atria l preparations. Low concentrations of NO donors (nanomolar to micromol ar) gradually increased the beating rate, whereas high (millimolar) co ncentrations decreased it. The increase in rate was (1) enhanced by su peroxide dismutase (50 to 100 U/mL, n=6), (2) prevented by the guanyly l cyclase inhibitors 6-anilino-5,8-quinolinedione (5 mu mol/L, n=6) or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (10 mu mol/L, n=6), and ( 3) mimicked by 8-bromo-cGMP (n=6) with no additional positive chronotr opic effect of SIN-1 (n=5). The response to 10 mu mol/L SNP (n=28) or 50 mu mol/L SIN-1 (n=16) was unaffected by ICa-L antagonism with nifed ipine (0.2 mu mol/L) but was abolished after blockade of the hyperpola rization-activated inward current (I-f) by Cs+ (2 mmol/L) or nylamino) -1,2-dimethyl-6-(methylamino)pyrimidinium chloride (1 mu mol/L). The e ffect on I-f was further evaluated in rabbit isolated patch-clamped si noatrial node cells (n=21), where we found that 5 mu mol/L SNP or SIN- I caused a reversible Cs+-sensitive increase in this current (+130% at -70 mV and +250% at -100 mV). In conclusion, NO donors can affect pac emaker activity in a concentration-dependent biphasic fashion. Our res ults 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 tachy cardia in pathological conditions associated with an increase in myoca rdial production of NO.