title: Nitric oxide does not modulate the hyperpolarization-activated current, I(f), in ventricular myocytes from spontaneously hypertensive rats.
abstract: OBJECTIVE
  : In sinoatrial (SA) node cells, nitric oxide (NO) exerts a dual effect on the hyperpolarization-activated current, I(f), i.e. in basal conditions NO enhances I(f) whereas in the presence of beta-adrenergic stimulation it decreases it. Recent studies have shown that I(f) is present in ventricular myocytes from hypertrophied or failing hearts where it may promote abnormal automaticity. Since these pathological conditions are associated with increased sympathetic tone and upregulation of myocardial NO production, we set out to investigate whether I(f) is similarly modulated by NO in hypertrophied ventricular myocytes.
  
  
  METHODS
  Left ventricular myocytes were isolated from 18-20-month-old spontaneously hypertensive rats (SHRs). Membrane current was measured under whole-cell or amphotericin-perforated patch-clamp conditions, at 35 degrees C.
  
  
  RESULTS
  Application of diethylamine-NO (DEA-NO, 1-100 microM) did not alter the amplitude or voltage dependence of activation of I(f) under basal conditions (half-activation voltage, V(h): control -82.9+/-2.6, DEA-NO -84.0+/-2.6 mV). Similarly, I(f) was not affected by the inhibition of endogenous NO production (L-NMMA, 500 microM) or guanylate cyclase (ODQ, 10 microM). Forskolin (10 microM) or isoprenaline (100 nM) elicited a positive shift in V(h) but subsequent application of DEA-NO did not further affect the properties of I(f).
  
  
  CONCLUSIONS
  Our results show that, unlike in SA node cells, in SHR ventricular myocytes basal and adrenergically stimulated I(f) is not modulated by exogenous NO or by constitutive NO or cGMP production.
authors.affiliation: Department of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, OX3 9DU, Oxford, UK. simon.bryant@cardiov.ox.ac.uk
authors.forename: S M
authors.initials: SM
authors.lastname: Bryant
authors.forename: C E
authors.initials: CE
authors.lastname: Sears
authors.forename: L
authors.initials: L
authors.lastname: Rigg
authors.forename: D A
authors.initials: DA
authors.lastname: Terrar
authors.forename: B
authors.initials: B
authors.lastname: Casadei
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000666:Amphotericin B / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology*; D006332:Cardiomegaly / Q000503:physiopathology*; D005576:Colforsin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009589:Nitrogen Oxides; D010069:Oxadiazoles / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012849:Sinoatrial Node / Q000187:drug effects*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: C116907:1H-(1,2,4)oxadiazolo(4,3-a)-quiloxalin-1-one; D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D006834:Hydrazines; C102260:NOR 4; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D010069:Oxadiazoles; D011725:Pyridines; C110881:S-nitro-N-acetylpenicillamine; D005576:Colforsin; D019323:omega-N-Methylarginine; D000666:Amphotericin B; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine; D019001:Nitric Oxide Synthase; D000262:Adenylyl Cyclases; D006162:Guanylate Cyclase; D010396:Penicillamine; D007545:Isoproterenol