Essential role of diastolic oscillatory potentials in adrenergic control of guinea pig sino-atrial node discharge

BACKGROUND: The diastolic oscillatory after-potential V(os )and pre-potential ThV(os )play an essential role in the pacemaker mechanism of sino-atrial node (SAN). The aim of this study was to investigate whether these oscillatory potentials are also involved in adrenergic control of SAN discharge. METHODS: V(os )and ThV(os )were visualized by superfusing guinea pig SAN in high [K(+)](o). The actions of adrenergic agonists on oscillatory potentials were studied by means of a microelectrode technique. Statistical significance was determined by means of Student's paired t-test. RESULTS: In non-spontaneous SAN, norepinephrine (NE) decreased the resting potential into a voltage range ("oscillatory zone") where increasingly larger ThV(os )appeared and initiated spontaneous discharge. In slowly discharging SAN, NE gradually increased the rate by increasing the amplitude and slope of earlier-occurring ThV(os )and of V(os )until these oscillations fused with initial diastolic depolarization (DD(1)). In the presence of NE, sudden fast rhythms were initiated by large V(os )that entered a more negative oscillatory zone and initiated a large ThV(os). Recovery from NE exposure involved the converse changes. The β-adrenergic agonist isoproterenol had similar actions. Increasing calcium load by decreasing high [K(+)](o), by fast drive or by recovery in Tyrode solution led to growth of V(os )and ThV(os )which abruptly fused when a fast sudden rhythm was induced. Low [Ca(2+)](o )antagonized the adrenergic actions. Cesium (a blocker of I(f)) induced spontaneous discharge in quiescent SAN through ThV(os). In spontaneous SAN, Cs(+)increased V(os )and ThV(os), thereby increasing the rate. Cs(+ )did not hinder the positive chronotropic action of NE. Barium increased the rate, as Cs(+ )did. CONCLUSION: Adrenergic agonists: (i) initiate SAN discharge by decreasing the resting potential and inducing ThV(os); (ii) gradually accelerate SAN rate by predominantly increasing size and slope of earlier and more negative ThV(os); (iii) can induce sudden fast rhythms through the abrupt fusion of large V(os )with large ThV(os); (iv) increase V(os )and ThV(os)by increasing cellular calcium; and (v) do not modify the oscillatory potentials by means of the hyperpolarization-activated current I(f). The results provide evidence for novel mechanisms by which the SAN dominant pacemaker activity is initiated and enhanced by adrenergic agonists.