Electrophysiological basis for the enhanced cardiac arrhythmogenic effect of isoprenaline in aged spontaneously hypertensive rats.
We used normotensive (WKY) and spontaneously hypertensive rats (SHR) of 2, 6 and 18 months of age to get insight into the mechanisms responsible for the increased incidence of ventricular arrhythmias in hypertensive heart disease. We studied: (1) isoprenaline-induced spontaneous activity in isolated papillary muscle; (2) action potential characteristics; (3) beta-adrenoceptor and A1-adenosine receptor number and affinity; and (4) intracellular cyclic AMP (cAMP) levels. The saturation binding assay was performed in enzymatically isolated ventricular myocytes using the hydrophilic antagonist 3H-CGP 12177 for beta-adrenoceptors and 3H-DPCPX for A1-adenosine receptors. cAMP was measured by a competitive binding assay in myocytes before and after exposure to isoprenaline. Intracellular action potential was recorded from papillary muscles by means of 3 M KCl-filled glass microelectrodes. The presence of isoprenaline-induced automaticity was assessed by interrupting the electrical stimulation periodically. In isolated papillary muscles, isoprenaline (10 nM) induced spontaneous activity more frequently in 18-month-old SHR (90.0%) than in 6-(25.0%, P < 0.05) and 2-month-old SHR (0%, P < 0.001). No age-related statistically significant differences in isoprenaline-induced automaticity were observed in WKY. The incidence of isoprenaline-induced automaticity was higher in 18-month-old SHR than in age-matched WKY (22.2%, P < 0.05). KD and Bmax for beta-adrenoceptors and A1-receptors were not significantly modified in different groups. cAMP levels before and after isoprenaline stimulation were significantly lower in 18-month-old SHR than in age-matched WKY. Action potential duration (APD) was markedly prolonged in both normotensive and hypertensive rats during aging. APD was significantly prolonged in 18-month-old SHR compared to the WKY. A "diastolic depolarization", caused by the presence of delayed after-depolarizations, became apparent in the oldest animals. The slope of the delayed after-depolarization was increased by isoprenaline (1-10 nM) in 18-month-old SHR and this effect was significantly greater than that observed in 18-month-old WKY (P < 0.05). In conclusion, beta-adrenergic responsiveness is enhanced in hypertensive rats during aging, resulting in a greater incidence of abnormal automaticity. This effect does not appear to be related to changes in beta-adrenoceptor or A1-receptor density or affinity; it is likely that the electrophysiological alterations may play a role in this phenomenon.
Barbieri
M
M
Institute of Pharmacology, University of Ferrara, Italy.
Varani
K
K
Cerbai
E
E
Guerra
L
L
Li
Q
Q
Borea
P A
PA
Mugelli
A
A
D000200:Action Potentials / Q000187:drug effects; D000375:Aging / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY
D007545:Isoproterenol