Dopamine stimulation of cardiac beta-adrenoceptors: the involvement of sympathetic amine transporters and the effect of SKF38393.
1. Mechanisms underlying beta-adrenoceptor stimulation by dopamine were examined on guinea-pig Langendorff-perfused hearts and isolated cells from the right atrium, by using the chronotropic effects and the enhancement of L-type Ca2+ current (ICa,L) in the presence of prazosin as indicators of beta-adrenoceptor stimulation. Dopamine-induced overflow of noradrenaline (NA) concentrations was measured by high-performance liquid chromatography. 2. Dopamine caused positive chronotropic effects with an EC50 of 2.5 microM and induced NA overflow with a similar EC50 (1.3 microM). The chronotropic effect of dopamine was abolished by bisoprolol (1 microM). 3. The effects of dopamine were maintained during prolonged application, whereas the effects of tyramine faded with time. Dopamine (3 microM) restored the chronotropic effects and the NA release suppressed by pretreatment with tyramine, suggesting a de novo synthesis of NA during the exposure to dopamine. 4. Dopamine (3 microM)-induced NA release was not affected by tetrodotoxin, omega-conotoxin, rauwolscine, ICI118551 or sulpiride, but was inhibited by desipramine, a NA uptake inhibitor (IC50 approximately 1 microM). It was also not affected by GBR12909 and bupropion, dopamine uptake inhibitors in the central nervous system. 5. SKF38393, a D1 receptor partial agonist, potently inhibited the 3 microM dopamine-induced release of NA (IC50 approximately 0.1 microM). D1 receptors are not involved in the DA-induced release of NA, since SCH23390 (3 microM), a potent D1 antagonist, inhibited the NA release only slightly, and dihydrexidine (1 microM) and chloro-APB (1 microM), full D1 agonists, caused no significant NA release. 6. SKF38393 inhibited tyramine-induced overflow of NA, and potentiated the field stimulation-induced NA release. SKF38393 and desipramine retarded the decay of the stimulation-induced tachycardia in a similar manner. These results indicate that SKF38393 is a potent monoamine transport inhibitor and a useful tool for the functional evaluation of indirectly-acting sympathomimetic agonists in the heart. In the presence of SKF38393 (10 microM), dopamine at 1 microM showed no chronotropic effect. 7. Voltage clamp experiments with isolated atrial cells revealed that dopamine is a weak partial agonist. The EC50 for ICa,L stimulation by dopamine was high (13 microM). As a result, dopamine at 1 microM did not affect ICa,L. Bisoprolol abolished the stimulation of ICa,L by dopamine (30 microM), and dihydrexidine (1 microM) did not affect ICa,L. 8. It was concluded that the cardiac effects of dopamine at clinically relevant concentrations (< 1 microM) result almost exclusively from the indirect effect of beta adrenoceptor stimulation, involving the release of NA from sympathetic nerve terminals. The roles of the direct stimulation of beta adrenoceptors by dopamine at these concentrations and the stimulation of postjunctional D1 receptors seem negligible. The desipramine- and SKF38393-sensitive monoamine transporter mediates the release of NA.
Habuchi
Y
Y
Department of Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Tanaka
H
H
Nishio
M
M
Yamamoto
T
T
Komori
T
T
Morikawa
J
J
Yoshimura
M
M
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology*; D000588:Amines / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D004298:Dopamine / Q000378:metabolism / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D008562:Membrane Glycoproteins / Q000187:drug effects* / Q000378:metabolism; D026901:Membrane Transport Proteins; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009479:Neuropeptides; D018377:Neurotransmitter Agents / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D013565:Sympatholytics / Q000378:metabolism; D013566:Sympathomimetics / Q000378:metabolism; D050492:Vesicular Biogenic Amine Transport Proteins
D000588:Amines; D018491:Dopamine Agonists; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D011943:Receptors, Adrenergic, beta; D013565:Sympatholytics; D013566:Sympathomimetics; D050492:Vesicular Biogenic Amine Transport Proteins; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D004298:Dopamine; D009638:Norepinephrine