Electrophysiological effects of endothelin-1 and their relationship to contraction in rat renal arterial smooth muscle.
The electophysiological effects of endothelin-1 (ET-1) and their relationship to contraction remain unclear in the renal circulation. Using endotheliumdenuded arteries from the main branch of the renal artery proximal to the kidney of the rat, we have examined its effects on tension and conducted parallel patch-clamp measurements using freshly isolated smooth muscle cells from this tissue. Pharmacological experiments revealed that ET-1 produced constriction of renal arteries dependent on the influx of extracellular Ca(2+), mediated solely through ET(A) receptor stimulation. Current-clamp experiments revealed that renal arterial myocytes had a resting membrane potential of approximately 32 mV, with the majority of cells exhibiting spontaneous transient hyperpolarizations (STHPs). Application of ET-1 produced depolarization and in those cells exhibiting STHPs, either caused their inhibition or made them occur regularly. Under voltage-clamp conditions cells were observed to exhibit spontaneous transient outward currents (STOCs) inhibited by iberiotoxin. Application of voltage-ramps revealed an outward current activated at approximately -30 mV, sensitive to both 4-AP and TEA. Taken together these results suggest that renal arterial myocytes possess both delayed rectifying K(+) (K(V)) and Ca(2+)-activated K(+) (BK(Ca)) channels. Under voltage-clamp, ET-1 attenuated the outward current and reduced the magnitude and incidence of STOCs: effects mediated solely as a consequence of ET(A) receptor stimulation. Thus, in conclusion, activation of ET(A) receptors by ET-1 causes inhibition of K(V) and BK(Ca) channel activity, which could promote and/or maintain membrane depolarization. This effect is likely to favour L-type Ca(2+) channel activity providing an influx pathway for extracellular Ca(2+) essential for contraction.
Betts
L C
LC
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, United Kingdom.
Kozlowski
R Z
RZ
D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010456:Peptides, Cyclic / Q000494:pharmacology; D026902:Potassium Channel Blockers; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology; D012077:Renal Artery / Q000187:drug effects* / Q000502:physiology; D019789:Tetraethylammonium / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects*
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D026902:Potassium Channel Blockers; D017466:Receptors, Endothelin; D019789:Tetraethylammonium; D015761:4-Aminopyridine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium