Characterization of K+ channel-dependent as well as -independent components of pinacidil-induced vasodilation.
The mechanisms of pinacidil-induced direct vasodilation were studied in vitro in RMA and RAO. In RMA, pinacidil produced dose-dependent relaxations of norepinephrine (5 microM)-induced contractions with an IC50 of 0.2 microM. This component of pinacidil relaxation appeared to be dependent on K+ conductance because pretreatment with tetraethylammonium (10 mM), Ba++ (0.5 mM), glyburide (1 microM) and 20 mM K+ all caused a rightward shift of the pinacidil dose-response curve (DRC) and a corresponding increase in the pinacidil IC50. However, additional relaxation effects of pinacidil were still evident in the presence of various K+ channel blockers. Pinacidil also showed a relaxation DRC under the condition of 80 mM K+ contraction in both RMA and RAO with IC50 values of 27 and 50 microM, respectively. Pinacidil could also produce maximal relaxation in RMA and RAO remained unaffected in 145 mM K+ (zero Na+) depolarizing solution suggesting a lack of dependence on Na(+)-Ca++ exchange mechanism for this action of pinacidil. Studies using 1 or 3 min pulse labeling with 45Ca showed an absence of an inhibitory effect of pinacidil (at 50 and 100 microM) on unidirectional 45Ca influx stimulated by high-K+. Net 45Ca uptake studies showed that pinacidil inhibited high-K+ stimulated 45Ca uptake at 100 but not at 50 microM. Ryanodine (10-100 microM) was used as a tool to investigate the role of sarcoplasmic reticulum (SR) in this action of pinacidil. Under the condition in which ryanodine (10-100 microM) treatment was found to cause the SR to be nonfunctional, pinacidil relaxation DRC remained unaltered, suggesting a lack of a stimulatory effect of pinacidil on SR Ca++ accumulation. These data thus show that the K+ channel-independent effect of pinacidil does not involve to any significant degree an effect of pinacidil on plasmalemmal voltage-sensitive Ca++ channels, SR Ca++ stores, Na(+)-Ca++ exchange or membrane hyperpolarization.(ABSTRACT TRUNCATED AT 250 WORDS)
Meisheri
K D
KD
Cardiovascular Diseases Research, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan.
Swirtz
M A
MA
Purohit
S S
SS
Cipkus-Dubray
L A
LA
Khan
S A
SA
Oleynek
J J
JJ
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D020110:Pinacidil; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D011817:Rabbits; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000502:physiology; D012964:Sodium / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*
D006146:Guanidines; D015221:Potassium Channels; D012433:Ryanodine; D020110:Pinacidil; D012964:Sodium; D011188:Potassium; D002118:Calcium