Divergent mechanisms of ATP-sensitive K+ channel-induced vasodilation in renal afferent and efferent arterioles. Evidence of L-type Ca2+ channel-dependent and -independent actions of pinacidil.
K+ channel openers (PCOs), such as pinacidil, elicit vasodilation primarily by hyperpolarization-induced inhibition of L-type Ca2+ channel activation. The physiological role of other mechanisms suggested to contribute to PCO-induced vasodilation is not well established. In the renal microcirculation, L-type Ca2+ channels play a prominent role in vasoconstriction of the afferent arteriole (AA) but are absent or physiologically silent in the efferent arteriole (EA). Thus, L-type Ca2+ channel-dependent and -independent mechanisms can readily be distinguished in this model. In the present study, we found that pinacidil potently inhibited Bay K 8644-induced AA vasoconstriction. Pinacidil also preferentially inhibited angiotensin II-induced AA vasoconstriction (approximately ninefold greater potency than EA). These results are consistent with an AA effect of pinacidil on L-type Ca2+ channel activation. Unexpectedly, 10 mumol/L pinacidil inhibited AA and EA responses to similar extents (84 +/- 10% and 71 +/- 9%, respectively). In both AAs and EAs, glibenclamide restored normal reactivity, indicating an involvement of the ATP-sensitive K+ channels. In the EA, however, pretreatment with diltiazem did not alter the effects of pinacidil. Nevertheless, 45 mmol/L KCl reversed the EA actions of pinacidil, indicating an essential requirement for a normal K+ gradient. These findings suggest that the EA actions of pinacidil involve alterations in membrane potential but not changes in L-type Ca2+ channel activity. Overall, our findings do support the premise that L-type Ca2+ channel modulation is involved in PCO-induced vasodilation in the renal microcirculation.(ABSTRACT TRUNCATED AT 250 WORDS)
Reslerova
M
M
Department of Pharmacology and Therapeutics, University of Calgary, Canada.
Loutzenhiser
R
R
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000502:physiology*; D000704:Analysis of Variance; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D004110:Diltiazem / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply*; D008833:Microcirculation / Q000187:drug effects; D020110:Pinacidil; D015221:Potassium Channels / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D012079:Renal Circulation / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology*
D002120:Calcium Channel Agonists; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D006146:Guanidines; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D000804:Angiotensin II; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D020110:Pinacidil; D000255:Adenosine Triphosphate; D004110:Diltiazem