title: Role of protein kinase C in Ca channel blocker-induced renal arteriolar dilation in spontaneously hypertensive rats--studies in the isolated perfused hydronephrotic kidney.
abstract: The present study examined the role of L-/T-type Ca channels and the interaction between these channels and protein kinase C (PKC) in hypertension. The isolated perfused hydronephrotic rat kidney model was used to visualize directly the renal microvascular effects of L-/T-type Ca channel blockers (nifedipine and mibefradil, respectively). Nifedipine reversed the angiotensin II-induced constriction of afferent, but not efferent, arterioles in kidneys from Wistar-Kyoto rats (WKY), and similar magnitude in dilation was observed in spontaneously hypertensive rats (SHR). Although mibefradil elicited dilation of both arterioles, the afferent arteriolar dilation was less in SHR than in WKY (57+/-5% vs. 80+/-4% reversal at 1 micrommol/L). The pretreatment with staurosporine did not alter the angiotensin II-induced afferent arteriolar constriction in WKY, but attenuated this response in SHR. Furthermore, staurosporine enhanced the nifedipine-induced afferent arteriolar dilation (62+/-3% vs. 50+/-3% reversal at 10 nmol/L), and restored the attenuated afferent arteriolar response to mibefradil in SHR. The pretreatment with thapsigargin (a blocker of IP3-mediated intracellular calcium release) prevented the angiotensin II-induced afferent arteriolar constriction in WKY, but caused a significant constriction of afferent arterioles in SHR and efferent arterioles in WKY and SHR; in this setting, mibefradil did not alter efferent arteriolar tone. In conclusion, although both L-type (nifedipine) and T-type Ca channel blockers (mibefradil) exerted potent vasodilation of rat renal microvessels, these actions were modified by PKC, which determined the afferent arteriolar sensitivity to these blockers in SHR. Furthermore, the enhancement in nifedipine-induced afferent arteriolar dilation by staurosporine in SHR suggests that L-type Ca channel activity is augmented in hypertensive animals.
authors.affiliation: Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan. khayashi@sc.itc.keio.ac.jp
authors.forename: Koichi
authors.initials: K
authors.lastname: Hayashi
authors.forename: Shu
authors.initials: S
authors.lastname: Wakino
authors.forename: Yuri
authors.initials: Y
authors.lastname: Ozawa
authors.forename: Koichiro
authors.initials: K
authors.lastname: Homma
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kanda
authors.forename: Ken
authors.initials: K
authors.lastname: Okubo
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takamatsu
authors.forename: Satoru
authors.initials: S
authors.lastname: Tatematsu
authors.forename: Hiroo
authors.initials: H
authors.lastname: Kumagai
authors.forename: Takao
authors.initials: T
authors.lastname: Saruta
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001160:Arterioles / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006869:Hydronephrosis / Q000473:pathology; D006973:Hypertension / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000378:metabolism; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D008833:Microcirculation; D009543:Nifedipine / Q000494:pharmacology; D010477:Perfusion; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D019311:Staurosporine / Q000378:metabolism / Q000494:pharmacology; D019284:Thapsigargin / Q000378:metabolism / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D000804:Angiotensin II; D020748:Mibefradil; D019284:Thapsigargin; D011493:Protein Kinase C; D019311:Staurosporine; D009543:Nifedipine; D002118:Calcium