Loss of cerebrovascular Shaker-type K(+) channels: a shared vasodilator defect of genetic and renal hypertensive rats.
The cerebral arteries of hypertensive rats are depolarized and highly myogenic, suggesting a loss of K(+) channels in the vascular smooth muscle cells (VSMCs). The present study evaluated whether the dilator function of the prominent Shaker-type voltage-gated K(+) (K(V)1) channels is attenuated in middle cerebral arteries from two rat models of hypertension. Block of K(V)1 channels by correolide (1 micromol/l) or psora-4 (100 nmol/l) reduced the resting diameter of pressurized (80 mmHg) cerebral arteries from normotensive rats by an average of 28 +/- 3% or 26 +/- 3%, respectively. In contrast, arteries from spontaneously hypertensive rats (SHR) and aortic-banded (Ao-B) rats with chronic hypertension showed enhanced Ca(2+)-dependent tone and failed to significantly constrict to correolide or psora-4, implying a loss of K(V)1 channel-mediated vasodilation. Patch-clamp studies in the VSMCs of SHR confirmed that the peak K(+) current density attributed to K(V)1 channels averaged only 5.47 +/- 1.03 pA/pF, compared with 9.58 +/- 0.82 pA/pF in VSMCs of control Wistar-Kyoto rats. Subsequently, Western blots revealed a 49 +/- 7% to 66 +/- 7% loss of the pore-forming alpha(1.2)- and alpha(1.5)-subunits that compose K(V)1 channels in cerebral arteries of SHR and Ao-B rats compared with control animals. In each case, the deficiency of K(V)1 channels was associated with reduced mRNA levels encoding either or both alpha-subunits. Collectively, these findings demonstrate that a deficit of alpha(1.2)- and alpha(1.5)-subunits results in a reduced contribution of K(V)1 channels to the resting diameters of cerebral arteries from two rat models of hypertension that originate from different etiologies.
Tobin
Ann A
AA
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Joseph
Biny K
BK
Al-Kindi
Hamood N
HN
Albarwani
Sulayma
S
Madden
Jane A
JA
Nemetz
Leah T
LT
Rusch
Nancy J
NJ
Rhee
Sung W
SW
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology; D015153:Blotting, Western; D002536:Cerebral Arteries / Q000378:metabolism / Q000502:physiology; D006973:Hypertension / Q000235:genetics* / Q000503:physiopathology*; D006978:Hypertension, Renovascular / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012701:Serotonin / Q000494:pharmacology; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics* / Q000502:physiology*; D014664:Vasodilation / Q000235:genetics* / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D012333:RNA, Messenger; D051637:Shaker Superfamily of Potassium Channels; D014665:Vasodilator Agents; D012701:Serotonin; D000109:Acetylcholine