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.
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
Ann A
AA
Tobin
Biny K
BK
Joseph
Hamood N
HN
Al-Kindi
Sulayma
S
Albarwani
Jane A
JA
Madden
Leah T
LT
Nemetz
Nancy J
NJ
Rusch
Sung W
SW
Rhee
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