Changes in the vascular beta-adrenoceptor-activated signalling pathway in 2Kidney-1Clip hypertensive rats.
1. beta-Adrenoceptor (beta-AR)-mediated vasodilation, which plays an important physiological role in the regulation of vascular tone, is decreased in two-kidney, one clip (2K-1C) renal hypertension. In this study, downstream pathways related to vascular beta-AR activation were evaluated in 2K-1C rats. 2. Relaxation responses to isoprenaline, forskolin and 8-Br-cAMP were diminished in aortas without endothelium from 2K-1C when compared to those in normotensive two kidney (2K). Basal adenosine-3',5'-monophosphate (cAMP), as well as isoprenaline-induced increase in cAMP levels, was not different between 2K and 2K-1C aortas. 3. Contractile responses to caffeine, after depletion and reloading of intracellular Ca(2+) stores, were greater in 2K-1C than in 2K. The presence of isoprenaline during the Ca(2+)-reloading period abolished the differences between groups by increasing caffeine contraction in 2K without changing this response in 2K-1C aortas. Inhibition of the sarcolemmal Ca(2+)ATPase with thapsigargin markedly attenuated isoprenaline vasodilation in both 2K and 2K-1C and abolished the differences between groups. 4. Blockade of ATP-sensitive K(+) channels (K(ATP)) channels with glibenclamide significantly decreased isoprenaline vasodilation in 2K-1C without affecting this response in 2K. Both vascular gene and protein expression of protein kinase A (PKA), as well as phosphoserine-containing proteins, were increased in 2K-1C vs 2K rats. 5. In conclusion, decreased isoprenaline vasodilation in 2K-1C hypertensive rats is related to impaired modulation of the sarcolemmal Ca(2+)ATPase activity. Moreover, K(ATP) channels may play a compensatory role on isoprenaline-induced relaxation in renal hypertension. Both Ca(2+)ATPase and K(ATP) channel functional alterations, associated with decreased beta-AR vasodilation, are paralleled by an upregulation of protein kinase A (PKA) and phosphoserine proteins expression.
Department of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil. Elena-Glaucia.Callera@ircm.qc.ca
Glaucia E
GE
Callera
Ester
E
Yeh
Rita C A
RC
Tostes
Luciana C
LC
Caperuto
Carla R O
CR
Carvalho
Lusiane M
LM
Bendhack
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D002110:Caffeine / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000187:drug effects / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000737:chemistry / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D005905:Glyburide / Q000494:pharmacology; D006978:Hypertension, Renovascular / Q000503:physiopathology*; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D007668:Kidney / Q000601:surgery; D008297:Male; D008565:Membrane Proteins / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D015221:Potassium Channels; D012333:RNA, Messenger; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D012508:Sarcolemma / Q000187:drug effects / Q000201:enzymology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019284:Thapsigargin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D008565:Membrane Proteins; D015221:Potassium Channels; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; C117780:mitochondrial K(ATP) channel; D005576:Colforsin; D010656:Phenylephrine; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002110:Caffeine; D019284:Thapsigargin; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D005905:Glyburide