thapsigargin and Hypertension--Renovascular

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.

Topics: 8-Bromo Cyclic Adenosine Monophosphate; Animals; Aorta, Thoracic; Caffeine; Calcium-Transporting ATPases; Colforsin; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Disease Models, Animal; Gene Expression; Glyburide; Hypertension, Renovascular; Isoproterenol; Kidney; Male; Membrane Proteins; Muscle, Smooth, Vascular; Phenylephrine; Potassium Channels; Rats; Rats, Wistar; Receptors, Adrenergic, beta; RNA, Messenger; Sarcolemma; Signal Transduction; Thapsigargin; Vasoconstriction; Vasodilation

1. The aim of this study was to test the hypothesis that impaired calcium (Ca2+) recycling by sarcoplasmic reticulum (SR) Ca2+-ATPase takes place in aortae from 1 kidney-1 clip (1K-1C) hypertensive rats. 2. The contractile response elicited when Ca2+ is released from the SR with phenylephrine and caffeine in Ca2+-free Krebs solution was greater in 1K-1C than in 1K rat aorta. In the arteries submitted to intracellular Ca2+ store depletion and reloading, this response was not different between 1K-1C and 1K rat aortae. Thapsigargin decreased the phasic contractile responses to phenylephrine in 1K and 1K-1C rat aortae and increased the tone that developed during the refilling period in 1K-1C rat aortae. 3. Our data support the hypothesis that the 1K-1C rat aorta has defective intracellular Ca2+ regulation that may be implicated in an inadequate SR buffering ability.

Topics: Animals; Aorta; Caffeine; Calcium; Calcium-Transporting ATPases; Enzyme Inhibitors; Evaluation Studies as Topic; Hypertension, Renovascular; Inositol 1,4,5-Trisphosphate; Male; Phenylephrine; Rats; Rats, Wistar; Ryanodine; Sarcoplasmic Reticulum; Thapsigargin; Vasoconstriction