The Dilemma of Non-Interference: Myanmar, Human Rights, and the ASEAN Charter

In October 2009, the Association of South East Asian Nations (ASEAN) established the Asian Intergovernmental Commission on Human Rights (AICHR), the first regional human rights organization in southeast Asia.One of the first tasks AICHR faces is how to approach Myanmar, a member of ASEANruled by a military junta that frequently commits horrific human rights abuses.This article examines the history of ASEAN\u27s interactions with Myanmar and explores the options available for AICHR to approach the human rights situation within the country

The Dilemma of Non-Interference: Myanmar, Human Rights, and the ASEAN Charter

In October 2009, the Association of South East Asian Nations (ASEAN) established the Asian Intergovernmental Commission on Human Rights (AICHR), the first regional human rights organization in southeast Asia.One of the first tasks AICHR faces is how to approach Myanmar, a member of ASEANruled by a military junta that frequently commits horrific human rights abuses.This article examines the history of ASEAN\u27s interactions with Myanmar and explores the options available for AICHR to approach the human rights situation within the country

Nitric oxide blunts myogenic autoregulation in rat renal but not skeletal muscle circulation via tubuloglomerular feedback: NO blunts renal myogenic autoregulation via TGF

This rat renal blood flow (RBF) study quantified the impact of nitric oxide synthase (NOS) inhibition on the myogenic response and the balance of autoregulatory mechanisms in the time domain following a 20 mmHg-step increase or decrease in renal arterial pressure (RAP). When RAP was increased, the myogenic component of renal vascular resistance (RVR) rapidly rose within the initial 7–10 s, exhibiting an ∼5 s time constant and providing ∼36% of perfect autoregulation. A secondary rise between 10 and 40 s brought RVR to 95% total autoregulatory efficiency, reflecting tubuloglomerular feedback (TGF) and possibly one or two additional mechanisms. The kinetics were similar after the RAP decrease. Inhibition of NOS (by l-NAME) increased RAP, enhanced the strength (79% autoregulation) and doubled the speed of the myogenic response, and promoted the emergence of RVR oscillations (∼0.2 Hz); the strength (52%) was lower at control RAP. An equi-pressor dose of angiotensin II had no effect on myogenic or total autoregulation. Inhibition of TGF (by furosemide) abolished the l-NAME effect on the myogenic response. RVR responses during furosemide treatment, assuming complete inhibition of TGF, suggest a third mechanism that contributes 10–20% and is independent of TGF, slower than the myogenic response, and abolished by NOS inhibition. The hindlimb circulation displayed a solitary myogenic response similar to the kidney (35% autoregulation) that was not enhanced by l-NAME. We conclude that NO normally restrains the strength and speed of the myogenic response in RBF but not hindlimb autoregulation, an action dependent on TGF, thereby allowing more and slow RAP fluctuations to reach glomerular capillaries

Ryanodine receptor and capacitative Ca2+ entry in fresh preglomerular vascular smooth muscle cells

Ryanodine receptor and capacitative Ca2+ entry in fresh preglomerular vascular smooth muscle cells.BackgroundA multiplicity of hormonal, neural, and paracrine factors regulates preglomerular arterial tone by stimulating calcium entry or mobilization. We have previously provided evidence for capacitative (store-operated) Ca2+ entry in fresh renal vascular smooth muscle cells (VSMCs). Ryanodine-sensitive receptors (RyRs) have recently been identified in a variety of nonrenal vascular beds.MethodsWe isolated fresh rat preglomerular VSMCs with a magnetized microsphere/sieving technique; cytosolic Ca2+ ([Ca2+]i) was measured with fura-2 ratiometric fluorescence.ResultsRyanodine (3 μmol/L) increased [Ca2+]i from 79 to 138 nmol/L (P = 0.01). Nifedipine (Nif), given before or after ryanodine, was without effect. The addition of calcium (1 mmol/L) to VSMCs in calcium-free buffer did not alter resting [Ca2+]i. In Ca-free buffer containing Nif, [Ca2+]i rose from 61 to 88 nmol/L after the addition of the Ca2+-ATPase inhibitor cyclopiazonic acid and to 159 nmol/L after the addition of Ca2+ (1 mmol/L). Mn2+ quenched the Ca/fura signal, confirming divalent cation entry. In Ca-free buffer with Nif, [Ca2+]i increased from 80 to 94 nmol/L with the addition of ryanodine and further to 166 nmol/L after the addition of Ca2+ (1 mmol/L). Mn2+ quenching was again shown. Thus, emptying of the sarcoplasmic reticulum (SR) with ryanodine stimulated capacitative Ca2+ entry.ConclusionPreglomerular VSMCs have functional RyR, and a capacitative (store-operated) entry mechanism is activated by the depletion of SR Ca2+ with ryanodine, as is the case with inhibitors of SR Ca2+-ATPase

Modulation of the myogenic mechanism: concordant effects of NO synthesis inhibition and O 2 − dismutation on renal autoregulation in the time and frequency domains

Renal blood flow autoregulation was investigated in anesthetized C57Bl6 mice using time- and frequency-domain analyses. Autoregulation was reestablished by 15 s in two stages after a 25-mmHg step increase in renal perfusion pressure (RPP). The renal vascular resistance (RVR) response did not include a contribution from the macula densa tubuloglomerular feedback mechanism. Inhibition of nitric oxide (NO) synthase [NG-nitro-l-arginine methyl ester (l-NAME)] reduced the time for complete autoregulation to 2 s and induced 0.25-Hz oscillations in RVR. Quenching of superoxide (SOD mimetic tempol) during l-NAME normalized the speed and strength of stage 1 of the RVR increase and abolished oscillations. The slope of stage 2 was unaffected by l-NAME or tempol. These effects of l-NAME and tempol were evaluated in the frequency domain during random fluctuations in RPP. NO synthase inhibition amplified the resonance peak in admittance gain at 0.25 Hz and markedly increased the gain slope at the upper myogenic frequency range (0.06–0.25 Hz, identified as stage 1), with reversal by tempol. The slope of admittance gain in the lower half of the myogenic frequency range (equated with stage 2) was not affected by l-NAME or tempol. Our data show that the myogenic mechanism alone can achieve complete renal blood flow autoregulation in the mouse kidney following a step increase in RPP. They suggest also that the principal inhibitory action of NO is quenching of superoxide, which otherwise potentiates dynamic components of the myogenic constriction in vivo. This primarily involves the first stage of a two-stage myogenic response

<html>Activation of Phospholipase Cγ₁ Protects Renal Arteriolar VSMCs from H₂O₂-Induced Cell Death</html>

We evaluated the effect of hydrogen peroxide (H2O2) on viability of vascular smooth muscle cells (VSMCs) of renal resistance arterioles and determined whether responses are modulated by activation of PLCγ1

Endothelin A and B receptors of preglomerular vascular smooth muscle cells

BACKGROUND: The endothelin (ET) receptors are subclassified into ET(A,) which are purely vasoconstrictive, and ET(B). The ET(B) receptors may cause either vasodilation by stimulating the release of nitric oxide from endothelial cells, or vasoconstriction of vascular smooth muscle cells (VSMC). The relative contribution of ET(A) and ET(B) receptors to calcium signaling and vasoconstriction in the renal microcirculation is not clear. Our goal was to study the cytosolic calcium concentration ([Ca(2+)](i)) responses of fresh rat preglomerular VSMC and afferent arterioles to agonists and antagonists of ET(A) and ET(B) receptors in rats. METHODS: Fresh VSMC and afferent arterioles were isolated using the magnetized microsphere/sieving technique, followed by gentle collagenase digestion. [Ca(2+)](i) was measured with fura-2 ratiometric fluorescence. RESULTS: Afferent arterioles and VSMC responded to ET-1 stimulation with a rapid peak increase in [Ca(2+)](i) (Delta= 287 +/- 81 and 342 +/- 55 nmol/L, respectively). The ET(B) receptor agonist IRL 1620 stimulated a rise in [Ca(2+)](i) in afferent arterioles (106 +/- 35 nmol/L); subsequent addition of ET-1 at the IRL 1620 nadir to stimulate ET(A) receptors caused a second peak that was twice as large (213 +/- 44 nmol/L). In VSMC, the ET(B) agonist peak increase was 99 +/- 12 nmol/L; addition of ET-1 then increased [Ca(2+)](i) by 294 +/- 23 nmol/L. The ET(B) inhibitor BQ-788 prevented stimulation of [Ca(2+)](i) by IRL 1620 in afferent arterioles and VSMC; subsequent stimulation of ET(A) receptors with ET-1 caused an increase in [Ca(2+)](i) (239 +/- 17 and 248 +/- 22 nmol/L). Pretreatment with the selective ET(A) inhibitor PD 156707 attenuated but did not abolish the responses to ET-1, suggesting that the residual [Ca(2+)](i) response was caused by ET(B) stimulation. CONCLUSION: These results indicate that fresh preglomerular VSMC as well as afferent arterioles have both ET(A) and ET(B) receptors, and that the rapid peak [Ca(2+)](i) responses to the ET(B) agonist IRL 1620 are less than half that of subsequent stimulation of ET(A) receptors with ET-1. The similarity of findings in isolated VSMC and afferent arterioles suggests that responses in VSMC in our arteriolar preparation overshadow any potential contribution of endothelial cells when reagents are administered abluminally

Defective G protein activation of the cAMP pathway in rat kidney during genetic hypertension.

The development of hypertension in the spontaneously hypertensive rat (SHR) is associated with renal dysfunction and vasoconstriction. The kidneys of young SHRs exhibit exaggerated reactivity to angiotensin II (Ang-II) and attenuated responses to vasodilators that normally activate the cAMP signal to buffer hormone-induced vasoconstriction. The present study investigates the mechanism(s) responsible for this abnormality in activation of the cAMP second-messenger pathway in hypertensive animals. Renal vascular reactivity was assessed in 7-week-old anesthetized SHRs and normotensive Wistar-Kyoto rats. The animals were pretreated with indomethacin to block prostanoid production throughout an experiment. Ang-II was injected into the renal artery either alone or mixed with the vasodilator fenoldopam, a dopamine-receptor agonist. These two opposing vasoactive agents were administered before and during intrarenal infusion of NaF or cholera toxin, two activators of G proteins that stimulate cAMP production. The results show that Ang-II reduced renal blood flow by 45% in both strains. In Wistar-Kyoto rats, fenoldopam reduced the Ang-II-induced decrease in renal blood flow from -45% to -30%. This protective effect of fenoldopam was increased further during infusion of NaF or cholera toxin (-18% or -19% decrease in renal blood flow). In SHRs, fenoldopam failed to attenuate Ang II-mediated vasoconstriction (-45% vs. -44%). In contrast, fenoldopam effectively blunted the Ang-II-induced vasoconstriction when it was given concurrently with NaF or cholera toxin (-27 or -31% decrease in renal blood flow). These findings provide evidence for defective interaction between receptor coupling and activation of guanine nucleotide stimulatory factor proteins in the renal microcirculation of 7-week-old SHRs. Such a deficiency could play an important role in renal dysfunction associated with the development of genetic hypertension

Angiotensin II receptors and renin release in rat glomerular afferent arterioles

Angiotensin II receptors and renin release in rat glomerular afferent arterioles. The purpose of recent studies was to investigate the expression of angiotensin II (Ang II) receptor sites in afferent arterioles freshly isolated from the rat kidney, and the role of Ang II on renin release by these vessels. The method of isolation and purification of renal microves-sels was based on iron oxide infusion into the kidneys and separation of the afferent arterioles from glomeruli and connective tissue with the aid of a magnetic field, successive passages through various sieves, and harvesting with collagenase. Ang II receptor characteristics were evaluated by radioligand binding studies using the non-peptide Ang II antagonists of AT1 (Dup-753 and -532) and AT2 (PD-123319 and CGP-42112) receptors. AT1 antagonists displaced up to 80% of the Ang II binding with high affinity (3 nM), whereas the remaining 20% showed low affinity for the Dup compounds and CGP-42112 (>10 µM), and intermediate affinity for PD-123319 (12 µM). These data suggest the existence of two Ang II receptor subtypes in the renal vasculature of the rat. In separate experiments, renin release by isolated afferent arterioles in vitro was 9 ng/hr/mg under control conditions. Ang II (0.1 µM) inhibited renin secretion by 20%, whereas the adenylyl cyclase activator forskolin (10 µM) stimulated renin secretion by 50%. In arterioles isolated from rats chronically treated with a converting enzyme inhibitor (perindoprilate) to reduce endogenous formation of Ang II, renin release increased 20-fold under control conditions in vitro and was further stimulated by forskolin. These results demonstrate that this preparation is a useful tool to study the functional role of Ang II and the control of renin release in the afferent arterioles

Angiotensin II receptors and renin release in rat glomerular afferent arterioles

Angiotensin II receptors and renin release in rat glomerular afferent arterioles. The purpose of recent studies was to investigate the expression of angiotensin II (Ang II) receptor sites in afferent arterioles freshly isolated from the rat kidney, and the role of Ang II on renin release by these vessels. The method of isolation and purification of renal microves-sels was based on iron oxide infusion into the kidneys and separation of the afferent arterioles from glomeruli and connective tissue with the aid of a magnetic field, successive passages through various sieves, and harvesting with collagenase. Ang II receptor characteristics were evaluated by radioligand binding studies using the non-peptide Ang II antagonists of AT1 (Dup-753 and -532) and AT2 (PD-123319 and CGP-42112) receptors. AT1 antagonists displaced up to 80% of the Ang II binding with high affinity (3 nM), whereas the remaining 20% showed low affinity for the Dup compounds and CGP-42112 (>10 µM), and intermediate affinity for PD-123319 (12 µM). These data suggest the existence of two Ang II receptor subtypes in the renal vasculature of the rat. In separate experiments, renin release by isolated afferent arterioles in vitro was 9 ng/hr/mg under control conditions. Ang II (0.1 µM) inhibited renin secretion by 20%, whereas the adenylyl cyclase activator forskolin (10 µM) stimulated renin secretion by 50%. In arterioles isolated from rats chronically treated with a converting enzyme inhibitor (perindoprilate) to reduce endogenous formation of Ang II, renin release increased 20-fold under control conditions in vitro and was further stimulated by forskolin. These results demonstrate that this preparation is a useful tool to study the functional role of Ang II and the control of renin release in the afferent arterioles