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

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

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

Regulation of angiotensin II receptor AT1 subtypes in renal afferent arterioles during chronic changes in sodium diet.

Studies determined the effects of chronic changes in sodium diet on the expression, regulation, and function of different angiotensin II (ANG II) receptor subtypes in renal resistance vessels. Rats were fed low- or high-sodium diets for 3 wk before study. Receptor function was assessed in vivo by measuring transient renal blood flow responses to bolus injections of ANG II (2 ng) into the renal artery. ANG II produced less pronounced renal vasoconstriction in rats fed a low- compared with high-sodium diet (16% vs. 56% decrease in renal blood flow, P < 0.001). After acute blockade of ANG II formation by iv enalaprilat injection in sodium-restricted animals, ANG II produced a 40% decrease in renal blood flow, a level between untreated dietary groups and less than high salt diet. Intrarenal administration of angiotensin II receptor type 1 (AT1) receptor antagonists losartan or EXP-3174 simultaneously with ANG II caused dose-dependent inhibition of ANG II responses. Based on maximum vasoconstriction normalized to 100% ANG II effect in each group, AT1 receptor antagonists produced the same degree of blockade in all groups, with an apparent maximum of 80-90%. In contrast, similar doses of the angiotensin II receptor type 2 (AT2) receptor ligand CGP-42112 had only a weak inhibitory effect. In vitro equilibrium-saturation 125I-ANG II binding studies on freshly isolated afferent arterioles indicated that ANG II receptor density was lower in the low- vs. high-sodium animals (157 vs. 298 fmol/mg, P < 0.04); affinity was similar (0.65 nM). Losartan and EXP-3174 displaced up to 80-90% of the ANG II binding; fractional displacement was similar in both diet groups. In contrast, the AT2 receptor analogues PD-123319 and CGP-42112 at concentrations < 10(-6) M had no effect on ANG II binding. RT-PCR assays revealed the expression of both angiotensin II receptor type 1A (AT(1A)) and angiotensin II receptor type 1B (AT(1B)) subtypes in freshly isolated afferent arterioles, while there was very little AT2 receptor expression. Total AT1 receptor mRNA expression was suppressed by low sodium intake to 66% of control levels, whereas it was increased to 132% of control by high-sodium diet, as indicated by ribonuclease protection assay. Receptor regulation was associated with parallel changes in AT(1A) and AT(1B) expression; the AT(1A)/AT(1B) ratio was stable at 3.7. We conclude that AT1 receptors are the predominant ANG II receptor type in renal resistance vessels of 7-wk-old rats. Chronic changes in sodium intake caused parallel regulation of expression and amount of receptor protein of the two AT1 receptor genes that modulate receptor function and altered reactivity of renal vessels to ANG II

The Natriuretic Peptide Uroguanylin Elicits Physiologic Actions Through 2 Distinct Topoisomers

The peptide uroguanylin regulates electrolyte transport in the intestine and kidney. Human uroguanylin has two conformations that can be stably isolated, owing to their slow interconversion rate. The A isomer potently activates the guanylate cyclase-C receptor found primarily in the intestine. The B isomer, by contrast, is a very weak agonist of this receptor, leading to a widely-held assumption that it is physiologically irrelevant. We show here, however, that human uroguanylin B has potent natriuretic activity in the kidney. Interestingly, uroguanylin A and B both induce saliuretic responses, but the activity profiles for the two peptides differ markedly. The uroguanylin B dose-response curve is sigmoidal with a threshold dose near 10 nmol/kg body weight, whereas uroguanylin A has a comparable threshold, but a bell-shaped dose-response curve. Additionally, our study indicates a unique interplay between the A and B isoforms, such that the A form at high concentrations antagonizes the natriuretic action of the B form. These data show that the kidney contains a uroguanylin receptor whose pharmacological profile does not match that of the well-defined intestinal uroguanylin receptor (guanylate cyclase-C), an observation consistent with previous studies showing that the kidney of the guanylate cyclase-C knockout mouse remains responsive to uroguanylin. The results presented here also support the unconventional notion that distinct conformations of a single endocrine peptide can elicit different responses in different tissues

Superoxide Enhances Ca2+ Entry Through L-Type Channels in the Renal Afferent Arteriole

Reactive oxygen species regulate cardiovascular and renal function in health and disease. Superoxide participates in acute calcium signaling in afferent arterioles and renal vasoconstriction produced by angiotensin II, endothelin, thromboxane, and pressure-induced myogenic tone. Known mechanisms by which superoxide acts include quenching of nitric oxide and increased ADP ribosyl cyclase/ryanodine-mediated calcium mobilization. The effect(s) of superoxide on other calcium signaling pathways in the renal microcirculation is poorly understood. The present experiments examined the acute effect of superoxide generated by paraquat on calcium entry pathways in isolated rat afferent arterioles. The peak increase in cytosolic calcium concentration caused by KCl (40 mmol/L) was 99±14 nmol/L. The response to this membrane depolarization was mediated exclusively by L-type channels because it was abolished by nifedipine but was unaffected by the T-type channel blocker mibefradil. Paraquat increased superoxide production (dihydroethidium fluorescence), tripled the peak response to KCl to 314±68 nmol/L ( P <0.001) and doubled the plateau response. These effects were abolished by tempol and nitroblue tetrazolium, but not by catalase, confirming actions of superoxide and not of hydrogen peroxide. Unaffected by paraquat and superoxide was calcium entry through store-operated calcium channels activated by thapsigargin-induced calcium depletion of sarcoplasmic reticular stores. Also unresponsive to paraquat was ryanodine receptor–mediated calcium-induced calcium release from the sarcoplasmic reticulum. Our results provide new evidence that superoxide enhances calcium entry through L-type channels activated by membrane depolarization in rat cortical afferent arterioles, without affecting calcium entry through store-operated entry or ryanodine receptor–mediated calcium mobilization. # Novelty and Significance {#article-title-68