Renin Release Research Articles

COX-2 and the Kidney

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation. Nonselective NSAIDs inhibit both cyclooxygenase (COX)-1 and COX-2. Nephrotoxicity of nonselective NSAIDs has been well documented. The effects of selective COX-2 inhibitors on renal function and blood pressure are attracting increasing attention. In the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in the mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. Similar to nonselective NSAIDs, inhibition of COX-2 may cause edema and modest elevations in blood pressure in a minority of subjects. COX-2 inhibitors may also exacerbate preexisting hypertension or interfere with other antihypertensive drugs. Occasional acute renal failure has also been reported. Caution should be taken when COX-2 inhibitors are prescribed, especially in high-risk patients (including elderly patients and patients with volume depletion).

Activation of central opioid receptors determines the timing of hypotension during acute hemorrhage-induced hypovolemia in conscious sheep

After an initial compensatory phase, hemorrhage reduces blood pressure due to a widespread reduction of sympathetic nerve activity (decompensatory phase). Here, we investigate the influence of intracerebroventricular naloxone (opioid-receptor antagonist) and morphine (opioid-receptor agonist) on the two phases of hemorrhage, central and peripheral hemodynamics, and release of vasopressin and renin in chronically instrumented conscious sheep. Adult ewes were bled (0.7 ml x kg(-1) x min(-1)) from a jugular vein until mean arterial blood pressure (MAP) reached 50 mmHg. Starting 30 min before and continuing until 60 min after hemorrhage, either artificial cerebrospinal fluid (aCSF), naloxone, or morphine was infused intracerebroventricularly. Naloxone (200 microg/min but not 20 or 2.0 microg/min) significantly increased the hemorrhage volume compared with aCSF (19.5 +/- 3.2 vs. 13.9 +/- 1.1 ml/kg). Naloxone also increased heart rate and cardiac index. Morphine (2.0 microg/min) increased femoral blood flow and decreased hemorrhage volume needed to reduce MAP to 50 mmHg (8.9 +/- 1.5 vs. 13.9 +/- 1.1 ml/kg). The effects of morphine were abolished by naloxone at 20 microg/min. It is concluded that the commencement of the decompensatory phase of hemorrhage in conscious sheep involves endogenous activation of central opioid receptors. The effective dose of morphine most likely activated mu-opioid receptors, but they appear not to have been responsible for initiating decompensation as 1) naloxone only inhibited an endogenous mechanism at a dose much higher than the effective dose of morphine, and 2) the effects of morphine were blocked by a dose of naloxone, which, by itself, did not delay the decompensatory phase.

Estrogens, Salt, Blood Pressure, and Cardiovascular Disease in Women

Until recently cardiovascular disease in women has been a largely neglected and poorly understood issue, in part related to the misconception of a lower incidence among females compared with males, underrepresentation of females in clinical trials and observational studies until recently, and nontraditional presentation of symptoms in many females. Women have been typically viewed as largely protected from cardiovascular disease until menopause, and thereafter a rise in prevalence has been recognized, presumably related to hormonal decline. Hormonal replacement therapy (HRT) has been viewed as a useful prophylactic approach to ward off such events after menopause as well as to minimize menopausal symptoms. However, recent studies have yielded conflicting results regarding the protective effects of estrogen administration in preventing myocardial infarction and stroke.1–3 Indeed, the results of the Women’s Health Initiative have been interpreted as showing a neutral effect of estrogen administration in women in the 50 to 59 age decile and an adverse cardiovascular effect in older subjects.1 Whereas different pharmacological regimens may have been used in these replacement trials, the impact of these regimens on known risk factors for cardiovascular disease, such as blood pressure, lipoprotein profiles, insulin sensitivity, endothelin, C- reactive proteins, and other vasoactive substances, has not been carefully investigated. The relationship between estrogen and progesterone administration in the form of oral contraceptives and blood pressure, a major risk factor for stroke and cardiovascular disease, has been recognized for 4 decades.4 Population studies have documented a small but significant rise in systolic blood pressure in women receiving oral contraceptives in the 1970s, but only a small proportion of such women demonstrated a rise into the hypertensive range. Whereas epidemiologists remind us repeatedly that a …

A different vision of the osmolar regulation of renin secretion

in this issue, the proverbial question of osmotic regulation of renin secretion is revisited by Kurtz and Schweda ([9][1]) with rather surprising, yet apparently definitive, results. Since the development of osmotic diuretics, there has been much interest in whether renin secretion by the kidney is

Decreased intracellular calcium stimulates cAMP and renin release from isolated juxtaglomerular (JG) cells.

Intracellular calcium and cAMP are the two primary second messengers regulating renin release; cAMP stimulates renin release from juxtaglomerular (JG) cells while increased intracellular calcium inhibits it. We hypothesized that decreased intracellular calcium, which stimulates renin release, acts by stimulating adenylate cyclase, initiating cAMP-mediated renin secretion. We used a primary culture of JG cells isolated from C-57/B6 mice. 70–80% confluent JG cells in serum-free DMEM were incubated for 2 hr with or without (controls) 100 uM of the cytosolic calcium chelator 5′5 dimethyl BAPTA-AM to selectively decrease the intracellular calcium. Measurements of renin release and JG cell cAMP content were determined by radioimmunoassay. Basal renin release in controls was 1,404 ±321 ng AngI/ml/hr/mg prot. Addition of BAPTA-AM increased renin release by 172 ±34 % (p<0.05). The JG cell intracellular cAMP content in untreated controls was 6,198 ±1,770 fmole/ml/mg prot, and was increased 144 ±15% (p<0.05) by BAPTA-AM treatment. Thus, lowering intracellular calcium within the JG cell by chelation resulted in a significant increase in JG cell cAMP content as well as a significant increase in renin release. We conclude that the stimulation of renin induced by lowering the intracellular calcium concentration is due to a subsequent stimulation of adenylate cyclase, increasing the renin-stimulating second messenger cAMP. Supported by NIH RO-1 HL076469.

Cyclosporine A increases renin release from single juxtaglomerular cells in a calcium‐dependent manner

It is well known that the immunosuppressant cyclosporine A (CsA) stimulates the renin-angiotensin system, but the mechanism behind remains obscure. Cyclosporine A is an inhibitor of the calcium-activated phosphatase calcineurin, and it is possible that CsA exerts its effect on renin release through a direct effect in juxtaglomerular (JG)-cells. The aim of this study was to determine the effect of CsA on renin secretion, using electrophysiological methods on single rat JG cells. Membrane capacitance (Cm) was recorded as a measure of exocytosis. Results: Extracellular application of CsA (5 μM) increased membrane capacitance (Cm) by 10.7% ± 2.9% (n=5; P<0.05). When the experiments were repeated with a PKA-blocker (RpcAMPs (5 μM)) in the patch pipette, CsA (5 μM) still increased membrane capacitance significantly (15.8% ± 4.2% (n=4)), indicating that the increase in exocytosis is independent on the cAMP-PKA-pathway. The effect of CsA could be mimicked by chelating intracellular calcium using EGTA (0.1 mM) in the patch pipette. Under these experimental conditions, membrane capacitance increased 12.4% ± 3% (n=3). Addition of CsA (5 μM) did not result in any further increase in Cm (amounting to 11.8% ± 4.7% (n=3)), indicating a common signal transduction pathway. Conclusions Lowering intracellular calcium and cyclosporine A have common effects on Cm which could be due to calcineurin inhibition. In addition, calcineurin exerts a tonic supressor effect on renin release from juxtaglomerular cells. This study was supported by grants from Carlsbergfondet, the Novo Nordisk Foundation and the Danish Heart Foundation.

Molecular identification of a novel prostaglandin‐specific organic anion transporter (OAT‐PG) that is colocalized with prostaglandin producing enzyme Cox‐2 in the distal tubular cells.

Since Prostaglandins (PGs) are charged organic anions at physiological pH, PGs transport across the plasma membrane is a carrier-mediated process. In the kidney, especially at the distal tubules, prostaglandinE2 (PGE2) contributes to renal hemodynamics, renin release, and tubular sodium and water level regulation. In this study, we isolated a cDNA encoding a novel prostaglandin-specific transporter from mouse kidney. Because this transporter belongs to organic anion transporter (OAT) family (SLC22) structurally distinct from PGT (SLC0), we named it prostaglandin-specific organic anion transporter (OAT-PG). OAT-PG specifically mediated a transport of PGs, whereas other organic anions (para-aminohippurate, estrone sulfate, taurocholate), organic cations (TEA, choline), and zwitterion (carnitine) were not transported by OAT-PG. OAT-PG mRNA is expressed only in kidney. Immunohistochemical analysis showed that OAT-PG and cyclooxygenase-2 (cox-2) protein were colocalized at the renal distal tubular cells. We speculate OAT-PG and cox-2 would be functionally coupled in distal tubular cells for releasing PGE2 and contribute to renal physiological functions involving in PGE2 metabolism and signaling.

Adenosine A1 receptor antagonist improves intradialytic hypotension

Intradialytic hypotension is a most frequent complication of hemodialysis and may contribute to cardiovascular events and high mortality. There is a hypothesis that an increase in adenosine generation during hemodialysis may cause vasodilation and a decrease in cardiac output, which results in systemic hypotension. We studied whether this can be blocked by an adenosine A1 receptor antagonist. We investigated the effects of an A1 antagonist, FK352, injection in 30 chronic hemodialysis patients with frequent intradialytic hypotension by a prospective, multicenter, double-blind placebo-controlled study for 4 weeks after 4 weeks of the observation period. Intradialytic hypotension was defined as systolic blood pressure (SBP) less than 110 mmHg, with SBP drop of more than 30 mmHg from the predialysis level. The efficacy of FK352 was primarily assessed by the reduction rate of dialysis hypotension between the FK352 and placebo groups. Incidence of emergency treatments caused by hypotension was evaluated. FK352 (50 mg, intravenous) or an equivalent placebo was injected into the dialysis circuit 1 h after starting dialysis. Blood pressure and heart rate were monitored every 30 min during dialysis. FK352 significantly improved intradialytic hypotension (P=0.046), in that the reduction rates of intradialytic hypotension in the FK352 and placebo groups were -12.8% (Q1 (first quantile), Q3 (third quantile): -27.5, -1.7), and +8.3% (Q1, Q3: -16.6, +16.7), respectively. The frequency of discontinuation of dialysis was significantly reduced by FK352. No apparent side effects were observed from treatment with FK352. In conclusion, the A1 antagonist FK352 may offer a novel therapeutic option for chronic dialysis patients associated with intradialytic hypotension.

Conformational changes in prorenin during renin inhibition in vitro and in vivo

Some renin inhibitors induce changes in the conformation of prorenin in vitro and influence the quantification of active renin by immunoradiometric assays. Whether such changes in renin recognition by monoclonal antibodies exist after oral administration of aliskiren, the first orally available renin inhibitor, is not known. Two commercially available immunoradiometric assays (Cisbio and Nichols) were compared to determine immunoreactive active renin concentrations in plasma samples collected in a single oral dose crossover study comparing the renin inhibitor, aliskiren (300 mg), with the angiotensin II antagonist, valsartan (160 mg), in healthy male subjects. The addition of aliskiren to plasma samples in vitro, at concentrations of 1-100 micromol/l, increased active renin immunoreactivity in both the Cisbio and Nichols assays. In the crossover study, the two assays gave similar values for the plasma immunoreactive active renin concentration before treatment and following valsartan administration (intraclass coefficient for agreement between the two assays = 0.92). However, a Bland-Altman plot showed a systematic bias towards higher values (1.75-fold higher; 95% confidence interval = 1.02-3.01) in the Nichols than in the Cisbio assay following aliskiren administration. The difference between the results obtained with the two assays depended on incubation time. Depending on incubation conditions, circulating renin inhibitors interfere with the recognition of active renin molecules by the monoclonal antibodies used in commercially available assays. Careful consideration must therefore be given to the methodology used for quantifying immunoreactive plasma active renin when patients are treated with renin inhibitors, to avoid an overestimation of the magnitude of active renin release attributable to conformational changes in plasma prorenin.

Update on Cyclooxygenase-2 Inhibitors

Nonsteroidal anti-inflammatory drugs represent the most commonly used medications for the treatment of pain and inflammation, but numerous well-described side effects can limit their use. Cyclooxygenase-2 (COX-2) inhibitors were initially touted as a therapeutic strategy to avoid not only the gastrointestinal but also the renal and cardiovascular side effects of nonspecific nonsteroidal anti-inflammatory drugs. However, in the kidney, COX-2 is constitutively expressed and is highly regulated in response to alterations in intravascular volume. COX-2 metabolites have been implicated in mediation of renin release, regulation of sodium excretion, and maintenance of renal blood flow. This review summarizes the current state of knowledge about both renal and cardiovascular side effects that are attributed to COX-2 selective inhibitors.

Approaches to Establishing Angiotensin II as a Neurotransmitter Revisited

During the past 3 to 4 decades, there has been debate on the presence as well as the role of local tissue renin–angiotensin systems (RAS) in cardiovascular physiology and pathophysiology. Although it is now accepted that all components of the RAS are present in a variety of extrarenal tissues and their regulation may be independent of the circulating hormonal system, the factors contributing to this regulation are still not well understood. Also apparent is that our understanding of the relationships among various cell types expressing individual RAS components and production of specific angiotensin peptides in each tissue is still lacking. This is particularly true of the brain RAS, where even after 20years the question of whether there are angiotensinergic versus reninergic neurons or a complete functioning RAS in cerebrospinal fluid (CSF) or extracellular fluid or glia remains in question.1 Ever since early reports provided biochemical evidence of RAS components in brain, controversy regarding their cellular localization, independence from the circulating system, and authenticity of the proteins and peptides persists. It is well accepted that angiotensinogen is present in CSF/interstitial fluid and localization via immunocytochemistry and in situ hybridization histochemistry reveals that production of the precursor protein is primarily in glia, but also in neurons, within key cardiovascular nuclei. Lingering questions remain concerning local expression of authentic renin in tissues, especially given that prorenin or active renin can be sequestered from the circulation2 and other enzymes can exhibit similar proteolytic profiles under certain conditions. However, there is unequivocal evidence of discrete cells within the pituitary, choroid plexus, medulla oblongata, and hypothalamus that are positive for renin immunoreactivity colocalizing mainly with neurons, but in the medulla oblongata and subfornical organ, in glial elements as well. Evidence of renin mRNA in brain tissue provides a mechanism for local synthesis of the …

Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor AVE7688 in humans

Our objective was to define the pharmacodynamic profile of the new dual neutral endopeptidase (NEP)/angiotensin-converting enzyme (ACE) inhibitor AVE7688. We compared the effects of single oral doses of AVE7688 (5 and 25 mg) with those of 10 mg ramipril (R10), a selective ACE inhibitor, in a placebo-controlled crossover study in sodium-depleted normotensive subjects. We also compared the effects of 25 mg AVE7688 with those of a renin-angiotensin system (RAS) blockade induced by a high dose of an angiotensin II receptor antagonist (300 mg irbesartan) and a dual blockade of the RAS (150 mg irbesartan plus 10 mg ramipril) in sodium-replete normotensive subjects by use of the same study design. The in vivo inhibition of ACE and NEP was monitored by measuring the urinary excretion of N-acetyl-Ser-Asp-Lys-Pro (AcSDKP) and atrial natriuretic peptide (ANP), respectively. The intensity of RAS blockade was assessed by the increase in plasma active renin concentration. The 24-hour urine AcSDKP cumulative excretion increased significantly more after 25 mg AVE7688 (919 nmol [95% confidence interval (CI), 803-1052 nmol], P < .05) than after 5 mg AVE7688 (706 nmol [95% CI, 612-813 nmol]) or 10 mg ramipril (511 nmol [95% CI, 440-593 nmol]). The 25-mg dose of AVE7866 significantly and transiently (4 to 8 hours after drug intake) increased urinary ANP (2.02 +/- 1.05 ng/h, P < .05), whereas 5 mg AVE7688 (1.14 +/- 0.77 ng/h) and 10 mg ramipril (0.93 +/- 0.65 ng/h) had no effect compared with placebo (0.80 +/- 0.37 ng/h). In the low-salt panel the rise in plasma active renin concentration achieved 24 hours after dosing by 25 mg AVE7688 (247 pg/mL [95% CI, 157-389 pg/mL], P < .05) was significantly higher than that achieved by 5 mg AVE7688 (129 pg/mL [95% CI, 75-221 pg/mL]) or 10 mg ramipril (113 pg/mL [95% CI, 67-193 pg/mL]), which did not differ. In the high-salt panel group the effects of 25 mg AVE7688 on renin release did not significantly differ from those after administration of the combination of 150 mg irbesartan plus 10 mg ramipril or 300 mg irbesartan alone. All of these active drugs similarly decreased blood pressure compared with placebo. AVE7688 at a dose of 25 mg has a favorable pharmacodynamic profile compared with other RAS blockers. These results support further clinical studies of its long-term effects in essential or resistant hypertension, chronic proteinuric nephropathy, and chronic heart failure.

Point: The muscle metaboreflex does restore blood flow to contracting muscles

Imposed reductions in oxygen delivery to active skeletal muscle during dynamic exercise in conscious dogs evoke a powerful pressor response, termed the muscle metaboreflex. During submaximal work rates, the major mechanism used by this reflex is to increase cardiac output (CO), which generates a

Factor XII (Hageman factor) is a missing link between stress and hypercoagulability and plays an important role in the pathophysiology of ischemic stroke

A new hypothesis is presented on the function of factor XII, which is postulated to be a "missing link" between acute stress and transient hypercoagulability. The implications of this idea are developed to show how chronic stress, which involves activation of hypertension and migraine as well as hypercoagulability, can cause of cerebrovascular disease. "Acute stress" is defined as "the normal short-term physiological response to the perception of major threats or demands". "Chronic stress" is "the abnormal ongoing physiological response to the continuing perception of unresolvable major threats or demands". The factor XII hypothesis is as follows: Acute stress includes release of epinephrine by the adrenal medulla. Epinephrine activates platelets by binding to alpha-2A adrenergic receptors. Activated platelets convert pre-bound factor XII to its active form, which then initiates the intrinsic coagulation cascade. This can be called the "activated platelet initiation pathway" for coagulation. Neither tissue factor nor pre-formed thrombin is required. Thrombosis proceeds to completion, but only a minute amount of thrombin is formed, and the process normally stops at this point. In people who lapse into a state of chronic stress, essential hypertension, which is also a manifestation of stress, synergizes with hypercoagulability: there is both a baseline rise in blood pressure and systemic platelet activation as well as superimposed labile rises of both. Upregulation of these two stress parameters is atherogenic: epinephrine-activated platelets stimulating thrombin formation interact with endothelial cells activated by angiotensin II to cause, first, smooth muscle cell proliferation, which is a histological hallmark of atherosclerosis, and, lastly, a symptomatic thrombotic occlusion-the stroke. The migraine symptoms which often accompany this process are a marker of chronic stress and ongoing pathophysiologic damage. Therapeutic predictions are made regarding novel ways of blocking stress-induced hypercoagulability and hypertension. Hypercoagulability could be targeted by monoclonal antibodies directed against the platelet-specific alpha-2 adrenergic receptor or the (putative) platelet receptor for Factor XII; hypertension could be treated with monoclonal antibodies directed against the beta-adrenergic receptor in the juxtaglomerular apparatus or by surgical denervation of the kidneys, either of which would decrease the renin release which helps drive the hypertension.

Influence of the adenosine A1receptor on blood pressure regulation and renin release

The present study was performed to investigate the role of adenosine A1 receptors in regulating blood pressure in conscious mice. Adenosine A1-receptor knockout (A1R-/-) mice and their wild-type (A1R+/+) littermates were placed on standardized normal-salt (NS), high-salt (HS), or salt-deficient (SD) diets for a minimum of 10 days before telemetric blood pressure and urinary excretion measurements in metabolic cages. On the NS diet, daytime and nighttime mean arterial blood pressure (MAP) was 7-10 mmHg higher in A1R-/- than in A1R+/+ mice. HS diet did not affect the MAP in A1R-/- mice, but the daytime and nighttime MAP of the A1R+/+ mice increased by approximately 10 mmHg, to the same level as that in the A1R-/-. On the SD diet, day- and nighttime MAP decreased by approximately 6 mmHg in both A1R-/- and A1R+/+ mice, although the MAP remained higher in A1R-/- than in A1R+/+ mice. Although plasma renin levels decreased with increased salt intake in both genotypes, the A1R-/- mice had an approximately twofold higher plasma renin concentration on all diets compared with A1R+/+ mice. Sodium excretion was elevated in the A1R-/- compared with the A1R+/+ mice on the NS diet. There was no difference in sodium excretion between the two genotypes on the HS diet. Even on the SD diet, A1R-/- mice had an increased sodium excretion compared with A1R+/+ mice. An abolished tubuloglomerular feedback response and reduced tubular reabsorption can account for the elevated salt excretion found in A1R-/- animals. The elevated plasma renin concentrations found in the A1R-/- mice could also result in increased blood pressure. Our results confirm that adenosine, acting through the adenosine A1 receptor, plays an important role in regulating blood pressure, renin release, and sodium excretion.

Alternative renin regulatory pathways and the NKCC1 isoform

the macula densa is one of the classic regulatory pathways that control the release of renin from the juxtaglomerular cells ([11][1]). It senses the distal luminal NaCl concentration in the thick ascending limb and sends a signal to increase renin secretion in response to sustained decreases in

Increase in heme oxygenase-1 levels ameliorates renovascular hypertension

The heme oxygenase system (HO-1 and HO-2) catalyzes the conversion of heme to free iron, carbon monoxide (CO), a vasodepressor, and biliverdin, which is further converted to bilirubin, an antioxidant. HO-1 induction has been shown to suppress arachidonic acid metabolism by cytochrome P450 (CYP450) monooxygenases and cyclooxygenases (COX), and to decrease blood pressure in spontaneously hypertensive rats (SHR). The Goldblatt 2K1C model is a model of renovascular hypertension in which there is increased expression of COX-2 in the macula densa and increased renin release from the juxtaglomerular apparatus of the clipped kidney. We examined whether HO-1 overexpression, as a prophylactic approach, would attenuate renovascular hypertension and evaluated potential mechanisms that may account for its effect. 2K1C rats were treated with cobalt protoporphyrin (CoPP) or tin mesoporphyrin (SnMP) one day before surgery and weekly for three weeks thereafter. We measured systolic blood pressure, HO activity, HO-1, HO-2, COX-1 and COX-2 protein expression, heme content, and nitrotyrosine levels as indices of oxidative stress. Urinary prostaglandin excretion (PGE2), plasma renin activity (PRA), and plasma aldosterone levels were also measured. CoPP administration induced renal HO-1 expression by 20-fold and HO activity by 6-fold. This was associated with a reduction in heme content, nitrotyrosine levels, COX-2 expression and urinary PGE2 excretion, and attenuation of the development of hypertension in the 2K1C rats. There was no decrease in plasma renin activity; however, plasma aldosterone levels were significantly lower. In the 2K1C SnMP-treated rats, blood pressure was significantly higher than that of untreated 2K1C rats throughout the study, and the difference in the size of the smaller left clipped kidney compared to the nonclipped right kidney was significantly increased. These findings define an action of prolonged HO-1 induction to interrupt and counteract the influence of the renin-angiotensin-aldosterone system (RAAS) to increase in blood pressure in the 2K1C model of renovascular hypertension. Multiple mechanisms include a decrease in oxidative stress as indicated by the decrease in cellular heme and nitrotyrosine levels, an anti-inflammatory action as evidenced by a decrease in COX-2 and PGE2, interference with the action of angiontensin II (Ang II) as evidenced by an increase in PRA in the face of a decrease in PGE2 and aldosterone, as well as the inhibition of aldosterone synthesis.

Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers

The renin-angiotensin system plays a critical role in cardiovascular function, but little is known about the effects of specific cyclooxygenase 2 (COX-2) inhibition on this system in healthy humans under physiologic conditions. Twenty-one healthy female volunteers received, in a randomized, double-blind, crossover study, celecoxib 200 mg twice a day, indomethacin 50 mg three times a day, or placebo for 4 days and a single dose, each, on day 5. On day 5 of each treatment, the following parameters were assessed with subjects in an upright position before and after administration of 20 mg furosemide intravenously: plasma renin activity (PRA), plasma aldosterone, serum and urine electrolytes, and creatinine. Index metabolites of prostanoids were analyzed by gas chromatography-tandem mass spectrometry in 24-hour urine on day 4 and in 2-hour urines before and after furosemide administration. Baseline and furosemide-stimulated PRA were reduced to a similar degree by celecoxib and indomethacin. Plasma aldosterone and urinary excretion of potassium showed changes consistent with the alteration of PRA. Urinary excretion rates of prostaglandin E(2), (PGE(2)), 7alpha-hydroxy-5, 11-diketotetranor-prosta-1,16-dioic acid (PGE-M), and 2,3-dinor-thromboxane B(2) (TxB(2)) were not reduced by celecoxib, whereas indomethacin led to a decrease of 40%, 45%, and 80%, respectively. Both active treatments inhibited urinary excretion of 2,3-dinor-6-keto-PGF(1alpha) and 6-keto-PGF(1alpha) by 60% and 40%, respectively. Renin-release in healthy humans with normal salt intake is COX-2 dependent. While COX-1 is critical for renal and systemic PGE(2) production, renal prostacyclin synthesis is apparently COX-2 dependent. Finally, the previously demonstrated shift of the thromboxane-prostacyclin balance toward prothrombotic thromboxane by specific COX-2 inhibition is confirmed.

Putting the Brakes on Renin Release

Modulation of renin release from juxtaglomerular cells is critical for appropriate adjustments of the cardiovascular and renal systems to internal and external stresses, and dysregulation of renin release participates in the pathophysiology of hypertension, vascular disease, heart failure, and chronic renal disease. This justifies investments in research to elucidate the fundamental mechanisms regulating renin release. These investments have yielded, and continue to yield, high returns, as exemplified by Schweda et al1 in this issue of Hypertension , showing that A1 receptors mediate high perfusion pressure–induced inhibition of renin release, whereas prostaglandins (PGs) participate in low perfusion pressure–mediated stimulation of renin release. The purpose of this commentary is to discuss how Schweda et al’s findings confirm and challenge present-day models of renin release. As comprehensively reviewed by Davis and Freeman2 and Keeton and Campbell,3 investigators recognized early on that three systems, namely the sympathetic nervous system, the macula densa apparatus, and the intrarenal baroreceptor, are the primary physiological mechanisms regulating renin release from juxtaglomerular cells. A key development was the recognition that the two most important biochemical accelerators of renin release are catecholamines (mediating sympathetically induced renin release) and PGI2 (mediating macula densa–induced and intrarenal baroreceptor–stimulated renin release).4 Subsequently, a third autocoid, adenosine (acting via A1 receptors), was proposed to serve as a molecular brake on renin release and thereby to moderate the effects of catecholamines and PGI2 on renin secretion.5 Because cAMP is a critical second messenger mediating the exocytosis of renin from juxtaglomerular cells, adenylyl cyclase unifies these concepts because β-adrenoceptors and PGI2 receptors accelerate, whereas A1 receptors brake the rate of cAMP production. The results reported by Schweda et al corroborate the accelerator/brake model of renin release because they report that PGs mediate stimulation of renin release …

Blood Pressure–Dependent Inhibition of Renin Secretion Requires A1 Adenosine Receptors

Renal perfusion pressure (RPP) regulates renin release with a reduction of RPP stimulating and an elevation inhibiting renin secretion. The precise sensing and effector mechanisms by which changes in arterial pressure are linked to the exocytosis of renin are not well-defined. The present experiments were designed to study the potential role of adenosine as a mediator of this renal baroreceptor mechanism. In isolated perfused mouse kidneys a stepwise reduction of RPP from 90 mm Hg to 65 and 40 mm Hg stimulated renin secretion rates (RSR) 1.4-fold and 3.6-fold, whereas stepwise elevations of RPP from 90 mm Hg to 115 and 140 mm Hg suppressed RSR to 64% or 40% of baseline. Inactivation of A1 adenosine receptors by either pharmacological blockade (DPCPX 1 micromol/L) or genetic deletion (A1AR(-/-) mice) did not modify the stimulation of renin release by a low RPP, but completely prevented the suppression of renin secretion by higher perfusion pressures. In vivo, the induction of arterial hypertension by either acute (single subcutaneous injection) or chronic (osmotic minipump for 72 hours) application of phenylephrine significantly reduced plasma renin concentration (PRC) in wild-type mice to approximately 40% of control, whereas it did not significantly affect PRC in A1AR(-/-) mice. Together these data demonstrate that A1 adenosine receptors are indispensable for the inhibition of renin secretion by an increase in blood pressure, suggesting that formation and action of adenosine is responsible for baroreceptor-mediated inhibition of renin release. In contrast, the stimulation of the renin system by a low blood pressure appears to follow different pathways.