The role of prostaglandins in the alpha- and beta-adrenoceptor mediated renin release response to graded renal nerve stimulation

The role of prostaglandins in the renin release response to renal nerve stimulation (RNS) at different intensities was examined in the anaesthetized dog. The animals were divided into two groups receiving either low or high level RNS, defined by the frequencies of stimulation producing reduction in renal blood flow by 5% or less and 50%. Indomethacin or diclofenac sodium (5 mg/kg i.v.), prostaglandin synthesis inhibitors, did not affect the renin release response to high level RNS by 31±8% (P<0.01). Addition of metoprolol, (0.5 mg/kg i.v.) beta-1-adrenoceptor antagonist, to indomethacin or diclofenac sodium resulted in a greater reduction (68±6%P<0.01) of the renin release response to high level RNS compared to that produced by either drug alone. Metoprolol, alone, reduced the renin release response to high level RNS by 37±14% (P<0.05). Phenoxybenzamine (0.6 g·kg^–1·min^–1), alphaadrenoceptor antagonist, into the renal artery practically abolished the renal vasoconstrictor response to high level RNS and reduced the renin release response by 50±7% (P<0.01). Addition of metoprolol to phenoxybenzamine practically abolished the renal vasoconstrictor response and the renin release response to high level RNS; 94±4% (P<0.01). Addition of phenoxybenzamine to indomethacin or diclofenac sodium practically abolished the renal vasoconstrictor response to high level RNS but did not produce any greater reduction of the renin release response than that produced by either drug alone. These findings suggest that low level RNS results in renin release which is not dependent on prostaglandins. High level RNS results in renin release which is partly mediated by beta-1-adrenoceptors and partly related to alpha-adrenoceptor mediated renal vasoconstriction. Prostaglandins are not involved in the beta-adrenoceptor mediated renin release but are involved in the renin release deriving from alpha-adrenoceptor mediated renal vasoconstriction.     

Pre-and postjunctional beta-adrenoceptor mediated effects on transmitter release and effector response in the isolated rat portal vein

Pre-and postjunctional control mechanisms of the portal vein of spontaneously hypertensive rats (SHR) were characterized. Emphasis was placed on the influence of the presynaptic beta-adrenoceptor mediated mechanism for regulation of neuronal noradrenaline (NA) release (studied as tritium overflow) and its consequences for the contractile response under in vitro conditions. It was found that isoprenaline increased, whereas dl/-propranolol decreased the release of neuronal NA during transmural nerve stimulation, while effector responses remained unaltered. d-Propranolol and the beta-1 selective adrenoceptor antagonist, metoprolol, did not affect these two variables. It is concluded that the presynaptic beta-adrenoceptors in the rat portal vein are mainly of the beta-2 type and mediate facilitation of neuronal transmitter release and that concomitant changes of the effector responses of this tissue are below the level of detection under the present experimental conditions.     

Nitric oxide in responses of regional kidney perfusion to renal nerve stimulation and renal ischaemia

The mechanisms underlying the relative insensitivity of medullary blood flow (MBF) to sympathetic drive remain unknown. We tested the effects of nitric oxide synthase blockade on regional kidney perfusion responses to electrical renal nerve stimulation (RNS) in pentobarbitone-anaesthetized rabbits. Under control conditions, RNS reduced renal blood flow (RBF), cortical blood flow (CBF) and MBF in a frequency-dependent manner. MBF was always reduced less than CBF or RBF. N^G-nitro-l-arginine increased mean arterial pressure (31±3 mmHg), reduced RBF (–8±1 ml/min) and MBF (–33±6 units), enhanced responses to RNS of RBF (from –48±6% to –58±6% at 2 Hz), CBF (from –38±6% to –43±4% at 2 Hz) and, particularly at low frequencies, MBF (from +1±18% to –32±11% at 2 Hz) and potentiated the RBF hyperaemic response following RNS (by 27±6% at 4 Hz). When glyceryl trinitrate was co-infused with N^G-nitro-l-arginine to restore basal nitrergic tone, responses to RNS and the subsequent hyperaemia were indistinguishable from control. Since resting renovascular tone or perfusion pressure has little impact on MBF responses to RNS, these present observations suggest that NO contributes to the blunted MBF response to RNS. Paradoxically, NO seems to blunt renal hyperaemia following acute RNS-induced ischaemia.     

Doxorubicin-induced hypotension in the beagle dog

Rapid intravenous administration of doxorubicin (0.18–3.0 mg/kg) lowered systemic arterial pressure in anesthesized beagle dogs. The threshold hypotensive dose was between 0.375 and 0.75 mg/kg; doses of 1.5–3.0 mg/kg produced up to 75% depression of arterial pressure for periods of 15 to >30 min. Respiratory difficulty was also present at these doses. When doxorubicin (1.5 mg/kg) was given repeatedly, the magnitude of the hypotensive response decreased with each succeeding dose. Pretreatment with either atropine (1.0 mg/kg) ordl-propranolol (0.5 mg/kg) did not alter the fall in arterial pressure due to doxorubicin administration. In contrast, the response was almost completely eliminated when compound 48/80 (1 mg/kg) was given 1 h prior to doxorubicin (1.5 mg/kg). Also, the intensity and duration of the hypotensive response was decreased by pretreatment with the H₁ histamine blocker tripelennamine (6 mg/kg), while the response was almost completely eliminated in animals pretreated with a combination of tripelennamine (6 mg/kg) and the H₂ histamine blocker cimetidine (15 mg/kg). Significant increases in plasma histamine were detected immediately after the injection of doxorubicin (1.5 mg/kg).Thus, rapid release of histamine following administration of low doses of doxorubicin decreases systemic arterial pressure; this response can be attenuated by agents that alter the action of histamine.     

Effect on renin release of inhibiting renal nitric oxide synthesis in anaesthetized dogs

Nitric oxide plays an important role in the regulation of basal renal blood flow. This study was performed to examine whether selective inhibiti± of renal nitric oxide synthesis affects renin release in vivo. Accordingly, in six barbiturate-anaesthetized dogs renin release was examined before and after intrarenal infusion of the selective inhibitor of nitric oxide synthesis, N^G-nitro-l -arginine (NOARG). NOARG was infused into the renal artery to yield a renal arterial blood concentration of 0.4 μmol ml^-1. NOARG did not change systemic arterial blood pressure and glomerular filtration rate, but reduced basal renal blood flow by 26 ± 2%. Urine flow, sodium and potassium excretion were reduced after inhibition of renal nitric oxide synthesis. Basal renin release (3 ± 2 μg AI min^-1) was not altered by NOARG infusion (1 ± 1 μg AI min^-1). To stimulate renin release the renal artery was constricted to a renal perfusion pressure of 50 mmHg. At this perfusion pressure infusion of NOARG reduced renin release significantly from 48 ± 11 μg AI min^-1to 14 ± 4 μg AI min^-1. In conclusion, inhibition of renal nitric oxide synthesis reduces basal renal blood flow and reduces renin release stimulated by renal arterial constriction. These findings indicate that renal nitric oxide modulates both renal blood flow and renin release in vivo.     

Analysis of beta-adrenoceptors mediating renin release produced by isoproterenol in conscious dogs

Types of beta-adrenoceptors mediating renin release induced by isoproterenol were investigated in conscious dogs. The nonselective beta-adrenoceptor blocking drugs propranolol, D-32, and pindolol significantly inhibited increases in heart rate and plasma renin activity and a fall of blood pressure produced by intravenous infusion of isoproterenol (10 microgram . kg-1 . 20 min-1). d-Propranolol and d-D-32 did not inhibit these three responses to isoproterenol. The selective beta 1-adrenoceptor blocking drug atenolol, at the oral dose of 6 mg/kg, which selectively suppressed isoproterenol-induced tachycardia, significantly inhibited the renin release caused by isoproterenol. By contrast, the renin release induced by isoproterenol was not modified by the selective beta 2-adrenoceptor blocking drug IPS-339 at an oral dose of 3 mg/kg, which fully and selectively antagonized the fall of blood pressure in response to isoproterenol. There was good correlation between suppression of isoproterenol-induced renin release and that of isoproterenol-induced tachycardia after various beta-adrenoceptor blocking drugs. These results lead to the conclusion that in conscious dogs the beta-adrenoceptors mediating release are mainly of the beta 1 type.     

Prostaglandins and nitric oxide in regional kidney blood flow responses to renal nerve stimulation

We examined the roles of cyclooxygenase products and of interactions between the cyclooxygenase and nitric oxide systems in the mechanisms underlying the relative insensitivity of medullary perfusion to renal nerve stimulation (RNS) in anaesthetized rabbits. To this end we examined the effects of ibuprofen and N^G-nitro-l-arginine (L-NNA), both alone and in combination, on the responses of regional kidney perfusion to RNS. Under control conditions, RNS produced frequency-dependent reductions in total renal blood flow (RBF; –82±3% at 6 Hz), cortical laser-Doppler flux (CLDF; –84±4% at 6 Hz) and, to a lesser extent, medullary laser-Doppler flux (MLDF; –46±7% at 6 Hz). Ibuprofen did not affect these responses significantly, suggesting that cyclooxygenase products have little net role in modulating renal vascular responses to RNS. L-NNA enhanced RBF (P=0.002), CLDF (P=0.03) and MLDF (P=0.03) responses to RNS. As we have shown previously, this effect of L-NNA was particularly prominent for MLDF at RNS frequencies 1.5 Hz. Subsequent administration of ibuprofen, in L-NNA-pretreated rabbits, did not affect responses to RNS significantly. We conclude that counter-regulatory actions of NO, but not of prostaglandins, partly underlie the relative insensitivity of medullary perfusion to renal nerve activation.     

Renin stimulation by isoproterenol and theophylline in the isolated perfused kidney.

The intrarenal mechanisms of renin release were studied in the isolated perfused rabbit kidney during stimulation by isoproterenol, 0.01 mug/kg per min, and by theophylline, 0.87 mg/kg per min. In the absence of urinary flow during the early stages of perfusion, isoproterenol caused a 17% increase of renal vein serum renin concentration (RVSRC) (P less than 0.001) without changing renal blood flow, renal vascular resistance, or serum potassium. dl-Propranolol, 2.0 mg/kg per min. abolished this isoproterenol-induced renin release. A moderate reduction in perfusion pressure prior to the infusion of isoproterenol resulted in a marked additional stimulation of renin release. Studies during and following ureteral occlusion demonstrated that theophylline stimulates renin release by decreasing renal vascular resistance, whereas the concomitant increase in sodium transport to the macula densa exerted an opposite effect. dl-Propranolol did not affect theophylline-induced renin secretion. It is concluded that single exogenous stimuli may activate more than one intrarenal mechanism simultaneously. Isoproterenol has a direct renin-stimulatory effect on intrarenal beta-adrenergic receptors that may be reinforced by baroreceptor stimulation. Theophylline stimulates renin via a baroreceptor mechanism, with simultaneous renin suppression via a sodium-macula densa effect.     

Effect of reduced chloride reabsorption on renin release in the isolated rat kidney

To investigate the relationship between tubular reabsorption of chloride and renal renin release in the isolated perfused rat kidney, perfusate renin activity was measured during substitution of either nitrate or thiocyanate for varying amounts of perfusate chloride but with maintained perfusate sodium concentration. Renin rose significantly as perfusate chloride fell; there was a sevenfold increase between perfusion with normal chloride and almost complete substitution of chloride by nitrate. With a normal perfusate chloride the addition of furosemide 10^–4 M to the perfusate also led to an increase in renin and a reduction in tubule chloride reabsorption. For all these experiments there was a significant negative correlation between renin and absolute tubular reabsorption of chloride (r=–0.68,P<0.001), but no such relationship with absolute sodium reabsorption. Renin release in a nonfiltering kidney, produced by elevating perfusate albumin concentration, increased approximately 40-fold. Thus increasing plasma oncotic pressure elevates renin by mechanisms additional to cessation of tubular chloride absorption. However, substitution of chloride in the perfusate by nitrate in this nonfiltering kidney did not further elevate renin release. We conclude that renin release is influenced by a signal dependent on, and inversely proportional to, chloride reabsorption in the thick ascending limb of the Loop of Henle.     

Inhibitory effect of endothelin on renin release in dog kidneys

To investigate the effect of endothelin on renin release, experiments were performed in barbiturate-anaesthetized dogs with denervated kidneys. Intrarenal infusion of endothelin (1 ng min^-1kg^-1body wt) reduced renal blood flow (RBF) from 145 ± 10 ml min^-1to 98 ± 9 ml min^-1without altering renin release (1 ± 1 μg angiotensin I (AI) min^-1). Renin release was then increased either by renal arterial constriction or ureteral occlusion. When renal arterial pressure was reduced to 50 mmHg, renin release averaged 79 ± 20 μg AI min^-1in six dogs and fell significantly to 24 ± 6 μg AI min^-1during endothelin infusion. During ureteral occlusion the inhibitory effect of endothelin on renin release either during inhibition of β-adrenergic activity with propranolol or after inhibiting prostaglandin synthesis by indomethacin during intrarenal infusion of isoproterenol was examined. After propranolol administration ureteral occlusion increased renin release from 5 ± 2 μg AI min^-1to 38 ± 12 μg AI min^-1in six dogs. Subsequent intrarenal endothelin infusion (1 ng min^-1kg^-1body wt) during maintained ureteral occlusion reduced renin release to 10 ± 3 μg AI min^-1. In six other dogs prostaglandin synthesis was inhibited by indomethacin. Subsequent infusion of isoproterenol (0.2 μg min^-1kg^-1body wt) to stimulate β-adrenoceptor activity increased renin release from 13 ± 4 μg AI min^-1to 68 ± 8 μg AI min^-1during ureteral occlusion. Intrarenal endothelin infusion (1 ng min^-1kg^-1body wt) reduced renin release to 22 ± 3 μg AI min^-1during continuous isoproterenol infusion and ureteral occlusion. Hence endothelin inhibits renin release induced by renal arterial constriction or ureteral occlusion. Similar inhibitory effects whether renin release was raised by increasing prostaglandin synthesis or by stimulating β-adrenergic activity suggest a direct effect of endothelin on the juxtaglomerular cells.     

Renin secretion from permeabilized juxtaglomerular cells requires a permeant cation

 The cytosolic concentration of chloride correlates directly with renin secretion from renal juxtaglomerular granular (JG) cells. In the present study, the mechanism by which chloride stimulates renin release was investigated in a preparation of permeabilized rat glomeruli with attached JG cells. An isosmotic increase in the concentration of chloride by 129 mM stimulated renin release 16- to 20-fold. Substitution of K⁺ by the impermeant cation N-methyl-d-glucamine (NMDG) abolished this response, while substitution with Na⁺ caused marginal inhibition. Substitution with Cs⁺ had no effect. Addition of sucrose, which permeates the secretory granules poorly, also abolished the stimulation of renin secretion by KCl. The response to KCl was not affected by K⁺-channel antagonists or by agonists of K⁺ channels. Chloride channel blockers were also without effect on the secretory response to KCl. When the ATP concentration was lowered from 1 to 0.1 mM renin release was stimulated, while an increase in the ATP concentration from 1 to 5 mM had no effect. Blockers of ATP-sensitive (K_ATP) channels did not modify the response to chloride. The present data suggest that chloride stimulates renin release after entry of KCl into the renin secretory granules which results in swelling and release of renin. Received: 3 July 1998 / Received after revision: 9 September 1998 / Accepted: 8 October 1998     

Further studies on renal nerve stimulation induced release of noradrenaline and dopamine from the canine kidney in situ

The renal venous outflow of dopamine and noradrenaline were studied in the canine kidney in situ in connection with renal nerve stimulation (RNS). RNS (0.5-4 Hz) caused frequency-dependent increases in the outflow of both catecholamines, which could be detected already at 0.5 Hz. The ratio dopamine/noradrenaline in renal venous plasma (approximately 0.15) was not influenced by varying the RNS parameters but was significantly enhanced (to about 0.25) by pretreatment with guanethidine according to a procedure previously used to demonstrate renal dopaminergic vasodilatation. The unstimulated kidney removed conjugated dopamine (which represents 98–99% of the total dopamine in plasma). During RNS the conjugated dopamine outflow to renal venous blood increased, but measurements of conjugated dopamine were less reliable than measurements of free dopamine to assess dopamine release from the kidney. When studying the renal nerve contributions to the renal venous outflow of dopamine and noradrenaline more accurate estimates may be obtained by correcting for the removal of catecholamines delivered to the kidney in arterial plasma. Such corrections were performed with endogenous adrenaline or radiolabelled noradrenaline. The two methods of correction yielded similar results and showed that RNS reduced catecholamine extraction in the kidney. The high ratio of dopamine/noradrenaline in kidney tissue (with a preferential distribution of dopamine to the cortex) and the dopamine outflow to renal venous plasma during RNS support the existence of specific dopaminergic nerves in the dog kidney.     

Effects of bradykinin and papaverine on renal autoregulation and renin release in the anaesthetized dog

The present study on six anaesthetized dogs investigates the influences of two different vasodilators, bradykinin and papaverine, on the relationship between autoregulation of renal blood flow and glomerular filtration rate, sodium excretion and renin release. At control conditions renal blood flow and glomerular filtration rate was autoregulated to the same levels of renal arterial pressure, 55 ± 3 and 58 ± 3 mmHg, respectively. Renin release increased from 0.3±0.1 to 22±4 μg AI min^-1, and sodium excretion decreased from 99 +29 to 4.6 ± 3.3 μmol min^-1 when renal arterial pressure was reduced from 122±6 to 44±2 mmHg. Infusion of bradykinin (50 ng kg^-1 min^-1) increased renal blood flow by 50% at control blood pressure without changing glomerular filtration rate, and both renal blood flow and glomerular filtration rate autoregulated to the same pressure levels as during control. Sodium excretion increased threefold at control renal arterial pressure, but was unchanged at low renal arterial pressure. Bradykinin did not change renin release neither at control nor low renal arterial pressure. Papaverine infusion at a rate of 4 mg min^-1 increased renal blood flow 50% without changing glomerular filtration rate. The lower pressure limits of renal blood flow and glomerular filtration rate autoregulation were increased to 94±6 and 93±6 mmHg, respectively. Sodium excretion increased sixfold at control renal arterial pressure and was still as high as the initial control values at low renal arterial pressure (97±27 μmol min^-1) accompanied by only a small increase in renin release (1.4±0.3 to 6±2 μg AI min^-1). We conclude that bradykinin does not influence autoregulatory pressure limits of renal blood flow and glomerular filtration rate nor the accompanying increase in renin release during reductions in renal arterial pressure. Papaverine on the other hand maintains high sodium chloride delivery to macula densa at low renal arterial ressure, suppressing renin release and impairing autoregulation through effects on the tubulo-glomerular feedback mechanism.     

Further studies on properties of renin granules isolated from rat kidney cortex

The properties of renin granules isolated from rat renal cortex were studied. Renin granules were thermolabile since in 10 min at 0°C twice as much renin was released as at +37°C. Addition of Ca++ (10^-6 M-10^-2 M) did not affect the spontaneous release at +37°C, pH 6.5, during 10 or 30 min incubation. However, when pH was elevated to above 7, renin release was significantly increased by Ca++ (10^-3 M). Additions of various amounts of KCl, NaCl or MgCl₂, which increased the osmolality less than 20 mOsm/kg, did not affect the stability of the renin granules. Mg-ATP (0.5 and 5 mM) as well as Mg-GTP (5 mM) stabilized renin granules at +37°C, pH 6.5, but the corresponding nitrogen analogues Mg-AMP-PNP and Mg-GMP-PNP (0.5 and 5 mM) were not effective. Neither did Mg-AMP (5 mM) nor ATP (5 mM) without Mg++ affect the renin release. No stabilization was observed by Mg-ATP and Mg-GTP in the purified granule preparations. The results suggest the importance of the cleavage of the terminal phosphate in the stabilization process. When the granules prepared at 300 mOsm/kg were first kept at hyperosmotic medium (range 300–1650 mOsm/kg) and then moved back to 300 mOsm/kg, the granules tend to lyse the more the greater was the reduction of the osmolality. The granules were more stable in isotonic sucrose than in isotonic ionic medium.     

Plasma Renin Activity Following Central Infusion of Angiotensin II and Altered CSF Sodium Concentration in the Conscious Goat

To study central influences on the renal release of renin, angiotensin II was infused into the lateral cerebral ventricle of conscious hydrated goats. CSF sodium concentration was increased or lowered by similar infusions of hypertonic NaCl or of isotonic fructose solution. Infusion of anglotensin II in doses from 0.5 to 1 μg caused a drop in plasma renin activity (PRA) and elicited a rise in blood pressure, antidiuresis, natriuresis, and thirst. Intraventricular infusion of hypertonic NaCl also suppressed PRA, induced anti-diuresis, natriuresis, and an inconsistent rise in blood pressure. Lowering of CSF [Na⁺] by infusion of isotonic fructose caused a rise in PRA and was followed by a water diuresis in the non-hydrated animal. The fructose infusions caused some decrease in renal K⁺ excretion but no consistent change in renal Na⁺ excretion. The results indicate that angiotensin II and changes in sodium balance modulate renal renin release also via the central nervous system.     

Evidence for an intrarenal beta receptor in control of renin release.

Infusion of isoproterenol intravenously in normal dogs at rates of 0.10 or 0.018 mug/min per kg body wt increased renin secretion; at the lower infusion rate arterial pressure (AP) and renal blood flow (RBF) were unchanged. Isoproterenol was also infused into the renal artery in normal dogs at 0.10 mug/min per kg; renin secretion increased in association with an increase in RBF but AP was unchanged. Plasma K concentration was consistently decreased in all three of the above experiments and because hypokalemia is known to increase renin release isoproterenol was not infused intrarenally at the lower rate; the decrease in plasma K level precluded relating the entire response in renin release to isoproterenol. Intrarenal infusion of propranolol at 0.05 mg/kg per h in Na-depleted dogs decreased renin secretion whereas intravenous infusion at the same dose failed to alter renin release. Intrarenal infusion of propranolol at this rate in Na-depleted dogs with a denervated, nonfiltering kidney also decreased renin release. In contrast, intrarenal infusion of phentolamine or phenoxybenzamine in normal dogs failed to alter renin secretion in doses that blocked alpha-adrenergic receptors. These experiments provide strong evidence for an intrarenal beta-adrenergic receptor that mediates renin release, and it seems likely from the experiment in the denervated, nonfiltering kidney that the receptor is located in the juxtaglomerular cells.     

Cyclooxygenase‐2 and the renal renin–angiotensin system

In the kidney, cyclooxygenase‐2 (COX‐2) is expressed in the macula densa/cTALH and medullary interstitial cells. The macula densa is involved in regulating afferent arteriolar tone and renin release by sensing alterations in luminal chloride via changes in the rate of Na⁺/K⁺/2Cl^? cotransport, and administration of non‐specific cyclooxygenase inhibitors will blunt increases in renin release mediated by macula densa sensing of decreases in luminal NaCl. High renin states [salt deficiency, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers, diuretic administration or experimental renovascular hypertension] are associated with increased macula densa/cTALH COX‐2 expression. Furthermore, there is evidence that angiotensin II and/or aldosterone may inhibit COX‐2 expression. In AT1 receptor knockout mice, COX‐2 expression is increased similar to increases with ACE inhibitors or AT1 receptor blockers. Direct administration of angiotensin II inhibits macula densa COX‐2 expression. Previous studies demonstrated that alterations in intraluminal chloride concentration are the signal for macula densa regulation of tubuloglomerular feedback and renin secretion, with high chloride stimulating tubuloglomerular feedback and low chloride stimulating renin release. When cultured cTALH or macula densa cells were incubated in media with selective substitution of chloride ions, COX‐2 expression and prostaglandin production were significantly increased. A variety of studies have indicated a role for COX‐2 in the macula densa mediation of renin release. In isolated perfused glomerular preparations, renin release induced by macula densa perfusion with a low chloride solution was inhibited by a COX‐2 inhibitor but not a COX‐1 inhibitor. In vivo studies in rats indicated that increased renin release in response to low‐salt diet, ACE inhibitor, loop diuretics or aortic coarctation could be inhibited by administration of COX‐2‐selective inhibitors. In mice with genetic deletion of COX‐2, ACE inhibitors or low‐salt diet failed to increase renal renin expression, although renin significantly increased in wild type mice. In contrast, in COX‐1 null mice there were no significant differences in either the basal or ACE inhibitor‐stimulated level of renal renin activity from plasma or renal tissue compared with wild type mice. In summary, there is increasing evidence that COX‐2 expression in the macula densa and surrounding cortical thick ascending limb cells is regulated by angiotensin II and is a modulator of renal renin production. These interactions of COX‐2 derived prostaglandins and the renin–angiotensin system may underlie physiological and pathophysiological regulation of renal function.     

Interaction of renal beta 1-adrenoceptors and prostaglandins in reflex renin release

Anesthetized dogs with isolated carotid sinus preparation were used to examine the mechanisms involved in the increase in renin secretion rate produced by carotid baroreceptor reflex renal nerve stimulation (RNS) at constant renal perfusion pressure. Lowering carotid sinus pressure by 41 +/- 5 mmHg for 10 min increased mean arterial pressure and heart rate, caused no or minimal renal hemodynamic changes, decreased urinary sodium excretion, and increased renin secretion rate. Metoprolol, a beta 1-adrenoceptor antagonist, given in the renal artery, did not affect the decrease in urinary sodium excretion but attenuated the increase in renin secretion rate, from 1,764 +/- 525 to 412 +/- 126 ng/min (70 +/- 8%). Indomethacin or meclofenamate, prostaglandin synthesis inhibitors, did not affect the decrease in urinary sodium excretion but attenuated the increase in renin secretion rate, from 1,523 +/- 416 to 866 +/- 413 ng/min (51 +/- 18%). Addition of metoprolol to indomethacin-pretreated dogs attenuated the increase in renin secretion rate from 833 +/- 327 to 94 +/- 60 ng/min (86 +/- 10%). These results indicate that reflex RNS at constant renal perfusion pressure results in an increase in renin secretion rate that is largely mediated by renal beta 1-adrenoceptors and is partly dependent on intact renal prostaglandin synthesis. The beta 1-adrenoceptor-mediated increase in renin secretion rate is independent of and not in series with renal prostaglandins.     

The effects of 11-deoxycorticosterone and antidiuretic hormone (pitressin) on fluid exchange and electrolyte excretion by normal and starved polyuric-polydipsic rabbits

Summary The effects of 11-deoxycorticosterone (DOC) and antidiuretic hormone (pitressin) (ADH) on fluid exchange and Na⁺ excretion have been studied in normal rabbits and in rabbits showing a typical polyuric-polydipsic response to 4 days starvation. DOC (0.5 mg/kg body wt/day i.m. during 4 days starvation) significantly reduced total Na⁺ excretion to 48% (mean) of the level observed over 4 days starvation alone, while water intake and urine output volumes fell to 71% and 73% of their previous values respectively. ADH (0.1 units/kg body wt/day i.m. during 4 days starvation) caused water intake and urine output to fall to 55% and 44% of the levels observed during starvation alone, whithout significantly affecting Na⁺ output. These occurrences were correlated with the gradients of [Na⁺], [K]⁺, [urea] and hydration in renal tissue at the end of 4 day periods. Similar observations were made on groups of rabbits which failed to show a polyuric-polydipsic response. The findings are interprected in terms of metabolic, endocrine and physical factors likely to affect tubular function and Na⁺ output during starvation and polyuria-polydipsia.     

Long-term elevations of dietary sodium produce parallel increases in the renal excretion of urodilatin and sodium

The effects of dietary sodium intake on the renal excretion of urodilatin and of sodium were examined in six healthy male subjects. The 24-day study period was divided into three phases of 8 days each. Subjects Ingested 2.8 mequiv sodium (kg body weight)^–1 day^–1 during the first phase, 5.6 mequiv (kg body weight)^–1 day^–1 during the second phase, and 8.4 mequiv (kg body weight)^–1 day^–1 during the third phase. The excretion of both sodium (P<0.002) and urodilatin (P<0.006) increased in response to the increasing dietary sodium, while urine flow did not change. Urinary urodilatin excretion correlated closely with renal sodium excretion (P<0.001). Serum aldosterone levels (P<0.01) as well as serum renin levels (P<0.05) significantly decreased with increasing sodium intake. Plasma [Arg]vasopressin levels increased significantly (P<0.05). Plasma atrial natriuretic factor and cGMP levels as well as urinary cGMP excretion rates were unaltered by the changes in sodium intake. We conclude from these results that the renal natriuretic peptide, urodilatin, but not the main cardiac member of the natriuretic peptide family may be involved in the regulation of day-to-day sodium balance.