The role of endogenous angiotensin II in antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

We examined the possible involvement of endogenous angiotensin II (ANG II) in norepinephrine (NE) overflow and antidiuresis induced by renal nerve stimulation (RNS). RNS at a frequency of 0.5-2.0 Hz, which did not influence renal hemodynamics, produced significant reductions in urine flow and urinary excretion of sodium, and elevations in NE secretion rate (NESR) and renin secretion rate (RSR). Intrarenal arterial (i.r.a.) infusion of phentolamine (10 micrograms/kg/min) abolished the RNS-induced antidiuresis. In dogs receiving captopril (15 micrograms/kg/min i.v.), RNS-induced antidiuresis and increase in NESR were significantly attenuated. The i.r.a. administration of propranolol at 5 micrograms/kg/min, a dose that inhibited completely the RNS-induced increase in RSR, did not influence the alterations in NESR and urine formation in response to RNS. During ANG II infusion (1 ng/kg/min i.r.a.), RNS produced a reduction in urine formation and an increase in NESR, at a magnitude similar to that seen without ANG II infusion. These results suggest that RNS at a low frequency increased the NESR and RSR without affecting renal hemodynamics and that the antidiuretic effect was probably produced via the activation of postsynaptic alpha-adrenoceptors, but not via the ANG II receptor, located on the renal tubules. The release of NE appears to be modulated by ANG II through the activation of a facilitatory prejunctional mechanism, which is maximally stimulated by endogenously and locally generated basal levels of ANG II.     

Effects of endothelin-1 on antidiuresis and norepinephrine overflow induced by stimulation of renal nerves in anesthetized dogs.

The effects of endothelin-1 (ET-1) on renal function and norepinephrine (NE) overflow induced by renal nerve stimulation (RNS) were examined in anesthetized dogs, and comparisons were made with effects of Bay K 8644, a calcium channel agonist. RNS at a low frequency (0.5-2.0 Hz) produced significant decreases in urine flow and urinary excretion of sodium and increased NE secretion rates without influencing renal hemodynamics. RNS, at a high frequency of 2.5-5.0 Hz which diminishes renal hemodynamics, affected urine formation and NE secretion rate more potently than did low-frequency RNS. Intrarenal arterial infusion of ET-1 (1.0 ng/kg/min) decreased the baseline level of renal blood flow by 25% and that of urinary excretion of sodium by 54-69% but did not alter basal levels of NE secretion rate. During ET-1 infusion, low-frequency RNS-induced antidiuresis was observed to an extent similar to that seen without ET-1 infusion, whereas increase in NE secretion rate elicited by RNS was significantly inhibited by ET-1 infusion (45-65% of the values without ET-1 infusion). In addition, in the case of high-frequency RNS, ET-1 did not affect antidiuretic responses but did inhibit the increase in NE secretion rate by approximately 55%. In contrast, alterations in renal excretory responses and NE secretion rate elicited by RNS were not influenced by Bay K 8644 infusion (1.0 micrograms/kg/min), a dose that decreased renal blood flow to the same degree as did 1.0 ng/kg/min of ET-1.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of K-351 on adrenergically induced renin release and renal vasoconstriction in anesthetized dogs

Effect of 3-4-dihydro-8-(2-hydroxy-3-isopropylaminopropoxy)-3-nitroxy-2H-1-b enzopyran (K-351) infused into the renal artery on renin release during graded renal nerve stimulation (RNS) was investigated in pentobarbital-anesthetized dogs. K-351 (20 micrograms/min) produced significant suppression of the RNS-induced renin release; the renin secretion responses to RNS at lower frequencies (0.5 and 1 Hz) were almost abolished, and those at the highest frequency (3 Hz) were attenuated. K-351 also suppressed an increase in renal vascular resistance during RNS at 3 Hz. The same extent of inhibition in the renin secretion response to RNS was also obtained during infusion of DL-propranolol (100 micrograms/min). Inhibitory effect of K-351, prazosin, or phentolamine on the renal vasoconstriction induced by RNS and norepinephrine (NE) injected into the renal artery, an approximately 50% reduction in renal blood flow, was also assessed. K-351 and prazosin exerted a greater inhibitory effect on RNS-than on NE-induced vasoconstriction, and the opposite was true of phentolamine. The potency of K-351 in reducing the vasoconstriction due to RNS or NE was roughly estimated to be 10-30 times less than that of prazosin. These results suggest that K-351 shares beta- and alpha-adrenoceptor blocking properties, which effectively contribute to the suppression of adrenergically induced renin release and renal vasoconstriction.     

EFFECT OF ANGIOTENSIN-CONVERTING ENZYME INHIBITION ON RENAL NOREPINEPHRINE SPILLOVER RATE AND BAROREFLEX RESPONSES IN CONSCIOUS RABBITS

1. To evaluate the effects of angiotensin-converting enzyme (ACE) inhibition on sympathetic nerve activity, renal and total norepinephrine (NE) spillover rates were examined under control conditions and during enalaprilat infusion at rest and in response to sodium nitroprusside (SNP)-induced hypotension. 2. Resting renal and total NE spillover rate during enalaprilat infusion were similar to control values. 3. During SNP infusion at 10 μg/kg per min, renal NE spillover rate increased by 26% in enalaprilat-treated group and by 39% in controls, in response to falls in mean arterial pressure (MAP) of 25 and 19% respectively. 4. During sympathetic stimulation induced by SNP, total NE spillover rate was significantly increased in both groups, but the 50% (s.e.m. = 12) increase in the enalaprilat-treated group was less (P<0.05) than the 97% (s.e.m. = 16) change observed in controls. 5. Enalaprilat treatment resulted in a higher renal to total NE spillover ratio (P<0.05). The ratio fell in parallel in both groups during SNP-induced hypotension. 6. This study indicates that the sympathetic nervous system interacts dynamically with the renin-angiotensin system during hypotensive stimulation but this occurs predominantly at sites other than the kidney.     

Effects of a novel Ca2+ entry blocker, CD-349, and TMB-8 on renal vasoconstriction induced by angiotensin II and vasopressin in dogs.

The effects of a Ca2+ entry blocker CD-349 and an intracellular Ca2+ release inhibitor TMB-8 on renal vasoconstriction induced by angiotensin II (ANG II) and arg-vasopressin (AVP) were examined in anesthetized dogs. Intrarenal bolus injection of ANG II (3-10 ng/kg), AVP (5-20 ng/kg) or a Ca2+ entry promotor Bay K 8644 (0.1-0.4 micrograms/kg) produced a dose-dependent decrease in renal blood flow (RBF). Intrarenal infusion of CD-349 (0.03-0.3 micrograms/kg/min) suppressed the RBF responses to ANG II, AVP, and Bay K 8644. The RBF responses to ANG II and AVP were augmented slightly by intrarenal infusion of Bay K 8644 (0.3 micrograms/kg/min). Intrarenal infusion of TMB-8 (0.03-0.1 mg/kg/min) also suppressed the RBF responses to ANG II and AVP, whereas it did not affect the RBF response to Bay K 8644. These results suggest that vasoconstriction induced by ANG II or AVP is mediated both by the influx of Ca2+ through dihydropyridine-sensitive Ca2+ channels and the release of Ca2+ from TMB-8-sensitive Ca2+ pools in the in vivo dog kidney.     

Effects of arotinolol on hemodynamics and adrenergically induced renin release and renal vasoconstriction

Effects of 5-[2-[(3-tert-butylamino-2-hydroxypropylthio)-4-thiazolyl]-2- thiophenecarboxamide hydrochloride (arotinolol, S-596) on hemodynamic and adrenergically induced renin release and renal vasoconstriction were investigated in pentobarbital anesthetized dogs. Arotinolol (1 mg/kg i.v.) decreased systemic blood pressure (SBP), heart rate (HR) and renin secretion rate without change in renal blood flow. Degree of hypotension induced by arotinolol and basal plasma renin activity prior to the injection of the drug showed significant correlation. Arotinolol (20 micrograms/min) produced significant suppression of renal nerve stimulation (RNS)-induced renin release and attenuated an increase in renal vascular resistance during RNS at 3 Hz. The same extent of inhibition in the renin secretion response to RNS was also obtained during the infusion of dl-propranolol (100 micrograms/min). The renal vasoconstriction induced by RNS and norepinephrine (NE) was inhibited dose-dependently during the infusion of arotinolol (10, 30 and 100 micrograms/min), phentolamine (3, 10 and 30 micrograms/min) or prazosin (1, 3 and 10 micrograms/min). Arotinolol and prazosin exerted a greater inhibitory effect on RNS- than NE-induced vasoconstriction, and the opposite was true of phentolamine. Arotinolol dose-dependently decreased SBP and HR in a dose range of 0.01 to 3.0 mg/kg. The greater reduction in HR was observed with arotinolol at a lower dose range (0.01 to 0.1 mg/kg) than with propranolol. Arotinolol produced larger reduction of SBP, and less increase in carotid, vertebral, renal and external iliac vascular resistances than propranolol. These results suggest that arotinolol posesses a- and beta-adrenoceptor blocking properties, which effectively contribute to the suppression of the adrenergically induced renin release and renal vasoconstriction, and to the hypotensive effect.     

Exogenous L-arginine does not affect angiotensin II-induced renal vasoconstriction in man

Aims It has been suggested that provision of the substrate of nitric oxide (NO) synthesis, l-arginine, might influence the effects of renal vasoconstrictors. We have therefore studied the effects of pretreatment or concomitant administration of l-arginine on angiotensin II (ANG II)-increased renovascular resistance.
Methods The study was conducted in a double-blind, randomized, cross-over design. Eight healthy subjects were assigned to placebo or a continuous intravenous coinfusion of ANG II (5.0  ng  kg⁻¹ min⁻¹, infusion period 75  min) with l-arginine (17  mg  kg⁻¹ min⁻¹, infusion period 30  min). Nine further subjects received a continuous infusion of ANG II with or without pretreatment of l-arginine. Changes in renal plasma flow (RPF) were estimated by the steady state clearance of PAH.
Results l-arginine alone increased RPF to 110±10% over baseline ( P <0.003). The ANG II-induced decrease in RPF was not affected by pretreatment or coinfusion of l-arginine.
Conclusions Our results demonstrate that a counterregulatory response of the renal vasculature to high levels of ANG II does not depend on exogenous l-arginine. In healthy subjects, this lack of functional antagonism at the renal vasculature is therefore not a result of NO substrate availability.     

Effects of bradykinin on renal nerve stimulation-induced antidiuresis and norepinephrine overflow in anesthetized dogs

We examined effects of bradykinin on antidiuresis and norepinephrine overflow induced by renal nerve stimulation (RNS) in anesthetized dogs, with or without blockade of the B2 receptor by Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) or the endogenous nitric oxide generation by N(G)nitro-L-arginine (NOARG), a nitric oxide synthase inhibitor. RNS (0.5-2.0 Hz) produced significant decreases in urine flow, urinary and fractional excretions of sodium, and increases in norepinephrine secretion rate (NESR), without affecting systemic and renal hemodynamics. Intrarenal arterial infusion of bradykinin (5 ng/kg per minute) significantly suppressed the RNS-induced antidiuresis and increase in NESR. Hoe 140 (100 ng/kg per minute) did not affect the RNS-induced renal actions, but in the presence of Hoe 140, bradykinin-induced suppressive actions on reductions in urine formation and increases in NESR in response to RNS were abolished. RNS during intrarenal arterial infusion of NOARG (40 microg/kg per minute) led to potent reductions in urine formation and decreased renal blood flow and glomerular filtration rate. Simultaneously, NESR was markedly increased. During NOARG infusion, bradykinin-induced decreases in renal actions elicited by RNS were markedly attenuated. These findings suggest that bradykinin suppresses the RNS-induced norepinephrine overflow and renal actions via nitric oxide production mediated by activation of B2 receptor. Renal noradrenergic neurotransmission may be inhibited by bradykinin at the prejunctional level, when its local production in the kidney is enhanced.     

Effect of angiotensin II on aldosterone secretion in canine adrenal gland in situ

To investigate the effect of angiotensin (ANG) II on aldosterone (ALDO) secretion, we measured arterial and adrenal venous plasma aldosterone concentrations in anesthetized dogs. The intraadrenal arterial infusion of ANG II (0.3 ng/kg/min) or potassium chloride (KCl) (0.6 mg/min) increased ALDO secretion. The changes in ALDO secretion in response to ANG II were tested during the concomitant arterial infusion of two graded doses of losartan (10 and 100 ng/kg/min), PD 123319 (50 and 500 ng/kg/min), nifedipine (25 and 250 ng/kg/min), or TMB-8 (2 and 20 microg/kg/min). All of these test drugs except PD123319 inhibited the ANG II-induced increase in ALDO secretion. Losartan did not affect the KCl-induced increase in ALDO secretion. These results indicate that ANG II acts on ANG II type 1 receptors in the adrenal gland and enhances ALDO secretion. They also suggest the involvement of both intracellular and extracellular calcium in the aldosterone response to stimulation by ANG II. Under these in vivo experimental conditions, the KCl-stimulated ALDO secretion does not appear to involve ANG II formation in the adrenal gland.     

Effect of L-NG-nitro-arginine, inhibitor of nitric oxide synthesis, on autoregulation of renal blood flow in dogs.

The present experiments were designed to evaluate the importance of nitric oxide in the regulation of renal hemodynamics and the autoregulation of renal blood flow (RBF) in anesthetized dogs. RBF was measured by an electromagnetic flowmeter, and renal arterial pressure (RAP) was varied by an adjustable aortic clamp. The RAP-RBF relations were examined during the intrarenal infusion of saline or agents. The intrarenal infusion of L-NG-nitro-arginine (L-NNA, 40 micrograms/kg.min) at normal RAP decreased RBF and urine flow (UF), while the infusion of L-arginine.HCI (1 mg/kg.min) increased RBF and UF. Both agents did not affect the glomerular filtration rate and mean arterial pressure. The autoregulation of RBF was impaired during the L-NNA infusion. The L-arginine infusion did not affect autoregulatory efficiency. When L-NNA (40 micrograms/kg.min) and L-arginine were infused simultaneously into the renal artery, the autoregulation of RBF was maintained. However, a higher dose of L-NNA (200 micrograms/kg.min) impaired the autoregulation of RBF. These results suggest that the basal production and/or the release of nitric oxide contributes to the regulation of renal hemodynamics and urine formation. During the reduction of RAP, nitric oxide may play an important role in the autoregulation of RBF.     

Effects of sodium nitroprusside on renal functions and NO-cGMP production in anesthetized dogs

Although the renal nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) system plays an important role in maintaining urinary sodium and water excretion, effects of an authentic NO donor sodium nitroprusside (SNP) on urine formation have been controversial. In this study, we examined whether SNP increases renal NO release and cGMP production and induces natriuresis in the denervated kidney of anesthetized dogs. The intrarenal arterial infusion of SNP at 10, 30, and 100 ng/kg/min did not affect renal function or NO-cGMP production. The higher dose of SNP (1,000 ng/kg/min) reduced systemic blood pressure and urine flow rate. The antidiuresis was observed also in the contralateral control kidney, the degree of which was larger than that observed in the ipsilateral SNP-infused kidney. During the SNP infusion, reductions in urinary Na+ excretion, fractional Na+ excretion, and urinary nitrite + nitrate excretion occurred in the control kidney but not in the SNP-infused kidney. Urinary cGMP excretion and renal venous plasma cGMP concentration were significantly increased during the SNP infusion in the SNP-infused kidney but not in the control kidney. These renal effects of SNP were similar to those obtained by intrarenal arterial infusion of a specific NO donor, NOC 7 (300 ng/kg/min). These results suggest that SNP can produce nitric oxide and increase cGMP levels in the kidney and suppress sodium reabsorption, but the natriuretic property of SNP may be masked by its counteracting effects including the systemic hypotension in anesthetized dogs.     

Effects of adenosine on adrenergically induced renal vasoconstriction in dogs

The role of exogenous and endogenous adenosine in the neural control of renal blood flow was studied in anesthetized dogs. The plasma norepinephrine (NE) concentration was measured by high-performance liquid chromatography and the renal NE secretion rate was calculated. Renal nerve stimulation (1-3 Hz) reduced renal blood flow and increased NE secretion rate. The intrarenal arterial injection of NE (0.3-1.0 micrograms) also reduced renal blood flow. Infusion of adenosine (10-100 micrograms/min) into the renal artery attenuated the increase in NE secretion rate induced by renal nerve stimulation, but the nerve stimulation-induced decrease in renal blood flow was unaffected. On the other hand, adenosine potentiated the NE-induced renal blood flow response. Similar results were obtained with an adenosine potentiator, dipyridamole (1-10 micrograms/min). An adenosine receptor blocker, theophylline (0.3-1.0 mg/min), potentiated the NE secretion rate response induced by nerve stimulation, without any change in the renal blood flow response. The NE-induced renal blood flow response was attenuated by theophylline. These results suggest that adenosine inhibits neural NE release and enhances vasoconstriction in the dog kidney during sympathetic stimulation under in vivo conditions. These post- and presynaptic mechanisms may thus be activated by endogenous adenosine.     

EFFECTS OF ATRIAL NATRIURETIC PEPTIDE ON PHENYLEPHRINE-INDUCED RENIN RELEASE IN DOGS

1. The effect of atrial natriuretic peptide (ANP) on alpha-adrenoceptor agonist-induced renin release was examined in the de-ennervated kidney of the anaesthetized dog pretreated with propranolol (1 mg/kg, intravenous). 2. Phenylephrine (50 ng/kg per min) infused into the renal artery increased the renal secretion rate of renin (RSR) without affecting systemic blood pressure or renal blood flow. 3. Although basal RSR was unaffected, the phenylephrine-induced increase in RSR was abolished during intrarenal arterial infusion of ANP (10 ng/kg per min). 4. The results suggests that exogenously administered ANP could suppress alpha-adrenoceptor-mediated renin release in the dog.     

Chronic infusion of enalaprilat into hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension and cardiac hypertrophy by restoring neurotransmitters and cytokines

The renin–angiotensin system (RAS) in the brain is involved in the pathogenesis of hypertension. We hypothesized that inhibition of angiotensin-converting enzyme (ACE) in the hypothalamic paraventricular nucleus (PVN) attenuates angiotensin II (ANG II)-induced hypertension via restoring neurotransmitters and cytokines. Rats underwent subcutaneous infusions of ANG II or saline and bilateral PVN infusions of ACE inhibitor enalaprilat (ENL, 2.5 μg/h) or vehicle for 4 weeks. ANG II infusion resulted in higher mean arterial pressure and cardiac hypertrophy as indicated by increased whole heart weight/body weight ratio, whole heart weight/tibia length ratio, left ventricular weight/tibia length ratio, and mRNA expressions of cardiac atrial natriuretic peptide and beta-myosin heavy chain. These ANG II-infused rats had higher PVN levels of glutamate, norepinephrine, tyrosine hydroxylase, pro-inflammatory cytokines (PICs) and the chemokine monocyte chemoattractant protein-1, and lower PVN levels of gamma-aminobutyric acid, interleukin (IL)-10 and the 67-kDa isoform of glutamate decarboxylase (GAD67), and higher plasma levels of PICs, norepinephrine and aldosterone, and lower plasma IL-10, and higher renal sympathetic nerve activity. However, PVN treatment with ENL attenuated these changes. PVN microinjection of ANG II induced increases in IL-1β and IL-6, and a decrease in IL-10 in the PVN, and pretreatment with angiotensin II type 1 receptor (AT1-R) antagonist losartan attenuated these changes. These findings suggest that ANG II infusion induces an imbalance between excitatory and inhibitory neurotransmitters and an imbalance between pro- and anti-inflammatory cytokines in the PVN, and PVN inhibition of the RAS restores neurotransmitters and cytokines in the PVN, thereby attenuating ANG II-induced hypertension and cardiac hypertrophy.     

Effects of N-acetyl-L-cysteine on renal haemodynamics and function in early ischaemia-reperfusion injury in rats

1. Renal ischaemia-reperfusion (IR) severely compromises kidney function and has been shown to cause persistent abnormalities in intrarenal blood flow. The aim of the present study was to examine whether N-acetyl-L-cysteine (NAC), a thiol-containing anti-oxidant, improves renal haemodynamics and function during early reperfusion in rats subjected to renal IR. 2. Male Sprague-Dawley rats were divided into groups receiving either isotonic saline (IR-Saline; n = 8) or NAC (IR-NAC; n = 8) prior to (200 mg/kg, i.p., 24 and 12 h before acute experimentation) and during acute renal clearance experiments (bolus 150 mg/kg followed by a continuous infusion of 43 mg/kg per h, i.v.). During acute experimentation, thiobutabarbital-anaesthetized rats were subjected to a right-sided nephrectomy, followed by left kidney IR (40 min renal artery occlusion). Left kidney function and blood flow and intrarenal cortical and outer medullary perfusion measured by laser-Doppler flowmetry was analysed at baseline, during ischaemia and for 80 min of reperfusion. 3. Renal IR produced an approximate 85% reduction in glomerular filtration rate (GFR) and a pronounced increase in fractional urinary sodium excretion, throughout reperfusion, with no statistically significant differences between groups. 4. During reperfusion, total renal blood flow and cortical and outer medullary perfusion rapidly returned to levels not significantly different from baseline in both groups. The relative increase in renal vascular resistance in response to IR was more pronounced in NAC-treated rats compared with saline-treated animals (P < 0.05). 5. In conclusion, treatment with NAC did not improve kidney function during the first 80 min after renal IR. In addition, the marked reduction in GFR following reperfusion was not associated with any detectable abnormalities in intrarenal perfusion.     

Serotonin-induced renin release in the dog kidney

The effect of serotonin (5-HT) on renin release was examined in denervated kidney of the pentobarbital-anesthetized dog. The intrarenal arterial infusion of a large dose of 5-HT (1 micrograms/kg per min) increased the renin secretion rate with an initial decrease and a subsequent increase in renal blood flow. Systemic blood pressure or heart rate was unaffected. The renin release induced by 5-HT was suppressed during intrarenal arterial infusion of a 5-HT1 and 5-HT2 antagonist, methysergide (30 micrograms/kg per min), or a selective 5-HT2 antagonist, ketanserin (3 micrograms/kg per min). A cyclooxygenase inhibitor, indomethacin (5 mg/kg i.v.), also suppressed the 5-HT-induced renin release. These results suggest that stimulation of renal 5-HT receptors, probably of the 5-HT2 type, can induce renin release from the dog kidney, which may be dependent on renal prostaglandin production. The present results, however, do not allow us to conclude that the renal 5-HT receptors play a physiological role in the control of renin release.     

Regional blood flow responses to acute ANG II infusion: effects of nitric oxide synthase inhibition.

We hypothesized that nitric oxide (NO) opposes regional vasoconstriction caused by acute angiotensin II (ANG II) infusion in conscious rats. Mean arterial pressure (MAP), blood flow, and vascular conductance (regional blood flow/ MAP; ml/min/100 g/mm Hg) were measured and/or calculated before and at 2 min of ANG II infusion (0.05 or 1 microg/kg/min, i.a.) in the absence and presence of NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME), 0.25 or 1 mg/kg, i.a.]. ANG II reduced stomach and hindlimb conductance only after NOS inhibition. For example, whereas 0.05 microg/kg/min ANG II did not attenuate conductance in the stomach (i.e., 1.04+/-0.08 to 0.93+/-0.12 ml/min/100 g/mm Hg), this variable was reduced (i.e., 0.57+/-0.14 to 0.34-/+0.05 ml/min/100 g/mm Hg; p < 0.05) when ANG II was infused after 0.25 mg/kg L-NAME. In addition, whereas hindlimb conductance was similar before and after administering 1 microg/kg/min ANG II (i.e., 0.13+/-0.01 and 0.09+/-0.02, respectively), this variable was reduced (i.e., 0.07+/-0.01 and 0.02+/-0.00, respectively; p < 0.05) when ANG II was infused after 1 mg/kg L-NAME. These findings indicate that NO opposes ANG II-induced vasoconstriction in the stomach and hindlimb. In contrast, whereas both doses of ANG II decreased (p < 0.05) vascular conductance in the kidneys and small and large intestine regardless of whether NOS inhibition was present, absolute vascular conductance was lower (p < 0.05) after L-NAME. For example, 1 microg/kg ANG II reduced renal conductance from 3.34+/-0.31 to 1.22+/-0.14 (p < 0.05). After 1 mg/kg L-NAME, renal conductance decreased from 1.39+/-0.18 to 0.72+/-0.16 (p < 0.05) during ANG II administration. Therefore the constrictor effects of NOS inhibition and ANG II are additive in these circulations. Taken together, our results indicate that the ability of NO to oppose ANG II-induced constriction is not homogeneous among regional circulations.     

Postglomerular vasoconstriction to angiotensin II and norepinephrine depends on intracellular calcium release

The current study was performed to determine the effect of calcium store depletion with cyclopiazonic acid (CPA) on the pre- and postglomerular vasoconstrictor responses to angiotensin II (ANG II) and norepinephrine (NE). CPA treatment significantly attenuated the afferent arteriolar response to 10 nM ANG II by 51% and to 1000 nM NE by 19%. Efferent arteriolar responses to ANG II and NE were also greatly attenuated in the presence of CPA. These data demonstrate that afferent and efferent arteriolar responses to ANG II and NE depend on release of calcium from CPA-sensitive intracellular stores. Furthermore, the postglomerular response to these agents exhibits a greater dependency on calcium release from intracellular stores.     

Effects of a novel alpha 1-adrenoceptor antagonist, SGB-1534, on adrenergically induced renal vasoconstriction in dogs

The alpha 1-adrenoceptor antagonistic effect of SGB-1534, a novel phenylpiperazine derivative, was examined in the renal vascular bed of pentobarbital-anesthetized dogs. Renal nerve stimulation (RNS, 1 ms duration, 2, 3 and 4 Hz) or intrarenal bolus injection of methoxamine (0.5, 1 and 2 micrograms/kg) or guanabenz (1, 3 and 10 micrograms/kg) produced a frequency- or dose-dependent decrease in renal blood flow (RBF). Both the RBF responses to RNS and methoxamine were inhibited dose dependently by an intrarenal infusion of SGB-1534 (1-30 ng/kg per min) or prazosin (30-300 ng/kg per min). When the equipotent inhibitory doses of the antagonists were compared, the antagonistic potency of SGB-1534 on the RBF responses evoked by RNS and methoxamine was about 30 times greater than that of prazosin. Prazosin also attenuated the RBF response to guanabenz, whereas SGB-1534 had little effect. These results suggest that SGB-1534 has a selective alpha 1-adrenoceptor-blocking property and that it inhibits neurally mediated renal vasoconstriction. The alpha 1-adrenoceptor antagonistic potency and selectivity of SGB-1534 may be greater than that of prazosin.     

Adenosine inhibits renin release induced by suprarenal-aortic constriction and prostacyclin

Summary The purpose of this study was to determine whether adenosine can attenuate the renin release response to a reduction in renal perfusion pressure. To this end, the secretion rate of renin was measured in six beta-blocked dogs at ambient arterial blood pressure and after a reduction of renal perfusion pressure to 80 mmHg. These measurements were made during a control period, an intrarenal infusion of adenosine at 10 and 30 g/min, and a recovery period. During the control and recovery periods renal artery hypotension significantly increased the secretion rate of renin. However, during the intrarenal infusions of adenosine, renin secretion rate did not increase significantly. Analysis of variance indicated that both doses of adenosine reduced the renin response to renal artery hypotension. In another six dogs with a single nonfiltering kidney, we again measured renin secretion during a control period, the intrarenal infusion of adenosine at 10 and 30 g/min, and a recovery period; however, in this study PGI₂ was used to stimulate renin release. Adenosine also significantly attenuated the renin release response to PGI2. We conclude that adenosine can inhibit the renin release response to both renal artery hypotension and PGI₂ and that this effect is most likely mediated by a direct action of adenosine on juxtaglomerular cells. Also, since PGI2 may be a mediator of the renin response to renal artery hypotension, the data are consistent with the hypothesis that adenosine inhibits the renin response to renal artery hypotension by attenuating the response of juxtaglomerular cells to PGI₂.This work was supported by NIH grant HL 35909, HL 40319 and HL 14192