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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.

We examined the participation of endothelin ET A and ET B receptors in modulation by endothelin-1 of adrenal catecholamine secretion during cholinergic activation in pentobarbital-anesthetized dogs. Drugs were infused intra-arterially into the adrenal gland. Splanchnic nerve stimulation (1 and 3 Hz) increased adrenal catecholamine output in a frequency-dependent manner. Endothelin-1 (0.2, 0.6, and 2 ng/kg/min) enhanced the catecholamine response induced by the 3-Hz nerve stimulation. Under pretreatment with an endothelin ET A receptor antagonist ( R )-2-[( R )-2-[( S )-2-[[1-(hexahydro-1 H -azepinyl)]carbonyl]amino-4-methylpentanoyl]amino-3-(2-pyridyl) propionic acid (FR139317) (1 μg/kg/min), endothelin-1 suppressed the 1- and 3- Hz nerve stimulation-induced catecholamine response in a dose-dependent manner. No inhibitory or facilitatory effect of endothelin-1 was observed under simultaneous pretreatment with FR139317 and an endothelin ET B receptor antagonist N - cis 2,6-dimethylpiperidinocarbonyl- l -γ-methylleucyl- d -1-methoxycarbonyltryptophanyl- d -norleucine (BQ-788) (1 μg/kg/min) or under pretreatment with BQ-788 alone. These results suggest that in the dog adrenal gland, endothelin-1 facilitates and inhibits adrenal catecholamine secretion during cholinergic activation by stimulating endothelin ET A and ET B receptors, respectively.

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.

SUMMARY 1. We examined whether zaprinast, a putative cGMP-specific phosphodiesterase inhibitor, affects neural control of renal function in pentobarbital-anaesthetized dogs. 2. Renal nerve stimulation (1Hz, 1ms duration) reduced urine flow rate, urinary Na+ excretion (UNaV) and fractional excretion of Na+ (FENa) with little change in either renal blood flow (RBF) or glomerular filtration rate (GFR). 3. Intrarenal arterial infusion of zaprinast (10 and 100 μg/kg per min) increased basal urine flow rate, UNaV and FENa but not RBF or GFR. Zaprinast infusion (100 μg/kg per min) also increased renal venous plasma cGMP concentration and urinary cGMP excretion. 4. Renal nerve stimulation-induced reductions in UNaV and FENa were attenuated during zaprinast infusion, whereas the reduction in urine flow rate was resistant to zaprinast. 5. Renal nerve stimulation increased the renal venous plasma noradrenaline concentration and renal noradrenaline efflux, which remained unaffected during infusion of zaprinast (100 μg/kg per min). 6. The results of the present study suggest that zaprinast induces natriuresis and counteracts adrenergically induced anti-natriuresis by acting on renal tubular sites in the dog kidney in vivo.

Intrarenal arterial infusion of C-type natriuretic peptide (CNP, 50 ng/kg per min) increased urine flow rate without affecting glomerular filtration rate. Intrarenal arterial bolus injection of angiotensin II (25, 50 and 100 ng) or of norepinephrine (0.25, 0.5 and 1.0 microg) reduced renal blood flow. The blood flow response induced by angiotensin II was slightly attenuated but the response induced by norepinephrine was unaffected during CNP infusion. These results suggest that exogenous CNP, even at the pharmacological dose that can induce diuresis, has little effect on the canine renal vasculature.

1. To clarify the possible role of tissue catecholamines in the development of hypertension, we investigated the effect of bilateral renal denervation on the catecholamine contents of central and peripheral tissues in spontaneously hypertensive rats (SHR). 2. Norepinephrine (NE) content in renal cortex, renal medulla, and adrenal gland was higher in 7 week old SHR than age-matched Wistar-Kyoto rats (WKY). Dopamine (DA) content in the brainstem and hypothalamus was also higher in SHR, but NE and epinephrine (EPI) content in these areas were not different between strains. Similar differences in catecholamines were observed in 9 week old rats in which a sham operation of bilateral renal denervation was performed 2 weeks previously. 3. Bilateral renal denervation produced an almost complete reduction of NE content in the kidney in both strains and prevented the development of hypertension. DA content in the brainstem was also decreased by renal denervation in SHR but not in WKY. NE and EPI content in central tissues were not affected by renal denervation. 4. These results suggest that DA content in brainstem area, as well as NE content in the kidney, have a relationship in the development of hypertension in SHR.

SUMMARY 1. Intrarenal arterial infusion of a direct adenylate cyclase activator (NKH477; 300 ng/kg per min) increased renal blood flow, urine flow rate and urinary sodium excretion in anaesthetized dogs. 2. Intrarenal arterial infusion of endothelin (ET)-1 (2 ng/kg per min) reduced basal values of these parameters and glomerular filtration rate, which were recovered by the addition of NKH477 during ET-1 infusion. 3. These results demonstrate that NKH477 can counteract ET-1-induced antinatriuresis, mainly by restoring glomerular filtration.

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.

Experiments were carried out to examine whether endogenous angiotensin II (A-II) is involved in the regulation of release of norepinephrine (NE) elicited by the stimulation of spinal sympathetic nerves in pithed rats. It was assessed in terms of the alterations in concentrations of arterial blood plasma A-II and NE elicited by nerve stimulation (5 Hz, 50 V, 1 msec for 45 s) in pithed rats under vehicle or captopril (3 mg/kg, i.v.) treatment. Comparative study with pentobarbital anesthetized rats showed that pithing rats have the characteristics of lower basal blood pressure and lower NE level, whereas they have higher basal A-II level. In pithed rats treated with vehicle, pressor response to nerve stimulation was accompanied by increases in both A-II and NE level. In rats treated with captopril, the nerve stimulation caused about 40% lower increases in pressor response and NE level than those observed in rats treated with vehicle. These results suggest that the sympathetic nerve-induced NE release is facilitated by endogenous A-II in pithed rats, and that captopril exerts its inhibitory effect on the pressor response to nerve stimulation through the suppression of this interaction.

We examined possible interactions between intra-renal angiotensin II (ANG II) formation and norepinephrine (NE) release during renal sympathetic nerve stimulation (RNS) in anesthetized dogs. During 10 min of continuous RNS (1.5-2 Hz), the ANG II formation rates (ANG II-FR) and NE secretion rates (NE-SR) were determined at I and 10 min. Under control conditions, almost the same extent of increase in the NE-SR was observed at I and 10 min of RNS, whereas a significant increase in ANG II-FR was observed at 10 min but not at 1 min. During intrarenal arterial infusion of enalaprilat or losartan, the increase in NE-SR and reduction in renal blood flow at 10 min of RNS were suppressed, whereas the NE release and vasoconstriction responses at I min remained unaffected. The RNS-induced increases in ANG II-FR were completely abolished during infusion of enalaprilat. These results suggest that NE release on continuous RNS is enhanced by concomitantly formed ANG II. and this interaction depends on the time-related changes in intrarenal ANG II formation during RNS in the canine kidney.

We examined the hypotensive effect of enalapril in relation to the local renin-angiotensin system of the kidney in spontaneously hypertensive rats (SHR). Oral administration of enalapril for 7 days decreased mean arterial blood pressure and renal tissue angiotensin II concentration without affecting plasma angiotensin II concentration in SHR. The enalapril treatment did not affect maximum binding of angiotensin II to renal tubules and glomeruli in SHR. In normotensive Wistar-Kyoto rats, no significant changes in mean arterial blood pressure, renal and plasma angiotensin levels were observed with enalapril treatment. Direct infusion of enalapril into the renal medullary interstitium decreased mean arterial blood pressure in association with the reduction of renal tissue angiotensin II concentration without changes in plasma angiotensin II concentration in SHR. These observations suggest that the inhibition of angiotensin conversion in the kidney is important for the hypotensive action of enalapril.

The present study was undertaken to evaluate the effects of an adenylate cyclase activator N,N-dimethyl-beta-alanine[3R-(3alpha, 4alphabeta, 5beta, 6beta, 6aalpha, 10alpha, 10abeta, 10balpha)]-5(acetyloxy)-3-ethenyldodecahydro-10, 10b-dihydroxy-3, 4a, 7, 7, 10a-pentamethyl-1-oxo-1H-naphtho [2,1-b] pyran-6-yl ester hydrochloride (NKH477) on renal functions and cyclic AMP production in the dog kidney. The intrarenal arterial infusion of NKH477 (30, 100 and 300 ng kg(-1) min(-1)) increased renal blood flow, glomerular filtration rate, urine flow rate, urinary Na+ and cyclic AMP excretion, fractional Na+ excretion and arterial and renal venous plasma cyclic AMP concentrations in a dose-dependent manner. The intrarenal arterial infusion of rolipram (0.3 microg kg(-1) min(-1)), a cyclic AMP-specific phosphodiesterase inhibitor, also caused the same renal responses as NKH477. The increasing effects of NKH477 on renal blood flow, fractional Na+ excretion and renal venous plasma cyclic AMP concentration were facilitated in the presence of rolipram. NKH477 reduced glomerular filtration rate and filtration fraction in the presence of rolipram. The increasing effects of NKH477 on urine flow rate and urinary Na+ excretion were not affected by rolipram. The present results suggest that NKH477 increases glomerular filtration and suppresses tubular sodium reabsorption through activation of cyclic AMP production, and thereby induces natriuresis. The results also demonstrate that renal cyclic AMP level during the activation of adenylate cyclase is regulated by phosphodiesterase IV in both the vascular and tubular sites.

We examined the role of nitric oxide (NO) in adrenal catecholamine secretion in response to splanchnic nerve stimulation (SNS) and exogenous acetylcholine (ACh) in anesthetized dogs. The NO synthase inhibitor N ω-nitro-l-arginine methyl ester (l-NAME), NO donor 3-(2-hydroxy-1-methyl-2-nitrosohydrazino)- N-methyl-1-propanamine (NOC 7), and ACh were administered intra-arterially into the adrenal gland. The increases in catecholamine output induced by ACh (0.75–3 μg) were enhanced byl-NAME (0.1–1 mg/min) and inhibited by NOC 7 (0.2–2 μg/min). Inhibition by NOC 7 (2 μg/min) was observed during treatment withl-NAME (1 mg/min). The increases in catecholamine output induced by SNS (1–2 Hz) were inhibited byl-NAME and by NOC 7. No inhibitory effect of NOC 7 was observed during treatment withl-NAME. These results suggest that NO may play an inhibitory role in the regulation of adrenal catecholamine secretion in response to exogenous ACh.

Atrial natriuretic peptide (ANP, 10 and 50 ng/kg per min), infused into the renal artery, suppressed decreases in renal blood flow induced by intrarenal arterial injection of angiotensin II (Ang II, 25-100 ng) and norepinephrine (NE, 0.25-1 microgram) in anesthetized dogs. Sodium nitroprusside (SNP, 0.1-5.0 micrograms/kg per min) slightly attenuated the blood flow response to Ang II but not the response to NE. 8-Bromo cyclic GMP (8bcGMP, 0.5-25 micrograms/kg per min) did not suppress the blood flow response to Ang II. Although at a high dose ANP attenuated the blood flow response to Bay K 8644 (1-4 micrograms), nifedipine pretreatment (20 micrograms/kg plus 1 microgram/kg per min i.v.) did not affect the inhibitory effect of ANP on the NE-induced response. The vaso-inhibitory effects of ANP therefore could not be related exclusively to stimulation of cGMP production or inhibition of voltage-dependent Ca2+ channels.

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.

Intravenous diltiazem (10-300 micrograms/kg), verapamil (10-300 micrograms/kg), nifedipine (1-100 micrograms/kg) and nicardipine (1-100 micrograms/kg) inhibited the tachycardia caused by cardiac sympathetic nerve stimulation (SNS, 0.5-4 Hz) in decentralized hearts of anesthetized dogs. The dose range of each drug required to inhibit the SNS-induced tachycardia was almost equivalent to that required to produce the increase in coronary blood flow and the decrease in blood pressure. Nifedipine and nicardipine were equi-active and about 10 times more potent than diltiazem and verapamil in inhibiting the SNS-induced tachycardia. They produced a slight but dose-dependent slowing of the resting heart rate. The negative chronotropic potency was approximately nicardipine, verapamil greater than nifedipine, diltiazem. Bay K 8644 (30 micrograms/kg) antagonized the inhibitory effects of diltiazem (100 micrograms/kg) and nifedipine (30 micrograms/kg) on the SNS-induced tachycardia. Tachycardia induced by intracoronary norepinephrine (0.03-0.3 micrograms) was suppressed by diltiazem (30-300 micrograms/kg) and nifedipine (10-100 micrograms/kg). The inhibitory effects of calcium entry blocking drugs on the sympathetic tachycardia appear to be explained by the interference of the beta-adrenoceptor-mediated increase in slow inward current in the sinoatrial (SA) node. It is also suggested that other mechanisms different from calcium entry blocking action contribute to the negative chronotropic response to these calcium entry blocking drugs.

SUMMARY 1. The effect of atrial natriuretic peptide (ANP) on α-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 α-adrenoceptor-mediated renin release in the dog.

The present study was designed to investigate the effect of bradykinin on renin release in relation to prostaglandins by use of indomethacin, a cyclooxygenase inhibitor, in pentobarbital-anesthetized rats. A nonhypotensive dose of bradykinin (1 microgram/kg X min), which was infused intrarenally, significantly increased plasma renin activity approximately 1.8-fold as compared to the control period. In indomethacin (5 mg/kg, i.v.)-pretreated rats, bradykinin did not significantly increase plasma renin activity. These results suggest that bradykinin does not directly increase plasma renin activity and that prostaglandins may participate in the bradykinin-induced renin release under these experimental conditions.

the effect of captopril (D-3-mercapto-2-methylpropanoyl-L-proline), a converting enzyme inhibitor, on the systemic blood pressure in pentobarbital anesthetized rats was investigated. Experiments were performed in four groups of rats: untreated, Na-restricted, furosemide treated and bilaterally nephrectomized, respectively. Intravenous injection of 1 mg/kg of captopril caused a significant hypotensive effect in the three groups of rats but not in the nephrectomized group. Individual values for the hypotensive effect produced by captopril and plasma renin activity obtained just before injection of captopril showed a highly significant correlation.

SUMMARY 1. The effects of prazosin and yohimbine on pressor responses to sympathetic nerve stimulation and intravenous injections of noradrenaline, phenylephrine and clonidine were examined in pithed rats to determine the postjunctional location of α2-adrenoceptors in the vascular smooth muscle. 2. Prazosin antagonized the pressor responses to phenylephrine and to sympathetic nerve stimulation more effectively than the responses to noradrenaline and to clonidine. 3. Yohimbine antagonized the pressor responses to noradrenaline and to clonidine more effectively than the responses to sympathetic nerve stimulation and to phenylephrine. 4. These results suggest that α2-adrenoceptors as well as α1-adrenoceptors produce vasoconstriction in the rat vasculature and support the hypothesis that α1-adrenoceptors are predominantly located within the neuroeffector junction in contrast to an extrajunctional location of α2-adrenoceptors.

Phenylephrine (1 microgram/min) was infused into the renal artery of pentobarbitone anaesthetized dogs. Systemic blood pressure and renal blood flow were monitored. Arterial and renal venous blood samples were collected before and 10 min after the start of the infusion. Plasma prostaglandin E2 concentration and plasma renin activity were measured by radioimmunoassay. This dose of phenylephrine did not affect systemic blood pressure and renal blood flow. However, both prostaglandin E2 and renin secretion rates were increased by the infusion of phenylephrine. These results suggest that renal alpha-adrenoceptors participate in prostaglandin and renin release independent of the changes in systemic blood pressure and renal blood flow.