Urinary excretion of renin and its biochemical properties in dogs.

The amount and biochemical properties of renin excreted by anesthetized dogs were investigated to elucidate the significance of urinary excretion in the metabolism of renin. Mean arterial blood pressure was 127 +/- 4 mm Hg, renal blood flow was 170 +/- 8 ml/min, glomerular filtration rate, 38.6 +/- 2.3 ml/min, and urine flow rate, 0.37 +/- 0.09 ml/min (n = 11). Urinary renin concentration (URC) was 9.2 +/- 2.1 ng angiotensin I (ANG I)/ml X hr (n = 11), as determined by radioimmunoassay for ANG I generated by incubation with semipurified homologous renin substrate. The ANG I-producing activity was inhibited by more than 90% by a specific antibody to dog kidney renin. The renin secretion rate from the left kidney into the renal vein was 76.4 +/- 13.3 ng ANG I/ml X hr per min (n = 11), and the simultaneous urinary excretion rate of renin was 2.3 +/- 0.4 ng ANG I/ml X hr per min (n = 11). Molecular weight of the urinary renin was 40,000 daltons. The pH dependent curves of the angiotensin-forming capacity of renin showed an optimum between pH 5.5 to 6.0, and the estimated Michaelis constant was 0.42 microM. These biochemical parameters were similar to the findings in the case of renin in the plasma and the kidney. Moreover, neither acid nor trypsin treatment altered the renin activity in the urine. Thus, the active form of renin with a molecular weight 40,000 was excreted into the urine in dogs. Urinary excretion of renin was a small percentage of the renin secretion rate, thereby indicating the minor role of urinary excretion in the metabolism of renin.

Effects of [D-Ala2]-methionine-enkephalin on blood pressure, heart rate, and baroreceptor reflex sensitivity in conscious cats.

Effects of intracerebroventricular (i.c.v) injection of [D-Ala2]-methionine-enkephalinamide (DAME) on blood pressure (BP), heart rate, and baroreceptor reflex sensitivity were studied in conscious cats. DAME was administered at doses between 5 and 100 nmoles. Blood pressure and heart rate increased dose dependently. The sensitivity of the baroreceptor reflex was attenuated for 15 to 60 minutes after DAME administration; this was independent of the BP changes. The effects of enkephalin on BP and baroreceptor reflex were abolished by i.c.v. naloxone. DAME caused pathological changes in the electroencephalogram (EEG) characterized by sharp waves in the hippocampus recordings and a loss of theta activity in the electrocorticogram. Behavioral changes were characterized by decreased physical mobility and anxiousness. These behavioral and EEG changes lasted for a longer period of time than the cardiovascular changes; they were also counteracted by naloxone. It is concluded that DAME produces a centrally mediated vasopressor response and a baroreceptor reflex attenuation and that, with respect to the time course, the effects on the baroreceptor reflex are separated from those on BP behavior and EEG, but not on heart rate. The fact that all effects of enkephalin on the parameters tested in the present experiment were completely antagonized by naloxone suggests that they are mediated by naloxone-sensitive enkephalin brain receptors.

Angiotensin II induces cardiac phenotypic modulation and remodeling in vivo in rats.

Cardiac phenotypic modulation and remodeling appear to be involved in the pathophysiology of cardiac hypertrophy and heart failure. We undertook this study to examine whether angiotensin II (Ang II) in vivo, independent of blood pressure, contributes to cardiac phenotypic modulation and remodeling. A low dose (200 ng/kg per minute) of Ang II was continuously infused into rats by osmotic minipump for 24 hours or 3 or 7 days to examine the effects on the expression of cardiac phenotype-related or fibrosis-related genes. This Ang II dose caused a small and gradual increase in blood pressure over 7 days. Left ventricular mRNAs for skeletal alpha-actin, beta-myosin heavy chain, atrial natriuretic polypeptide, and fibronectin were already increased by 6.9-, 1.8-, 4.8-, and 1.5-fold, respectively, after 24 hours of Ang II infusion and by 6.9-, 3.3-, 7.5-, and 2.5-fold, respectively, after 3 days, whereas ventricular alpha-myosin heavy chain and smooth muscle alpha-actin mRNAs were not significantly altered by Ang II infusion. Ventricular transforming growth factor-beta 1 and types I and III collagen mRNA levels did not increase at 24 hours and began to increase by 1.4-, 2.8-, and 2.1-fold, respectively, at 3 days. An increase in left ventricular weight occurred 3 days after Ang II infusion. Treatment with TCV-116 (3 mg/kg per day), a nonpeptide selective angiotensin type 1 receptor antagonist, completely inhibited the above-mentioned Ang II-induced increases in ventricular gene expressions and weight. Hydralazine (10 mg/kg per day), which completely normalized blood pressure, did not block cardiac hypertrophy or increased cardiac gene expressions by Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)

Transforming growth factor-beta 1 expression and phenotypic modulation in the kidney of hypertensive rats.

We have previously reported that renal mRNA levels for transforming growth factor-beta 1, fibronectin, and collagens were increased in 32-week-old stroke-prone spontaneously hypertensive rats (SHRSP) with severe nephrosclerosis. To elucidate the mechanism of hypertension-induced nephrosclerosis, we examined gene expression and localization of transforming growth factor-beta 1 and cellular phenotype in the kidney of 25-week-old SHRSP with moderate renal damage. Renal mRNA was measured by Northern blot analysis. The localization of transforming growth factor-beta 1 and cellular phenotype was determined by immunohistochemistry. In the kidney of 25-week-old SHRSP, renal transforming growth factor-beta 1 mRNA was elevated compared with Wistar-Kyoto rats (WKY), whereas renal collagen mRNAs of SHRSP were not increased. Immunoreactive transforming growth factor-beta 1 in SHRSP was mainly localized in glomerular cells. Furthermore, alpha-smooth muscle actin and desmin were significantly expressed in SHRSP glomerular cells, in contrast to negligible expression of these proteins in WKY. alpha-Smooth muscle actin staining was also observed in interstitial cells, and vimentin, another phenotypic marker, was expressed in atrophic tubular cells of SHRSP, despite no staining of these proteins in WKY. Furthermore, all these phenotypic changes in SHRSP were associated with increased cell proliferation, as shown by the increased number of proliferating cell nuclear antigen-positive cells. Treatment of SHRSP with cilazapril and nifedipine (from the age of 13 to 25 weeks) prevented the increase in transforming growth factor-beta 1 expression and the cellular phenotypic modulation and was accompanied by a reduction of urinary albumin excretion and inhibition of cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of angiotensin II in renal injury of deoxycorticosterone acetate-salt hypertensive rats.

To investigate the role of angiotensin II (Ang II) in hypertension-induced tissue injury, we gave TCV-116 (1 mg/kg per day PO), a nonpeptide Ang II type I receptor antagonist, or enalapril (10 mg/kg per day PO) to deoxycorticosterone acetate (DOCA)-salt hypertensive rats for 3 weeks and examined the effects on tissue mRNA levels for transforming growth factor-beta 1 (TGF-beta 1) and extracellular matrix components. Tissue mRNA levels were measured by Northern blot analysis. Renal mRNA levels for TGF-beta 1; types I, III, and IV collagen; and fibronectin in DOCA-salt hypertensive rats were increased by severalfold (P < .01) compared with sham-operated rats. In the aorta of DOCA-salt hypertensive rats, TGF-beta 1 and fibronectin mRNA levels were increased, but types I, III, and IV collagen mRNAs did not increase. In the heart, increased mRNA was found only for fibronectin. Thus, these gene expressions are regulated in a tissue-specific manner. TCV-116 or enalapril did not lower blood pressure in DOCA-salt hypertensive rats. However, the increase in renal mRNAs for TGF-beta 1 and extracellular matrix components in DOCA-salt hypertensive rats was significantly inhibited by treatment with TCV-116 or enalapril, which was associated with a significant decrease in urinary protein and albumin excretions and histological improvement of renal lesions. In contrast, in the aorta and heart these gene expressions were not affected by TCV-116 or enalapril. Thus, local Ang II may contribute to renal injury of DOCA-salt hypertension by stimulating the gene expression of TGF-beta 1 and extracellular matrix components.

Dissociation between in vivo and in vitro measurements of converting enzyme activity after chronic oral treatment with captopril in rats.

Intravenous administration of captopril (20 micrograms) produced inhibition of angiontensin I pressor responses by 70 percent and of plasma-converting enzyme activity by 72 percent. Oral treatment with captopril (50 mg/kg/day) for 1 week inhibited angiotensin I pressor responses more (84 percent) than plasma-converting enzyme activity (23 percent). Four month oral treatment of normotensive and spontaneously hypertensive rats with captopril (50 mg/kg/day) led to 68 and 71 percent inhibition of angiotensin I pressor responses, but produced increases in plasma-converting enzyme activity of 123 and 94 percent, respectively. In spontaneously hypertensive rats, elevated converting enzyme activity in the medulla oblongata was measured after this treatment. It is concluded that plasma-converting enzyme activity measurements can be dissociated from the in vivo inhibition of converting enzyme. Chronic oral captopril treatment results in an induction of converting enzyme biosynthesis not only in peripheral tissue but also in the brain.

Effect of the platelet-activating factor antagonist, TCV-309, and the cyclo-oxygenase inhibitor, ibuprofen, on the haemodynamic changes in canine experimental endotoxic shock.

1. The present study was conducted in order to examine the effects of the platelet-activating factor (PAF) antagonist, TCV-309, and the cyclo-oxygenase inhibitor, ibuprofen, on the acute haemodynamic responses to endotoxin in anaesthetized dogs. 2. Endotoxin (2 mg kg-1, i.v.) induced a severe hypotension by decreasing both total peripheral resistance (TPR) and cardiac output. Endotoxin also decreased central venous pressure and increased effective vascular compliance (EVC), indicating a blood pooling in the capacitance vessels. 3. The endotoxin-induced hypotension but not the fall in cardiac output, was markedly attenuated by ibuprofen. Ibuprofen abolished the decrease in TPR and even caused a systemic vasoconstriction. Ibuprofen abolished the increase in EVC. 4. The hypotension caused by endotoxin was attenuated by TCV-309 to a lesser extent than ibuprofen. However, the reduction in cardiac output produced by endotoxin was markedly attenuated by the PAF antagonist. TCV-309 also abolished the increase in EVC. In contrast to ibuprofen, TCV-309 did not affect the decrease in TPR caused by endotoxin. 5. Combined treatment with ibuprofen and TCV-309 markedly attenuated the endotoxin-induced hypotension, but not the fall in cardiac output. Nevertheless, when compared with animals treated with ibuprofen alone, treatment with ibuprofen and TCV-309 partly attenuated the endotoxin-induced reduction in cardiac output and systemic vasoconstriction. 6. These data indicate that dilatation of both resistance vessels and capacitance vessels contributes to the endotoxin-induced hypotension. It is suggested that (i) both prostanoids and PAF are involved in dilatation of capacitance vessels, (ii) prostanoids, but not PAF cause dilatation of resistance vessels and(iii) PAF may partly contribute to prostanoid-independent reduction in cardiac output in acute canine experimental endotoxin shock.

Renal vascular effects of the selective endothelin receptor antagonists in anaesthetized rats.

1. Endothelin (ET) is a potent vasoconstrictor peptide which has been shown to have an important role in the regulation of systemic and renal haemodynamics. In order to elucidate the role of endogenous ET in the kidney, we examined the effects of ET receptor antagonists on systemic and renal vasculature in normotensive anaesthetized rats. 2. Intravenous injection of a selective ETA receptor antagonist, FR139317 (0.5 mumol kg-1, for 20 min) induced a very small fall in blood pressure. Similarly, a non-selective ETA/ETB receptor antagonist, TAK-044 (12.5 mumol kg-1, for 20 min) slightly decreased blood pressure. A selective ETB receptor antagonist, BQ-788 (0.5 mumol kg-1, for 20 min) had no effect of blood pressure. 3. FR139317 and TAK-044 did not affect renal blood flow or calculated renal vascular resistance. In contrast, BQ-788 significantly reduced renal blood flow by 18.2 +/- 2.4% and increased renal vascular resistance. Furthermore, the renal vascular action of BQ-788 was not observed when combined with FR139317. 4. Pretreatment with a nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 37 mumol kg-1, i.v.) and a cyclo-oxygenase inhibitor ibuprofen (44 mumol kg-1, i.v.) completely abolished the BQ-788-mediated renal vasoconstriction. 5. These results indicate that activation of ETB receptors by endogenous ET acts as a physiological brake for the ETA-mediated renal vasoconstriction; this effect appears to be mediated by stimulation of NO and/or vasodilator prostaglandin(s) release.

Attenuation of adrenomedullin-induced renal vasodilatation by NG-nitro L-arginine but not glibenclamide.

1. The present study was conducted in order to elucidate the in vivo contribution of nitric oxide (NO) and the glibenclamide-sensitive potassium channel in the renal action of adrenomedullin in anaesthetized dogs. 2. Intrarenal arterial infusion of adrenomedullin (20 ng kg-1 min-1) elicited a pronounced increase in renal blood flow with no changes in systemic blood pressure. The renal vasodilator action of adrenomedullin was markedly attenuated by pretreatment with NG-nitro L-arginine (L-NOARG), but this was reversed by continuous infusion of L-arginine. 3. Pretreatment with glibenclamide almost completely blocked the renal vasodilatation induced by lemakalim, but had no effect on the renal vasodilator and diuretic action of adrenomedullin. 4. Intrarenal arterial infusion of adrenomedullin induced diuresis and natriuresis. Diuretic and natriuretic action of adrenomedullin was also attenuated by L-NOARG. L-Arginine partly reversed the effect of L-NOARG and adrenomedullin-induced diuresis and natriuresis. 5. These data indicate that the in vivo renal vasodilator action of adrenomedullin is mediated by the release of NO. The glibenclamide-sensitive potassium channel is not involved in the renal action of adrenomedullin, at least, not in anaesthetized dogs. Since the inhibition of L-NOARG of adrenomedullin-induced diuresis occurred concomitantly with the attenuation of the renal vasodilator action of adrenomedullin, direct involvement of NO in adrenomedullin-induced diuresis remains to be established.

Effects of an AT1 receptor antagonist, an ACE inhibitor and a calcium channel antagonist on cardiac gene expressions in hypertensive rats.

1. This study was undertaken to determine whether the AT1 receptor directly contributes to hypertension-induced cardiac hypertrophy and gene expressions. 2. Stroke-prone spontaneously hypertensive rats (SHRSP) were given orally an AT1, receptor antagonist (losartan, 30 mg kg-1 day-1), an angiotensin converting enzyme inhibitor (enalapril 10 mg kg-1 day-1), a dihydropyridine calcium channel antagonist (amlodipine, 5 mg kg-1 day-1), or vehicle (control), for 8 weeks (from 16 to 24 weeks of age). The effects of each drug were compared on ventricular weight and mRNA levels for myocardial phenotype- and fibrosis-related genes. 3. Left ventricular hypertrophy of SHRSP was accompanied by the increase in mRNA levels for two foetal phenotypes of contractile proteins (skeletal alpha-actin and beta-myosin heavy chain (beta-MHC)), atrial natriuretic polypeptide (ANP), transforming growth factor-beta-1 (TGF-beta 1) and collagen, and a decrease in mRNA levels for an adult phenotype of contractile protein (alpha-MHC). Thus, the left ventricle of SHRSP was characterized by myocardial transition from an adult to a foetal phenotype and interstitial fibrosis at the molecular level. 4. Although losartan, enalapril and amlodipine lowered blood pressure of SHRSP to a comparable degree throughout the treatment, losartan caused regression of left ventricular hypertrophy of SHRSP to a greater extent than amlodipine (P < 0.01). 5. Losartan significantly decreased mRNA levels for skeletal alpha-actin, ANP, TGF-beta 1 and collagen types I, III and IV and increased alpha-MHC mRNA in the left ventricle of SHRSP. Amlodipine did not alter left ventricular ANP, alpha-MHC and collagen types I and IV mRNA levels of SHRSP. 6. The effects of enalapril on left ventricular hypertrophy and gene expressions of SHRSP were similar to those of losartan, except for the lack of inhibition of collagen type I expression by enalapril. 7. Unlike the hypertrophied left ventricle, there was no significant difference between losartan and amlodipine in the effects on non-hypertrophied right ventricular gene expressions of SHRSP. 8. Our results show that hypertension causes not only left ventricular hypertrophy but also molecular transition of myocardium to a foetal phenotype and interstitial fibrosis-related molecular changes. These hypertension-induced left ventricular molecular changes may be at least in part mediated by the direct action of local angiotensin II via the AT1, receptor.

AT1 receptor-mediated stimulation by angiotensin II of rat aortic fibronectin gene expression in vivo.

Fibronectin plays an important role in various vascular diseases. A subpressor (200 ng kg-1 min-1) or pressor (1000 ng kg-1 min-1) dose of angiotensin II was continuously infused into rats by osmotic minipump for various times, to investigate the effects on aortic fibronectin gene expression. In rats infused with a subpressor dose of angiotensin II in which blood pressure was normal for 3 days, aortic fibronectin mRNA levels started to increase by 1.4 fold at 12 h and reached the maximal levels (increased by 3.1 fold) at 3 days. Treatment with TCV-116 (3 mg kg-1 day-1), a non-peptide selective AT1 receptor antagonist, completely inhibited the angiotensin II-induced increase in aortic fibronectin mRNA, while hydralazine (10 mg kg-1 day-1) did not block this effect. Similar results were also obtained for a pressor dose of angiotensin II. Thus, angiotensin II directly stimulates aortic fibronectin gene expression in vivo, which is mediated by the AT1 receptor but not by blood pressure.

Renal effects of the nitric oxide synthase inhibitor, L-NG-nitroarginine, in dogs.

L-NG-Nitroarginine (LNNA), an analog of L-arginine, was infused into the renal artery of anesthetized dogs to assess the contribution of nitric oxide production in the regulation of renal hemodynamics and urine formation. Following intrarenal arterial infusion of LNNA (15 micrograms/kg/min) for 25 min, renal blood flow (RBF) gradually decreased and there was no reversion even 60 min after cessation of infusion, with no change in mean arterial blood pressure (MBP) and heart rate. Urine flow (UF) decreased while the glomerular filtration rate (GFR) did not change. The highest dose of LNNA (75 micrograms/kg/min) remarkably decreased RBF and increased MBP. The renal vasocontriction and pressor responses induced by the highest dose of LNNA were significantly antagonized by an intravenous administration of L-arginine (100 mg/kg/min). LNNA is characterized as a potent and long-lasting renal vasoconstrictor and decreases GFR, UF, and sodium excretion. It is suggested that nitric oxide produced in the kidney may have a significant role in the regulation of basal renal circulation and exert diuresis and natriuresis.

Effects of endothelin on renal hemodynamics and renal function in anesthetized dogs.

Porcine endothelin was infused directly into the renal artery of anesthetized dogs to evaluate the renal action of endothelin. Endothelin (0.2 to 5.0 ng/kg/min) elicited a dose-dependent reduction in the renal blood blow with no changes in systemic blood pressure. Endothelin infusion (0.2 ng/kg/min) decreased the renal blood flow by 30% and urinary sodium excretion by 50% without any changes in the glomerular filtration rate. However, higher doses did reduce glomerular filtration rate. These data suggest that endothelin preferentially constricts efferent arterioles and that endothelin may enhance the renal reabsorption of sodium.

Renal vasodilating and diuretic actions of a selective endothelin ETB receptor agonist, IRL1620.

The effects of a selective agonist for endothelin ETB receptors, Suc-[Glu9,Ala11,15]endothelin-1-(8-21), IRL1620, on renal hemodynamics and urine formation were studied in anesthetized dogs. Intrarenal arterial infusion of IRL1620 at a dose of 50 ng/kg/min increased renal blood flow from 3.37 +/- 0.30 (mean +/- S.E.) to a maximal value of 4.43 +/- 0.45 ml/g kidney weight per min (ml/g/min) at 9.1 +/- 1.0 min after the start of infusion, with no change in systemic blood pressure and heart rate. Urine flow rate increased and urine osmolality, osmolar clearance and free water reabsorption decreased significantly whereas glomerular filtration rate remained unchanged. In dogs given ibuprofen (12.5 mg/kg, i.v.) after the start of infusion of the peptide, renal blood flow increased slightly but significantly from 3.78 +/- 0.82 to 4.17 +/- 0.96 ml/g/min (1.0 +/- 0.1 min), followed by a gradual reduction in renal blood flow. In dogs given L-NG-nitroarginine (75 micrograms/kg/min), the renal blood flow decreased following intrarenal administration of IRL1620 (50 ng/kg/min). It is suggested that IRL1620 enhances the release of nitric oxide and prostaglandins in the kidney and promotes renal vasodilation. The IRL1620-induced reduction of urine osmolality and free water reabsorption was affected by neither ibuprofen nor L-NG-nitroarginine, thereby suggesting that the suppression of urine concentration did not seem to be linked to the enhanced production of nitric oxide or prostaglandins in the kidney.

Role of angiotensin II in extracellular matrix and transforming growth factor-beta 1 expression in hypertensive rats.

The in vivo effects of alacepril (1-[(S)-3-acetylthio-2-methylpropanoyl]- L-prolyl-L-phenylalanine), an angiotensin converting enzyme inhibitor, and SC-52458 (5-[(3,5-dibutyl-1H-1,2,4-triazol-1- yl)methyl]-2-[2-(1H-tetrazol-5-ylphenyl)]pyridine), an angiotensin AT1 receptor antagonist, were examined on the cardiac and aortic gene expressions of extracellular matrices and TGF-beta 1 in young spontaneously hypertensive rats (SHR). In SHR, types I and III collagen mRNAs were increased in the left ventricle, and in contrast, fibronectin, collagen IV, and transforming growth factor-beta 1 (TGF-beta 1) mRNAs were increased in aorta, compared with those in Wistar-Kyoto rats. All the enhanced mRNAs in both organs in SHR were significantly inhibited by the short-term treatment with the above two drugs. Thus, angiotensin AT1 receptor may play an important role in the regulation of extracellular matrices and TGF-beta 1 expressions in SHR.

Effect of adrenomedullin on renal hemodynamics and functions in dogs.

In order to elucidate the role of adrenomedullin in the kidney, we investigated the effects of adrenomedullin on renal hemodynamics and urine formation in anesthetized dogs. Intrarenal arterial infusion of adrenomedullin (0.8, 4 and 20 ng.kg-1.min-1) elicited dose-dependent increases in renal blood flow (by 10, 26 and 37%, respectively) with no change in blood pressure or heart rate, indicating a renal vasodilatory action of adrenomedullin. The glomerular filtration rate did not increase with the lower two doses, but increased marginally by 9% at the highest dose. Infusion of adrenomedullin at the rates of 4 and 20 ng.kg-1.min-1 increased urine flow and the urinary excretion of sodium and potassium dose dependently. Arterial and renal venous plasma renin activity was unaffected by adrenomedullin. These findings indicate that adrenomedullin is a potent renal vasodilatory peptide with a diuretic action. Since the threshold for the renal vasodilatory action of adrenomedullin is close to its physiological concentration in human plasma, adrenomedullin may play an important role in the regulation of renal function.

Endothelin stimulates the renal production of prostaglandin E2 and I2 in anesthetized dogs.

The infusion of endothelin into the renal artery of anesthetized dogs (5 ng/kg per min) decreased the renal blood flow without changing the blood pressure, indicating that endothelin caused renal vasoconstriction. The renal secretion rate of prostaglandin E2 and I2 markedly increased and these increases were abolished by pretreatment with aspirin. Furthermore, the renal vasoconstrictor effect of endothelin was potentiated by aspirin, suggesting a role of prostaglandins in the renal action of endothelin.

Acute sino-aortic denervation in rats produces a selective increase of adrenaline turnover in the dorsal midline area of the caudal medulla oblongata and a reduction of adrenaline levels in the anterior and posterior hypothalamus.

Acute sino-aortic denervation produces an acute reduction of adrenaline stores in the anterior and posterior hypothalamus and a reduction of noradrenaline stores in the dorsal midline area of the caudal medulla oblongata. Furthermore, removal of baroreflex afferents results in an increase of adrenaline turnover in the DCMO but not in the hypothalamus. The present findings give evidence for participation of adrenergic mechanisms in central baroreflex regulation. The findings can be interpreted according to the adrenaline vasodepressor hypothesis of hypertension.

Plasma-converting enzyme activity does not reflect effectiveness of oral treatment with captopril.

Intravenous Captopril (20 microgram) in rats produced similar inhibition of the pressor responses to intravenous ANG I (70%) and of plasma-converting enzyme activity (CEA) measured fluorometrically (72%). One week oral treatment with Captopril (50 mg/kg per day) inhibited ANG I pressor responses more (84%) than plasma CEA (23%). Four-month oral treatment of normotensive and spontaneously hypertensive rats with Captopril (50 mg/kg per day) led to a 68% and 71% inhibition of the ANG I pressor responses, but to a 123% and 94% increase of plasma CEA, respectively. Thus, plasma CEA measurements can be dissociated from the in vivo inhibition of converting enzyme (CE). Chronic oral Captopril treatment induces CE biosynthesis.

Renal effects of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) in anesthetized dogs.

The effects of a synthetic alpha-human atrial natriuretic polypeptide (alpha-hANP) on renal hemodynamics and urine formation were investigated in anesthetized dogs. Intrarenal arterial infusion of the peptide (1.0 microgram/min) increased renal blood flow, glomerular filtration rate and urine flow with no change in systemic blood pressure. A lower dose of alpha-hANP (0.2 micrograms/min) produced a significant diuresis and natriuresis, while renal hemodynamics remained unchanged. The urinary excretion of Na, Cl and Ca was increased in proportion to the urine flow. We propose that alpha-hANP inhibits tubular reabsorption of electrolytes, and in higher dose produces renal vasodilation.