Role of AT1 receptors in the resetting of the baroreflex control of heart rate by angiotensin II in the rabbit.

Angiotensin II (Ang II) resets the baroreflex control of heart rate to a higher blood pressure. This action is apparently mediated via Ang II receptors in the area postrema, but it is not known if these are of the AT1 or AT2 subtype. In the present study the effects of losartan, a selective AT1 receptor antagonist, and PD 123319, a selective AT2 antagonist, on the cardiac baroreflex response to Ang II were investigated in conscious rabbits with chronically implanted arterial and venous catheters. Baroreflex curves were generated with intravenous infusions of phenylephrine and nitroprusside (2.6-25 micrograms/kg per min) and analyzed using a four-parameter logistic model to yield their upper and lower plateaus, arterial pressure at the midpoint of the heart rate range (BP50), and slope coefficient. From these four parameters, the gain and range of the baroreflex were calculated. Background intravenous infusion of Ang II at 10 ng/kg per min increased mean arterial pressure by 17 mmHg but did not change heart rate. Ang II shifted the baroreflex curve to the right as indicated by an increase in BP50 from 70.9 +/- 2.0 to 89.3 +/- 2.7 mmHg (P < 0.05), but did not change baroreflex gain significantly. Ang II did not alter the upper plateau of the baroreflex, but decreased the lower plateau from 119.4 +/- 10.3 to 73.6 +/- 11.5 beats per minute (bpm) (P < 0.05), extending the heart rate range by 52.5 bpm. Pretreatment with losartan completely abolished the pressor and cardiac baroreflex responses to Ang II. In contrast, PD 123319 had no effect on these responses. Administration of losartan alone to block endogenous Ang II shifted the baroreflex curve to the left as indicated by a decrease in BP50 from 71.2 +/- 2.7 to 64.7 +/- 2.5 mmHg (P < 0.05). These results demonstrate that the resetting of the baroreflex control of heart rate by Ang II is mediated by AT1 receptors, and that basal levels of endogenous Ang II exert a tonic action on the cardiac baroreflex to increase the setpoint around which the baroreflex regulates heart rate.

An effect of extrarenal beta adrenergic stimulation on the release of renin.

The present study was undertaken to examine whether the beta adrenergic agonist, isoproterenol, increases plasma renin activity (PRA) by activation of intrarenal or extrarenal pathways. The effects of intravenous (i.v.) and renal arterial infusion of isoproterenol on PRA and renin secretion rate (RSR) were compared in anesthetized dogs. In 12 studies in 9 dogs i.v. infusion of isoproterenol (0.009-0.018 mug/kg per min) was associated with an increase in PRA from 14.7 to 35.7 ng/ml per 3 hr (P < 0.001). PRA decreased to 19.4 ng/ml per 3 hr (P < 0.001) after cessation of the infusion. In innervated kidneys RSR increased from 1640 to 5062 U/min (P < 0.02) and decreased to 2132 U/min after cessation of the infusion (P < 0.05). In denervated kidneys the control RSR was significantly lower (455 U/min) but still increased during i.v. infusion of isoproterenol to 2762 U/min (P < 0.001) and decreased to 935 U/min (P < 0.001) after the infusion was stopped. These changes in PRA and RSR were associated with an increase in cardiac output averaging 49% and a large decrease in total peripheral resistance. These effects of i.v. isoproterenol to increase RSR were not mediated by changes in renal perfusion pressure since this was held constant by adjusting a suprarenal aortic clamp. In addition, there were no changes in glomerular filtration rate, renal plasma flow, or electrolyte excretion in either denervated or innervated kidneys during i.v. infusion of isoproterenol, and the concentration of potassium in plasma was unchanged. Prior hypophysectomy abolished the antidiuretic effect of i.v. isoproterenol but did not prevent the effect on RSR. In contrast, renal arterial infusion of isoproterenol at the same dose had no apparent effect on PRA and RSR in seven studies in five dogs and also did not produce changes in cardiac output, peripheral resistance or renal hemodynamics. These results do not provide evidence for a role of intrarenal beta adrenergic receptors in the control of renin release and indicate that the effect of beta adrenergic stimulation with isoproterenol to increase the release of renin is mediated by an extrarenal mechanism. Since the effect of i.v. isoproterenol occurred in the absence of changes in plasma potassium concentration, renal perfusion pressure, glomerular filtration rate, renal plasma flow, and electrolyte excretion and was not abolished by renal denervation, the possibility must be considered that the effect on renin secretion is mediated by circulatory factors. The changes in systemic hemodynamics which occurred with i.v. but not renal arterial infusion of isoproterenol may be involved in the initiation of such a pathway.

Effects of renin gene transfer on blood pressure and renin gene expression in a congenic strain of Dahl salt-resistant rats.

To investigate whether a BP-regulatory locus exists in the vicinity of the renin locus on rat chromosome 13, we transferred this chromosome segment from the Dahl salt-sensitive (S) rat onto the genetic background of the Dahl salt-resistant (R) rat. In congenic Dahl R rats carrying the S renin gene and fed an 8% salt diet, systolic BP was significantly lower than in progenitor Dahl R rats: 127 +/- 1 mmHg versus 138 +/- 4 mmHg, respectively (P < 0.05). Moreover, the decreased BP in the congenic Dahl R strain was associated with decreased kidney renin mRNA and decreased plasma renin concentration. These findings demonstrate that the Dahl S strain carries alleles in or near the renin locus that confer lower plasma renin concentration and lower BP than the corresponding alleles in the Dahl R strain, at least when studied on the genetic background of the Dahl R rat and in the environment of a high salt diet. The occurrence of coincident reductions in kidney renin mRNA, plasma renin concentration, and BP after interstrain transfer of naturally occurring renin gene variants strongly suggests that genetically determined variation in renin gene expression can affect BP.

Chronic exercise reduces sympathetic nerve activity in rabbits with pacing-induced heart failure: A role for angiotensin II.

BACKGROUND: Chronic exercise (EX) improves the quality of life and increases the survival of patients with chronic heart failure (CHF). Because sympathetic nerve activity is elevated in the CHF state, it is possible that EX is beneficial in this disease due to a decrease in sympathetic outflow. METHODS AND RESULTS: We evaluated arterial baroreflex function and resting renal sympathetic nerve activity (RSNA) in EX normal and CHF rabbits before and after angiotensin II type 1 (AT(1)) receptor blockade. Four groups of rabbits were studied: a normal non-EX group, a normal EX group, a CHF non-EX group, and a CHF EX group. EX lowered resting RSNA in rabbits with CHF but not in normal rabbits. In addition, EX increased arterial baroreflex sensitivity in the CHF group (heart rate slope: CHF 1. 7+/-0.3 bpm/mm Hg, EX CHF 4.9+/-0.3 bpm/mm Hg; P:<0.01; RSNA slope: CHF 2.2+/-0.2%max/mm Hg, EX CHF 5.7+/-0.4%max/mm Hg; P:<0.01. AT(1) receptor blockade enhanced baroreflex sensitivity in the non-EX CHF rabbits but had no effect in EX CHF rabbits. Concomitant with this effect, EX lowered the elevated plasma angiotensin II concentration in the CHF group. A significant positive correlation was observed between sympathetic nerve activity and plasma angiotensin II. CONCLUSIONS: These data strongly suggest that EX reduces the sympathoexcitatory state in the setting of CHF. Enhanced arterial baroreflex sensitivity may contribute to this reduction. In addition, EX lowers plasma angiotensin II concentration in CHF. These data further suggest that the lowering of angiotensin II may contribute to the decrease in sympathetic nerve activity after EX in the CHF state.

The renin-angiotensin system and body function.

Angiotensin II, the biologically active component of the renin-angiotensin system, acts throughout the body to produce an impressive number of cardiovascular, endocrine, metabolic, and behavioral effects. Major actions include elevation of arterial pressure, stimulation of aldosterone secretion, and a variety of effects on the kidneys, brain, and pituitary. Investigation of the role of the renin-angiotensin system in physiological regulation has been greatly facilitated by the availability of specific inhibitors of the formation or actions of angiotensin II, most notably converting-enzyme inhibitors and angiotensin receptor antagonists. Studies with these agents have clearly shown that the renin-angiotensin system plays an important role in the defense of body balance and blood pressure in hypovolemic state, including sodium deficiency and hemorrhage. The inhibitors also lower blood pressure in some forms of hypertension, and converting-enzyme inhibitors are proving to be effective antihypertensive agents.

Renin activity in dog brain: enzymological similarity to cathepsin D.

The distribution and biochemical properties of the renin activity present in the dog brain were compared with those of the lysosomal enzyme cathepsin D. Renin and cathepsin activity were present in all brain regions studied, in association with high angiotensinase activity. Brain renin activity was partially purified by ammonium sulfate fractionation and Sephadex gel filtration, resulting in the removal of angiotensinase activity. The specific brain renin activity increased approximately one hundred times during this procedure; cathepsin D activity accompanied the brain renin activity throughout the purification and showed a similar increase in specific activity. The renin and cathepsin activity in the partially purified preparation behaved identically during isoelectric focusing. The partially purified renin and cathepsin activity exhibited saturation kinetics with their respective substrates and were without activity above pH 6.0. Both enzyme activities were irreversibly inhibited by the pepsin inhibitor pepstatin, in nanomolar concentrations. These data, in conjunction with the literature concerning brain cathepsin, suggest that the renin activity in brain is due to cathepsin D, and that this renin activity exhibited by cathepsin D may be of limited significance under physiological conditions.

The effects of intracerebroventricular administration of renin on drinking and blood pressure.

The aim of the present investigation was to (a) determine if renin-substrate (angiotensinogen) is present in cerebrospinal fluid; (b) investigate the effects of intracerebroventricular administration of renin on drinking and blood pressure; and (c) determine if such effects are mediated via the formation of angiotensin II. Angiotensinogen concentration in cerebrospinal fluid was measured in 15 dogs and averaged 205 +/- 34 ng/ml. This value was approximately 1/5th of the corresponding plasma angiotensinogen concentration but the ratio of angiotensinogen:total protein in cerebrospinal fluid was approximately 15 times greater than in plasma. Intraventricular injection of hog renin (0.1 Goldblatt units) stimulated drinking in each of 8 dogs; the mean volume drunk in the 15 min period following the injection was 485 +/- 84 ml. When the renin was preceded by intraventricular saralasin acetate, a specific antagonist of angiotensin II, the drinking response was reduced to 8 +/- 6 ml. In eight pentobarbital anesthetized dogs, intraventricular dog or hog renin (0.05-0.25 Goldblatt units) increased systolic pressure from 152 +/- 10 to 168 +/- 10 mm Hg (P less than 0.001) and diastolic pressure from 101 +/- 8 to 116 +/- 7 mm Hg (P less than 0.001). This response, which lasted from 30 min to more than 3 h, was also abolished by saralasin acetate. These data indicate that centrally administered renin increases drinking and blood pressure and that these effects are mediated via the formation of angiotensin II.

An intrarenal effect of somatostatin on water excretion.

Intrarenal infusion of somatostatin in anesthetized dogs produced a prompt increase in urine flow in association with a decrease in urinary osmolality and an increase in free water clearance. These changes occurred in the absence of changes in arterial pressure, renal plasma flow, osmolar clearance, electrolyte excretion or cyclic AMP excretion. The diuretic effect occurred primarily in the infused kidney indicating a direct intrarenal action rather than suppression of vasopressin secretion. This diuretic action of somatostatin may result from inhibition of the action of vasopressin on the renal medulla but other possible mechanisms cannot be excluded.

Antidiuresis produced by injection of renin into the third cerebral ventricle of the dog.

The purpose of this study was to determine whether centrally administered renin stimulated vasopressin secretion. Vasopressin was not measured directly, but, instead, changes in urinary water excretion in anesthesized dogs undergoing a water excretion in anesthetized dogs undergoing a water diuresis were used as an index of changes in vasopressin secretion. Intraventricular injection of hog renin in a dose of 0.1 Goldblatt unit produced a marked decrease in urine flow which was associated with a decrease in free water clearance and an increase in urinary osmolatiy with no change in osmolar clearance. Sodium excretion increased significantly but there was no change in potassium excretion. These effects, which closely resemble those resulting from an increase in vasopressin secretion, were prevented by hypophysectomy. The antidiuretic effect clearly resulted from an action of renin in the central nervous system since renin had no effect on urine flow or osmolality when administered intravenously. Intraventricular administration of saralasin acetate, a specific antagonist of angiotensin II, completely blocked the effects of intraventricular renin indicating that these effects were mediated via the formation of angiotensin II. The data therefore indicate that there is an interaction between injected renin, brain angiotensinogen, and converting enzyme resulting in the formation of angiotensin II which stimulates the secretion of vasopressin. Additional studies are required to determine whether the brain renin-angiotensin system plays a physiological role in the regulation of a vasopressin secretion.

Analysis of the action of angiotensin II on the baroreflex control of heart rate in conscious rabbits.

There is considerable evidence that angiotensin II (Ang II) attenuates the baroreflex control of heart rate (HR), but the mechanism and site of this action have not been precisely defined. In the present study the effects of systemically and centrally administered Ang II on the baroreflex control of HR were investigated in conscious, chronically prepared rabbits. Baroreflex curves (HR vs. mean arterial pressure) were generated with iv infusions of phenylephrine or nitroprusside. Background infusion of Ang II at 10 ng/kg.min increased mean arterial pressure from 77.3 +/- 3.0 to 94.3 +/- 4.1 mm Hg (P less than 0.001) without changing HR [212.1 +/- 7.2 to 218.0 +/- 9.8 beats/min (bpm)] and shifted (reset) the baroreflex curve with phenylephrine to a higher pressure level (P less than 0.001) without changing its slope (-1.40 +/- 0.40 to -1.65 +/- 0.46 bpm/mm Hg; P = 0.4). Background infusion of an equipressor dose of phenylephrine did not shift the baroreflex curve or change its slope. Ang II also shifted the baroreflex curve with nitroprusside to a higher pressure level (P less than 0.01), but again the slope was not significantly changed (-2.30 +/- 1.25 to -1.51 +/- 0.52 bpm/mm Hg; P = 0.2). Background intraventricular infusion of Ang II at 1 ng/kg.min had the same effects as iv infusion of Ang II at 10 ng/kg.min; the curve was shifted to a higher pressure level (P less than 0.001), but the slope was not changed (-0.76 +/- 0.47 to -1.143 +/- 0.48 bpm/mm Hg). Intravenous infusion of Ang II at 1 ng/kg.min had no effect on the baroreflex. The resetting of the baroreflex with phenylephrine by iv Ang II (10 ng/kg.min) was not blocked by propranolol: atropine markedly reduced the baroreflex response to phenylephrine in both the absence and presence of Ang II. These results indicate that in conscious rabbits, Ang II resets the baroreflex control of HR, but does not change its sensitivity. This effect apparently results from an action of Ang II on the brain that is mediated by withdrawal of vagal tone to the heart. The resetting of the baroreflex by Ang II can explain the ability of the peptide to increase arterial pressure without decreasing HR.

Angiotensin II concentration in cerebrospinal fluid after intraventricular injection of angiotensinogen or renin.

To determine if the brain enzyme which has renin-like activity in vitro can form angiotensin in vivo, angiotensin II concentration in cerebrospinal fluid (CSF) was measured before and at various intervals after injection of partially purified renin substrate (angiotensinogen) into the third cerebral ventricle of anesthetized dogs. The injection increased CSF angiotensinogen concentration 3-fold, but despite this, CSF angiotensin II concentration, which was undetectable (less than 6.25 fmol/ml) before injection, did not change. Arterial blood pressure was also unchanged after the injection. In contrast, both CSF angiotensin II concentration and arterial pressure increased after an inventricular injection of renin. These results demonstrate that angiotensin II is formed centrally after administration of exogenous renin but not after injection of angiotensinogen. The results thus fail to demonstrate renin activity in the brain in vivo.

Effect of vasopressin blockade on blood pressure regulation during hemorrhage in conscious dogs.

The role of vasopressin in the regulation of blood pressure during nonhypotensive hemorrhage was assessed in conscious dogs. An antagonist of the vasoconstrictor activity of vasopressin was administered (10 microgram/kg) to four normal dogs five min prior to the commencement of a 15 min arterial hemorrhage (1 ml/kg/min). The withdrawn blood was reinfused 15 min after completion of the hemorrhage. In the absence of vasopressin blockade, blood pressure and heart rate did not change significantly, while plasma renin activity increased from 3.8 +/- 0.9 to 10.8 +/- 3.1 ng/ml/3h (P less than 0.005), and plasma corticosteroid concentration increased from 1.5 +/- 0.8 to 8.6 +/- 2.0 microgram/dl (P less than 0.001). Following vasopressin blockade, the same hemorrhage decreased mean arterial pressure from 96 +/- 264 +/- 7 mmHg (P less than 0.001), increased heart rate from 71 +/- 10 to 130 +/- 23 beats/min (P less than 0.05), increased plasma renin activity from 7.1 +/- 0.8 to 30.3 +/- 6.7 ng/ml/3h (P less than 0.005) and increased plasma corticosteroid concentration from 1.9 +/- 0.7 to 11.4 +/- 1.2 microgram/dl (P less than 0.001). These data indicate that vasopressin plays an important role in blood pressure regulation during mild hemorrhage in conscious dogs.

The role of adrenocorticotropin in the cortisol and aldosterone responses to angiotensin II in conscious dogs.

The role of ACTH in the cortisol and aldosterone responses to iv angiotensin II (AII) infusion, (5, 10, and 20 ng kg-1 min-1) in dogs was evaluated by examining the effect of AII infusion in conscious dogs pretreated with dexamethasone to suppress endogenous ACTH secretion. AII infusion in untreated dogs produced dose-related increases in plasma cortisol and aldosterone concentrations. The plasma ACTH concentration also increased. Dexamethasone treatment lowered the basal cortisol concentration from 1.7 +/- 0.1 to 0.7 +/- 0.1 micrograms/dl (P less than 0.05) and the ACTH concentration from 52 +/- 3 to 41 +/- 4 pg/ml (P less than 0.05), and abolished the cortisol response to all doses of AII, indicating that ACTH was necessary for the response. On the other hand, the basal aldosterone concentration was not significantly affected by dexamethasone, although the aldosterone response to the highest dose of AII was reduced. Additional experiments were performed to determine if the cortisol and aldosterone responses to AII (20 ng kg-1 min-1) in dexamethasone-treated dogs are restored if the ACTH concentration is maintained near control levels by iv infusion of synthetic alpha ACTH-(1-24) (0.3 ng kg-1 min-1). AII still failed to increase the plasma cortisol concentration in this group of dogs; however, the aldosterone response was fully restored. To evaluate the effect of elevated ACTH levels on the steroidogenic effects of AII, dogs were treated with dexamethasone and a higher dose of ACTH (0.4 ng kg-1 min-1). This dose of ACTH increased the plasma cortisol concentration from 1.7 +/- 0.1 to 3.5 +/- 0.8 micrograms/dl (P less than 0.05), but did not significantly affect the plasma aldosterone concentration. In the presence of constant elevated levels of ACTH, AII (10 and 20 ng kg-1 min-1) increased the plasma cortisol concentration in dexamethasone-treated dogs, although the response to the 10 ng kg-1 min-1 dose was smaller than the response in untreated dogs. Infusion of AII at 5 ng kg-1 min-1 did not increase the plasma cortisol concentration. In contrast, the increased plasma aldosterone produced by AII infusion in dexamethasone-treated dogs was not altered in the presence of elevated ACTH levels. Finally, AII infusion did not alter the clearance of cortisol. Collectively, these results demonstrate that an increase in plasma ACTH is necessary for the cortisol response to AII infusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of endogenous angiotensin II in the control of vasopressin secretion during hypovolemia and hypotension in conscious rabbits.

In order to investigate the physiological role of angiotensin II (ANG II) in the control of vasopressin (VP) secretion, the VP responses to hypotension induced by hemorrhage (20 ml/kg, n = 10) or nitroprusside infusion (1-10 micrograms/kg.min, n = 9) were studied with or without blockade of ANG II formation by the converting enzyme inhibitor captopril in conscious rabbits. Administration of captopril (5 mg/kg, iv) caused a small decrease in mean arterial pressure but did not enhance the hypotensive response to subsequent hemorrhage or nitroprusside infusion. The renin response to both stimuli was enhanced by captopril, whereas the increase in plasma ANG II concentration was attenuated. Plasma VP (PAVP) concentration increased during hemorrhage (2.0 +/- 0.2-113.6 +/- 47.7 pg/ml, P less than 0.01) and nitroprusside infusion (2.1 +/- 0.3-5.1 +/- 1.0 pg/ml, P less than 0.01). Captopril did not change basal plasma PAVP, nor did it attenuate the VP responses to hemorrhage or nitroprusside. Indeed, captopril tended to enhance the VP responses to hemorrhage (2.3 +/- 0.3-147.1 +/- 65.9 pg/ml) and nitroprusside infusion (1.9 +/- 0.2-15.4 +/- 6.0 pg/ml). The relationship between log PAVP and mean arterial pressure during hemorrhage and nitroprusside infusion in the presence of captopril was not different than in the absence of captopril. These results indicate that in conscious rabbits, the renin-angiotensin system does not contribute to the increase in VP secretion during hypotension induced by hemorrhage or nitroprusside infusion.

Mechanism of the dipsogenic action of tetradecapeptide renin substrate in dogs.

Dogs with chronically implanted third ventricular cannulae showed significant drinking responses to central injections of angiotensin II and tetradecapeptide renin substrate (TDP). The threshold dose for angiotensin II was 1 pmol and for TDP was 70 pmol. Although central injections of TDP led to drinking and appearance of angiotensin II in cerebrospinal fluid, renin substrate prepared from dog cerebrospinal fluid had no effect. The dipsogenic action of TDP was blocked by prior administration of converting enzyme inhibitor SQ20881 (P less than 0.01) but was not affected by either pepstatin or N-acetyl-pepstatin. Thus, converting enzyme acts directly on TDP to produce angiotensin I and then angiotensin II. The results of the present study do not provide evidence for the presence of an enzyme in the brain with renin-like activity.

Role of vasopressin in blood pressure regulation during adrenal insufficiency.

The effect of adrenal insufficiency on the plasma concentrations of two vasoactive hormones, vasopressin and angiotensin II, was studied in conscious dogs. In addition the role of vasopressin in the maintenance of blood pressure during adrenal insufficiency was studied using [1-(beta-mercapto-beta, beta-cyclopentamethylenepropionic acid),2-(O-methyl)tyrosine]arginine vasopressin, a specific antagonist of the vasoconstrictor action of vasopressin. Dogs were bilaterally adrenalectomized and maintained on daily cortisol and deoxycorticosterone acetate injections. Withdrawal of steroids for 4 days resulted in a 4-fold increase in plasma vasopressin concentration (P less than 0.05) and a 3-fold increase in plasma angiotensin II concentration (P less than 0.001); mean arterial pressure did not change significantly. Administration of the vasopressin antagonist in adrenalectomized dogs maintained on steroids had no effect on blood pressure. In marked contrast, vasopressin blockade in dogs with adrenal insufficiency decreased mean arterial pressure by 22 +/- 5 mm Hg (P less than 0.001). These results demonstrate the plasma angiotensin II and vasopressin concentrations increase during adrenal insufficiency in conscious dogs, and that vasopressin plays an important role in blood pressure regulation in this hypovolemic state.

Effects of carotid occlusion and angiotensin II on vasopressin secretion in intact and vagotomized conscious rabbits.

Experiments were performed in conscious rabbits with sectioned aortic depressor nerves to determine whether there is an interaction between angiotensin II (Ang II) and the baroreceptor reflexes in the control of arginine vasopressin (AVP) secretion. Baroreceptor reflexes were activated by a 5- or 10-min period of bilateral carotid occlusion with or without background infusion of Ang II at 10 or 20 ng/kg.min. Carotid occlusion increased mean arterial pressure, right atrial pressure, and heart rate, but did not change plasma AVP (PAVP) concentration. Infusion of Ang II at 10 ng/kg.min increased PAVP from 4.0 +/- 0.9 to 6.3 +/- 1.8 pg/ml (P less than 0.05). Carotid occlusion during Ang II infusion produced the same cardiovascular changes as before Ang II, but still failed to increase PAVP. Because increased atrial pressure can inhibit AVP secretion, the experiments were repeated in acutely vagotomized rabbits. Vagotomy increased heart rate but did not change mean arterial pressure or PAVP. Carotid occlusion after vagotomy increased PAVP from 2.2 +/- 0.2 to 3.3 +/- 0.5 pg/ml (P less than 0.05). Ang II infusion again increased PAVP but did not enhance the AVP response to carotid occlusion (2.9 +/- 0.4 to 3.9 +/- 0.7 pg/ml). These results provide further evidence for a role of the carotid sinus baroreceptors and vagal afferents in the control of AVP secretion and demonstrate that Ang II stimulates AVP secretion in rabbits. However, they do not reveal any interaction between Ang II and the baroreceptor reflexes in the control of AVP secretion.

Localization of angiotensinogen in rat liver by immunocytochemistry.

Plasm angiotensinogen, the protein precursor of angiotensin, is produced by the liver. The present study investigated the location of angiotensinogen in sections of rat liver using the unlabeled peroxidase-antiperoxidase bridge technique of Sternberger. Specific reaction products of the antibody localization method were most pronounced in the cytoplasm of hepatocytes in the pericentral zone of the liver lobule. Controls, in which antibody was preabsorbed with angiotensinogen, did not form reaction product. The gradient of angiotensinogen observed within liver lobules resembled that demonstrated by metabolic zonation. The distribution of angiotensinogen differed from the scattered distributions found for other plasma proteins.

Effect of tetradecapeptide renin substrate on blood pressure, plasma renin activity, and vasopressin and adrenocorticotropin concentrations.

The effects of third ventricular injection of tetradecapeptide renin substrate (TDP) and natural renin substrate prepared from dog cerebrospinal fluid were compared in anesthetized dogs. Central injection of 350 pmol TDP caused a long lasting increase in arterial blood pressure, a reduction in PRA, and increases in plasma levels of vasopressin, and ACTH. In marked contrast, central administration of equimolar doses of natural renin substrate had no effect on these variables. Intracranial administration of the converting enzyme inhibitor SQ 20881 prevented the effects of central injection of TDP. Thus, TDP exerts its effects via conversion to angiotensin II and does not necessitate the postulation of the action of an enzyme with renin-like activity in the brain.

Effect of baroreceptor denervation on the inhibition of renin release by vasopressin.

Previous studies have suggested that the inhibition of renin secretion by acute administration of vasopressin in conscious dogs results from a reflex reduction in renal nerve activity. In the present investigation, this hypothesis was tested by studying the effect of total baroreceptor denervation or selective low pressure baroreceptor denervation on the suppression of PRA by vasopressin in conscious, chronically prepared dogs. In eight sham-operated dogs, a 45-min infusion of vasopressin (2.0 ng/kg.min, iv) decreased PRA from 10.5 +/- 1.9 to 5.9 +/- 1.0 ng/ml.3 h (P less than 0.01). Mean arterial pressure did not change (110 +/- 10 to 107 +/- 7 mm Hg), but heart rate decreased from 84 +/- 9 to 69 +/- 8 beats/min (P less than 0.05). In contrast, vasopressin infusion failed to significantly decrease PRA in seven sinoaortic/cardiac denervated dogs (9.5 +/- 1.7 to 7.4 +/- 2.0 ng/ml.3 h), although decreases did occur in three of the dogs. Mean arterial pressure increased from 104 +/- 5 to 125 +/- 6 mm Hg (P less than 0.01), but heart rate did not change (112 +/- 4 to 107 +/- 5 beats/min). When renal perfusion pressure was maintained at the preinfusion level in three sinoaortic/cardiac denervated dogs, vasopressin infusion failed to decrease PRA (2.3 +/- 0.6 to 2.4 +/- 0.6 ng/ml.3 h). In six cardiac denervated dogs, vasopressin infusion decreased PRA from 5.3 to 0.9 to 3.1 +/- 0.7 ng/ml.3 h (P less than 0.01). Results obtained with two lower doses of vasopressin (0.5 and 1.0 ng/kg.min) were generally similar to the responses observed during infusion at 2.0 ng/kg.min. Angiotensin II (5.0 ng/kg.min) suppressed PRA in all groups of dogs. These experiments demonstrate that the inhibition of renin secretion by acute administration of vasopressin in conscious dogs is prevented by total baroreceptor denervation, but not by denervation of the low pressure baroreceptors alone. These results suggest that the suppression of renin release by vasopressin is a reflex response resulting from activation of the high pressure baroreceptors.