Effects of angiotensin II and vasopressin on human smooth muscle cells in vitro

Arterial smooth muscle cell hyperplasia is a histopathological marker of both hypertension and the initial stages of atherogenesis. In order to determine if vasoactive agents could promote arterial smooth muscle cell proliferation, two potent pressor hormones, angiotensin II and vasopressin, were tested in cell culture. Either one of these agents was added daily to cultures of human aortic smooth muscle cells maintained in homologous serum (HS) or fetal bovine serum (FBS). After 7 days, angiotensin II significantly enhanced cell proliferation in both types of sera. While vasopressin was found to be inhibitory in FBS, it also stimulated cell growth in HS. Furthermore, both peptides in HS induced an increase in average cell size. Comparative studies were conducted with human uterine smooth muscle cells and 3T3 mouse fibroblasts in order to determine the specificity of the growth effects for human vascular smooth muscle. The above in vitro studies suggest that angiotensin II and vasopressin, by modulating both number and size of arterial smooth muscle cells, may play a direct and until now unexpected role in the development of chronic vascular disease in man.     

The effect of angiotensin II and vasopressin on renal haemodynamics

A comparison was made of the vascular actions of two hormones having a renal site of action, angiotensin II and vasopressin, using laser Doppler flowmetry to measure perfusion of the cortical and papillary regions of the kidney. Angiotensin II infusion caused dose-related increases in blood pressure and reductions in cortical perfusion, the latter responses being potentiated in the presence of the converting enzyme inhibitor, cilazapril. However, angiotensin II had no effect on papillary perfusion either before or following cilazapril. The reasons for this differing vasoconstrictor ability of angiotensin II at the cortex and papilla are unclear, but it could be due to medullary generation of prostaglandin or bradykinin. Administration of equipressor doses of vasopressin caused graded reductions in both cortical and papillary perfusions, and subsequent cilazapril significantly enhanced the papillary responses. This study demonstrates that the regulation of blood flow through the different regions of the kidney can be differentially regulated by the peptide hormones angiotensin II and vasopressin.     

Effects of histamine, vasopressin, and angiotensin II on hepatosplanchnic hemodynamics, liver function, and hepatic metabolism in cats.

Continuous i.v. infusions of histamine (5 mug/kg - min), vasopressin (10 mU/kg -min), or angiotensin II (0.5 mug/kg - min) were given to fasting cats. Hepatic arterial flow was decreased 30% by histamine, increased 30% by vasopressin, and not significantly affected by angiotensin, whereas portal venous flow was increased 25% by histamine, decreased 40% by vasopressin, and not significantly affected by angiotensin. The hepatic arterial conductance was decreased about 25% by histamine and angiotensin, and not significantly affected by vasopressin. The gastrointestinal conductance was decreased about 40% by vasopressin and angiotensin, and increased 25% by histamine. The conductance in the intrahepatic low pressure vessels was not affected by histamine and vasopressin, but decreased 25% during the infusion of angiotensin. These hemodynamic effects, however, were not accompanied by changes in the liver function or hepatic metabolism as judged from the splanchnic elimination of ethanol, the hepatic uptake and excretion of ICG, the hepatic oxygen consumption, and lactate and ketone production. This indicates that the functional capacity of the liver and thereby the number of sinusoids perfused is not markedly influenced by these drugs. Vasopressin caused a decrease in the oxygen consumption and an increase in the lactate production in the prehepatic splanchnic area, which may be due to a redistribution of the gastrointestinal blood flow.     

Effects on renal sodium and potassium excretion of vasopressin and oxytocin in conscious dogs

Renal effects of arginine vasopressin and oxytocin were studied in conscious dogs, made water-diuretic by a waterload equivalent to 2% of body weight. Body water and content of sodium were maintained by separate servo-controlled infusions. Peptides were infused for 60 min at rates of 50 pg kg^-1 min^-1 (arginine vasopressin) or 1 ng kg^-1 min^-1 (oxytocin), either separately or combined. Infusions increased plasma arginine vasopressin to 1.9 ± 0.2 (arginine vasopressin alone) and 1.8 ± 0.3 pg kg^-1 (arginine vasopressin plus oxytocin and plasma oxytocin to 72 ± 5 (oxytocin alone) and 77 ± 8 pg ml^-1 (oxytocin plus arginine vasopressin). Arginine vasopressin or arginine vasopressin plus oxytocin increased urine osmolality similarly by a factor of 13, decreased urine flow to between 5 and 7% of control and decreased free water clearance. Oxytocin reduced urine flow and free water clearance and increased urine osmolality by a factor of 2. Oxytocin and arginine vasopressin separately increased excretion of sodium from 4 ± 2 to 15 ± 6 μmol min^-1 and from 7 ± 4 to 25 ± 13 μmol min^-1, respectively. Arginine vasopressin plus oxytocin led to a pronounced natriuresis (13 ± 4 to 101 ± 27 μmol min^-1). Arginine vasopressin and arginine vasopressin plus oxytocin increased the excretion of potassium by a factor of 2.5. Oxytocin and arginine vasopressin plus oxytocin increased urinary Na⁺/K⁺ ratio by a factor of 3.7. It is concluded, that oxytocin at plasma concentrations of 70–80 pg ml^-1 has modest antidiuretic and natriuretic effects and that the combined action of arginine vasopressin oxytocin may elicit supra-additive natriuretic effects.     

Central actions of angiotensin II on heart rate and blood pressure in mongrel dogs

Angiotensin II is produced physiologically in response to renal ischaemia due to hypotension. It's effect on heart rate and blood pressure were studied on anaesthetised mongrel dogs. Angiotensin II was given in different concentrations, by intravenous, intraarterial in carotid artery and intracerebroventricular routes. Cervical vagotomy and carotid sinus inactivation were done is abolish the reflex inhibition produced by baroreflexes. Rise of B.P. is due to mainly peripheral vasopressor action of angiotensin II, however it is shown to have a central component as well. This is demonstrated by ICV injections. Tachycardia due to central action is also demonstrated in this study. Both actions are significant. This study also confirm the earlier findings that angiotensin II passes the blood brain barrier.     

Effects of receptor blockade on metabolism and renal actions of vasopressin in conscious dogs

Vasopressin – but not the V₂ receptor agonist [deamino-cis1,D-Arg8]-vasopressin (dDAVP) – may mediate natriuresis in dogs. The present study investigated this phenomenon by use of nonpeptide antagonists to V_1a and V₂ receptors 1-{1-[4- (3-acetylaminopropoxy)benzoyl]-4-piperidyl}-3,4-dihydro-2 (1H)-quinolinone (OPC-21268) and 5-dimethylamino-1-{4- (2-methylbenzoylamino)-benzoyl}-2,3,4,5-tetrahydro-1H-benzazepine (OPC-31260), respectively) hypothesising that only V_1a inhibition would reduce the natriuresis. In conscious dogs vasopressin secretion was suppressed by water loading (2% body weight) and replaced by infusion of vasopressin (50 pg min^?1 kg^?1) resulting in physiological plasma concentrations (plasma levels of AVP (pAVP) = 2.0 ± 0.1 pg mL^?1). In this setting, OPC-21268 did not change the rate of sodium excretion. OPC-31260 increased water excretion 12-fold without significant changes in sodium excretion. Heart rate, mean arterial blood pressure, glomerular filtration rate, and clearance of endogenous Li⁺ were unchanged. During vasopressin infusion, both antagonists increased pAVP, OPC-21268 by 20% and OPC-31260 by 100% (2.0 ± 0.2–4.0 ± 0.3 pg mL^?1). In the absence of vasopressin infusion, OPC-31260 did not increase pAVP. Thus, the increase in pAVP appeared to be due to a decrease in metabolic clearance rate. The results indicate that the present dose of V_1a receptor inhibitor OPC-21268 does not reduce sodium excretion and that both vasopressin antagonists inhibit vasopressin metabolism.     

Reflex limb dilatation following norepinephrine and angiotensin II in conscious dogs.

Effects of intravenous and intra-arterial norepinephrine (NE) and angiotensin II (AN) were compared in 18 conscious dogs instrumented with Doppler or electromagnetic flow probes on the iliac, mesenteric, and renal arteries, and catheters in the aorta and iliac arteries. NE and AN administered intravenously constricted the mesenteric and renal beds, and constricted the iliac bed when administered directly into the iliac artery. In contrast, intravenous NE and AN caused striking reflex increases in iliac flow and reductions in iliac resistance, respectively, in 12 of 18 dogs studied. The reflex iliac dilatation was not prevented by beta blockade with propranolol, cholinergic blockade with atropine, or prostaglandin synthetase inhibition with indomethacin. However, the responses were abolished by either phentolamine, 1 mg/kv iv, or after local blockade of the limb with either phentolamine, 0.5 mg/kg, or with tripelennamine, 2 mg/kg. The dilatation was not prevented by either bilateral carotid sinus and aortic nerve section or by bilateral vagotomy alone, but was prevented by a combination of these procedures. Thus, intravenous NE and AN cause striking reflex iliac dilatation in the limb in the conscious dog; the afferent arc of this reflex involves both arterial baroreceptor and vagal pathways, while the efferent mechanism involves an interaction of alpha-adrenergic and histaminergic receptors.     

Arginine vasopressin metabolism in dogs. II. Modeling and system analysis.

System modeling and analysis methods were applied to interpret data regarding arginine vasopressin (AVP) metabolism in dogs. Based on this analysis a new nonlinear 3-pool model of AVP distribution and disposal was proposed and quantified; the model pools included the plasma, a receptor pool, and an extravascular nonreceptor pool. The receptor pool mediated a portion of the rapid flux of hormone between the plasma and the extravascular pool. Mathematical analysis indicated that the plasma AVP impulse response (bolus) data would be insufficient to uniquely estimate all the model constants, but additional plasma impulse data using 125I-labeled AVP, which does not bind to physiologic hormone receptors, would allow unique model quantification. Other required measurements were the urinary excretion of intact hormone, and plasma AVP degradation. The model was successfully fitted to the data from 10 dogs. The results suggest that, in the normal dogs studied, plasma contained 25% of the total AVP, 19% was bound to receptors, and the remaining 56% was in the extravascular pool. Eighty percent of the flux of AVP from the vascular compartment was mediated by the receptor pool; 98% of AVP degradation occurred in the extravascular pool; and urine excretion and plasma degradation made up the remainder.     

Effects on renal sodium and potassium excretion of vasopressin and oxytocin in conscious dogs.

Renal effects of arginine vasopressin and oxytocin were studied in conscious dogs, made water-diuretic by a waterload equivalent to 2% of body weight. Body water and content of sodium were maintained by separate servo-controlled infusions. Peptides were infused for 60 min at rates of 50 pg kg-1 min-1 (arginine vasopressin) or 1 ng kg-1 min-1 (oxytocin), either separately or combined. Infusions increased plasma arginine vasopressin to 1.9 +/- 0.2 (arginine vasopressin alone) and 1.8 +/- 0.3 pg kg-1 (arginine vasopressin plus oxytocin and plasma oxytocin to 72 +/- 5 (oxytocin alone) and 77 +/- 8 pg ml-1 (oxytocin plus arginine vasopressin). Arginine vasopressin or arginine vasopressin plus oxytocin increased urine osmolality similarly by a factor of 13, decreased urine flow to between 5 and 7% of control and decreased free water clearance. Oxytocin reduced urine flow and free water clearance and increased urine osmolality by a factor of 2. Oxytocin and arginine vasopressin separately increased excretion of sodium from 4 +/- 2 to 15 +/- 6 mumol min-1 and from 7 +/- 4 to 25 +/- 13 mumol min-1, respectively. Arginine vasopressin plus oxytocin led to a pronounced natriuresis (13 +/- 4 to 101 +/- 27 mumol min-1). Arginine vasopressin and arginine vasopressin plus oxytocin increased the excretion of potassium by a factor of 2.5. Oxytocin and arginine vasopressin plus oxytocin increased urinary Na+/K+ ratio by a factor of 3.7.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamics of central infusion of angiotensin II in normal and sodium-depleted dogs.

The intraventricular (IVT) administration of angiotensin II (AII) (100 ng.kg-1.min-1) produced significant elevations of arterial blood pressure in pentobarbital-anesthetized dogs on either normal or sodium-deficient diets. In both groups of dogs the intraventricular administration of AII caused comparable and significant elevations in blood pressure averaging 15 +/- 2 and 17 +/- 4 mmHg, respectively, within 10 min after onset of the infusion. The rises in blood pressure were due to increased peripheral resistance (2.87 +/- 1.20 vs. 1.67 +/- 0.43 units). At the peak of the pressor response bradycardia was a constant feature in sodium-depleted animals, but was not present in the normal ones. In both groups of dogs regional cerebral blood flow (rCBF), determined by the xenon-133 washout method, remained unchanged during the development of the pressor response, and peripheral plasma renin activity failed to increase in response to the central infusion of AII. In conclusion, sodium deprivation appears not to influence the sensitivity of the central AII receptor because comparable pressor responses and hemodynamic changes were obtained following the intraventricular administration of AII in both normal and sodium-depleted dogs.