High Concentrations Of Angiotensin Research Articles

Circulating renin-angiotensin-aldosterone system activity in cats with systemic hypertension or cardiomyopathy.

BackgroundActivity of the circulating renin‐angiotensin‐aldosterone system (RAAS) has not been comprehensively characterized in cats with systemic hypertension (SH) or cardiomyopathy (CM), and the effects of furosemide or amlodipine treatment on the RAAS have not been fully evaluated in cats.Hypothesis/ObjectivesTo document RAAS activity in cats with SH or CM compared to healthy cats and determine how RAAS profiles change with furosemide or amlodipine treatment.AnimalsSixty‐six client‐owned cats: 15 with SH (7 amlodipine‐treated, 8 untreated), 17 with advanced CM (7 furosemide‐treated, 10 not furosemide‐treated), and 34 healthy cats.MethodsEquilibrium concentrations of RAAS peptides and aldosterone were quantified in serum samples by liquid chromatography‐mass spectrometry. Variables were compared between groups using Kruskal‐Wallis analysis with post hoc Holms‐corrected Dunn's testing.ResultsCompared with healthy cats, cats with CM had higher concentrations of angiotensin I, aldosterone, and plasma renin activity (all P < .01), and these differences remained significant (P < .03) after considering subgroups of untreated or furosemide‐treated cats. Compared with healthy cats, untreated cats with SH showed no differences in RAAS biomarkers, whereas amlodipine‐treated cats had higher concentrations of angiotensins I, II, III, IV, and 1‐7, aldosterone, and plasma renin activity (all P < .03). Multivariable analysis determined that furosemide and amlodipine treatments were independent predictors of increased RAAS biomarker concentrations.Conclusions and Clinical ImportanceCats with CM had increased RAAS activity, whereas cats with untreated SH did not. Furosemide and amlodipine both led to nonspecific activation of both classical and alternative RAAS pathways in cats.

The influence of angiotensin on the uptake of noradrenaline by the isolated heart of the rabbit.

Abstract The influence of angiotensin on the removal of noradrenaline (10 ng/ml) from the perfusion medium and on the net-uptake of noradrenaline (5 and 20 μg/ml) was examined in the rabbit isolated heart. Concentrations of angiotensin, known to augment the output of noradrenaline from rabbit heart during sympathetic nerve stimulation, did not inhibit the removal of infused noradrenaline from the perfusion fluid. Only very high concentrations of angiotensin (13 μg/ml) significantly diminished the loss of noradrenaline. The positive inotropic effect of noradrenaline was not potentiated by angiotensin. On the other hand, cocaine, in doses which enhance the output of noradrenaline during sympathetic stimulation greatly reduced the loss of noradrenaline from the perfusion fluid. Neither angiotensin (130 ng/ml) nor metanephrine (5 and 20 μg/ml) significantly influenced the net-uptake of noradrenaline from high concentrations. The observations made support the assumption that an increase of transmitter liberation rather than inhibition of transmitter inactivation is responsible for the increase caused by angiotensin in the output of noradrenaline during stimulation of sympathetic nerves.

Differences Among Angiotensin II Type 1 Receptor Blockers: Characteristics of Candesartan Cilexetil

Several angiotensin II type 1 (AT 1 ) receptor blockers are now available for the treatment of hypertension. Although the agents in this class all act by blocking the AT 1 -receptor, they differ in their pharmacokinetics and binding characteristics. One of the newest AT 1 -receptor blockers, candesartan cilexetil, is administered in an inactive form and is rapidly and completely converted to the active drug, candesartan, during gastrointestinal absorption. In vitro studies have shown that candesartan has the highest receptor affinity of all the available AT 1 -receptor blockers and is not displaced from the receptor by high concentrations of angiotensin II. The tight and long-lasting binding of candesartan to the AT 1 -receptor provides effective blockade of the negative cardiovascular effects of angiotensin II.

Angiotensin-converting enzyme activity and contractile effects of angiotensin I and II in human uteroplacental arteries

OBJECTIVE: Our purpose was to study local angiotensin-converting enzyme activity and the mechanical effects of angiotensin I and II in human uteroplacental arteries. STUDY DESIGN: Angiotensin-converting enzyme activity was measured by a simple radioimmunoassay with tritiated benzoyl-glycyl-glycyl-glycine as substrate in isolated human intramyometrial arteries from nonpregnant ( n = 8) and term pregnant women ( n = 8) and placental ( n = 8) stem villous arteries. Moreover, in these vessels the mechanical effects of angiotensin I and II were investigated in organ bath experiments. Endothelium-infact and endothelium-denuded arteries were used, and the integrity of the endothelium was examined by histologic studies. RESULTS: The activity of angiotensin-converting enzyme ranked the intramyometrial arteries from pregnant women > > intramyometrial arteries from nonpregnant women >fetal stem villous arteries. Angiotensin-converting enzyme activity was unaffected by removal of the endothelium. Angiotensin II 10 −5 mol/L produced contractile responses in the intramyometrial arteries without significant differences between arteries from nonpregnant and pregnant women. In fetal stem villous arteries the effects of angiotensin II 10 −5 mol/L were less pronounced. As for angiotensin II, the contractile responses to angiotensin I 10 −5 mol/L showed marked development of tachyphylaxis. In the endothelium-denuded preparations the contractile responses to angiotensin I 10 −5 mol/L were significantly enhanced in intramyometrial arteries from nonpregnant women but remained unchanged in intramyometrial arteries from pregnant women and in fetal stem villous arteries. In all preparations pretreatment with captopril or perindopril (10 −5 mol/L) markedly reduced angiotensin-converting enzyme activity, whereas no effects were observed on the contractile responses to angiotensin I. Saralasi 10 −5 mol/L completely abolished the contractile responses to angiotensin I and II. CONCLUSION: Local angiotensin-converting enzyme activity in human intramyometrial arteries seems to be markedly increased during pregnancy and shows marked differences between maternal and fetal uteroplacental arteries. High concentrations of angiotensin I may imply direct effects on the angiotensin II receptor independent of the local angiotensin-converting enzyme activity.

Vascular angiotensin and the sympathetic nervous system: do they interact?

We tested the hypothesis that local vascular formation of angiotensin (ANG) II and the sympathetic nervous system potentiate each other. Isolated rat hindquarters were perfused with an artificial medium, and ANG I and II release was measured by high-performance liquid chromatography and radioimmunoassay. Electrical stimulation of the lumbar sympathetic chain (0.5, 2, and 8 Hz) did not affect vascular ANG release in Sprague-Dawley (SD) rats. Hypertensive, ren-2 transgenic (TG+) rat hindquarters released significantly more ANG I (110 +/- 19 vs. 65 +/- 21 fmol/30 min in SD rats) and ANG II (235 +/- 22 vs. 140 +/- 30 fmol/30 min); however, nerve stimulation did not alter ANG release in TG+ rats. Captopril inhibited vascular ANG II release by 90%, but neither captopril nor ANG II receptor blockade by losartan affected the pressor response to nerve stimulation in SD and TG+ rats. Isoproterenol failed to increase either vascular ANG release or pressor response to nerve stimulation in SD or spontaneously hypertensive rat hindquarters. Exogenous renin, which increased vascular ANG release approximately 100-fold, prolonged the pressor responses to nerve stimulation. We conclude that the vascular renin-ANG system does not interact with the sympathetic nervous system locally. However, high concentrations of ANG II, which can be induced by circulation-derived renin, may prolong the duration of sympathetic nerve-induced vasoconstriction.

Effect of luminal angiotensin II on proximal tubule fluid transport: role of apical phospholipase A2

Recent micropuncture studies showed the existence of high concentrations of angiotensin II (ANG II) in proximal tubular fluid. In the present study, we have examined the effect of luminal ANG II, alone and in combination with peritubular ANG II, on fluid transport (JV) in the isolated perfused rabbit proximal convoluted tubule. In comparison with peritubular ANG II, luminal ANG II caused a similar but more potent biphasic effect on JV. At 10(-11) M, luminal ANG II maximally increased JV to 204 +/- 22% of the baseline compared with 142 +/- 10% by peritubular ANG II at 10(-10) M. At 10(-8) M, luminal ANG II suppressed JV to 9.7 +/- 16% of the baseline compared with 64 +/- 14% by peritubular ANG II. When luminal and peritubular ANG II were combined at concentrations that impose similar effect on JV, the effects of luminal and peritubular ANG II were not additive. However, when combined at concentrations that would otherwise impose opposing effects on JV, the stimulatory effect predominated. In support of the role of apical phospholipase A2 (PLA2) on the effect of luminal ANG II, ANG II stimulated PLA2 activity in isolated brush-border membrane vesicles, and addition of PLA2 inhibitor, mepacrine or dibucaine, to the luminal perfusate attenuated the effect of luminal ANG II on JV. In summary, these studies show a potent effect of luminal ANG II on proximal tubule JV involving activation of brush-border membrane PLA2. When combined, luminal and peritubular ANG II exert their effects in concert on proximal tubule JV.

Facilitation of noradrenergic transmission by angiotensin in hypertensive rats.

We examined the angiotensin-induced potentiation of noradrenergic transmission in the isolated mesenteric arteries of one-kidney, one clip (1K1C) hypertensive rats. The angiotensin converting enzyme activity measured in plasma did not change during the development of hypertension, whereas the activity measured in the aortic tissue was significantly augmented 28 days after the renal artery was clipped. Although the pressor responses to nerve stimulation were basically unaltered, a significant increase in the sensitivity to norepinephrine developed during hypertension. The 1K1C preparations presented an increased sensitivity to the facilitatory effect of angiotensin II on the response to periarterial nerve stimulation. The facilitatory effect of angiotensin II on both nerve stimulation and exogenous norepinephrine was blocked by saralasin. Angiotensin I induced similar facilitatory action on noradrenergic transmission that was inhibited by saralasin. When a high concentration of angiotensin I was used, the facilitatory effect was significantly higher in mesenteric arteries from 1K1C rats than in controls. Captopril reduced the facilitatory effect of angiotensin I in 1K1C preparations, whereas the responses of the normotensive control rats were unaffected by captopril. These findings are consistent with angiotensin I acting directly on angiotensin II receptors or with angiotensin I being converted to angiotensin II by an alternative pathway not involving angiotensin converting enzyme.

Distribution of angiotensin II receptor subtypes in rat and human kidney.

Angiotensin II initiates a variety of physiological effects in the kidney by binding to high-affinity receptors on plasma membranes. Recently, two subtypes of angiotensin II receptors have been distinguished on the basis of differences in signal transduction mechanisms, binding affinity to agonists and antagonists, and inhibition of binding by dithiothreitol. To evaluate the density and distribution of these receptor subtypes in the kidney, we performed an in situ autoradiographic study on frozen tissue sections obtained from rat and human kidneys. Sections were incubated with 125I-[Sar1,Ile8]angiotensin II and binding specificity was verified by competition with unlabeled [Sar1]angiotensin II. Angiotensin II receptor subtypes were characterized by competition with the nonpeptide receptor antagonists, DuP 753 (type 1) and PD123177 (type 2). Both rat and human kidney exhibited a high concentration of angiotensin II receptors in glomeruli and in the longitudinal bands traversing the outer portion of the medulla, corresponding to the medullary vascular bundles. Binding affinity (Kd = 0.6 +/- 0.4 nM), determined in rat kidney, was similar to that reported previously in isolated glomeruli and membrane vesicles prepared from renal tubules. Angiotensin II binding was almost completely inhibited by DuP 753, whereas PD123177 had little effect. Thus the predominant angiotensin II receptor subtype in both rat and human kidney is type 1. The distribution of angiotensin II receptors correlates well with the intrarenal sites at which the peptide has its major physiological effects.

Role of Angiotensin in Lethal Cerebral Hypoperfusion During Treatment of Acute Hypertension

A 23-year-old man developed lethal cerebral hypoperfusion associated with angiographically demonstrable cerebral arterial spasm while being treated for acute angiotensinogenic hypertension due to a traumatic coarctation of the aorta. This complication occurred even though the treatment maintained his blood pressure at normotensive to mildly hypertensive levels, without producing more than rare and fleeting periods of hypotension. To explain this enigmatic development, we propose that the high concentration of angiotensin II in the blood constricted the cerebral arteries and thus prevented adequate cerebral autoregulation when his blood pressure was lowered by drug therapy.

A high molecular weight form of angiotensin I is generated in rat serum incubated with synthetic and native angiotensin I.

A high molecular weight form of angiotensin I, 'big angiotensin I' with m.w. 25000 was generated in rat serum incubated with angiotensin I (m.w. 1296). Angiotensin I and 'big angiotensin I' were separated by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and extracted from the gels. Only sera with high concentrations of angiotensin I (2000-4300 ng per ml) incubated at neutral pH at 24 degrees C for several hours, contained 'big angiotensin I'. 'Big angiotensin I' was stable in sera, where angiotensin I was rapidly degraded. The proportion of 'big angiotensin I' to angiotensin I in sera, where angiotensin I was stable, was approx. 5%. In addition to 'big angiotensin I', which was generated during the incubations, a serum protein with m.w. 60000 was extracted from the SDS-PAGE. This protein had angiotensin I-like activity in the radioimmunoassay, and it was isolated from the unincubated sera in concentrations at the detection limit of the radioimmunoassay.

Chronotropic effects of angiotensin I, angiotensin II, bradykinin and vasopressin in guinea pig atria

Chronotropic responses to angiotensin I and angiotensin II, vasopressin and bradykinin were measured in guinea pig isolated right atria. Angiotensin II (100–30 000 pg/ml) was slightly more potent than angiotensin I and caused a maximum tachycardia of 30–40 b/min; only 20% of the maximum response to (−)-noradrenaline. Propranolol (1 μM) or reserpine pretreatment (1 mg/kg i.p., 24 h) did not alter the response to angiotensin II or bradykinin. Converting enzyme inhibition by captopril (10 μg/ml) did not affect resting rate nor the response to angiotensin II but shifted the location of the angiotensin I curve by 40 fold to the right. Bradykinin (5–500 ng/ml) caused small increases in rate while vasopressin 1–100 ng/ml was completely without effect. These results suggest that angiotensin II has a small positive chronotropic effect that is not dependent on tissue noradrenaline release or β-adrenoceptors and that tissue converting enzyme is active in right atria. Relatively high concentrations of angiotensin and bradykinin were required to directly stimulate the sino-atrial node compared with plasma levels measured during physiological stimuli. Therefore these effects on atria are probably of little physiological significance for peptide concentrations in plasma but may be important in relation to local tissue generation of angiotensin II.

Modulation of converting enzyme activity by hypoxia and its physiological effects.

To explore the haemodynamic consequences of the reduction in converting enzyme activity by acute alveolar hypoxia we made sequential haemodynamic observations in seven saline-infused and 12 bradykinin-infused anaesthetized, catheterized dogs. They were ventilated initially with room air and then for 50 minutes with hypoxic gas mixtures. Within two minutes after starting hypoxic ventilation, converting enzyme activity decreased, arterial angiotensin II concentrations dropped, and, in the bradykinin-infused dogs, arterial bradykinin concentrations rose. Both groups of dogs experienced a rise in systemic and pulmonary arterial blood pressure in response to hypoxia, but by different mechanisms. In the saline-infused (control) dogs there was increased systemic (+40%) and pulmonary (+90%) vascular resistance while cardiac output was unchanged or slightly reduced. Bradykinin-infused dogs demonstrated reduced systemic vascular resistance (-40%), no increase in pulmonary vascular resistance and a 100% increase in cardiac output. Return to room air breathing restored converting enzyme activity, releasing high concentrations of angiotensin II. Oxygen tension thus regulates converting enzyme activity and hence the circulating levels of angiotensin II and bradykinin.

Corticosteroid production in vitro by adrenal tissue from rats with inherited hypothalamic diabetes insipidus (brattleboro strain)

Steroid profiles formed by adrenal tissue from rats of the Brattleboro strain homozygous for the recessive gene causing diabetes insipidus (DI rats) were compared with those formed by glands from heterozygotes (non-diabetic: non-DI) during incubation in vitro. The most striking observation was that glands from DI rats showed a greatly reduced capacity to produce certain steroids with mineralocorticoid activity, particularly deoxycorticosterone (DOC) and 18-hydroxy-DOC (18-OH-DOC), and to a lesser degree, aldosterone (ald). Corticosterone (B) and 18-hydroxy-B were produced in similar amounts by glands from DI and non-DI animals. The impairment of DOC and 18-OH-DOC production in adrenals from DI animals was a feature of both capsule (mostly zona glomerulosa) and inner zone incubations. In incubations of tissue from DI animals, the addition of ACTH, or a low concentration of angiotensin amide to the incubation media stimulated corticosterone alone in inner zone incubations, but was without effect on other steroids, or on capsule incubations: with non-DI tissue, ACTH (but not the low concentration of angiotensin) stimulated corticosterone production, but again there was no effect on other steroids, or on the glomerulosa. Higher concentrations of angiotensin, or the addition of LH had only marginally significant effects. Addition of a “physiological” concentration of ADH to adrenal tissue from normal Wistar rats had no effect on the steroid profile. The results suggest the existence of as yet unidentified adrenocortical stimulators or inhibitors which exert effects on production of specific steroids, especially DOC and 18-OH-DOC, and which are effective both on the zona glomerulosa and on the inner adrenocortical zones.

The effect of angiotensin upon the vasculature of the isolated perfused rat kidney.

1. The effect of angiotensin II-amide upon the intrarenal distribution of perfusate was studied in the isolated rat kidney. 2. Low concentrations of angiotensin, 4·86 pmol/l (0·005 μg/l), reduced the flow rate through the papilla but did not alter total flow. 3. Higher concentrations of angiotensin, 0·486 nmol/l (0·5 μg/l), reduced total renal flow but did not decrease papillary perfusion. 4. In these experiments the perfusion pressure was maintained constant, indicating that the changes in flow were due to a direct effect of angiotensin upon the renal vasculature.

Potentiation by Various Smooth Muscle Stimulants of an Isolated Sympathetic Nerve‐Seminal Vesicle Preparation from the Guinea‐Pig1

AbstractThe contractions of the seminal vesicle in response to hypogastric nerve stimulation or coaxial stimulation were recorded with a balloon inserted in the lumen of the seminal vesicle.Adrenaline (A), noradrenaline (NA), acetylcholine (Ach), histamine (Hi), serotonin (5‐HT), barium chloride and high concentrations of angiotensin were found to potentiate the motor response of the seminal vesicle to sympathetic nerve stimulation. This potentiation occurred with concentrations 10–100 times smaller than those giving a direct contraction of the organ. Prostaglandins (PGE1, PGE2 and PGF2a) in low concentrations (1–10 ng/ml) exerted no effect or caused a slight decrease in the response to sympathetic nerve stimulation, while higher concentrations (100 ng–1 μg/ml) enhanced the response to nerve stimulation. This effect was pronounced with PGE1, but rather weak with the other prostaglandins. Oxytocin, vasopressin and felypressin were without effect on the seminal vesicle preparation. It is concluded that the seminal vesicle responds to smooth muscle stimulants in a similar way as the vas deferens.