The effect of sublingual captopril versus intravenous enalaprilat on angiotensin II plasma levels

A 44-year-old woman, with a history of familial adenomatous polyposis, complicated by carcinoma of the colon, for which a proctocolectomy had been performed, now presented with metastasis located in the pancreas. Treatment consisted of chemotherapy followed by a partial pancreaticoduodenectomy. Due to ischemia, resection of the small intestines was performed the same day. After admission, a transesophageal echocardiography showed an ejection fraction of 40%. Because enteral administration of drugs was impossible, intravenous enalaprilat 2 mg once a day for 1 day followed by sublingual captopril 25 mg twice a day were started. Blood samples were taken before and after administration. After 1 day of sublingual captopril treatment the angiotensin II level decreased with more than 50%, comparable to the decrease seen after intravenous administration of enalaprilat. Sublingual captopril has been used in the treatment of hypertensive crisis and heart failure. Although frequently reported, no study has investigated the effect on angiotensin II levels after sublingual administration in heart failure patients. This case-report demonstrated that sublingual administration of 25 mg captopril twice a day yielded a considerable decrease in angiotensin II plasma levels which was comparable to the effect seen after an intravenous administration of 2 mg enalaprilat.     

Mechanisms of angiotensin II chronotropic effect in anaesthetized dogs.

1. The chronotropic effect of angiotensin II (5 micrograms in 1 ml of Tyrode solution), injected directly into the sinus node artery of 24 anaesthestized and vagotomized dogs pretreated with a beta-adrenoceptor antagonist, was evaluated before and after the administration of: (a) an angiotensin II AT1 receptor antagonist (losartan, 50 micrograms kg-1 min-1 infused i.v. for 120 min), (b) an alpha-adrenoceptor antagonist (prazosin, 1 mg kg-1 i.v. bolus injected), (c) a Ca2+ channel blocker (nifedipine 50, 100 and 200 micrograms kg-1 i.v. bolus injected) and (d) a protein kinase inhibitor (staurosporine, 800 nM infused via the sinus node artery at 0.6 ml min-1 for 15 min). 2. Losartan and staurosporine by themselves had no effect on basal systemic arterial pressure and heart rate, whereas prazosin and nifedipine caused significant diminutions of both parameters. 3. Angiotensin II induced significant increases in heart rate, the mean augmentations being 29 +/- 2 beats min-1. Losartan, nifedipine and staurosporine significantly decreased the chronotropic effect of angiotensin II, the mean respective diminutions being 65 +/- 8, 40 +/- 9 and 64 +/- 10%, whereas prazosin had no effect. 4. This work has demonstrated that angiotensin II exerts in vivo a significant positive chronotropic effect that is mediated via AT1 receptors located in the region of the sinoatrial node. This effect is independent of the adrenergic system. It is decreased by the inhibition of the production of protein kinases, most probably of protein kinase C, and by the blockade of the voltage-sensitive L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)     

The specificity of the dipsogenic effect of angiotensin II

The specificity of choice in drinking by sheep was examined when a cafeteria of water and of 900 mmol/1 solutions of NaCl and KCl was presented, during intracarotid infusion of angiotensin II (800–1200 ng/min) or 4M NaCl (1.6 ml/min), and following 48 hr of water deprivation or following Na depletion. Water was the fluid of predominant choice with angiotensin II, 4M NaCl infusion and water deprivation. The hypertonic NaCl was the clear choice of the Na deficient animals. With a cafeteria of 300 mmol/1 solutions, there was no clear discrimination between NaCl and water with intracarotid angiotensin II infusion. A 2 choice study of taste preference for water or NaCl concentrations with free access indicated sheep elect to take more of higher NaCl concentrations than the rat, and that 300 mmol/1 NaCl is not less preferred than water in sheep. The data indicated, overall, that the dipsogenic effect of supraphysiological cerebral blood concentrations of angiotensin II is biased to water drinking when the choice is between water and 900 mM NaCl and KCl solutions. It does not induce any specific salt appetite.     

Hyperhydrating effect of acute administration of angiotensin II in rats.

Water intake, urine output, and fluid exchange (water intake less urine output) were measured in rats at hourly intervals for 7 hours and at 24 hours following acute administration of angiotensin II (AII, 200 micrograms/kg SC). AII induced the expected abrupt increase in water intake and a more gradual increase in urine output. The change in fluid exchange (fluid exchange of the AII-treated group less fluid exchange of controls) became positive within the first hour after treatment with AII, decreased linearly with time, and reached 0 at approximately 10 to 12 hours after treatment with AII. When AII was administered intracerebroventricularly (50 ng), similar results were observed. In this case, the change in fluid exchange (delta F) reached 0 in about 6 hours. Imposition of a water load (1% of body weight, IP) on the group receiving AII SC failed to affect the time required for delta F to reach 0 if the water load was disregarded. However, inclusion of the load as a part of intake extended the time the rats remained in positive fluid balance beyond that of the nonloaded, AII-treated control group. In the case of the larger water load (3% of body weight, IP), delta F returned to that of controls in about 4 to 5 hours if the water load was disregarded. However, inclusion of the load as part of intake extended the period of hyperhydration well beyond that of both the nonloaded, AII-treated group and the AII-treated group given the 1% load.(ABSTRACT TRUNCATED AT 250 WORDS)     

Participation of angiotensin II in learning and memory. II. Interactions of angiotensin II with dopaminergic drugs

The effect of angiotensin II (ATII) and of its interactions with dopaminergic drugs injected post-trial on retention in active avoidance tasks in shuttle-box-trained rats were studied. ATII at doses of 0.10 and 0.50 micrograms administered intracerebroventricularly (i.c.v.) immediately after training improved retention. The dopaminergic receptor agonist apomorphine at a dose of 0.10 mg/kg injected intraperitoneally (i.p.) facilitated retention whereas elymoclavine (a dopaminergic agonist) at a dose of 2.5 mg/kg i.p. had no effect. ATII at a dose of 0.10 micrograms i.c.v. administered after apomorphine 0.10 mg/kg or elymoclavine 2.5 mg/kg exerted a stronger retention-facilitating effect. The dopaminergic receptor antagonist haloperidol at a dose of 1 mg/kg i.p. markedly impaired retention. ATII at a dose of 0.50 micrograms administered after haloperidol (1 mg/kg) did not exercise its retention-facilitating effect. It is concluded that the retention facilitating effects of ATII are realized through interactions with brain dopaminergic transmission.     

Evidence for the histamine-mediated myotropic effect of angiotensin II in the rabbit aorta.

Histamine H1-receptor antagonist mepyramine and H2-receptor antagonist metiamide, respectively diminished and potentiated angiotensin II(A II)-induced myotropic responses in the rabbit aortic strips. The responses of the octapeptide were also inhibited in the presence of histidine decarboxylase inhibitor, 2-hydroxy-5-carbomethoxybenzoxyamine and restored when subcontractile quantities of histamine are added to the inhibitor-containing medium. Inhibition of histamine degradation by aminoguanidine potentiates A II's responses. These results are taken as evidences indicating A II-induced histamine synthesis in the test preparation.     

Local formation of angiotensin II in the rat aorta: effect of endothelium.

1. The local formation of angiotensin II (AII) from its precursors, angiotensin I (AI) and tetradecapeptide (TDP) renin substrate, was studied in intact (with endothelium) and rubbed (without endothelium) aortic rings of the rat. 2. AI and TDP renin substrate maximally contracted intact tissues in a similar way to AII. The same observations were made in rubbed tissues. 3. The maximal response and the sensitivity of the aorta to these agonists were greater in rubbed than in intact tissues. 4. In intact preparations, methylene blue increased the contractile response to AII and TDP to the same extent as endothelium removal. 5. In intact preparations, AII receptor blockade completely suppressed all contractile responses, converting enzyme inhibition completely blocked the responses to AI and TDP, and renin inhibition partially blocked the responses to TDP. 6. In rubbed preparations, AII receptor blockade completely inhibited all contractile responses, converting enzyme inhibition completely suppressed the responses to AI but only partially inhibited those to TDP, and renin inhibition partially blocked the responses to TDP. 7. In conclusion, the formation of AII from TDP and its blockade by a converting enzyme inhibitor and a renin inhibitor shows that converting enzyme and a renin-like aspartic proteinase are present in the aortic wall. Furthermore, the results show that the endothelium is not essential for the conversion of the TDP to AII, but modulates the responses to locally formed AII through the release of endothelium-derived relaxing factor (EDRF).     

Participation of angiotensin II in learning and memory. I. Interaction of angiotensin II with saralasin

The effects of the octapeptide angiotensin II (AT II) on acquisition and retention in active avoidance tasks in shuttle-box-trained rats were studied. AT II at doses of 0.1, 0.5 and 1 microgram administered intracerebroventricularly (i.c.v.) 15 min before training facilitated learning and retention. AT II injected immediately after training also improved retention when tests were given 24 h post-trial. Saralasin at a dose of 1 microgram i.c.v. administered 15 min before training did not influence acquisition but antagonized the learning-facilitating effect of AT II. Saralasin at a dose of 5 micrograms injected immediately after training improved retention but abolished the retention-facilitating effect of AT II. It is suggested that the AT II effects on memory processes in active avoidance tasks are realized through specific angiotensin receptors in the brain structures.     

Diurnal variation in the effect of angiotensin II on nociception

The aim of this study was to investigate the effect of angiotensin II (Ang II) on nociception at particular time points of a 24-h cycle using different pain stimuli. A parallel investigation of phasic and tonic pain tests revealed different diurnal patterns of pain responses. Phasic pain test (mechanical paw pressure) in rats was characterized with shortest latencies during the dark phase, when the average of motor activity is greatest. Ang II (0.1 microg/animal) increased the latency of pain responses to mechanical and thermal stimulations mainly during the active dark phase. With regard to tonic pain, regardless of a weak circadian fluctuation of the number of pain responses (writhes) in mice, there was a tendency to attenuate the diurnal pattern of nociception. In contrast to the effect of Ang II on the phasic pain, it exerted an antinociceptive effect in the writhing test during the light phase. In summary, Ang II exerted an antinociceptive effect at the time points that have naturally high pain sensitivity.     

The effect of angiotensin II on endogenous noradrenaline release in man.

1. Considerable data from animal studies suggest that angiotensin II exerts a facilitatory effect on noradrenaline release. We sought evidence for such an effect in man by examining how a subpressor dose of angiotensin II (1.5 ng kg-1 min-1) influences the haemodynamic and plasma noradrenaline responses to physiological stimulation of the sympathetic nervous system. 2. The physiological stimuli investigated were a cold pressor test, the response to standing from lying, bicycle exercise and forearm isometric exercise. 3. The presence of the angiotensin II infusion had no effect on the systolic blood pressure, diastolic blood pressure, heart rate or plasma noradrenaline responses to stimulation of the sympathetic nervous system. 4. We have therefore found no evidence to support the enhancement of noradrenaline release by this low dose of angiotensin II in man.     

Dipsogenic effect of angiotensin II, bombesin and tachykinins in the duck

The effect on drinking behaviour of intracerebroventricular injections of angiotensin II, bombesin, eledoisin and substance P was studied in the duck. While substance P was almost completely ineffective, angiotensin II, bombesin and eledoisin elicited a clear dipsogenic response which was dose-dependent and apparently specific. Angiotensin II was about 10 times more potent than bombesin and far more potent than eledoisin. These results confirm once more the wide phylogenetic distribution of the dipsogenic response to angiotensin II. Furthermore, they show that bombesin and eledoisin, which potently inhibit water intake in the rat, exert in the duck a dipsogenic effect strictly parallel to that elicited in the pigeon. On the basis of the animal species so far tested it is possible to hypothesize that bombesin and tachykinins stimulate water intake in birds, while inhibiting drinking in mammals.     

Influence of the adrenal gland on the pressor effect and antagonistic potency of angiotensin II analogs.

In ganglion blocked vagotomized rats, several 1,8-substituted angiotensin II analogs (250 ng/kg/min, i.v.) antagonized the pressor effect of angiotensin II. Dose ratios measured at the ED20 levels were: [Sar1,Ile8]-28; [Gac1,Ile8]- 19;[MeAla1,Ile8i1- 16;[MeIle1,Ile8]- 10;[sar1,Ala8]- 9;[me2Gly1,Ile8]- 4. Elimination of aspajtic acid in position 1 of [Ile8]-angiotensin II significantly reduced the antagonistic potency of the analog. No antagonistic effect was observed with [Phe4,Ile8] and [Ala4,Ile8]-angiotensin II even when infused at 6 mug/kg/min. During infusion, a partial rise in blood pressure was observed with all the above 1,8-substituted angiotensin II analogs. Phentolamine (100 mug/rat) injected 30 min after the start of the analog infusion reduced and sometimes abolished the pressor effect. However, phenoxybenzamine )Pbz, 2 mg/kg) injected 30 min prior to the analog infusion diminished but did not completely abolish the initial pressor effect. In adrenalectomized rats, the pressor effect was reduced by approximately 50 percent and disappeared completely 15-30 min after start of the infusion. Under these conditions, dose ratios of [Sar1,Ile8]-,[MeAla1,Ile8]- and [Gac1,Ile8]-angiotensin II were significantly reduced. Noradrenaline, 83 ng/kg/min. increased the ED20 value of angiotensin II(ratio 1.79) in normal rats but did not do so in adrenalectomized rats. In these rats no regular correlation was found between the angiotensin II ED20 values and initial blood pressure. These data indicate that under the present experimental conditions, the low pressor effect observed with these angiotensin II antagonists appears to be due to both adrenal catecholamine release and a direct vasoconstrictor effect. Variations in antagonistic activity of angiotensin II analogs, apart from changes introduced in the molecule, may be the manifestation of a complex interaction between angiotensin II, its antagonists, and the sympathoadrenal system.     

Participation of angiotensin II in learning and memory. III. Interactions of angiotensin II with GABAergic drugs

The experiments were carried out on male albino rats trained and tested for retention (24 hr later) in a shuttle-box. Angiotensin II (AT II) 0.10 micrograms intracerebroventricularly (i.c.v.), gamma-aminobutyric acid (GABA) 100 micrograms i.c.v., bicuculline 0.5 and 1.0 mg/kg intraperitoneally (i.p.), and picrotoxin 0.5 and 1.0 mg/kg i.p. administered independently or in combinations immediately after training. AT II was found to improve retention. GABA also facilitated retention. Combination of AT II + GABA potentiated the memory-improving effect of AT II. Bicuculline and picrotoxin at a dose of 0.5 mg/kg did not affect retention, while at a dose of 1.0 mg/kg they improved it. Combinations of AT II + bicuculline (0.5 mg/kg) and AT II + picrotoxin (0.5 mg/kg) abolished the retention-improving effect of AT II. Bicuculline (0.5 mg/kg) or picrotoxin (0.5 mg/kg) abolished the retention-facilitating effect of the combination of AT II + GABA as well as the potentiating action of GABA on the memory effect of AT II. These results suggest the participation of GABAergic transmission in the CNS in the mechanisms of the long-term memory-improving effect of AT II.     

The effect of chronic captopril therapy on platelet angiotensin II receptor density and vascular responsiveness to angiotensin II infusion

Summary The density of angiotensin II (Ang II) receptors on the platelet and the vascular responsiveness to infused angiotensin II before and after two weeks of captopril therapy were examined in ten healthy male volunteers. There was a significant increase in blood flow to the forearm, but no significant changes in either the density of angiotensin II receptors or the pressor response to infused angiotensin II following captopril therapy. The study demonstrates that long term reduction of angiotensin II formation by captopril in man does not increase the responsiveness of the receptors to infused angiotensin, nor results in an up regulation of the angiotensin receptors. It also provides further evidence that some of the long term vasodilator effects of captopril may be mediated by mechanisms other than inhibition of angiotensin I (Ang I) converting enzyme.     

Lead exposure effect on angiotensin II renal vasoconstriction

Low levels of chronic lead exposure can produce hypertension and endothelial dysfunction, which could be associated with oxidative stress, changes in vascular tone and an imbalance of endothelial-derived vasoconstriction and vasodilator factors. The aim was to investigate the effect of chronic lead-exposure on angiotensin II-induced vasoconstriction in isolated perfused kidney and microvessels. Male Wistar rats (230-250 g) were treated for 12 weeks with lead acetate (100 ppm, Pbgroup) or pure water (control group). We evaluated the vascular reactivity in the kidneys and renal microvessels in the presence and absence of N(omega)-nitro-L-arginine methyl ester (L-NAME) in both groups. The nitrite concentration in renal perfusate was measured as an index of NO released, renal abundance of 3-nitrotyrosine was measured as well as endothelial NO synthase (eNOS) expression. Oxidative stress was measured by using the oxidative fluorescence dye dihydroethidium (DHE) to evaluate in situ production of superoxide and identified by confocal microscopy. Lead-exposure significantly increased blood pressure, eNOS protein expression, oxidative stress and vascular reactivity to angiotensin II. L-NAME potentiated vascular response to angiotensin II in control group but had no effect on the Pb-group. Nitrites released from the kidney of lead-group was lower compared to the control group while 3-nitrotyrosine was higher. This data suggest that lead-induced hypertension could be caused partially by an altered NOsystem.     

Mechanisms of the angiotensin II effects on the exploratory behavior of rats in open field. II. Interaction of angiotensin II with yohimbine

The effects of the octapeptide angiotensin II (AT II) and its interaction with yohimbine, an alpha 2-adrenoceptor antagonist, on the exploratory behavior of male rats in open field were studied. AT II (0.1 and 0.5 microgram intracerebroventricularly, i.c.v) increased the open field behavior, mainly ambulation and rearing. Yohimbine (1 and 3 mg/kg) significantly reduced the stimulatory effects of AT II, mainly on ambulation. It is suggested that the augmented release of noradrenaline (NA) resulting from alpha 2-adrenoceptor blockade decreases the exploratory behavior effects of AT II. An interaction between AT II receptors and NA-ergic neurotransmission in the brain might be taken into consideration as an explanation of the influence of yohimbine on AT II effects in open field behavior.     

Enalapril treatment discloses an early role of angiotensin II in inflammation- and oxidative stress-related muscle damage in dystrophic mdx mice

Inhibitors of angiotensin converting enzymes (ACE) are clinically used to control cardiomyopathy in patients of Duchenne muscular dystrophy. Various evidences suggest potential usefulness of long-term treatment with ACE inhibitors to reduce advanced fibrosis of dystrophic muscle in the mdx mouse model. However, angiotensin II is known to exert pro-inflammatory and pro-oxidative actions that might contribute to early events of dystrophic muscle degeneration. The present study has been aimed at evaluating the effects of an early treatment with enalapril on the pathology signs of exercised mdx mouse model. The effects of 1 and 5 mg/kg enalapril i.p. for 4–8 weeks have been compared with those of 1 mg/kg α-methyl-prednisolone (PDN), as positive control. Enalapril caused a dose-dependent increase in fore limb strength, the highest dose leading to a recovery score similar to that observed with PDN. A dose-dependent reduction of superoxide anion production was observed by dihydroethidium staining in tibialis anterior muscle of enalapril-treated mice, approaching the effect observed with PND. In parallel, a significant reduction of the activated form of the pro-inflammatory Nuclear Factor-kB has been observed in gastrocnemious muscle. Histologically, 5 mg/kg enalapril reduced the area of muscle necrosis in both gastrocnemious muscle and diaphragm, without significant effect on non-muscle area. In parallel no significant changes have been observed in both muscle TGF-β1 and myonuclei positive to phosphorylated Smad2/3. Myofiber functional indices were also monitored by microelectrodes recordings. A dose-dependent recovery of macroscopic chloride conductance has been observed upon enalapril treatment in EDL muscle, with minor effects being exerted in diaphragm. However a modest effect, if any, was found on mechanical threshold, a functional index of calcium homeostasis. No recovery was observed in creatine kinase and lactate dehydrogenase. Finally the results suggest the ability of enalapril to blunt angiotensin-II dependent activation of pro-inflammatory and pro-oxidant pathways which may be earlier events with respect to the pro-fibrotic ones, and may in part account for both functional impairment and muscle necrosis. The PDN-like profile may corroborate the combined use of the two classes of drugs in DMD patients so to potentiate the beneficial effects at skeletal muscle level, while reducing both spontaneous and PDN-aggravated cardiomyopathy.     

Pharmacological characteristics of the positive inotropic effect of angiotensin II in the rabbit ventricular myocardium.

1. In order to elucidate the mechanism underlying the positive inotropic effect (PIE) of angiotensin II (AII), we measured changes in phosphoinositide hydrolysis and contractile force induced by AII in the rabbit ventricular myocardium. 2. AII (1.0 nM-3 microM) produced a PIE in a concentration-dependent manner in the presence of bupranolol (0.3 microM) and prazosin (0.1 microM), the maximal response being about 40% of that to isoprenaline and the EC50 30 nM. 3. The PIE of AII was associated with a concentration-dependent increase in the total duration of contraction; the time to peak force and the relaxation time were prolonged. 4. AII (10 nM-30 microM) elicited an accumulation of [3H]-inositol monophosphate in a concentration-dependent manner in rabbit ventricular slices prelabelled with myo-[3H]-inositol. 5. The PIE and the accumulation of [3H]-inositol monophosphate induced by AII were inhibited by a non-selective AII receptor antagonist, saralasin (10 nM-1 microM) and by a selective AT1 receptor antagonist, losartan (10 nM-1 microM), but not a selective AT2 receptor antagonist, PD 123319 (1 microM). 6. A tumour-promoting phorbol ester, phorbol 12,13-dibutyrate (PDBu, 10-100 nM), inhibited the AII-induced PIE and [3H]-inositol monophosphate accumulation in a concentration-dependent manner. 7. These results suggest that AII exerts a PIE through activation of AT1 receptors and subsequent acceleration of phosphoinositide hydrolysis. Activation of protein kinase C by PDBu may inhibit the AII-induced stimulation of phosphoinositide hydrolysis and thereby the PIE of AII in the rabbit ventricular myocardium.