Specific Angiotensin Receptor Antagonist Research Articles

Difficult choice: angiotensin receptor antagonists

The paper is focussed on the therapeutic choice of angiotensin receptor antagonists (ARA). The author presents the data on the comparison between different sartans and their benefits which are not explained by the blood pressure reduction. The findings from large multi-centre studies (EUTOPIA, DOHSAM, and OLIVUS-Ex) are also discussed. The evidence presented justifies specific ARA choices, despite the fact that at a first glance, this medication class appears homogeneous.

Human brain contains a novel non-AT1, non-AT2 binding site for active angiotensin peptides

Aims To determine whether the novel non-AT1, non-AT2 binding site for angiotensins recently discovered in rodent brains occurs in the human brain. Main methods Radioligand binding assays of 125I-sarcosine 1, isoleucine 8 angiotensin II binding were carried out in homogenates of the rostral pole of the temporal cortex of human brains containing 0.3 mM parachloromercuribenzoate (PCMB), 10 µM losartan to saturate AT1 receptors, 10 µM PD123319 to saturate AT2 receptors, with or without 10 µM angiotensin II to define specific binding. Competition binding assays employed a variety of angiotensin peptides, specific angiotensin receptor antagonists, several neuropeptides and an endopeptidase inhibitor to determine pharmacological specificity for this binding site. Key findings The novel non-AT1, non-AT2 binding site was present in similar amounts in female and male brains: Bmax 1.77 ± 0.16 and 1.52 ± 0.17 fmol/mg initial wet weight in female and male brains, respectively. The K D values, 1.79 ± 0.09 nM for females, and 1.53 ± 0.06 nM for males were also similar. The binding site shows pharmacological specificity similar to that in rodent brains: sarcosine 1, isoleucine 8 angiotensin II > angiotensin III > angiotensin II > angiotensin I ’ angiotensin IV > angiotensin 1–7. Shorter angiotensin fragments and non-angiotensin peptides showed low affinity for this binding site. Significance The presence in human brain of this novel non-AT1, non-AT2 binding site supports the concept that this binding site is an important component of the brain angiotensin system. The functional significance of this binding site, either as a novel angiotensin receptor or a highly specific angiotensinase remains to be determined.

The AT2 receptor—A matter of love and hate

In 1989, the development of specific angiotensin receptor antagonists which distinguish between two angiotensin receptor subtypes (AT1 and AT2) led to a breakthrough in angiotensin research. It turned out, that the AT1 receptor was almost entirely responsible for the “classical” actions of angiotensin II related to the regulation of blood pressure as well as volume and electrolyte balance. However, actions and signal transduction mechanisms coupled to the AT2 receptor remained enigmatic for a long time. The present review summarizes the current knowledge of AT2 receptor distribution, signaling and function with an emphasis on growth/anti-growth, differentiation and the regeneration of neuronal tissue.

The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis

Regardless of the primary cause, progressive renal deterioration with sclerosis is a hallmark of many renal diseases. Several studies have shown the superiority of angiotensin-converting enzyme inhibitors compared with other antihypertensive agents in providing protection from progressive renal deterioration. Furthermore, animal studies have shown that angiotensin II antagonists in excess of antihypertensive doses can also ameliorate or reverse glomerulosclerosis, leading to the hypothesis that angiotensin II has nonhemodynamic effects that mediate the renoprotective effects shown in these investigations. Although historically angiotensin II has been associated with salt and fluid homeostasis, recent data show that angiotensin II induces cell growth and matrix accumulation in glomerular cells. Plasminogen activator inhibitor-1 has been shown to be the major inhibitor of tissue plasminogen activator and urokinase-like plasminogen activator, with potentially important effects not only on thrombosis/fibrinolysis, but also on matrix degradation because of the proteolytic actions of these substances. Angiotensin II has been shown to influence the actions of plasminogen activator inhibitor-1 and, consequently, its thrombotic and sclerotic effects. Various studies, both in vitro and in vivo, have shown that direct hemodynamic actions, modulation of endothelial injury, and growth factor actions also may be important in the development of sclerosis. These factors can be directly modulated by angiotensin II inhibition. Sclerosis may even be reversed when therapies augment matrix degradation processes, both by directly increasing proteolytic activity and by downregulating inhibitors of matrix degradation. These observations indicate that angiotensin II is important in fibrotic as well as thrombotic renal injuries that lead to progressive renal disease and also in the development of therapies such as specific angiotensin receptor antagonists to prevent or reverse these conditions.

Opposite effects of angiotensin II and IV in the lateral nucleus of the amygdala

In this study the effects of angiotensin II and norleucine 1-angiotensin IV have been studied in a horizontal in vitro slice preparation of female rat brains. Extracellular field potentials of the lateral nucleus of the basolateral amygdala were recorded. The results show that angiotensin II significantly increased the amplitude of field potentials induced by the electrical stimulation of the lateral nucleus, whereas norleucine 1-angiotensin IV caused a significant decrease in the amplitude of field potentials. The angiotensin-induced effects could be blocked by specific angiotensin receptor antagonists. These opposite effects of angiotensin II and IV on electrophysiological parameters are in agreement with behavioral studies that have demonstrated that angiotensin II and IV produce opposite effects on the retention of an inhibitory shock-avoidance response and correlate with their different effects on the blood vessels.

Left ventricular stretch stimulates angiotensin II--mediated phosphatidylinositol hydrolysis and protein kinase C epsilon isoform translocation in adult guinea pig hearts.

Stretch of neonatal cardiomyocytes activates phospholipase C with production of inositol trisphosphate and diacylglycerol in part by formation of angiotensin II (Ang II). However, the response of this pathway to physical stimuli in the adult heart is poorly understood. Thus, in isovolumic perfused guinea pig hearts, we characterized stretch-mediated phosphatidylinositol (PI) hydrolysis and protein kinase C (PKC) isoform translocation using elevated diastolic pressure. Balloon dilatation (minimum diastolic pressure, 25 mm Hg) of the left ventricle (LV) stimulated PI hydrolysis. Pretreatment of stretched hearts with the specific angiotensin (AT1) receptor antagonist losartan abolished stretch-mediated accumulation of inositol phosphates. To examine PKC isoform expression and activation under these conditions, whole-heart extracts were examined by immunoblot analysis. Ang II translocated PKC epsilon to the particulate fraction. 4 beta-Phorbol 12-myristate 13-acetate but not an inactive congener translocated PKC epsilon to the particulate fraction and produced a decrease in myocardial contractile function. Mechanical stretch also translocated PKC epsilon to the particulate fraction; however, this was attenuated but not abolished by losartan. We conclude that in the adult heart, LV dilation produced stretch-mediated activation of phospholipase C, which resulted in PI hydrolysis and PKC epsilon activation in part by stimulation of the local renin angiotensin system. In contrast to stretch-mediated inositol phosphate accumulation, PKC epsilon translocation is not prevented by AT1 receptor blockade, indicating that this PKC isoform can be activated in response to mechanical deformation by an Ang II-independent mechanism in the adult myocardium.

Angiotensin-Responsive Adrenal Glomerulosa Cell Proteins: Characterization by Protease Mapping, Species Comparison, and Specific Angiotensin Receptor Antagonists

Angiotensin-Responsive Adrenal Glomerulosa Cell Proteins: Characterization by Protease Mapping, Species Comparison, and Specific Angiotensin Receptor Antagonists

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: EXPERIENCE WITH ANGIOTENSIN II ANTAGONISTS IN HYPERTENSIVE PATIENTS

1. The availability of orally active specific angiotensin receptor antagonists (AT(1) antagonists) has opened new therapeutic choices and provided probes to test the specific role of the renin-angiotensin system in the pathogenesis of cardiovascular disease. 2. The data available so far suggest that the antihypertensive efficacy of angiotensin receptor antagonists is comparable to that of angiotensin-converting enzyme (ACE) inhibitors. This provides further evidence that this latter class of drugs exerts its effect mainly through blockade of the renin-angiotensin enzymatic cascade. As expected, the association of a diuretic exerts an equally strong additive effect to the antihypertensive efficacy of both classes of drugs. 3. The most common side effect of ACE inhibitors, dry cough, does not occur with AT(1) antagonists, which confirms the long-held view that this untoward effect of the ACE inhibitors is due to renin-angiotensin-independent mechanisms. 4. Long-term studies with morbidity/mortality outcome results are needed, before a definite position can be assigned to this newcomer in the orchestra of modern antihypertensive drugs. Notwithstanding, this new class of agents already represents an exciting new addition to our therapeutic armamentarium.

Novel Drugs and Current Therapeutic Approaches in the Treatment of Heart Failure

Treatment of heart failure attempts to reduce symptoms, increase functional capacity and prolong survival. Optimal therapy usually requires a combination of several drugs. At present, ACE inhibitors are the drugs of first choice, but must be combined with diuretics in symptomatic patients. Digitalis glycosides are still an important supplement to diuretics and ACE inhibitors. Specific angiotensin receptor antagonists such as losartan have an effect comparable with that of ACE inhibitors and may possess certain advantages because of their direct effect at the receptor level. Extensive research has been conducted in the treatment of heart failure. Newer direct acting vasodilators such as flosequinan and epoprostenol have demonstrated improved exercise tolerance but have an adverse effect on mortality. Positive inotropic agents consisting of a heterogeneous group of drugs have been evaluated. Although novel agents such as xamoterol, milrinone, pimobendan and vesnarinone have demonstrated improved haemodynamics and improved symptoms, they are not advisable at present due to increased mortality related to treatment or a high incidence of adverse events. beta-Blockers, used judiciously, may improve functional capacity as well as mortality and may be an important supplement to current conventional treatment. The new generation of beta-blockers with vasodilating properties such as carvedilol and bucindolol appear promising.

Microinfusion of aminopeptidase M into the paraventricular nucleus of the hypothalamus in normotensive and hypertensive rats

Normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) received aminopeptidase M (AmM) delivered into the paraventricular nucleus of the hypothalamus (PVN). Resulting changes in blood pressure were recorded in both anesthetized and alert animals. The findings indicate significant dose-determined decreases in blood pressure in members of both strains with SHR more responsive than WKY rats. The respective drops in blood pressure for members within each strain were equivalent for the anesthetized and alert conditions. Pretreatment with the specific angiotensin receptor antagonist, sarthran, [Sar 1, Thr 8]Anll, into the PVN greatly diminished these responses, suggesting the involvement of the brain angiotensin system. Additionally, a sympathetic nervous system blocker, hexamethonium, and the arginine vasopressin antagonist, Pmp 1, OMeTyr 2[Arg]vasopressin, were peripherally administered to assess the potential contributions of these systems to cardiovascular regulation by the brain angiotensin system. The use of these blockers, individually and combined, attenuated responsiveness to infusion of AmM into the PVN. We conclude that AmM can act as a hypotensive agent in both SHR and WKY rats, and that this decrease in blood pressure is at least partially mediated via the brain angiotensin system although other systems may play a role.

Kinin and angiotensin II receptor antagonists in rats with chronic renal failure

To assess the potential of the kallikrein-kinin and renin-angiotensin systems in mediating the cardio- and renoprotective effects of angiotensin converting enzyme (ACE) inhibitors in rats with chronic renal failure. Spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats subjected to five-sixths nephrectomy were randomly assigned to treatment with vehicle, a kinin antagonist (Hoe 140) or an ACE inhibitor (cilazapril) or both drugs, intraperitoneally via osmotic minipumps for 4 weeks. In addition, the effects of a chronic infusion of a specific angiotensin receptor antagonist (losartan) alone or in combination with an ACE inhibitor (enalapril) were also investigated in nephrectomized SHR for 2 weeks. In nephrectomized SHR and WKY rats, cilazapril alone significantly reduced systolic blood pressure, urinary protein excretion, heart weight and serum creatinine. In nephrectomized SHR, Hoe 140 alone or cilazapril in combination with Hoe 140 (7 or 70 mu g/kg per day) induced no changes in these parameters, other than those associated with the effects of cilazapril alone. In nephrectomized WKY rats, cilazapril in combination with Hoe 140 (70 mu g/kg per day) slightly, but not significantly, attenuated the antihypertensive effect of cilazapril but did not affect the other parameters. These results were confirmed by morphological analysis of kidneys. All the drug regimens provided effective protection against an increase in focal glomerular sclerosis. Enalapril did not modify the antihypertensive and renoprotective effects of losartan in nephrectomized SHR. The present results indicate that the kallikrein-kinin system might not be a major factor in the cardio- and renoprotective effects of ACE inhibitors in rats with chronic renal failure.

Angiotensin II receptor blockade in TGR(mREN2)27: effects of renin???angiotensin-system gene expression and cardiovascular functions

To study the effect of angiotensin II receptor AT1 blockade on blood pressure, gene expression and pathomorphology of transgenic rats harbouring the mouse Ren-2 gene [TGR(mREN2)27], that develop fulminant hypertension while exhibiting suppressed components of the circulating renin-angiotensin system. TGR(mREN2)27 were treated orally with the newly developed AT1-specific angiotensin receptor antagonist Telmisartan, 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl) methyl]-[1,1'-biphenyl]-2-carboxylic acid, in three doses (0.1, 1 and 3 mg/kg body weight) for 9 weeks. The concentrations of the renin-angiotensin system components were analysed in plasma and tissues by radioimmunoassay. Messenger RNA levels for the angiotensinogen and renin genes were quantified by RNAase protection assay in several tissues. Heart hypertrophy and kidney morphology and function were monitored at the end of the treatment. In contrast to 0.1 mg/kg, 1 and 3 mg/kg Telmisartan normalized tail blood pressure measured once a week. Plasma renin and angiotensin II concentration increases were dose-dependent. The renin-angiotensin system genes in various cardiovascular organs were differentially regulated by angiotensin II receptor blockade. Treatment with Telmisartan stimulated angiotensinogen gene expression in the liver, kidney and heart, whereas it remained unchanged in the hypothalamus, thymus and adrenal gland. In the kidney, the expression of the endogenous, but not of the mouse Ren-2 gene, was increased in parallel to the renin concentration. Telmisartan reduced the severe glomerulosclerosis and proteinuria as well as cardiac hypertrophy observed in untreated TGR(mREN2)27 even with the lowest dose of 0.1 mg/kg, at which the blood pressure of the rats still exceeded 225 mmHg and the plasma renin-angiotensin system parameters were unchanged. From these experiments using a specific antagonist we can conclude that high blood pressure in TGR(mREN2)27 is angiotensin II-dependent. Furthermore, the expression of the renin-angiotensin system genes seems to be regulated not only by blood pressure and the plasma renin-angiotensin system but also by other, tissue-specific mechanisms. Pathomorphological changes in the kidney and in the heart do not seem to be caused by the systemic hypertension exclusively, but are also influenced by angiotensin II directly.

Role of paraventricular nucleus in control of blood pressure and drinking in rats

The present investigation examined the abilities of angiotensin (ANG) II and III to produce increases in blood pressure and drinking when microinfused into the paraventricular nucleus (PVN) of the hypothalamus of the Sprague-Dawley rat. Dose-dependent elevations in systemic blood pressure and heart rate were measured to both ANG II and III in the anesthetized rat, with ANG II more potent than ANG III at the two highest doses examined. Pretreatment with the specific ANG receptor antagonist [Sar1,Thr8]ANG II (sarthran), blocked subsequent ANG II- and III-induced elevations in blood pressure, suggesting that these responses were dependent on the activation of ANG receptors. A similar analysis in awake rats yielded nearly equivalent results. A final experiment demonstrated that microinfusions of ANG II and III into the PVN produced drinking in a dose-dependent manner, with greater consumption to ANG II than ANG III. Again, sarthran was found to block the dipsogenic response. Histological examination revealed that the location of the injection site was linked to the character of the ANG-dependent response. These data suggest that the PVN may play a critical role in mediating central ANG effects on body water homeostasis and blood pressure regulation. Furthermore, it appears that subnuclei of the PVN may participate differentially in ANG-mediated actions.

Hypotensive effects of sarthran in normotensive and spontaneously hypertensive rat strains

The specific angiotensin receptor antagonist [Sar1, Thr8]AII (sarthran) was intracerebroventricularly (ICV) infused in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) normotensive controls. The results extend earlier findings by determining that: 1) the hypotensive effect of ICV-infused sarthran could be enhanced in anesthetized as compared with alert animals; 2) SHRs revealed a greater hypotensive response as compared with WKY rats; and 3) no sarthran-induced agonistic effects were observed in contrast with previous results using alert SHRs. These findings support the use of sarthran as a potent angiotensin receptor antagonist to investigate the role of the brain angiotensin system in the control of normal and dysfunctional blood pressure.

Aminopeptidase-induced elevations and reductions in blood pressure in the spontaneously hypertensive rat

In vitro results indicated that human placenta-derived aminopeptidase A (APA) was very effective at hydrolyzing aspartate from the angiotensin molecule, thus converting angiotensin II to angiotensin III, but was not active against angiotensin III. In vivo experiments revealed significant elevations in blood pressure when APA was intracerebroventricularly infused into anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive control rats (WKY), with maximum mean (+/- s.e.m.) increases of 30.0 +/- 2.5 and 32.5 +/- 3.7 mmHg, respectively. By contrast, in vitro incubation results utilizing leucine aminopeptidase M (LAP-M) indicated very active degradation of angiotensin III, with less rapid degradation of angiotensin II. The intracerebroventricular infusion of LAP-M significantly reduced blood pressure, particularly in the SHR, but also in WKY, -65.8 +/- 5.1 and -42.5 +/- 6.1 mmHg, respectively. Pretreatment with the specific angiotensin receptor antagonist, Sar1, Thr8 angiotensin II (sarthran) significantly diminished the subsequent APA-induced increase in blood pressure in members of both strains. Pretreatment with sarthran has previously been shown to significantly diminish LAP-M-induced decreases in blood pressure in SHR. Thus, the effects of these aminopeptidases appear to be primarily dependent upon the brain angiotensinergic system, and are consistent with the hypothesis that angiotensin III is the primary active form of central angiotensin.

Intracerebroventricularly infused [ d-Arg 1]angiotensin III, is superior to [ d-Asp 1]angiotensin II, as a pressor agent in rats

Two d-amino acid substitution angiotensin analogues were compared against native angiotensin II (AII) and angiotensin III (AIII) for their resistance to brain tissue-induced degradation and for pressor potency when intracerebroventricularly (i.c.v.) infused in Sprague-Dawley rats. The in vitro results indicate that [ d-Asp 1]AII was very resistant to degradation, AII and [ d-Arg 1]AIII were degraded at similar rates, while AIII was the most rapidly degraded. In vivo results revealed that AII, AIII and [ d-Arg 1]AIII produced greater pressor responses than [ d-Asp 1]AII. Intracerebroventricular pretreatment with the aminopeptidase A inhibitor, amastatin, siginificantly reduced the subsequent pressor response to i.c.v. infused [ d-Asp 1]AII presumably by inhibiting its conversion to AIII. In contrast, pretreatment with the aminopeptidase B inhibitor, bestatin, potentiated the subsequent pressor response to i.c.v. infused [ d-Arg 1]AIII, presumably by inhibiting the conversion of [ d-Arg 1]AIII to the less active hexapeptide AII(3–8). Next, i.c.v. pretreatment with the specific angiotensin receptor antagonist, [Sar 1, Thr 8]AII (Sarthran) was found to greatly diminish the subsequent pressor responses to i.c.v. infused [ d-Asp 1]AII and [ d-Arg 1]AIII, suggesting that these analogues are having their effect at the same brain angiotensin receptor site. These results support the hypothesis that AIII, or AIII-like ligands, may serve as the active form of brain angiotensin.

Cochlear blood flow autoregulation in Wistar-Kyoto rats

Wistar-Kyoto rats (WKY) were intra-arterially infused with angiotensin II (AII) or phenylephrine for 10 min. Both vasoactive compounds produced an initial increase in cochlear blood flow (CoBF) as measured by laser Doppler flowmetry, followed by a slow steady return to baseline, despite sustained elevations in systemic blood pressure. These results suggest autoregulation of CoBF in the WKY rat. In a second experiment, All was infused directly into the anterior inferior cerebellar artery (AICA) which feeds the cochlear artery. Significant reductions in CoBF were noted without changes in systemic blood pressure. Pretreatment with the specific angiotensin-receptor antagonist, sarthran (Sar 1, Thr 8-AII), diminished subsequent AII-induced reductions in CoBF. These results indicate that All binding to vascular receptors may induce vasoconstriction in the supplying vessels of the cochlea, and thus, the interaction of blood-home All and vascular angiotensin receptors may participate in the autoregulation of CoBF.

Increased blood pressure induced by central application of aminopeptidase inhibitors is angiotensinergic-dependent in normotensive and hypertensive rat strains

Two aminopeptidase inhibitors, amastatin (AM) and bestatin (BE), were employed in 3 strains of rats, sponteneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD), to investigate the central angiotensinergic system. The results indicate that intracerebroventricular (i.c.v.) injections of AM and BE induced pressor elevations in all 3 strains of rats. In order to test for the possibility of spillage into peripheral vasculature, members from all 3 strains were peripherally infused with AM, BE, or 0.15 NaCl via jugular vein catheters. The SHRs were significantly more responsive to the aminopeptidases than the normotensive strains, however their overall pressor responses were only 33% of those to i.c.v. infusion. Next, in order to test the notion that these aminopeptidase inhibitors are having their effect via the central angiotensinergic system, and not some other peptidergic system, the specific angiotensin receptor antagonist, Sar 1, Thr 8-AII (sartran) was employed. Intracerebroventricular pretreatment with sarthran prevented subsequent pressor responses to i.c.v. AM and BE in members of all 3 strains, thereby suggesting that these aminopeptidase inhibitors are having their effect via the central angiotensinergic system.

Leucine aminopeptidase M-induced reductions in blood pressure in spontaneously hypertensive rats.

Leucine aminopeptidase M significantly reduced blood pressure for up to 40 minutes when infused intracerebroventricularly into anesthetized spontaneously hypertensive rats (SHR) from a mean +/- SEM of 190 +/- 4 to 94 +/- 7 mm Hg and also in normotensive Wistar-Kyoto (WKY) rats from 138 +/- 5 to 68 +/- 8 mm Hg. Cerebrospinal fluid levels of angiotensin II (Ang II) and III were measured by radioimmunoassay and indicated drops with leucine aminopeptidase M infusion in SHR (from 36 +/- 6 to 11 +/- 1 pg/100 microliters) and in WKY rats (from 33 +/- 9 to 13 +/- 1 pg/100 microliters). Pretreatment with the specific angiotensin receptor antagonist [Sar1, Thr8]Ang II (sarthran) significantly diminished the subsequent leucine aminopeptidase M-induced decreases in blood pressure in SHR and facilitated recovery to base level blood pressure and heart rate in blood strains. Thus, exogenous application of leucine aminopeptidase M into the brain lateral ventricles of SHR is temporarily effective at reducing blood pressure, and this effect appears dependent on the brain angiotensinergic system. This treatment also reduced blood pressure in WKY rats; however, pretreatment with sarthran was reasonably ineffective at preventing subsequent leucine aminopeptidase M-induced decreases in blood pressure.

Pressor responses to amastatin, bestatin and Plummer's inhibitors are suppressed by pretreatment with the angiotensin receptor antagonist sarthran

The aminopeptidase inhibitors, amastatin (AM) and bestatin (BE), and carboxypeptidase inhibitor Plummer's (PL) were applied intracerebroventricularly (ICV) in rats following pretreatment with the angiotensin receptor antagonist sarthran (Sar 1,Thr 8-AII) or artificial cerebrospinal fluid. Angiotensin II (AII) was also included as a comparison vasoactive peptide. Pressor responses were recorded at 30 min intervals for 90 min to ascertain the duration of the antagonistic effect of sarthran on subsequent injections of AM, BE, PL and AII. Sarthran was effective in suppressing pressor activity to AII- and PL-induced pressor activity until 60 min following pretreatment, and AM- and BE-induced pressor responses until 90 min following pretreatment. These data suggest that AM, BE and PL are having their presser effects via the central angiotensinergic system and that the patterns of AM, BE, PL and AII recovery from the influence of a specific angiotensin receptor antagonist are similar. The results are consistent with the concept that these inhibitors may increase endogenously synthesized angiotensins which are associated with pressor responses.