Specific Angiotensin Research Articles

Renal hemodynamics in rats with myocardial infarction: selective antagonism of angiotensin receptor subtypes.

Rats with congestive heart failure demonstrate striking intrarenal vasoconstriction that contributes to reduced renal excretory function. The importance of specific angiotensin II receptor subtypes (AT1, AT2) for mediating changes in renal hemodynamics was studied in anesthetized rats 1 mo after myocardial infarction (MI) created by coronary artery ligation. AT1 antagonism with losartan alone decreased mean arterial pressure (MAP), total peripheral resistance (TPR), and renal resistance (RR) in control and MI rats to a similar extent without affecting renal blood flow (RBF) or RBF as a percentage of cardiac output (%RBF/CO). In contrast, AT2 antagonism with PD-123319 alone significantly reduced MAP and RR in MI rats without affecting these parameters in control rats. TPR and %RBF/CO were not changed significantly in either group. In contrast, combined AT1- and AT2-receptor inhibition lowered TPR and RR and increased RBF and %RBF/CO, thus the effects of renin or ACE inhibition were mimicked in MI rats. We conclude that angiotensin II acts at both AT1 and AT2 receptor sites in rats with reduced cardiac mass to modulate renal hemodynamics.

The neuronal role of angiotensin II in thirst, sodium appetite, cognition and memory.

Within the past two decades, a great deal has been learnt about the renin-angiotensin system in the brain. The renin-angiotensin system is one of the best-studied enzyme-neuropeptide systems in the brain. The diversity of localization of this peptide throughout the brain has implied a variety of potential functions. Besides its classical role in the regulation of blood pressure and body-fluid homeostasis, it has more subtle functions involving complex mechanisms such as learning and memory. The profound effects on behaviour produced by angiotensin are of broad interest to neuroscientists. The mechanisms of action differ depending on whether angiotensin is locally synthesized and whether regulation is governed by neural or metabolic inputs impinging on the neurones. Its central action is mediated through peptidergic receptors present on neurones. The description of the receptor subtypes AT1 and AT2 for angiotensin II and the development of non-peptidic specific angiotensin receptor subtype antagonists have opened a new area in this field of research. The AT1 site, which preferentially binds to angiotensin II and angiotensin III, appears to mediate the classical angiotensin functions concerned with maintenance of blood pressure and body-fluid control. In addition, most of the behavioural effects described so far are linked with AT1, although so-called psychotropic effects are presumed to be mediated by receptor systems other than the known specific angiotensin receptors. In fact, evidence for the existence of such receptors with high-affinity binding has been reported. The central action of angiotensin II mediated by AT2 is as yet unclear. Most reports concerning this receptor subtype suggest a role in differentiation and development, since the number of binding sites is higher in fetal and young rats than in adults. Furthermore, the neuronal effect of angiotensin II in the inferior olivary nucleus which is blocked specifically by AT2 antagonists suggests an involvement in motor control. Over the next few years we should find answers to many of the questions currently unanswered about angiotensin function and, given the rapid progress in research on this neuropeptide, it may serve as a model for the action of peptides on neuronal function in general.

Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: FUNCTIONS OF ANGIOTENSIN PEPTIDES IN THE ROSTRAL VENTROLATERAL MEDULLA

SUMMARY It was first shown several years ago that the rostral part of the ventrolateral medulla (VLM) contains a high density of receptor binding sites for angiotensin II (AngII). In the present paper we briefly review recent studies aimed at determining the actions of both exogenous and endogenous angiotensin peptides in the rostral VLM, as well as their specific sites of action. The results of these studies have shown that angiotensin peptides can excite pressor and sympathoexcitatory neurons in the rostral VLM, but do not appear to affect non‐cardiovascular neurons in this region. It is known that pressor neurons in the rostral VLM include both catecholamine and non‐catecholamine neurons. There is evidence that, at least in conscious rabbits, both of these types of neurons are activated by AngII. The specific endogenous angiotensin peptide or peptides that affect pressor neurons in the rostral VLM have not yet been definitively identified. It is also possible that different angiotensin peptides may have different effects on pressor neurons in the rostral VLM, mediated by different receptors. Further studies will be needed to define these different functions as well as the specific receptors and cellular mechanisms that subserve them.

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.

Effects of angiotensin-converting enzyme inhibition on arterial, venous and capillary functions in cat skeletal muscle in vivo.

The aim of the present study was to analyse quantitatively, on a cat gastrocnemius muscle preparation in vivo, the effects of local angiotensin-converting enzyme (ACE) inhibition by enalaprilat on total regional vascular resistance (tone) and its distribution to the large-bore arterial resistance vessels (> 25 microns), the small arterioles (< 25 microns) and the veins. Associated effects on capillary pressure and fluid exchange were also studied. Close-arterial infusion of enalaprilat (0.05-0.20 mg kg muscle tissue min-1) elicited a moderate dilator response in all three consecutive sections of the muscle vascular bed, an increase in capillary pressure and transcapillary fluid filtration. This dilation could be abolished by the selective bradykinin B2-receptor antagonist Hoe 140 (2 mg kg-1 min-1, i.a.), indicating that the dilator mechanism of ACE inhibition was an increased local concentration of bradykinin, and hardly at all a decreased concentration of angiotensin (AT) II. The generalized dilator response to ACE inhibition along the vascular bed suggested a relatively uniform distribution of ACE from artery to vein and this was further supported by the finding that a close-arterial infusion of AT I (0.04-0.32 microgram kg-1 min-1), which was vasoactive only after conversion to AT II by local ACE, elicited a generalized constrictor response in all three vascular sections. In contrast, infused AT II (0.01-0.16 microgram kg-1 min-1) constricted almost selectively the large-bore arterial vessels. The specific angiotensin AT1-receptor antagonist losartan (2 mg kg-1 min-1, i.a.) abolished the constrictor response to AT II but did not affect vascular tone under control conditions, indicating that AT II is not involved in the initiation of basal vascular tone in muscle. These results, taken together, indicate that under basal conditions vascular ACE contributes to the local control of vascular tone in skeletal muscle by degrading the endogenous dilator bradykinin, and not by converting AT I into vasoconstrictor AT II.

Characterisation of angiotensin II receptor mediated responses and inhibition of intimal hyperplasia in experimental vein grafts by the specific angiotensin II receptor inhibitor, L158,809

This study characterises pharmacologically the angiotensin II receptor in experimental vein grafts and examines the effect of the angiotensin II receptor (type 1) antagonist (L158,809) on the formation of vein graft intimal hyperplasia in vivo, as well as the in vitro physiological response to angiotensin II of vein grafts after chronic oral L158,809 treatment. Thirty New Zealand White rabbits had a right carotid interposition bypass graft using the external jugular vein and were killed on the 28th postoperative day. To characterise the angiotensin II receptors, concentration response curves to angiotensin II were obtained in vitro in the presence or absence of L158,809. To determine the effect of L158,809 on the development of intimal hyperplasia, 10 animals received chronic oral therapy with L158,809 (10 mg/kg/day; begun 5 days before surgery and continued until harvest) and 10 animals received vehicle only as controls. These grafts were harvested either for histology (n = 6 per group) or for in vitro isometric tension studies to angiotensin II. The monophasic contractile response to angiotensin II in the untreated vein grafts could be inhibited in a concentration dependent manner by L158,809 with first order kinetics. Chronic oral treatment with L158,809 produced a 48% decrease in intimal thickness from 82 +/- 1 micron (mean +/- S.E.M.) in the controls to 43 +/- 7 microns in the treated vein grafts (p = 0.002). There was also a significant decrease (45%) in the medial thickness between the control (76 +/- 6 microns) and L158,809 treated (42 +/- 6 microns) vein grafts (p = 0.007). The responses to angiotensin II were abolished in the vein grafts by chronic L158,809 therapy. This study suggests that vein graft angiotensin II responses are mediated through a type 1 receptor and that chronic inhibition with L158,809, significantly reduces intimal hyperplasia and medial hypertrophy in experimental vein grafts and concomitantly abolishes the in vitro responses to angiotensin II. Therefore, angiotensin II acting through AT1 receptors mediates a significant part of the intimal hyperplastic response in vein grafts.

Remodelling of resistance arteries in genetically hypertensive rats by treatment with valsartan, an angiotensin II receptor antagonist.

1. In the present study, New Zealand genetically hypertensive (GH) rats were treated with valsartan, a specific angiotensin II (AT1) receptor antagonist, to measure the effects on blood pressure (BP), cardiac hypertrophy and the structure of resistance arteries. Normotensive (N) rats were used as controls. 2. Valsartan (val) was given to GH rats at three different doses (10, 3 or 0.3 mg/kg per day, via osmotic mini-pumps implanted i.p.) from age 4-10 weeks. Untreated GH (mini-pump + vehicle) and N rats (mini-pump + vehicle) were used as controls. BP was measured weekly and at the end of the experiment, left ventricular (LV) mass was recorded and the structure of mesenteric resistance arteries (MRA) was determined using stereological methods. 3. BP fell in a dose-dependent fashion, being reduced to normotensive levels by 10 mg/kg; LV mass was significantly reduced (P < 0.0001) to below normotensive values in the GH group given 10 mg/kg val and significantly reduced (P < 0.001), although not normalized, in the other two treatment groups. 4. In MRA, the media/lumen (M/L) ratio was reduced by val according to dose level, to below normotensive values in GHval10, and to levels not different from normotensive values in the GHval3 and GHval0.3 groups. 5. The hypertrophy of smooth muscle cells in GH rats was reduced with val treatment at all doses. 6. Reversal of cardiac and vascular hypertrophy occurred even when BP was not reduced to normotensive levels, indicating an effect on vessel growth but without any retardation of body growth. 7. These results suggest that the vascular structural changes seen after val and angiotensin converting enzyme inhibitor treatment are probably due to the blocking of angiotensin rather than any bradykinin effect.

Regulation of the gene-encoding angiotensin II receptor in vascular tissue.

Specific angiotensin (Ang)-dependent mechanisms significantly contribute to vascular development and function, and to the pathophysiology of hypertension. The effects of Ang II are mediated by binding to specific receptors. The focus of most studies has been changes in vascular function and structure in response to Ang II. Relatively little is known regarding the molecular basis of changes in the vascular Ang II receptor. We have recently found that, without altering blood pressure, Ang II infusion at a dose of 25 ng.kg.min-1 decreases expression of the gene-encoding Ang II type 1 (AT1) receptor in both the aorta and resistant arteries. This suggests that exogenous Ang II negatively regulates AT1 mRNA expression in these tissues. Furthermore, hypertension induced by reduced renal mass plus high salt intake upregulates AT1 mRNA expression in the hypertrophied aorta and heart. In this model, the reduction of Ang II formation by captopril without decreasing blood pressure prevents the increase in AT1 mRNA in the aorta but not in the heart. This suggests that the regulation of AT1 gene expression in the heart may be pressure-dependent while there is an Ang II-dependent mechanism operant in the aorta. The precise tissue-specific control mechanisms for AT1 gene expression remain to be defined.

Carbocyclic thromboxane A 2 enhances the angiotensin II-induced DNA synthesis in smooth muscle cells

The present study describes the influence of carbocyclic thromboxane A 2 on the proliferative effects of angiotensin II on vascular smooth muscle cells. Angiotensin II (10 −7 M) and carbocyclic thromboxane A 2 (10 −6 M) per se caused an increase in [ 3H]thymidine incorporation and cell number. The exposure of cells to both agonists resulted in a 2.5-fold elevation of the angiotensin II dependent effect on DNA synthesis and a 1.6-fold increase in cell number. 2-Ethoxy-1-[[2′-(1 H-tetrazol-5-yl)biphenyl-4-y1]methyl]-1 H-benzimidazole-7-carboxylic acid (CV-11974), the active metabolite of the specific non-peptide angiotensin AT 1 receptor antagonist (±)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2′-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylate (TCV-116, Candesartan) suppressed the effect of angiotensin II on cell growth as well as reduced the synergistic effect of carbocyclic thromboxane A 2. Simultaneous cell stimulation with carbocyclic thromboxane A 2 and angiotensin II for 30 min resulted in a 26 ± 9% elevation of the angiotensin II-induced increase of c-fos mRNA (100%).

Angiotensin Receptors in Myometrium and Myometrial Vessels from Uteri of Women during the Follicular and Luteal Phases of the Menstrual Cycle and in Late Pregnancy

1. Receptors for angiotensin II were identified and characterized in membrane fractions from myometrial samples obtained at non-pregnant hysterectomy in women of reproductive age. Specific binding was also measured in paired samples of vascular and "vessel-free' myometrium. 2. A single class of high-affinity receptor sites was identified in the total myometrial preparations (n = 10), with a median equilibrium dissociation constant (Kd) of 0.122 nmol/l (range 0.065-0.465 nmol/l) and concentration of receptor sites (Bmax) of 149 fmol/mg protein (range 105-435 fmol/mg). Receptor characterization studies using losartan (an angiotensin type 1 receptor antagonist) and PD123177 (an angiotensin type 2 receptor antagonist) showed the myometrium to contain almost entirely type 2 receptors. 3. The median Kd and Bmax for specific angiotensin II binding in isolated myometrial vessel homogenates were 0.086 nmol/l (range 0.060-0.433) and 260 fmol/mg protein (range 197-737 fmol/mg) respectively. Vascular specific binding density was always higher in dissected out myometrial vessels than in paired vessel-free myometrium (median 372 compared with 120 fmol/mg protein; n = 20; P < 0.001). The specific binding in the paired samples was strongly correlated (r = 0.8904, P < 0.0001). 4. The specific binding of 125I-labelled angiotensin II in "vessel-free' myometrium was higher in samples from the follicular phase than in samples from the luteal phase (median 144 compared with 37 fmol/mg; P < 0.02). A similar trend was found in the vessels themselves, but this failed to reach statistical significance (459 compared with 225 fmol/mg; P = 0.051). 5. It is suggested that the down-regulation of the angiotensin type 2 receptors in the luteal (secretory) phase is a preparation for pregnancy, removing an inhibitory factor to uterine growth and vascularization and allowing greater prostacyclin synthesis.

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.

Losartan and Low-Dose Hydrochlorothiazide in Patients With Essential Hypertension

Angiotensin II acts at the cellular level through specific angiotensin II subtype I, AT-1 receptors. Losartan is the first of a new class of antihypertensive agents that specifically block angiotensin II at AT-1 receptors. By acting on complementary and different pharmacologic mechanisms, the concomitant use of low doses of hydrochlorothiazide with losartan may offer an additive antihypertensive activity with fewer adverse experiences. This double-blind study evaluated losartan concomitantly administered with hydrochlorothiazide as initial therapy in 703 patients with essential hypertension. The greatest reduction in blood pressure was observed in the 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide group (17.2 mm Hg in sitting systolic blood pressure and 13.2 mm Hg in sitting diastolic blood pressure [P < or = .001]), and the effects of the two components appeared to be additive. Seventy-eight percent of the patients treated with 50 mg of losartan potassium and 12.5 mg of hydrochlorothiazide had an excellent or good antihypertensive response (sitting diastolic blood pressure < 90 mm Hg or > or = 90 mm Hg with a reduction of 10 mm Hg or more). Peak (6 hours after dosing) and trough placebo-adjusted ratios for the losartan-hydrochlorothiazide groups ranged from 62% to 85%, indicating that there was a smooth reduction in sitting diastolic blood pressure that was sustained over 24 hours. The most common clinical adverse experiences (> or = 4%) that occurred with an incidence slightly greater than that reported by the placebo-treated patients were headache, asthenia or fatigue, dizziness, sinusitis, and upper respiratory infection. The concomitant administration of losartan potassium, 50 mg, with 12.5 mg of hydrochlorothiazide once daily produced an additive reduction in trough sitting systolic and diastolic blood pressure and was well tolerated.

A monoclonal antibody to mammalian angiotensin II AT1 receptor recognizes one of the angiotensin II receptor isoforms expressed by the eel (Anguilla anguilla)

Using labelled ligand-binding methods, previous studies have identified specific angiotensin II receptors (Ang II-Rs) in eel liver, kidney and intestine membranes. Isoelectric focusing on polyacrylamide gels also showed that there are two Ang II-R isoforms in eel liver, focusing at isoelectric points (pI) 6.5 and 6.7. These may have different functions. In contrast, eel enterocyte plasma membrane and renal brush border membranes contain only the pI 6.5 form. To characterize the eel receptors more fully, a newly developed monoclonal antibody (6313/G2) which selectively recognizes the AT1 subtype of mammalian Ang II-R was used. In ligand-binding experiments, the preincubation of eel liver membranes with 6313/G2 antibody eliminated the specific [3,5-3H]Tyr4-Ile5-Ang II binding. Moreover, Ang II-receptor complexes from solubilized liver membranes, which were immunoprecipitated by 6313/G2-coated beads, had a pI of 6.5. In immunoblotting experiments, the antibody recognized the isoform focusing at pI 6.5 in eel intestine and liver preparations, but not the liver pI 6.7 isoform. Immunoblotting of SDS gels showed that the antibody bound to a single protein of molecular mass of 75 kDa in eel liver, gill and kidney and to a doublet of molecular mass of about 74 and 75 kDa in intestinal membrane preparations. Immunocytochemistry of paraffin-embedded and cryostat sections of eel liver, kidney, intestine and gill showed that antibody 6313/G2 bound to uniformly distributed intracellular sites and cell surface membranes in proximal tubular cells, absorptive intestinal cells, hepatocytes and chloride cells. It also stained endothelium and both the longitudinal and circular layers of smooth muscle cells in the intestine. The data suggest that the previously described Ang II-R from eel liver, kidney and intestine may be similar to the mammalian AT1 subtype.

Angiotensin II-forming activity in a reconstructed ancestral chymase.

The current model of serine protease diversity theorizes that the earliest protease molecules were simple digestive enzymes that gained complex regulatory functions and restricted substrate specificities through evolution. Among the chymase group of serine proteases are enzymes that convert angiotensin I to angiotensin II, as well as others that simply degrade angiotensins. An ancestral chymase reconstructed with the use of phylogenetic inference, total gene synthesis, and protein expression had efficient and specific angiotensin II-forming activity (turnover number, about 700 per second). Thus, angiotensin II-forming activity is the more primitive state for chymases, and the loss of such activity occurred later in the evolution of some of these serine proteases.

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.

Effects of angiotensin II antagonists on the contractile and hydrosmotic effect of AT II and AT III in the toad (Bufo arenarum)

The effects of peptide and non-peptide angiotensin II receptor antagonists on the responses to angiotensin II were examined using aortic rings and skin isolated from the toad. The contractile responses of aortic rings to (Ala-Pro-Gly) angiotensin II were inhibited by angiotensin II analogue Leu8 angiotensin II, with a pA2 value of 7.6. Similarly, the concentration response curve for (Ala-Pro-Gly) angiotensin II was displaced to the right by the specific angiotensin receptor subtype antagonist DuP 753, with a pA2 value of 6.0. In contrast, the angiotensin receptor subtype 2 antagonists PD 123177 and CGP 42112A did not modify the contractile response to (Ala-Pro-Gly) angiotensin II. None of the antagonists was able to alter the contractile response to norepinephrine. Both Leu8 angiotensin II (10(-8) mol.1(-1)) and DuP 753 (10(-6) mol.1(-1)) partially inhibited angiotensin III-induced contractions in toad aorta. Angiotensin III, in turn, exhibited lower activity than [Asn1-Val5] angiotensin II in this preparation, its molar potency ratio being 0.293. Previous work from this laboratory reported that osmotic water permeability in the skin of the toad Bufo arenarum was increased by angiotensin II, the effect being blocked by the peptide antagonist Leu8 angiotensin II. The hydrosmotic response to [Asn1-Val5] angiotensin II(10(-7) mol.1(-1)) was significantly inhibited by DuP 753 (10(-6) and 5 x 10(-6) mol.1(-1)), whereas the response was not inhibited by a tenfold higher concentration of either PD 123177 or CGP 42112A. DuP 753 (10(-6) mol.1(-1) also inhibited the hydrosmotic response to angiotensin III (10(-7) mol.1(-1)). These results suggest that receptors for angiotensin II present isolated toad aorta and skin exhibit pharmacological features similar to those characterized as angiotensin subtype 1 in mammalian tissues.

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.

Hypertension in minorities: Blacks

Hypertension is known to occur much more frequently in blacks than in the general population, roughly 33% to 50% more frequently. In addition, severe hypertension occurs 3 to 7 times more commonly in blacks than whites and is associated with an excessive amount of target organ damage. Thus, damage to the heart, kidneys, and cerebral structures may occur as much as three to five times more frequently in blacks than the general population and is associated with a much greater mortality. Because of differences in clinical presentation, delays in entering the medical care system, and some pathophysiologic features specific for the black population, treatment becomes somewhat more challenging and should be tailored for this population. Because of economic factors often found in minority populations, inexpensive effective drugs such as diuretics and beta-blockers, which are preferred drugs according to the JNC-V, often should be given first consideration in this population. However, calcium channel blockers seem to be quite effective in this group, equal to in the white population, although they are somewhat more expensive. Angiotensin converting enzyme inhibitors, if given in proper dosage and especially with low dose diuretics, are also quite effective in this population. Tissue specific angiotensin converting enzyme inhibitors may be more effective, but further studies are needed. Studies have shown that effective treatment of the black population, in spite of the differences and the more challenging situation, can result in improved survival and reduction in morbidity and mortality from the various complications.

Cardiovascular and renal protective effects of losartan in spontaneously hypertensive rats with diabetes mellitus.

1. Cardiovascular and renal benefits of a specific angiotensin II (AII) receptor antagonist, losartan (LOS), were assessed in diabetic rats with renal impairment. 2. Uninephrectomized SHR made diabetic by streptozotocin administration were given LOS (5 mg/kg per day, i.p.) alone, captopril (CAP) (50 mg/kg per day, i.p.) alone, or a combination of CAP and LOS via osmotic minipumps for 8 weeks. 3. Both CAP alone and LOS alone completely blocked the development of hypertension in diabetic SHR in the same manner. CAP + LOS did not enhance the antihypertensive effects of LOS alone or CAP alone. 4. CAP + LOS, LOS alone and CAP alone significantly decreased urinary protein excretion and serum creatinine to the same extent. 5. These results indicate that both LOS and CAP exert antihypertensive and renoprotective effects in this model: these actions are mainly through inhibition of AII production.

Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension.

Although angiotensin converting enzyme (ACE) inhibitors are known to attenuate the development of hypoxic pulmonary hypertension in rats, the precise mechanism of this protective effect remains unknown. Thus we utilized specific angiotensin II (ANG II)-receptor antagonists to investigate whether ANG II is involved directly in the hemodynamic and structural changes of pulmonary hypertension, and we tested whether the protective effects of ACE inhibition can be attributed partly to potentiation of bradykinin. During 14 days of hypobaric hypoxia, rats received, via intraperitoneal osmotic minipumps, either 1) the ACE inhibitor captopril, 2) captopril plus the bradykinin B2-receptor antagonist CP-0597, 3) the ANG II type 1 receptor antagonist losartan, 4) the ANG II type 2 receptor antagonist PD-123319, or 5) saline. At 14 days, mean pulmonary arterial pressure (MPAP) was reduced (P < 0.05) in hypoxic rats treated with captopril (26.6 +/- 0.8 mmHg) or losartan (24.4 +/- 1.0 mmHg) compared with saline (32.0 +/- 1.4 mmHg) but was unaffected by PD-123319 (29.5 +/- 1.7 mmHg). Right ventricular hypertrophy was reduced in hypoxic rats treated with captopril or losartan compared with saline-treated rats. Morphometry showed less medial thickening and peripheral muscularization of small pulmonary arteries in hypoxic animals treated with captopril or losartan. Coadministration of CP-0597 did not reverse the protective effects of captopril on pulmonary vascular remodeling. These results suggest a novel role for endogenous ANG II, acting through the type 1 receptor, in the vascular remodeling associated with hypoxic pulmonary hypertension. The beneficial effects of ACE inhibition in this model can be attributed to reduced ANG II production rather than potentiation of bradykinin.