Renin-Angiotensin Inhibition in Combating Malignancy: A Review.

Our previous review of the literature assessed the existing knowledge (until 2000) about the possible link between angiotensin-converting enzyme inhibitors (ACEIs) and factors influencing the development of malignancies. We reviewed the literature for reports of statistical associations (or lack thereof) between ACEi treatment and incidence of specific cancers (e.g. breast, gastrointestinal, and skin). We concluded then that results from the epidemiological studies are conflicting, even taking the different methodology and endpoints into consideration, and thus inconclusive. Further investigation is needed beyond the observation period of most of these studies, and additional experimental studies are needed also to study the mechanisms by which agents blocking the renin-angiotensin system may obtain their inhibitory effect on tumor growth and metastasis. The present review elaborates further with more recent evidence from numerous human clinical studies from the past two decades (including large epidemiological studies, and long-term prospective and retrospective studies) on a protective association between ACEi treatment and the prognosis of patients with specific cancer types, malignancy characteristics or stage. Moreover, treatment with ACEI/angiotensin receptor blockers represents an adjuvant therapy with synergistic effects to chemotherapy and may improve patient outcomes (i.e. progression-free survival, and prolonged overall survival) in different types of cancers.

Blockade of platelet alpha2B-adrenergic receptors: a novel antiaggregant mechanism.

BACKGROUND: Platelets play a vital role in hemostasis and thrombosis. Catecholamines have a profound effect on platelet aggregation and atherothrombosis but the exact mechanism involved is insufficiently understood. In this report, we demonstrate the existence and role of alpha2B-adrenergic receptors (α2B-ARs) in normal human platelets. METHODS: Sixteen healthy individuals were recruited as donors of normal blood from which platelets were isolated. The presence of α2B-ARs in platelets was proven by Western blot analysis. In order to investigate their function, we performed light transmittance aggregometry and platelet function activity tests by examining the inhibitory effects of specific α2B-AR antibodies and of the selective α2B-AR antagonist ARC 239. RESULTS: Pretreatment of human platelets with agents that selectively block α2B-ARs showed a substantial inhibition in platelet aggregation that had been induced by adenosine diphosphate (ADP), by epinephrine and by arachidonic acid. The percent aggregation decreased from 81.5 ± 1.7% to 35.8 ± 5% and to 24 ± 4.6% for ADP with α2B-Abs and ARC 239 respectively, from 72.2 ± 1.9% to 25.5 ± 4.3% and to 8.8 ± 1.7% for epinephrine with α2B-Abs and ARC 239 respectively, and from 87 ± 2.1% to 47.9 ± 6.2% and to 61.2 ± 5.7% for arachidonic acid with α2B-Abs and ARC 239 respectively, p<0.05 for all. Additionally, collagen/epinephrine closure time increased from 120.8 ± 6.1s to 189.5 ± 39.5s (p=0.001). CONCLUSIONS: Our results reveal that contrary to previous knowledge, the α2B-AR subtype does exist in platelets and is an important regulator of aggregation. Inhibition of α2B-ARs in platelets may offer a novel therapeutic opportunity in the prevention of atherothrombotic events.

'Volume-expanded' hypertension: the effect of fluid overload and the role of the sympathetic nervous system in salt-dependent hypertension.

It is widely believed that salt-dependent hypertension is induced and maintained by expansion of intravascular fluid volume resulting from excessive retention of sodium. The purpose of this brief article is to present a series of arguments in support of the thesis that volume overload per se does not raise the arterial blood pressure. Several investigators in the 1960s and 1970s reported that excessive retention of salt - regardless of cause - leads to sympathetic activation mediated by the effects of the Na ion on α(2)-adrenergic receptors located mostly in the brainstem. In recent years, the cloning and characterization of α(2)-adrenergic receptors subtypes permitted differentiation of their hemodynamic effects via use of salt loading of nephrectomized animals submitted to genetic engineering or gene treatment. These studies indicate that sodium alters the balance between the sympathoinhibitory α(2A)-adrenergic receptors and the sympathoexcitatory α(2B)-adrenergic receptors, leading to a hyperadrenergic hypertensive state unrelated to volume overload.

Cardioprotective properties of bradykinin: role of the B(2) receptor.

Following the introduction of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension and ischemic heart disease, there has been increasing interest in the bradykinin-mediated aspects of ACE inhibition. Several preclinical and clinical studies have been conducted using genetically engineered animals or pharmacological agonists and antagonists of the two receptors of bradykinin, B(1)R and B(2)R. The results have mostly indicated that the B(1)R, whose expression is induced by tissue damage, seem to have mostly noxious effects, whereas the constitutively expressed B(2)R, when activated, exert mostly beneficial actions. Accumulating evidence in the recent literature suggests that the B(2)R have an important role in the process of ischemic post-conditioning that limits the ischemia/reperfusion injury of the myocardium. In this article, we describe a series of experiments conducted on mice submitted to acute myocardial infarct and treated either with ACE inhibition (which produces potentiation of bradykinin resulting in non-selective B(1)R and B(2)R activation) or with a potent and highly selective B(2)R agonist. These data suggest that this latter pharmacological approach offers functional and structural benefits and is therefore a promising cardioprotective therapeutic modality against acute ischemic events.

Cardioprotective effects of a selective B(2) receptor agonist of bradykinin post-acute myocardial infarct.

BACKGROUND: The cardioprotective benefits of bradykinin are attributable to activation of its B(2) receptor (B(2)R)-mediated actions and abolished by B(2)R antagonists. The current experiments evaluated the cardioprotective potential of a potent, long-acting B(2)R-selective agonist peptide analogue of bradykinin, the compound NG291. METHODS: We compared the extent of cardiac tissue damage and remodeling and expression pattern of selected genes in mice submitted to acute myocardial infarct (MI) and treated for 1 week with either NG291 [Hyp(3),Thi(5),(N)Chg(7),Thi(8)]-bradykinin or with saline delivered via osmotic minipump. RESULTS: Active treatment resulted in better ejection fraction (EF) 69 +/- 1% vs. 61 +/- 3.1% (P = 0.01), (vs. 85 +/- 1.3% in sham-operated controls), fractional shortening (FS) 38 +/- 4% vs. 32 +/- 8% (NS) (vs. 53 +/- 1.2 in sham-operated controls), and fewer markers of myocyte apoptosis (TUNEL-positive nuclei 4.9 +/- 1.1% vs. 9.7 +/- 0.03%, P = 0.03). Systolic blood pressure (SBP) at end point was normal at 110 +/- 4.2 in actively treated mice, but tended to be lower at 104 +/- 4.7 mm Hg in saline controls with decreased cardiac systolic capacity. Expression patterns of selected genes to factors related to tissue injury, inflammation, and metabolism (i.e., the B(1)R, B(2)R, endothelial nitric oxide synthase (eNOS), TNF-alpha, cardiomyopathy-associated 3 (Cmya3), and pyruvate dehydrogenase kinase isoenzyme 4 (PDK4)) showed that acute MI induced significant upregulation of these genes, and active treatment prevented or attenuated this upregulation, whereas the B(2)R agonist itself produced no difference in the myocardium of sham-operated mice. CONCLUSIONS: Treatment with a selective B(2)R agonist initiated at the time of induction of acute MI in mice had a beneficial effect on cardiac function, tissue remodeling, and inflammation-related tissue gene expression, which may explain its structural and functional benefits.

Hypertension in transgenic mice with brain-selective overexpression of the alpha(2B)-adrenoceptor.

BACKGROUND: Previous studies have shown that the presynaptic alpha(2B)-adrenoceptor subtype in the central nervous system has a sympathoexcitatory function and its activation leads to a hyperadrenergic hypertensive state. The purpose of this project was to develop a novel hyperadrenergic model, a transgenic (TG) mouse model with brain-selective overexpression of the alpha(2B)-adrenergic receptor (alpha(2B)-AR). METHODS: We used Southern blot analysis to confirm transgene, real-time PCR to assess gene expression, western Blot analysis and immunohistology to assess protein expression and localization in brain areas. Indirect blood pressure (BP) and heart rate were recorded. RESULTS: In TG mice there was a 1.8-fold increase in alpha(2B)-AR protein expression compared to wild-type (WT) mice. Immunostaining of brain sections revealed that concentration of alpha(2B)-AR was much more pronounced in TG than in WT mice. Systolic BP at 8 weeks of age was significantly elevated in TG 130 +/- 6 mm Hg, compared with WT control nontransgenic littermates of the same age 107 +/- 7 mm Hg, (P < 0.05), indicating that the TG mice had indeed developed hypertension. CONCLUSIONS: We have therefore documented that overexpression of the alpha(2B)-AR gene leads to increased production of alpha(2B)-AR protein in brain regions known to regulate central sympathetic outflow, thus resulting in sustained BP elevation. This is a unique model of experimental hypertension driven purely by overexpression of the alpha(2B)-AR that would result in an overactive sympathetic system and would be suitable for testing the pharmacologic properties of potential therapeutic agents.

Pleiotropic effects of statins may improve outcomes in atherosclerotic renovascular disease.

BACKGROUND: Atherosclerotic renovascular disease (ARD) coexists with arterial obstructive disease in the coronary, cerebral, and peripheral arteries that may remain underdiagnosed and untreated. METHODS: This retrospective study compares overall survival and renal survival (i.e., time to doubling of serum creatinine or end-stage renal disease (ESRD)) over an 11-year period in 104 ARD patients of whom 68 received statin therapy (group S) because of elevated lipid levels and 36 had no statin (group NS) because of normal lipid profile at entry. RESULTS: Atherosclerosis in another vascular bed was documented in 84%. Lipid profiles at end point were virtually identical in both the groups. Group S had mean survival 123months (confidence interval (CI) 113-134) with four deaths, and mean renal survival 122months (CI 113-131). Group NS had mean survival 33 months (CI 23-42) with 13 deaths, and mean renal survival 27 months (CI 17-37). CONCLUSIONS: Statin therapy was associated with lesser rate of progression of renal insufficiency (with 7.4% of S patients reaching renal end points vs. 38.9% of NS patients) and lower overall mortality (5.9 % in S vs. 36.1% in NS patients), P < 0.001 for both. Although both groups received what was deemed optimal therapy, they did have other differences that may have affected the outcomes (a limitation addressed by Cox multiple regression analysis). These results suggest the need for prospective randomized controlled studies in ARD patients in order to explore potential benefits of statins that may not be attributable solely to lipid lowering.

Angiotensin-converting enzyme inhibition after experimental myocardial infarct: role of the kinin B1 and B2 receptors.

We sought to define the contribution of each of the 2 kinin receptors (bradykinin 1 receptor [B(1)R] and bradykinin 2 receptor [B(2)R]) to the cardioprotection of angiotensin-converting enzyme (ACE) inhibition after acute myocardial infarct. Wild-type mice and gene knockout mice missing either B(1)R or B(2)R were submitted to coronary ligation with or without concurrent ACE inhibition and had evaluation of left ventricular systolic capacity by assessment of fractional shortening (FS). Baseline FS was similar in all of the animals and remained unchanged in sham-operated ones. At 3 weeks after myocardial infarct, in the wild-type group there was a 27% reduction of FS (P<0.5) without ACE inhibition and 8% with ACE inhibition; in the B(1)R(-/-) groups the FS was reduced by 24% and was no different (at 28%) with ACE inhibition; in the B(2)R(-/-) groups, however, the FS was decreased by 39% and with ACE inhibition was decreased further by 52%. Analysis of bradykinin receptor gene expression in hearts showed that when one receptor was missing, the other became significantly upregulated; but the B(1)R remained highly overexpressed in the B(2)R(-/-) mice throughout, whereas the overexpressed B(2)R became significantly suppressed in the B(1)R(-/-) mice in a manner quantitatively and directionally similar to that of wild-type mice. We conclude that both bradykinin receptors contribute to the cardioprotective bradykinin-mediated effect of ACE inhibition, not only the B(2)R as believed previously; but, whereas with potentiated bradykinin in the absence of B(1)R, the upregulation of B(2)R is simply insufficient to provide full cardioprotection, in the absence of B(2)R, the upregulated B(1)R actually seems to inflict further tissue damage.

Inhibition of the alpha(1D)-adrenergic receptor gene by RNA interference (RNAi) in rat vascular smooth muscle cells and its effects on other adrenergic receptors.

Sympathetic-induced vasoconstriction is mediated by various adrenergic receptor (AR) subtypes located on membranes of vascular smooth muscle cells (VSMC) located on the arterial wall, but is mostly attributed to activation of the alpha(1D)-AR. In order to study interaction and cross-talk among AR genes, we induced post-transcriptional silencing of the alpha(1D)-AR gene in cultured VSMC using the RNAi technique. A pSEC neo expression plasmid vector containing a small interfering RNA (siRNA) sequence selected to bind to the targeted mRNA of the alpha(1D)-AR gene was transfected into cultured VSMC from rat aorta. The RNA expression of all AR-subtype genes was assessed by Q-RT-PCR and the alpha(1D) and alpha(2A)-AR proteins quantified by Western blot. In siRNA-transfected cells, the alpha(1D)-AR protein levels decreased by 55%, 69% and 75% at 24 h, 48 h and 72 h, respectively (p<0.03-0.01) with progressive increases in its gene expression by 50%-61% and concurrent increase in alpha(2A)-AR protein peaking at 48 h. Decreases were noted in expression of the alpha(1A), alpha(2A), and beta(3) AR genes. We conclude that post-transcriptional silencing of the alpha(1D)-AR gene leads to significant decrease in receptor protein despite reactive increase in gene expression. However, suppression of one AR leads to reactive changes in other subtypes, indicating that cross-talk among related genes, whose products have overlapping functions, may partly offset anticipated effects in vivo.

Frequency of coronary artery disease in patients with renal artery stenosis without clinical manifestations of coronary insufficiency.

Atherosclerotic renal artery stenosis (RAS) and coronary artery disease (CAD) arise from the same multiple risk factors. The purpose of this study was to assess the frequency of previously undiagnosed CAD in patients with angiographically confirmed RAS, by conducting coronary arteriography in the same setting. Of 57 consecutive patients referred for renal arteriography on clinical grounds during a 14-month period, 28 had no RAS and 6 had RAS, but previously documented CAD. Of the remainder 23 patients, 17 (74%; CI 56%-92%) had both RAS and CAD (7 single vessel, 4 two-vessel, and 7 multivessel disease). The clinical characteristics, such as age, blood pressure (BP) levels, signs of heart failure, were no different between those with and without CAD, although the 4 diabetic patients, the 4 patients with fundoscopic findings of grade III retinopathy, 11 of 14 with peripheral arterial disease, and 7 of 8 patients with prior stroke belonged in the CAD group. None developed complications as a result of the two consecutive procedures. The data suggest that in patients with RAS the frequency of silent CAD is high and cannot be predicted on clinical grounds alone, therefore coronary angiography should be routinely recommended in the same setting.

Long-term inhibition of the central alpha(2B)-adrenergic receptor gene via recombinant AAV-delivered antisense in hypertensive rats.

BACKGROUND: Salt-induced hypertension is mediated via the alpha(2B)-adrenergic receptor (AR) subtype. In alpha(2B)-AR gene knockout mice, blood pressure (BP) does not rise with salt loading, and in rats with salt-induced hypertension, BP decreases transiently with antisense (AS) treatment targeting the alpha(2B)-AR gene. The present experiments were designed to explore the possibility of gene transfection in the brain by intracerebroventricular (ICV) delivery of AS-DNA via adeno-associated virus (AAV) to prolong alpha(2B)-AR inhibition and hence reversal of salt-dependent hypertension. METHODS: A recombinant AAV (rAAV) vector preparation encoding the alpha(2B)-AS fragment (previously tested in vitro for inhibition of alpha(2B)-AR protein production in cells) and containing green fluorescence protein (GFP) for visualization was injected ICV into subtotally nephrectomized, salt-fed rats. Control rats received rAAV-GFP (n = 8 per group). RESULTS: We observed that BP rose from a baseline of 120 +/- 10 to 184 +/- 12 mm Hg. Injection of rAAV-alpha(2B)-AS produced a 35 +/- 12 mm Hg fall in BP, lasting without evidence of diminishing for at least 16 days, whereas rAAV-GFP-injected rats showed a continued rise in BP. Rats treated with rAAV-alpha(2B)-AS treated had a 45% to 65% decrease in alpha(2B)-AR protein levels in key regulatory regions of the brain. Neither group had signs of immunologic response to the virus injection. CONCLUSIONS: These results indicate that our construct, when given by ICV means, could reach multiple sites of the central nervous system relevant to BP regulation and could safely inhibit the central alpha(2B)-adrenergic receptor, thereby achieving prolonged reversal of salt-induced hypertension.

Central plasmid antisense administration reduces blood pressure inhibiting alpha2B adrenoceptor gene expression in spontaneously hypertensive rats in vivo.

INTRODUCTION: The involvement of central alpha2B adrenoceptors (AR) in the maintenance of hypertension has been proven by a series of previous experiments, at least in a particular model of nephrogenic salt-induced hypertension. The aim of the present study was to investigate further the role of central alpha2B AR in hypertension by applying antisense technology in another experimental model, the spontaneously hypertensive rat (SHR). METHODS: Plasmid antisense DNA against the alpha2B gene was given by intracerebroventricular injection to salt-fed SHRs, while a control group received plasmid alone. RESULTS: There was a significant fall in blood pressure, by an average of 31 +/- 12 mmHg, within the first twenty hours after injection in the antisense group. On the first post-injection day the blood pressure fell from 204 +/- 5.3 mmHg to 176.8 +/- 2.9 mmHg (p = 0.02). However, no significant changes in blood pressure were noticed in the plasmid group. Body-weight in both groups remained stable during the experiment. A study of frozen brain sections of SHRs after antisense DNA injection suggested that the nucleus tractus solitarii was one of the expression sites, while there was no histological evidence of tissue disruption. CONCLUSION: Central injection of antisense DNA targeting alpha2B mRNA in the genetic model of hypertension of the SHR seems to have a significant hypotensive effect, at least on the first day of injection. The nucleus tractus solitarii seems to be the primary area of action of central alpha2B AR in SHRs.

Fixed-drug combinations as first-line treatment for hypertension.

As combinations of drugs from different classes that have synergistic or additive effect and properties to cancel out each others' untoward hemodynamic and metabolic effects become more and more widely used, their use as first-line therapy for the treatment of newly diagnosed hypertensive patients is growing in popularity as well. The possibility to begin therapy with a fixed 2-drug combination may be preferable to starting with monotherapy followed by upward titration and addition of other agents. More and more combinations are coming out on the market and proving their effectiveness in randomized controlled trials and in large multicenter studies. One suggestion is the "polypill," a fixed combination of multiple agents that address various components of the metabolic syndrome and coexisting common risk factors in both high-risk patients with conditions requiring polypharmacy, and in healthy asymptomatic individuals.

Role of bradykinin B1 and B2 receptors in normal blood pressure regulation.

With inhibition or absence of the bradykinin B2 receptor (B2R), B1R is upregulated and assumes some of the hemodynamic properties of B2R, indicating that both participate in the maintenance of normal vasoregulation or to development of hypertension. Herein we further evaluate the role of bradykinin in normal blood pressure (BP) regulation and its relationship with other vasoactive factors by selectively blocking its receptors. Six groups of Wistar rats were treated for 3 wk: one control group with vehicle alone, one with concurrent administration of B1R antagonist R-954 (70 microg x kg(-1) x day(-1)) and B2R antagonist HOE-140 (500 microg x kg(-1) x day(-1)), one with R-954 alone, one with HOE 140 alone, one with concurrent administration of both R-954 and HOE-140 plus the angiotensin antagonist losartan (5 mg x kg(-1) x day(-1)), and one with only losartan. BP was measured continuously by radiotelemetry. Only combined administration of B1R and B2R antagonists produced a significant BP increase from a baseline of 107-119 mmHg at end point, which could be partly prevented by losartan and was not associated with change in catecholamines, suggesting no involvement of the sympathoadrenal system. The impact of blockade of bradykinin on other vasoregulating systems was assessed by evaluating gene expression of different vasoactive factors. There was upregulation of the eNOS, AT1 receptor, PGE2 receptor, and tissue kallikrein genes in cardiac and renal tissues, more pronounced when both bradykinin receptors were blocked; significant downregulation of AT2 receptor gene in renal tissues only; and no consistent changes in B1R and B2R genes in either tissue. The results indicate that both B1R and B2R contribute to the maintenance of normal BP, but one can compensate for inhibition of the other, and the chronic inhibition of both leads to significant upregulation in the genes of related vasoactive systems.

A novel gene (Cmya3) induced in the heart by angiotensin II-dependent but not salt-dependent hypertension in mice.

OBJECTIVE: In previous studies using serial analysis of gene expression for elucidation of the molecular pathways of angiotensin II (Ang II)-induced hypertensive/ischemic cardiomyopathy in mice, we found that a hitherto unknown transcript, designated initially as 2310008C07Rik, an unknown expressed sequence tag (EST), was highly significantly upregulated in myocardial tissue. The current experiments were designed to further characterize this gene and to evaluate its expression in various types of hypertension. METHODS: Mice rendered hypertensive by Ang II infused intravenously at 30 ng/min for 6 h or by osmotic minipump at 0.9 mug/h for 7 or 14 days, were compared to saline-infused normotensive controls and to mice with hypertension induced by subtotal nephrectomy and 1% saline as drinking water. At end point, mice were euthanized, their tissues processed for gene expression analysis, and results were confirmed by ribonuclease protection assay. RESULTS: The Ang II-infused mice developed systolic blood pressure (BP) of 134 +/- 7, 158 +/- 13, and 149 +/- 15 mm Hg at 6 h, 7 days, and 14 days, respectively, compared to 102 +/- 9, 110 +/- 8, and 114 +/- 7 mm Hg in their respective controls and subtotally nephrectomized salt-fed mice had end point blood pressure of 153 +/- 5 v 112 +/- 7 mm Hg in controls. Through sequencing and expression analysis we found that the unknown transcript is part of the cardiomyopathy associated 3 (Cmya3) gene, being overexpressed in Ang II-induced but not salt-induced hypertension. CONCLUSIONS: The highly expressed 2310008C07Rik EST was found to be part of Cmya3 and its upregulation is due to Ang II-induced myocardial damage and not to BP elevation per se.

Angiotensin-converting enzyme regulates bradykinin receptor gene expression.

The angiotensin-converting enzyme (ACE) is a membrane-bound peptidyl dipeptidase known to act on a variety of peptide substrates in the extracellular space. Its most notable functions are the formation of angiotensin II and the degradation of bradykinin. In the current experiments, we found that exogenous ACE added to vascular smooth muscle cell culture strongly induces and upregulates the genes of bradykinin receptors B1 and B2. This transcriptional regulatory property of ACE was shown to be unrelated to its known enzymatic properties. Indeed, ACE at 3.75 microg/ml added in the culture medium of vascular smooth muscle cells was found to cause marked upregulation of the mRNA expression of the genes for the B1 and B2 receptors of bradykinin by 22- and 11-fold, respectively. This phenomenon was not altered by the addition of specific angiotensin II antagonists for the AT1 or AT2 receptors. Moreover, the ACE inhibitor captopril, which inhibited ACE enzymatic activity, did not block its effect at the bradykinin receptor gene transcription level. Expression of both receptor genes was completely abolished by actinomycin D. Furthermore, transcriptional upregulation was inhibited by curcumin, suggesting involvement of different transcriptional factors in this phenomenon. Electrophoretic mobility shift assay revealed increase in NF-kappaB and activator protein-1 protein binding for consensus sequences, between ACE-treated cells versus untreated cells. The data indicate a novel biological function of the ACE unrelated to its well-known enzymatic function as a peptidyl dipeptidase.

Age-related changes of bradykinin B1 and B2 receptors in rat heart.

Aging is a major risk factor for the development of vascular diseases, such as hypertension and atherosclerosis, that leads to end organ damage and especially heart failure. Bradykinin has been demonstrated to have a cardioprotective role by affecting metabolic processes and tissue perfusion under conditions of myocardial ischemia. Its actions are exerted via the bradykinin B1- and B2-type receptors (B1Rs and B2Rs), but the functional status of these receptors during the aging process is poorly understood. This study aims to investigate whether changes in B1R and B2R gene and protein expression in rat heart are associated with the age-related alterations of cardiac structure and function. Using real-time PCR, we found that B1R mRNA expression increased 2.9-fold in hearts of older rats (24 mo of age) compared with younger rats (3 mo of age), whereas B2R gene expression remained unchanged. Western blot analysis showed that expression of B2R at the protein level is approximately twofold higher in young rats compared with old rats, whereas the B1R protein is approximately twofold higher in old rats compared with young rats. The present results provide clear functional and molecular evidence that indicate age-related changes of bradykinin B1Rs and B2Rs in heart. Because the cardioprotective actions of bradykinin are physiologically mediated via the B2Rs, whereas the B1Rs become induced by tissue damage, these results suggest that age-related decreases in B2R protein levels may leave the heart vulnerable to ischemic damage, and increases in B1R expression and activity may represent a compensatory reaction in aging hearts.

Arterial compliance changes in diabetic normotensive patients after angiotensin-converting enzyme inhibition therapy.

BACKGROUND: Diabetes mellitus (DM) is known to cause increased arterial wall stiffness and increased cardiovascular risk, even in the absence of hypertension. This study was designed to investigate whether use of an angiotensin-converting enzyme (ACE) inhibitor may improve arterial stiffness in normotensive diabetics, using pulse wave velocity (PWV) as a surrogate marker. METHODS: We studied 42 patients (26 with type 2 DM, aged 56.5 +/- 9 years, 16 with type 1 DM, aged 41.5 +/- 11 years) by measuring PWV at baseline (compared to 15 age- and gender-matched normal subjects) and after 6 months of treatment with perindopril (4 mg/d). RESULTS: At baseline, PWV was significantly higher in DM patients versus controls (13.09 +/- 2.59 v 9.5 +/- 1.6 m/sec, respectively, P < .001). After 6 months, PWV decreased significantly to 11.68 +/- 3.08 m/sec (P < .003) for the whole DM group. However, the results were driven by the change in the younger type 1 DM (from 12.59 +/- 1.59 to 10.35 +/- 2.21 m/sec, P < .001), whereas in the type 2 DM it was insignificant (from 13.37 +/- 3.0 to 12.42 +/- 3.28 m/sec). Blood pressure and other hemodynamic and biochemical parameters remained unchanged. CONCLUSIONS: The results demonstrate that ACE inhibition can improve arterial elasticity and hence risk of cardiovascular complications even in normotensive diabetics. This short treatment was effective only in younger patients with type 1 diabetes, suggesting that early initiation of therapy before the onset of advanced structural alterations is likely to be more cardioprotective.