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.

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.

'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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Combination therapy as first-line treatment for hypertension.

With the cut-off point between "normal" and "high" blood pressure (BP) being pushed increasingly downward, especially for patients with multiple cardiovascular risk factors, most hypertensives need more than one antihypertensive agent to reach their target BP. In this article, we examine the rationale for combining drugs from different classes that have synergistic or additive effects and properties that might offset one another's adverse hemodynamic and/or metabolic reactions. We suggest circumstances in which the initiation of therapy with a fixed two-drug combination might be preferable to the usual practice of starting with monotherapy followed by upward titration and addition of other agents, and we briefly review the existing fixed drug combinations.

The effect of rapid decreases of blood pressure by different mechanisms on coronary flow and flow reserve in normal coronary arteries.

Background: Changes in mean blood pressure (MBP) alter coronary blood flow (CBF). We evaluated the acute effects of three hypotensive medications on CBF parameters in angiographically normal coronary arteries.

Methods: We performed CBF measurements using the Doppler wire at rest and during hyperemia produced by intracoronary adenosine (18 microg) as follows: 1) in the normal left circumflex coronary artery in 20 patients with coronary artery disease (measurements were performed without drugs, and after intravenous infusion of nitroprusside [0.

Mechanisms mediating the vasoactive effects of the B1 receptors of bradykinin.

Bradykinin normally exerts its vasodilatory effect via the B2 receptor (B2R), but in this receptor's absence, the B1 receptor becomes expressed and activated. To explore the mechanism of B1R-mediated vasodilation, 8 groups of B2R gene-knockout mice received a 2-week infusion of a B1R antagonist (300 microg x kg(-1) x d(-1)) or vehicle (groups 1 and 2), B1R antagonist or vehicle plus NO inhibition with Nomega-nitro-L-arginine methyl ester (groups 3 and 4), B1R antagonist or vehicle plus cyclooxygenase inhibition with indomethacin (groups 5 and 6), or B1R antagonist or vehicle plus blockade of vasoconstricting prostaglandin (PG) H2 and thromboxane A2 (TxA2) with SQ29548 (groups 7 and 8). The B1R antagonist produced significant (P<0.

Central alpha2B-adrenergic receptor antisense in plasmid vector prolongs reversal of salt-dependent hypertension.

Objective: Previous studies have shown that a fully functional alpha(2B)-adrenergic receptor (AR) is necessary for the development of salt-induced hypertension. The current studies were designed to explore the effect of prolonged inhibition of central alpha(2B)-AR gene expression by antisense (AS) DNA on this hypertension.

Methods: We developed a plasmid vector driven by a cytomegalovirus promoter, containing a green fluorescent protein reporter gene and AS for rat alpha(2B)-AR protein.