zd-7155 and icatibant

Angiotensin II is an octapeptide whose effects are mediated by two types of receptors. AT(1) receptors are responsible for the vasoconstrictor, positive inotropic and growth promoting properties, while AT(2) receptors have been linked to vasodilator and anti-mitogenic properties. In this study we investigated the effects of selective AT(2) receptor stimulation on myocardial contractility and lusitropy. Effects of selective AT(2) receptor activation were evaluated in rabbit right papillary muscles (n=96) by adding increasing concentrations of H-9395, an AT(2) receptor agonist, alone or in presence of a selective AT(1) receptor antagonist (ZD-7155), or alternatively, by adding increasing concentrations of angiotensin II in presence of ZD-7155. In the latter conditions, selective AT(2) receptor activation was also performed in presence of NG-nitro-L-Arginine, indomethacin, proadifen, hydroxocobalamin, apamin plus charybdotoxin, Hoe-140 or PD-123,319, as well as, after endocardial endothelium removal. Selective AT(2) stimulation induced a negative inotropic and lusitropic effect in the first three protocols. This effect was completely abolished after selective removal of the endocardial endothelium and blunted in presence of Hoe-140, hydroxocobalamin, apamin plus charybdotoxin and PD-123,319, but maintained in presence of NG-nitro-L-Arginine, indomethacin or proadifen. Selective AT(2) receptor stimulation induces a negative inotropic and lusitropic effect, which is modulated by endocardial endothelium and mediated by bradykinin B(2) receptors through NO release and calcium dependent potassium channels activation. Such findings may help to better understand the therapeutic effects of selective AT(1) antagonists, which are increasingly used for treating cardiovascular diseases.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Apamin; Bradykinin; Cardiovascular Agents; Charybdotoxin; Cyclooxygenase Inhibitors; Depression, Chemical; Dose-Response Relationship, Drug; Endocardium; Endothelial Cells; Enzyme Inhibitors; Hydroxocobalamin; Imidazoles; In Vitro Techniques; Indomethacin; Myocardial Contraction; Naphthyridines; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Oligopeptides; Papillary Muscles; Potassium Channel Blockers; Potassium Channels, Calcium-Activated; Proadifen; Pyridines; Rabbits; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Time Factors

Left ventricular remodeling after myocardial infarction (MI) involves the hypertrophic growth of cardiomyocytes and the accumulation of fibrillar collagen in the interstitial space. We evaluated the role of kinins in postinfarction ventricular remodeling and their potential contribution to the antiremodeling effects of ACE inhibition and angiotensin II type 1 (AT1) receptor blockade.. Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant. Additional groups of infarcted rats were treated with the ACE inhibitor lisinopril or the AT1 receptor antagonist ZD7155, each separately and in combination with icatibant. B2 kinin receptor blockade enhanced the interstitial deposition of collagen after MI, whereas morphological and molecular markers of cardiomyocyte hypertrophy (cardiac weight, myocyte cross-sectional area, prepro-atrial natriuretic factor mRNA expression) were not affected. Chronic ACE inhibition and AT1 receptor blockade reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition and AT1 receptor blockade on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy.. (1) Kinins inhibit the interstitial accumulation of collagen but do not modulate cardiomyocyte hypertrophy after MI. (2) Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition and AT1 receptor blockade. (3) The effects of ACE inhibition and AT1 receptor blockade on cardiomyocyte hypertrophy are related to a reduced generation/receptor blockade of angiotensin II.

Topics: Adrenergic beta-Antagonists; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Bradykinin; Bradykinin Receptor Antagonists; Collagen; Enzyme Induction; Extracellular Matrix; Gene Expression Regulation; Heart Ventricles; Hemodynamics; Hypertrophy; Kinins; Male; Myocardial Contraction; Myocardial Infarction; Myocardium; Naphthyridines; Nitric Oxide Synthase; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Single-Blind Method