icatibant and Hypertrophy

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

We previously showed that chronic angiotensin-converting enzyme (ACE) inhibition prevented the increase in aortic collagen in spontaneously hypertensive rats (SHRs) independently of blood pressure reduction. The aim of the present study was to determine whether the effects of ACE inhibition on aortic fibrosis were due to inhibition of angiotensin II formation, preservation of bradykinin, or a combination of both. Four week-old SHRs were treated for 4 months with the ACE inhibitor quinapril, quinapril with the bradykinin B2 receptor antagonist Hoe 140, or the angiotensin II AT1 receptor antagonist CI996. Control SHR and Wistar-Kyoto (WKY) rats received a placebo for the same period of time. At the end of the treatment, as compared to conscious SHR and WKY controls, quinapril completely prevented the development of hypertension, whereas quinapril-Hoe 140 and the AT1 receptor antagonist produced only a partial reduction of blood pressure. In relation with blood pressure changes, aortic hypertrophy was significantly prevented by quinapril but not by quinapril-Hoe 140 or CI996. In contrast, aortic collagen accumulation was completely prevented by all three treatments. The study provides evidence that in young live SHRs, the prevention of aortic collagen accumulation is independent of blood pressure changes and bradykinin preservation and involves exclusively angiotensin II inhibition through AT1 receptors.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Bradykinin; Bradykinin Receptor Antagonists; Collagen; Drug Therapy, Combination; Hemodynamics; Hypertension; Hypertrophy; Imidazoles; Isoquinolines; Male; Quinapril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Tetrahydroisoquinolines; Tetrazoles

To determine the roles played by kinins/nitric oxide and angiotensin II in the antitrophic effects of angiotensin converting enzyme inhibitors on mesenteric arteries after 3 weeks of streptozotocin diabetes by using blockers both of the angiotensin II AT1 receptor and of the bradykinin B2 receptor.. Male diabetic Wistar rats were randomly allocated to receive no treatment, the angiotensin converting enzyme inhibitors perindopril or ramipril, the AT1 receptor blocker ZD7155, the bradykinin B2 receptor blocker Hoe 140, the nitric oxide synthase inhibitor NG-nitro-L-arginine-methyl ester, concomitant administration of perindopril plus subcutaneous Hoe 140, perindopril plus NG-nitro-L-arginine, or ramipril plus Hoe 140 (Hoe 140 administered via an Alzet mini-osmotic pump).. After 3 weeks, the rats were killed, their blood collected and their mesenteric vessels removed. The mesenteric vascular weight was measured and the media wall: lumen area ratio was assessed using quantitative histomorphometric techniques.. Diabetes was associated with an increase in mesenteric weight and media wall:lumen area ratio. The angiotensin converting enzyme inhibitors, perindopril and ramipril, and the AT1 receptor antagonist ZD7155 reduced blood pressure and attenuated vascular weight and media wall:lumen area ratio. Concomitant administration of an angiotensin converting enzyme inhibitor with the kinin antagonist Hoe 140, administered either subcutaneously or via a mini-osmotic pump, or of the nitric oxide synthase inhibitor NG-nitro-L-arginine attenuated the effect of the angiotensin converting enzyme inhibitor on the mesenteric vascular weight and wall:lumen area ratios. Treatment with Hoe 140 or NG-nitro-L-arginine alone affected none of these parameters.. The antitrophic effect of angiotensin converting enzyme inhibitors on diabetic mesenteric arteries is mediated by inhibition of angiotensin II and by actions on the kinin-nitric oxide pathway.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Diabetic Angiopathies; Hypertrophy; Indoles; Kinins; Male; Mesenteric Arteries; Nitric Oxide; Nitroarginine; Perindopril; Rats; Rats, Wistar