dinoprost and icatibant

Experiments were designed to test the hypothesis that antioxidant treatment would increase the anti-hypertensive actions of endogenous kinins during angiotensin converting enzyme (ACE) inhibition. Four groups of rats, all given angiotensin II (Ang II) for 2 weeks, were studied: 1) control, 2) enalapril, 3) tempol or 4) both tempol and enalapril. Ang II significantly increased systolic blood pressure (BP) when compared with the baseline (170+/-8 vs. 128+/-4 mm Hg, P<0.05). Neither enalapril nor tempol alone was able to attenuate the elevation in BP (165+/-7 and 164+/-6 mm Hg, respectively). In contrast, combined administration of tempol and enalapril prevented the increase in BP (137+/-5 mm Hg). Plasma 8-isoprostane increased in Ang II-infused rats when compared with control untreated rats (69+/-14 vs. 23+/-0.5 pg/ml, P<0.05). Tempol alone or tempol plus enalapril significantly attenuated the increase in plasma 8-isoprostane (29+/-6 and 34+/-7 pg/ml, respectively). In additional experiments, we used the bradykinin B(2) antagonist, icatibant to determine if increased B(2) receptor contributes to the anti-hypertensive effect of combined tempol and enalapril in Ang II-infused rats. Icatibant decreased the ability of this combination to lower arterial pressure. Additionally, a significant increase in B(1) receptor protein expression in renal cortex of Ang II-infused rats was observed compared to control suggesting that bradykinin receptor activation could account for the effect of enalapril to enhance the actions of tempol. These data support the hypothesis that combined reduction of superoxide along with enhanced endogenous kinins may facilitate blood pressure lowering in Ang II hypertension.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antioxidants; Blood Pressure; Bradykinin; Chronic Disease; Cyclic N-Oxides; Dinoprost; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enalapril; Hydrogen Peroxide; Hypertension; Male; Oxidative Stress; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Spin Labels; Superoxides; Time Factors

Airway hyperresponsiveness is a cardinal feature of asthma. Lung C-fiber activation induces central and local defense reflexes that may contribute to airway hyperresponsiveness. Initial studies show that substance P (SP) activates C fibers even though it is produced and released by these same C fibers. SP may induce release of other endogenous mediators. Bradykinin (BK) is an endogenous mediator that activates C fibers. The hypothesis was tested that SP activates C fibers via BK release. Guinea pigs were anesthetized, and C-fiber activity (FA), pulmonary insufflation pressure (PIP), heart rate, and arterial blood pressure were monitored before and after intravenous injection of capsaicin (Cap), SP, and BK. Identical agonist challenges were repeated after infusion of an antagonist cocktail of des-Arg9-[Leu8]-BK (10(-3) M, B1 antagonist), and HOE-140 (10(-4) M, B2 antagonist). After antagonist administration, BK increased neither PIP nor FA. Increases in neither PIP nor FA were attenuated after Cap or SP challenge. In a second series of experiments, Cap and SP were injected before and after infusion of indomethacin (1 mg/kg iv) to determine whether either agent activates C fibers through release of arachidonic acid metabolites. Indomethacin administration decreased the effect of SP challenge on FA but not PIP. The effect of Cap on FA or PIP was not altered by indomethacin. In subsequent experiments, C fibers were activated by prostaglandin E2 and F2alpha. Therefore, exogenously applied SP stimulates an indomethacin-sensitive pathway leading to C-fiber activation.

Topics: Action Potentials; Adrenergic beta-Antagonists; Animals; Asthma; Blood Pressure; Bradykinin; Capsaicin; Cyclooxygenase Inhibitors; Dinoprost; Dinoprostone; Guinea Pigs; Heart Rate; Indomethacin; Lung; Nerve Fibers, Unmyelinated; Prostaglandins; Respiratory Hypersensitivity; Substance P

The effect of bradykinin (BK) on the contraction of rat mesangial cells (MC) was compared with that of various vasoactive agents. BK induced a dose-dependent contraction [one-half maximal effective dose (ED50) = 50 nM] inhibited by the B2 antagonist, HOE-140 (ED50 = 10 nM). BK-induced MC contraction was independent of extracellular calcium and was reduced by inhibition of protein kinase C (PKC). Neomycin completely prevented the increase in intracellular calcium and the formation of inositol 1,4,5-trisphosphate induced by BK but only reduced cell contraction. Inhibition of prostaglandin (PG) formation and administration of the endoperoxide antagonist SQ-27427 also partly decreased the effect of BK. Interestingly, only the addition of both neomycin and mepacrine resulted in a complete inhibition of cell contraction. These results suggest that BK, via a B2-kinin receptor, induces contraction of MC through two distinct mechanisms, one associated to the phospholipase C pathway and subsequent activation of PKC and the second one dependent on PG formation. These in vitro effects may be relevant in explaining the effects of BK and converting enzyme inhibitors on glomerular hemodynamics.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic beta-2 Receptor Antagonists; Angiotensin II; Animals; Arginine Vasopressin; Bombesin; Bradykinin; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cell Membrane; Cells, Cultured; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Endothelins; Fatty Acids, Unsaturated; Glomerular Mesangium; Indomethacin; Kinetics; Naphthalenes; Neomycin; Polycyclic Compounds; Prostaglandin Endoperoxides, Synthetic; Protein Kinase C; Quinacrine; Rats; Receptors, Adrenergic, beta-2; Surface Properties; Tetradecanoylphorbol Acetate; Thromboxane A2; Vasoconstrictor Agents

Desulfated hirugen (hirudin 54-65) at concentrations from 0.1 to 2 microM was found to relax PGF2 alpha-precontracted ring segments of porcine pulmonary arteries with intact endothelium. The relaxation was associated with a pronounced increase in cGMP in the vessels. This endothelium-dependent relaxant effect depended on the extracellular calcium ion concentration and was probably due to the release of endothelium-derived NO as indicated by its susceptibility to blockade of the NO synthesis by NG-nitro-L-arginine. In the presence of indomethacin (3 microM) the maximum hirugen effect was significantly diminished by about 25%. In contrast, neither the sulfated hirugen nor recombinant desulfato hirudin at equimolar concentrations exerted endothelium-dependent relaxation. Hence, the relaxant effect did not correspond to the anticoagulant activity. Desulfated hirugen can be assigned to the group of well-known peptides causing vasodilatation via an endothelium-dependent mechanism.

Topics: 1-Methyl-3-isobutylxanthine; Amino Acid Sequence; Animals; Arginine; Atropine; Bradykinin; Calcium; Captopril; Cyclic GMP; Dinoprost; Endothelium, Vascular; Hirudins; Histamine; Indomethacin; Ketanserin; Methiothepin; Molecular Sequence Data; Muscle, Smooth, Vascular; Nitric Oxide; Nitroarginine; Peptide Fragments; Phentolamine; Pulmonary Artery; Swine; Vasodilation

ACE inhibitors elicit the release of endothelium-derived relaxing factors in perfused isolated canine arteries (Mombouli and Vanhoutte, J. Cardiovasc. Pharmacol. 1991, 18: 926-927); this action is antagonized by bradykinin-receptor antagonists suggesting that it is mediated by local kinin generation. The effects of exogenous tissular kallikrein (porcine) were examined in vitro in the isolated canine coronary artery. Isometric tension was measured in blood vessel rings (with and without endothelium) contracted with prostaglandin F2 alpha. The kallikrein elicited relaxations in rings with, but not in those without, endothelium. This response was augmented by the angiotensin converting enzyme inhibitor perindoprilat, and it was antagonized by the selective B2-kinin receptor antagonist HOE 140 and aprotinin, an inhibitor of tissular kallikrein. These data suggest that in the canine coronary artery, kallikrein causes relaxations that may be mediated by kinins generated from endogenous kininogens present in the vascular wall.

Topics: Animals; Aprotinin; Bradykinin; Coronary Vessels; Dinoprost; Dogs; Endothelium, Vascular; In Vitro Techniques; Indoles; Kallikreins; Kinins; Oligopeptides; Receptors, Bradykinin; Receptors, Neurotransmitter; Vasodilation