2-3-dinor-6-ketoprostaglandin-f1alpha and icatibant

Bradykinin stimulates dose-dependent tissue plasminogen activator (tPA) release from human endothelium. Although bradykinin is known to cause vasodilation through B(2) receptor-dependent effects on NO, prostacyclin, and endothelium-derived hyperpolarizing factor production, the mechanism(s) underlying tPA release is unknown.. We measured the effects of intra-arterial bradykinin (100, 200, and 400 ng/min), acetylcholine (15, 30, and 60 microg/min), and nitroprusside (0.8, 1.6, and 3.2 microg/min) on forearm vasodilation and tPA release in healthy volunteers in the presence and absence of (1) the B(2) receptor antagonist HOE 140 (100 microg/kg IV), (2) the NO synthase inhibitor L-N:(G)-monomethyl-L-arginine (L-NMMA, 4 micromol/min intra-arterially), and (3) the cyclooxygenase inhibitor indomethacin (50 mg PO TID). B(2) receptor antagonism attenuated vasodilator (P:=0.004) and tPA (P:=0.043) responses to bradykinin, without attenuating the vasodilator response to nitroprusside (P:=0.36). L-NMMA decreased basal forearm blood flow (from 2.35+/-0.31 to 1. 73+/-0.22 mL/min per 100 mL, P:=0.01) and blunted the vasodilator response to acetylcholine (P:=0.013) and bradykinin (P:=0.07, P:=0. 038 for forearm vascular resistance) but not that to nitroprusside (P:=0.47). However, there was no effect of L-NMMA on basal (P:=0.7) or bradykinin-stimulated tPA release (P:=0.45). Indomethacin decreased urinary excretion of the prostacyclin metabolite 2, 3-dinor-6-keto-prostaglandin F(1alpha) (P:=0.04). The vasodilator response to endothelium-dependent (P:=0.019 for bradykinin) and endothelium-independent (P:=0.019) vasodilators was enhanced during indomethacin administration. In contrast, there was no effect of indomethacin alone (P:=0.99) or indomethacin plus L-NMMA (P:=0.36) on bradykinin-stimulated tPA release.. These data indicate that bradykinin stimulates tPA release from human endothelium through a B(2) receptor-dependent, NO synthase-independent, and cyclooxygenase-independent pathway. Bradykinin-stimulated tPA release may represent a marker for the endothelial effects of endothelium-derived hyperpolarizing factor.

Topics: 6-Ketoprostaglandin F1 alpha; Acetylcholine; Adrenergic beta-Antagonists; Adult; Bradykinin; Bradykinin Receptor Antagonists; Cyclooxygenase Inhibitors; Endothelium, Vascular; Female; Forearm; Humans; Indomethacin; Infusions, Intra-Arterial; Male; Nitric Oxide Synthase; Nitroprusside; omega-N-Methylarginine; Plethysmography; Receptor, Bradykinin B2; Regional Blood Flow; Tissue Plasminogen Activator; Vasodilation; Vasodilator Agents

1. We investigated the response to pressure (myogenic tone) and flow of rat mesenteric resistance arteries cannulated in an arteriograph which allowed the measurement of intraluminal diameter for controlled pressures and flows. Rats were treated for 3 weeks with NG-nitro-L-arginine methyl ester (L-NAME, 50 mg kg-1 day-1) or L-NAME plus the angiotensin I converting enzyme inhibitor (ACEI) quinapril (10 mg kg-1 day-1). 2. Mean blood pressure increased significantly in chronic L-NAME-treated rats (155 +/- 4 mmHg, n = 8, vs control 121 +/- 6 mmHg, n = 10; P < 0.05). L-NAME-treated rats excreted significantly more dinor-6-keto prostaglandin F1 alpha (dinor-6-keto PGF1 alpha), the stable urinary metabolite of prostacyclin, than control rats. The ACEI prevented the rise in blood pressure and the rise in urinary dinor-6-keto PGF1 alpha due to L-NAME. 3. Isolated mesenteric resistance arteries, developed myogenic tone in response to stepwise increases in pressure (42 +/- 6 to 847 +/- 10 mN mm-1, from 25 to 150 mmHg, n = 9). Myogenic tone was not significantly affected by the chronic treatment with L-NAME or L-NAME + ACEI. 4. Flow (100 microliters min-1) significantly attenuated myogenic tone by 50 +/- 6% at 150 mmHg (n = 10). Flow-induced dilatation was significantly attenuated by chronic L-NAME to 22 +/- 6% at 150 mmHg (n = 10, p = 0.0001) and was not affected in the L-NAME + ACEI group. 5. Acute in vitro NG-nitro-L-arginine (L-NOARG, 10 microM) significantly decreased flow-induced dilation in control but not in L-NAME or L-NAME + ACEI rats. Both acute indomethacin (10 microM) and acute NS 398 (cyclo-oxygenase-2 (COX-2) inhibitor, 1 microM) did not change significantly flow-induced dilatation in controls but they both decreased flow-induced dilatation in the L-NAME and L-NAME + ACEI groups. Acute Hoe 140 (bradykinin receptor inhibitor, 1 microM) induced a significant contraction of the isolated mesenteric arteries which was the same in the 3 groups. 6. Immunofluorescence analysis of COX-2 showed that the enzyme was expressed in resistance mesenteric arteries in L-NAME and L-NAME + ACEI groups but not in control. COX-1 expression was identical in all 3 groups. 7. We conclude that chronic inhibition of nitric oxide synthesis is associated with a decreased flow-induced dilatation in resistance mesenteric arteries which was compensated by an overproduction of vasodilator prostaglandins resulting in part from COX-2 expression. The decrease in flow-induced dilatation w

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cyclooxygenase 1; Cyclooxygenase 2; Drug Interactions; Enzyme Induction; Enzyme Inhibitors; Isoenzymes; Isoquinolines; Male; Membrane Proteins; Mesenteric Arteries; Muscle Contraction; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitroarginine; Prostaglandin-Endoperoxide Synthases; Quinapril; Rats; Rats, Wistar; Tetrahydroisoquinolines; Thromboxane B2; Vascular Resistance; Vasodilation