cyclic-gmp and icatibant

The present brief review summarizes the evidence for the possibility that endogenously released bradykinin plays a major role in protecting the heart against the consequences of acute myocardial injury. This evidence includes the facts that kinins are generated under myocardial ischemia; that when they are administered, they are cardioprotective (e.g., antiarrhythmic); that drugs that enhance the release of bradykinin from the ischemic heart reduce the ischemic injury and, conversely, drugs that block bradykinin receptors attenuate the reduction in ischemic injury resulting from the release of, or administration of, bradykinin. The possible mechanism of bradykinin in the cardioprotection afforded by ischemic preconditioning is summarized. Ischemic preconditioning can be defined as the marked reduction in the severity of ischemic changes that result from coronary artery occlusion when that occlusion is preceded by brief periods of myocardial ischemia, either regional or global, induced, for example, by complete or partial coronary artery occlusion or by rapid ventricular pacing. The possible mechanisms of cardioprotection elicited by bradykinin (and ischemic preconditioning) are summarized. The most likely is the generation of cyclic GMP within the ischemic myocardium following bradykinin-stimulated nitric oxide generation and release from endothelial cells.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Cyclic GMP; Heart; Humans; Myocardial Ischemia; Nitric Oxide

This study tested the hypothesis that endogenous bradykinin contributes to the effects of angiotensin AT(1) receptor blockade in humans. The effect of the bradykinin B(2) receptor antagonist d-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-d-Tic-Oic-Arg (HOE-140) (18 microg/kg/h i.v. for 6 h) on hemodynamic and endocrine responses to acute and chronic (1-month) treatment with valsartan (160 mg/day) was determined in 13 normotensive and 12 hypertensive salt-deplete subjects. Acute valsartan increased plasma renin activity (PRA) from 5.3 +/- 9.9 to 15.6 +/- 19.8 ng of angiotensin (Ang) I/ml/h (P < 0.001) and decreased aldosterone from 18.3 +/- 10.5 to 12.0 +/- 9.6 ng/dl (P < 0.001). Chronic valsartan significantly increased baseline PRA (10.5 +/- 15.5 ng of Ang I/ml/h; P = 0.004) but did not affect baseline angiotensin-converting enzyme activity or aldosterone. HOE-140 tended to increase the PRA response to valsartan, and it attenuated the decrease in aldosterone following chronic valsartan (P = 0.03). Acute valsartan decreased mean arterial pressure 12.7 +/- 6.9% (from 100.2 +/- 8.4 to 87.5 +/- 9.8 mm Hg in hypertensives and from 82.4 +/- 8.6 to 70.3 +/- 8.4 mm Hg in normotensives). HOE-140 did not affect the blood pressure response to either acute (effect of valsartan, P < 0.001; effect of HOE-140, P = 0.98) or chronic (valsartan, P = 0.01; HOE-140, P = 0.84) valsartan. Plasma cGMP was increased significantly during chronic valsartan (P = 0.048) through a bradykinin receptor-independent mechanism (effect of HOE-140, P = 0.13). Both acute (P < 0.001) and chronic (P < 0.001) valsartan increased heart rate. HOE-140 augmented the heart rate response to chronic valsartan (P = 0.04). These data suggest that endogenous bradykinin does not contribute significantly to the blood pressure-lowering effect of valsartan through its B(2) receptor.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Blood Pressure; Bradykinin; Bradykinin B2 Receptor Antagonists; Cross-Over Studies; Cyclic GMP; Diet, Sodium-Restricted; Female; Heart Rate; Humans; Hypertension; Male; Receptor, Bradykinin B2; Renin; Sodium; Tetrazoles; Valine; Valsartan

In this study, the interaction of natriuretic peptides (NP) and bradykinin (BK) signaling pathways was identified by measuring membrane potential (V(m)) and intracellular Ca(2+) using the patch-clamp technique and flow cytometry in HEK-293 cells. BK and NP receptor mRNA was identified using RT-PCR. BK (100 nM) depolarized cells activating bradykinin receptor type 2 (B(2)R) and Ca(2+)-dependent Cl(-) channels inhibitable by 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB; 10 μM). The BK-induced Ca(2+) signal was blocked by the B(2)R inhibitor HOE 140. [Des-Arg(9)]-bradykinin, an activator of B(1)R, had no effect on intracellular Ca(2+). NP [atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and urodilatin] depolarized HEK-293 cells inhibiting K(+) channels. ANP, urodilatin, BNP [binding to natriuretic peptide receptor (NPR)-A] and 8-bromo-(8-Br)-cGMP inhibited the BK-induced depolarization while CNP (binding to NPR-Bi) failed to do so. The inhibitory effect on BK-triggered depolarization could be reversed by blocking PKG using the specific inhibitor KT 5823. BK-stimulated depolarization as well as Ca(2+) signaling was completely blocked by the phospholipase C (PLC) inhibitor U-73122 (10 nM). The inositol 1,4,5-trisphosphate receptor blocker 2-aminoethoxydiphenyl borate (2-APB; 50 μM) completely inhibited the BK-induced Ca(2+) signaling. UTP, another activator of the PLC-mediated Ca(2+) signaling pathway, was blocked by U-73122 as well but not by 8-Br-cGMP, indicating an intermediate regulatory step for NP via PKG in BK signaling such as regulators of G-protein signaling (RGS) proteins. When RGS proteins were inhibited by CCG-63802 in the presence of BK and 8-Br-cGMP, cells started to depolarize again. In conclusion, as natural antagonists of the B(2)R signaling pathway, NP may also positively interact in pathological conditions caused by BK.

Topics: Boron Compounds; Bradykinin; Bradykinin B2 Receptor Antagonists; Carbazoles; Chloride Channels; Cyclic GMP; Estrenes; Flow Cytometry; HEK293 Cells; Humans; Inositol 1,4,5-Trisphosphate Receptors; Membrane Potentials; Natriuretic Peptides; Nitrobenzoates; Patch-Clamp Techniques; Potassium Channel Blockers; Protein Kinase Inhibitors; Pyrrolidinones; RGS Proteins; Signal Transduction; Thionucleotides; Type C Phospholipases

Postconditioning (PostC) maneuvers allow post-ischemic accumulation of autacoids, which trigger protection. We tested if PostC-triggering includes bradykinin (BK) B2 receptor activation and its downstream pathway.. Isolated rat hearts underwent 30 min ischemia and 120 min reperfusion. Infarct size was evaluated using nitro-blue tetrazolium staining. In Control hearts infarct size was 61+/-5% of risk area. PostC (5 cycles of 10 s reperfusion/ischemia) reduced infarct size to 22+/-4% (p<0.01). PostC protection was abolished by B2 BK receptor-antagonists (HOE140 or WIN64338), nitric oxide synthase-inhibitor (L-nitro-arginine-methylester), protein kinase G (PKG)-blocker (8-bromoguanosine-3',5'-cyclic-monophosphorothioate), and mitochondrial K(ATP) (mK(ATP))-blocker (5-hydroxydecanoate) each given for 3 min only. Since 3 min of BK-infusion (100 nM) did not reproduce PostC protection, protocols with Intermittent-BK infusion were used to mimic PostC: a) 5 cycles of 10 s oxygenated-no-BK/oxygenated+BK buffer; b) 5 cycles of 10 s oxygenated-no-BK/hypoxic+BK buffer. Both protocols with Intermittent-BK attenuated infarct size (36+/-5% and 38+/-4%, respectively; p<0.05 vs Control and NS vs PostC for both; NS vs each other). Intermittent-BK protection was abolished by the same antagonists used to prevent PostC protection. Intermittence of re-oxygenation only (5 cycles of 10 s oxygenated/hypoxic buffer) did not reproduce PostC. Yet, cardioprotection was triggered by intermittent mK(ATP) activation with diazoxide, but not by intermittent reactive oxygen species (ROS) generation with purine/xanthine oxidase. ROS scavengers (N-acetyl-L-cysteine or 2-mercaptopropionylglycine), given for 3 min only, abolished PostC-, Intermittent BK-and diazoxide-induced protection.. Intermittent targeting of specific cellular sites (i.e. BK B2 receptors and mK(ATP) channels) during early reperfusion triggers PostC protection via ROS signaling. Since neither intermittent oxygenation nor exogenous ROS generators can trigger protection, it is likely that intermittent autacoid accumulation and ROS compartmentalization may play a pivotal role in PostC-triggering.

Topics: Acetylcysteine; Adenosine Triphosphate; Animals; Bradykinin; Bradykinin B2 Receptor Antagonists; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Decanoic Acids; Hydroxy Acids; Mitochondria, Heart; Myocardial Infarction; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Oxidation-Reduction; Perfusion; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Wistar; Reactive Oxygen Species; Receptor, Bradykinin B2; Signal Transduction

Renal volume regulation is modulated by the action of cyclooxygenases (COX) and the resulting generation of prostanoids. Epithelial expression of COX isoforms in the cortex directs COX-1 to the distal convolutions and cortical collecting duct, and COX-2 to the thick ascending limb. Partly colocalized are prostaglandin E synthase (PGES), the downstream enzyme for renal prostaglandin E(2) (PGE(2)) generation, and the EP receptors type 1 and 3. COX-1 and related components were studied in two kidney-one clip (2K1C) Goldblatt hypertensive rats with combined chronic ANG II or bradykinin B(2) receptor blockade using candesartan (cand) or the B(2) antagonist Hoechst 140 (Hoe). Rats (untreated sham, 2K1C, sham + cand, 2K1C + cand, sham + Hoe, 2K1C + Hoe) were treated to map expression of parameters controlling PGE(2) synthesis. In 2K1C, cortical COX isoforms did not change uniformly. COX-2 changed in parallel with NO synthase 1 (NOS1) expression with a raise in the clipped, but a decrease in the nonclipped side. By contrast, COX-1 and PGES were uniformly downregulated in both kidneys, along with reduced urinary PGE(2) levels, and showed no clear relations with the NO status. ANG II receptor blockade confirmed negative regulation of COX-2 by ANG II but blunted the decrease in COX-1 selectively in nonclipped kidneys. B(2) receptor blockade reduced COX-2 induction in 2K1C but had no clear effect on COX-1. We suggest that in 2K1C, COX-1 and PGES expression may fail to oppose the effects of renovascular hypertension through reduced prostaglandin signaling in late distal tubule and cortical collecting duct.

Topics: Adrenergic beta-Antagonists; Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bradykinin; Cyclic GMP; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Hypertension, Renovascular; Kidney Cortex; Kidney Tubules, Collecting; Kidney Tubules, Distal; Loop of Henle; Male; Membrane Proteins; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Surgical Instruments; Tetrazoles

The development of nitrate tolerance has been found to be associated with vascular production of superoxide anion (O2-*), generated mainly by the eNOS and NADPH oxidase pathways. The aim of our study was to investigate whether long-term angiotensin-converting enzyme inhibition by ramipril is able to protect against nitrate tolerance in the aortas of eNOS-deficient (eNOS-/-) mice and to assess the implication of the NADPH oxidase pathway. Therefore, 3 types of treatment were given to wild-type (WT) and eNOS-/- mice: group 1 received ramipril for 5 weeks and a co-treatment with ramirpil plus nitroglycerine (NTG) during the last 4 days, group 2 received only NTG, and group 3 served as control. Relaxations to NTG (0.1 nmol/L to 0.1 mmol/L) were determined on U44619, a thromboxane analogue, precontracted rings, and O2-* production were assessed on aorta homogenates with the lucigenin-enhanced chemiluminescence technique. Cyclic guanosine monophosphate and reverse-transcriptase-polymerase chain reaction analyses were performed on whole mouse aortas. In WT group 2, the concentration-effect curves to NTG were significantly shifted to the right: the pD2 was 6.16 +/- 0.17 (n = 6) vs 6.81 +/- 0.10 (n = 6) in WT group 3 (not exposed to NTG; P < 0.05) and O2-* production was enhanced from 100% +/- 11% (n = 9) to 191% +/- 21% (n = 6; P < 0.01). In contrast, in WT group 1, the rightward shift was abolished: the pD2 value was 6.73 +/- 0.13 (n = 6; NS vs group 3 WT) and O2-* production was 117% +/- 6% (n = 7; NS vs group 3 WT). In eNOS groups 1 and 3, similar data were observed: the pD2 values were 7.58 +/- 0.08 and 7.38 +/- 0.11 (NS) vs 6.89 +/- 0.20 in eNOS group 2 (n = 6; P < 0.01). In the WT mice aortas, ramipril treatment significantly increased the cyclic guanosine monophosphate levels (reflecting nitric oxide availability), which returned to control values after in vivo co-treatment with a bradykinin BK2 antagonist (Icatibant). In both strains, candesartan, an AT1 blocker, was also able to protect against the development of nitrate tolerance. Moreover, before NTG exposure, ramipril treatment decreased p22phox and gp91phox (essential NADPH oxidase subunits) mRNA expression in aortas from both mice strains. In conclusion, long-term ramipril treatment in mice protects against the development of nitrate tolerance by counteracting NTG-induced increase in O2 production, which involves a direct interaction with the NADPH oxidase pathway and seems to be completely independ

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Bradykinin; Cyclic GMP; Female; In Vitro Techniques; Injections, Subcutaneous; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidases; Nitric Oxide Synthase Type III; Nitroglycerin; Oxidative Stress; Ramipril; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasodilation

Abdominal aortic banding induces upregulation of the angiotensin II (Ang II) type-2 (AT2) receptor, thereby decreasing the contractile response to Ang II in the thoracic aorta of the rat. The aim of this study was to use a mouse model to clarify the mechanisms by which the banding elicits upregulation of the aortic AT2 receptor and the subsequent attenuation of Ang II responsiveness. Concomitantly with the elevation in blood pressure and plasma renin concentration after banding, AT2-receptor mRNA levels in the thoracic aorta rapidly increased in mice within 4 days. Upregulation of the AT2 receptor, as well as blood pressure elevation after banding, was abolished by losartan administration. The contractile response to Ang II was depressed in aortic rings of banding mice but not of sham mice, and was restored by either the AT2-receptor antagonist PD123319 or the bradykinin B2-receptor antagonist icatibant. cGMP content in the thoracic aorta of banding mice was 9-fold greater than that of sham mice, and the elevation was reduced to sham levels 1 hour after intravenous injection of PD123319 or icatibant. When aortic rings were incubated with Ang II, cGMP content increased in banding rings but not in sham rings; the pretreatment with PD123319 or icatibant inhibited Ang II-induced cGMP production. These results suggest that aortic banding induces upregulation of the AT2 receptor through increased circulating Ang II via the AT1 receptor, thereby activating a vasodilatory pathway in vessels through the AT2 receptor via the kinin/cGMP system.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Animals; Aorta, Abdominal; Aorta, Thoracic; Aortic Valve Stenosis; Bradykinin; Bradykinin B2 Receptor Antagonists; Cyclic GMP; Hypertension; Imidazoles; Ligation; Losartan; Male; Mice; Mice, Inbred ICR; Models, Animal; Nitric Oxide; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Renin; RNA, Messenger; Up-Regulation; Vasoconstriction

Although ACE inhibitors can protect myocardium against ischemia/reperfusion injury, the mechanisms of this effect have not yet been characterized at the cellular level. The present study was designed to examine whether an ACE inhibitor, cilazaprilat, directly protects cardiac myocytes against hypoxia/reoxygenation (H/R) injury.. Neonatal rat cardiac myocytes in primary culture were exposed to hypoxia for 5.5 hours and subsequently reoxygenated for 1 hour. Myocyte injury was determined by the release of creatine kinase (CK). Both cilazaprilat and bradykinin significantly inhibited CK release after H/R in a dose-dependent fashion and preserved myocyte ATP content during H/R, whereas CV-11974, an angiotensin II receptor antagonist, and angiotensin II did not. The protective effect of cilazaprilat was significantly inhibited by Hoe 140 (a bradykinin B2 receptor antagonist), NG-monomethyl-L-arginine monoacetate (L-NMMA) (an NO synthase inhibitor), and methylene blue (a soluble guanylate cyclase inhibitor) but not by staurosporine (a protein kinase C inhibitor), aminoguanidine (an inhibitor of inducible NO synthase), or indomethacin (a cyclooxygenase inhibitor). Cilazaprilat significantly enhanced bradykinin production in the culture media of myocytes after 5.5 hours of hypoxia but not in that of nonmyocytes. In addition, cilazaprilat markedly enhanced the cGMP content in myocytes during hypoxia, and this augmentation in cGMP could be blunted by L-NMMA and methylene blue but not by aminoguanidine.. The present study demonstrates that cilazaprilat can directly protect myocytes against H/R injury, primarily as a result of an accumulation of bradykinin and the attendant production of NO induced by constitutive NO synthase in hypoxic myocytes in an autocrine/paracrine fashion. NO modulates guanylate cyclase and cGMP synthesis in myocytes, which may contribute to the preservation of energy metabolism and cardioprotection against H/R injury.

Topics: Adrenergic beta-Antagonists; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Bradykinin; Cell Hypoxia; Cells, Cultured; Cilazapril; Creatine Kinase; Cyclic GMP; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Guanidines; Indomethacin; Methylene Blue; Muscle Fibers, Skeletal; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Oxygen; Rats; Rats, Wistar; Staurosporine; Tetrazoles

Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms - AT1 and AT2. Although blood pressure is increased in AT2 knockout mice, the underlying mechanisms remain undefined because of the low levels of expression of AT2 in the vasculature. Here we overexpressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of Ang II into AT2-TG mice completely abolished the AT1-mediated pressor effect, which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice showed greatly increased cGMP production and diminished Ang II-induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na(+)/H(+) exchanger, promoting intracellular acidosis in VSM cells and activating kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest that AT2 in aortic VSM cells stimulates the production of bradykinin, which stimulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicted to have a beneficial clinical effect in controlling blood pressure.

Topics: Actins; Amiloride; Angiotensin II; Animals; Aorta; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cell Membrane; Cyclic GMP; Endothelium, Vascular; Imidazoles; Kinins; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Promoter Regions, Genetic; Pyridines; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Recombinant Fusion Proteins; Tunica Media; Vasoconstriction; Vasodilation

Increased beta-amyloid production is believed to play a central role in the pathogenesis of Alzheimer's disease. Amyloid is deposited not only in the brain of Alzheimer patients as senile plaques but also in the cerebral vessel wall leading to cerebral amyloid angiopathy. Freshly solubilised amyloid beta-(1-40) was previously reported to exert a vasoconstrictor effect. We investigated whether amyloid beta-(1-40) affects the nitric oxide (NO)/cyclic GMP pathway in primary cultured endothelial cells from bovine aorta and rat coronary microvessels. Surprisingly, a significant increase in cyclic GMP production after incubation with freshly dissolved amyloid beta-(1-40) was found. The stimulation of cyclic GMP production could be inhibited by the bradykinin B(2) receptor antagonist icatibant, the NO synthase inhibitor N-omega-nitro-L-arginine, the serine protease inhibitor 3, 4-dichloroisocoumarin and the selective plasma kallikrein inhibitor Pefabloc PK, suggesting activation of the plasma kallikrein-kinin system. This is supported by a three- to four-fold increase in kinins in the supernatant of both types of endothelial cells after incubation with amyloid beta-(1-40) at concentrations of 10(-7) and 10(-6) mol/l.

Topics: Amyloid beta-Peptides; Animals; Aorta; Bradykinin; Bradykinin Receptor Antagonists; Cattle; Cells, Cultured; Coronary Vessels; Coumarins; Cyclic GMP; Endothelium, Vascular; Enzyme Inhibitors; Isocoumarins; Kallikreins; Kinins; Microcirculation; Microscopy, Electron; Nitric Oxide Synthase; Nitroarginine; Peptide Fragments; Rats; Serine Proteinase Inhibitors

In the present study we tested the hypothesis whether an angiotensin AT2 receptor-mediated stimulation of the bradykinin (BK)/nitric oxide (NO) system can account for the effects of AT1 receptor antagonism on aortic cGMP described previously in SHRSP. Adult SHRSP were treated for 4 hours with angiotensin II (ANG II) (30 ng/kg per min IV) or vehicle (0.9% NaCl I.V.). Animals were pretreated with vehicle, losartan (100 mg/kg P.O.), PD 123319 (30 mg/kg I.V.), losartan plus PD 123319, icatibant (500 microg/kg I.V.), N(G)-nitro-L-arginine methyl ester (L-NAME; 1 mg/kg I.V.), or minoxidil (3 mg/kg I.V.). Mean arterial blood pressure (MAP) was continuously monitored over the 4-hour experimental period, and plasma ANG II and aortic cGMP were measured by RIA at the end of the study. ANG II infusion over 4 hours raised MAP by about 20 mm Hg. Losartan alone or losartan plus ANG II as well as minoxidil plus ANG II markedly reduced blood pressure when compared to vehicle-treated or ANG II-treated animals, respectively. Plasma levels of ANG II were increased 2-fold by ANG II infusion alone or by ANG II in combination with icatibant, L-NAME, or minoxidil. The increase in plasma ANG II levels was even more pronounced after losartan treatment. Aortic cGMP content was significantly increased by ANG II, losartan, losartan plus ANG II, and minoxidil plus ANG II by 60%, 45%, 68%, and 52%, respectively (P<.05). The effects of ANG II and of losartan plus ANG II on aortic cGMP content were both blocked by cotreatment with the AT2 receptor antagonist PD 123319. Icatibant and L-NAME abolished the effects of ANG II on aortic cGMP. Our results demonstrate the following: (1) ANG II increases aortic cGMP by an AT2 receptor-mediated action because the effect could be prevented by an AT2 receptor antagonist; (2) the effect of ANG II was not secondary to blood pressure increase because it remained under reduction of MAP with minoxidil; (3) losartan increased aortic cGMP most likely by increasing plasma ANG II levels with a subsequent stimulation of AT2 receptors; and (4) the effects of AT2 receptor stimulation are mediated by BK and, subsequently, NO because they were abolished by B2 receptor blockade as well as by NO synthase inhibition.

Topics: Angiotensin II; Animals; Aorta; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cerebrovascular Disorders; Cyclic GMP; Hypertension; Imidazoles; Losartan; Male; Minoxidil; Muscle, Smooth, Vascular; NG-Nitroarginine Methyl Ester; Pyridines; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Reference Values

Pepsanurin is a peptidic fraction resulting from pepsin digestion of plasma globulins, that inhibits ANP renal excretory actions. We studied whether kinin-like peptides mediate the anti-ANP effect by testing if pepsanurin: 1) was blocked by the kinin B2 receptor antagonist HOE-140, 2) was produced from kininogen, and 3) was mimicked by bradykinin. Anti-ANP activity was assessed in anesthetized female rats by comparing the excretory response to two ANP boluses (0.5 microgram i.v.) given before and after i.p. injection of test samples. Pepsanurin from human or rat plasma (1-5 mL/kg), and bradykinin (5-20 micrograms/kg), dose-relatedly inhibited ANP-induced water, sodium, potassium and cyclic GMP urinary excretion, without affecting arterial blood pressure. The same effect was exerted by pepsin hydrolysates of purified kininogen, whereas hydrolysates of kininogen-free plasma had no effect. HOE-140 (5 micrograms, i.v.) did not alter baseline, or ANP-induced excretion, but blocked the anti-ANP effects of pepsanurin. Histamine (15 micrograms/kg) plus seroalbumin hydrolysates did not affect ANP response, despite inducing larger peritoneal fluid accumulation as compared with pepsanurin or bradykinin. We concluded that kinins cleaved from kininogen mediate the anti-ANP effects of pepsanurin by activation of kinin B2 receptors, independently of changes in systemic arterial pressure or peritoneal fluid sequestration.

Topics: Adrenergic beta-Antagonists; Animals; Atrial Natriuretic Factor; Bradykinin; Cyclic GMP; Cysteine Proteinase Inhibitors; Diuresis; Diuretics; Female; Intercellular Signaling Peptides and Proteins; Kininogens; Kinins; Peptides; Rats; Rats, Sprague-Dawley

In bovine aortic endothelial cells (BAECs), we previously demonstrated B1 and B2 kinin receptor-mediated increases in intracellular guanosine-3',5'-cyclic monophosphate (cGMP). In this study, the B2 kinin receptor agonist bradykinin increased cGMP in rat microvascular coronary endothelial cells (RMCECs) and human umbilical vein endothelial cells (HUVECs), which could be prevented with the specific B2 kinin receptor antagonist icatibant but not with the B1 kinin receptor antagonist des-Arg9-[Leu8]bradykinin or with the nonpeptide kinin receptor antagonist WIN 64338. B2 kinin receptor mRNA could be detected in all three cell types using reverse transcription-polymerase chain reaction and subsequent Southern blotting. The B1 kinin receptor agonist des-Arg9-bradykinin increased cGMP in RMCECs but not in HUVECs. The response in RMCECs could be prevented by des-Arg9-[Leu8]bradykinin as well as by WIN 64338 but not by icatibant. In BAECs, the B1 kinin receptor-mediated cGMP synthesis could be prevented by icatibant and desensitized by preincubation with des-Arg9-bradykinin as well as bradykinin. We detected B1 kinin receptor mRNA in RMCECs and HUVECs but not in BAECs. In HUVECs, the detection of B1 kinin receptor mRNA is in contradiction to the cGMP measurements. In BAECs, the atypical B1 kinin receptor pharmacology, the heterologous desensitization of the receptor and the failure to detect B1 kinin receptor mRNA cannot be explained by a typical B1 kinin receptor subtype. Thus, B2 kinin receptors with similar pharmacology are constitutively expressed in each of the three endothelial cell types. However, the endothelial cell types are heterogeneous in the expression of typical B1 kinin receptors and the pharmacology of the B1 kinin receptor-mediated responses.

Topics: Animals; Aorta; Bradykinin; Bradykinin Receptor Antagonists; Cattle; Cells, Cultured; Coronary Vessels; Cyclic GMP; DNA Primers; Endothelium, Vascular; Humans; Microcirculation; Naphthalenes; Organophosphorus Compounds; Polymerase Chain Reaction; Rats; Receptor, Bradykinin B1; Receptors, Bradykinin; Species Specificity; Transcription, Genetic; Umbilical Veins

Bradykinin, applied locally to the airways, is a weak bronchoconstrictor agent in guinea pigs in vivo and it may cause constriction or dilatation of guinea pig airways smooth muscle in vitro. We examined the motor effect of bradykinin perfused through the lumen of isolated guinea pig tracheal tubes with or without nitric oxide (NO) synthase inhibitors. In the presence of NG-nitro-D-arginine methyl ester (D-NAME) or NG-monomethyl-D-arginine (D-NMMA) intraluminal bradykinin caused a moderate concentration-dependent relaxation. In contrast, in the presence of NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) tracheas developed a sustained increase in tone, and bradykinin caused a marked, concentration-dependent contraction, both effects being reversible by pretreatment with L-arginine, but not with D-arginine. The ability of bradykinin to relax (in the presence of D-NAME) or contract (in the presence of L-NAME) guinea pig tracheal tubes was not affected by indomethacin. Bradykinin contracted epithelium-denuded tracheas in the presence of either L-NAME or D-NAME. Both contraction and relaxation by bradykinin were blocked by the kinin B2 receptor antagonist, HOE 140. Baseline production of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in strips of guinea pig trachealis in vitro was markedly reduced by L-NAME, but not by D-NAME. Bradykinin increased baseline cyclic GMP concentration. These results indicate that bradykinin releases NO or a NO-related molecule, which, possibly by increasing cyclic GMP concentrations, mediates relaxation and opposes contraction induced by bradykinin itself, and further, that bradykinin releases NO from the tracheal epithelium.

Topics: Adrenergic beta-Antagonists; Animals; Arginine; Bradykinin; Culture Techniques; Cyclic GMP; Cyclooxygenase Inhibitors; Dose-Response Relationship, Drug; Enzyme Inhibitors; Epithelium; Guinea Pigs; Indomethacin; Isomerism; Male; Muscle Contraction; Muscle Relaxation; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; omega-N-Methylarginine; Trachea

These experiments compare the effects of a neutral endopeptidase inhibitor, retrothiorphan, 1-[(1-mercaptomethyl-2-phenyl)ethyl]amino-1-oxopropanoic acid, a converting enzyme inhibitor, enalaprilat, and the combination of the two inhibitors on changes in blood pressure and renal function induced by exogenous and endogenous bradykinin in deoxycorticosterone acetate (DOCA)-salt rats. Enalaprilat potentiated the exogenous bradykinin-induced hypotensive responses while retrothiorphan potentiated the effects on urinary cyclic-GMP (cGMP) and bradykinin. The combination potentiated the exogenous bradykinin-induced hypotensive effects and the bradykinin-induced urinary excretion of cGMP, bradykinin and prostaglandin. The bradykinin B2 receptor antagonist, Hoe 140, had no effect on the enalaprilat- and retrothiorphan-induced changes in blood pressure and renal function. In conclusion, while angiotensin-converting enzyme and neutral endopeptidase are involved in the vascular and renal catabolism of exogenous bradykinin, the effects of the peptidase inhibitors do not appear to depend on the protection of endogenous bradykinin under acute conditions in DOCA-salt rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cyclic GMP; Enalaprilat; Hypertension; Kidney; Male; Neprilysin; Rats; Rats, Wistar; Thiorphan

We investigated the effect of chronic angiotensin-covering enzyme (ACE) inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRsp). Animals were treated prenatally and, subsequently, up to the age of 20 weeks with the ACE inhibitor perindopril (0.01 and 1 mg/kg per day). The contribution of endogenous bradykinin potentiation to the actions of the ACE inhibitor was assessed by co-treatment with the bradykinin B2-receptor antagonist, icatibant (500 micrograms/kg/day s.c.), from 6 to 20 weeks of age and by measurement of myocardial prostacyclin and cyclic guanosine monophosphate (GMP) concentrations. Chronic high-dose treatment with perindopril attenuated the development of hypertension and left ventricular hypertrophy while low-dose perindopril treatment had no effect on these parameters. However, low-dose perindopril improved cardiac function of isolated perfused hearts as demonstrated by an increasing left ventricular pressure and dp/dtmax without change in heart rate. Low-dose perindopril further reduced lactate concentrations and the enzymatic activities of lactate dehydrogenase and creatine kinase in the coronary venous effluent and increased tissue concentrations of glycogen, adenosine triphosphate, and creatine kinase in the myocardium. Concomitant chronic bradykinin receptor blockade abolished all ACE inhibitor-induced effects on cardiac function and metabolism. Cardiac prostacylin concentrations were 3-fold elevated in perindopril-treated animals when compared to vehicle-treated controls, while cardiac cyclic GMP concentrations remained unchanged. Our data demonstrate that chronic ACE inhibitor treatment can improve cardiac function and metabolism independently of the antihypertensive and antihypertrophic drug actions by potentiation of endogenous bradykinin.

Topics: Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Cerebrovascular Disorders; Cyclic GMP; Epoprostenol; Heart; Hypertension; Hypertrophy, Left Ventricular; Indoles; Myocardium; Perindopril; Rats; Rats, Inbred SHR; Ventricular Pressure

To determine whether chronic angiotensin-converting enzyme (ACE) inhibition produces functional changes in the aorta normotensive rats, four groups of rats were studied in parallel for 6 weeks. Group 1 orally received ramipril and beta 2-kinin antagonist HOE140 500 micrograms/kg per day s.c. by injection for the remaining 2 weeks; group 3, hydralazine 100 mg/kg per day PO for 6 weeks; group 4 (control), subcutaneous injections of saline solution during the last 2 of 6 weeks. In aorta isolated from group 1 the relaxations induced by bradykinin, acetylcholine, and histamine were significantly potentiated compared with those of group 4. In group 3, despite a decrease in systolic blood pressure similar to that induced by ramipril treatment, the responses to these three endothelium-dependent vasodilators were not different from those of group 4. In group 2, bradykinin-induced relaxations were completely abolished whereas acetylcholine-induced and histamine-induced relaxations were to those of group 4. The inhibitory effect of the endothelium on serotonin-induced contractions was significantly increased in preparations of group 1 compared with those of groups 2 through 4. Indirect measurements of nitric oxide formation such as contractions evoked by NG-monomethyl-L-arginine (L-NMMA) and aortic cGMP content were also significantly enhanced in preparations from group 1 compared with those of groups 2 through 4. Moreover, because the relaxations to nitroglycerin and nitroprusside were similar in groups 1, 2, and 4 an alteration of the guanylate cyclase activity by ramipril treatment is quite unlikely. Thus long-term treatment with ramipril potentiates the endothelium-dependent responses in the rat aorta by enhancing nitric oxide availability.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arginine; Bradykinin; Cyclic GMP; Drug Synergism; Endothelium, Vascular; Hydralazine; Male; Nitric Oxide; omega-N-Methylarginine; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Wistar; Vasodilation

Cardiac anaphylaxis, an acute ischemic dysfunction comprising coronary vasoconstriction and arrhythmias, is a model of clinically recognized immediate hypersensitivity reactions affecting the heart. Bradykinin, a mediator of hypersensitivity, is also a potent coronary vasodilator, acting via nitric oxide and prostacyclin production. Because ischemia increases bradykinin outflow from the heart, we questioned whether bradykinin might mitigate anaphylactic coronary vasoconstriction. Antigen challenge of hearts isolated from presensitized guinea pigs was associated with an approximately 30% increase in bradykinin overflow. Furthermore, (1) when the half-life of bradykinin was prolonged with the kininase II/angiotensin-converting enzyme inhibitors captopril and enalaprilat, anaphylactic coronary vasoconstriction was attenuated and reversed, and arrhythmias were alleviated; (2) the bradykinin B2-receptor antagonist HOE 140 prevented these effects; and (3) HOE 140 exacerbated both anaphylactic coronary vasoconstriction and arrhythmias. During cardiac anaphylaxis, the coronary overflow of cGMP, a marker of nitric oxide production, and 6-ketoprostaglandin F1 alpha, a stable prostacyclin metabolite, increased two-fold and fourfold, respectively. Because neither enalaprilat nor HOE 140 affected these changes, the enhanced overflow of cGMP and 6-ketoprostaglandin F1 alpha is likely to reflect the actions of other hypersensitivity mediators (eg, histamine and leukotrienes). We postulate that bradykinin plays a protective role in cardiac anaphylaxis by accumulating at the luminal surface of the coronary endothelium and promoting, in an autocrine mode, a B2-receptor-mediated production of nitric oxide and prostacyclin in concentrations sufficient to elicit a paracrine effect on coronary vascular smooth muscle, thus opposing the vasoconstricting effects of other anaphylactic mediators.

Topics: Anaphylaxis; Animals; Arrhythmias, Cardiac; Bradykinin; Captopril; Coronary Vessels; Cyclic GMP; Epoprostenol; Guinea Pigs; Male; Nitric Oxide; Vasodilation

To further investigate the mechanisms of renal effects of neutral endopeptidase 24.11 (NEP) inhibition, we employed a specific NEP inhibitor, UK 73967 (UK), with or without a specific kinin receptor antagonist, Hoe 140 (Hoe), or nitric oxide (NO) synthase inhibitor, N-monomethyl-L-arginine (L-NMMA), in Sprague-Dawley rats, and evaluated the urinary NEP, kinins, cGMP and plasma atrial natriuretic peptide (ANP). None of the variables changed with vehicle injection. After injection of UK, NEP decreased significantly and urinary kinins, cGMP, urine volume (UV) and urinary sodium excretion (UNaV) increased significantly. Injected Hoe canceled the increase in UV and UNaV induced by UK. Plasma ANP did not show any difference between vehicle and UK groups. With a pretreatment of L-NMMA, injected UK decreased NEP and increased kinins, while urinary cGMP, UV and UNaV did not increase. In conclusion, augmented kinins may play an important role in the renal water-sodium metabolism by NEP inhibition, and NO may contribute to the kinins' action on this mechanism, while ANP may not contribute to it, at least in normotensive rats. Moreover, changes in urinary cGMP do not reflect the changes in plasma ANP, but rather, those in NO under this condition.

Topics: Adrenergic beta-Antagonists; Animals; Arginine; Atrial Natriuretic Factor; Bradykinin; Cyclic GMP; Cyclohexanecarboxylic Acids; Kidney; Kinins; Male; Neprilysin; Nitric Oxide; omega-N-Methylarginine; Protease Inhibitors; Rats; Rats, Sprague-Dawley

We investigated whether formation of endothelium-derived relaxing factor (EDRF) and endothelium-derived hyperpolarizing factor (EDHF) in porcine and bovine endothelial cells (PAECs) was stimulated by different kinin receptors and studied pharmacologic differences and similarities between the two types of bradykinin-induced relaxation of bovine or porcine coronary arteries. Cultured PAECs were used for [3H]bradykinin binding assay and for measurement of the endothelial free [Ca2+]i by the fura-2/AM method. In organ bath studies with strips of bovine and porcine coronary arteries (endothelium intact), changes in length were recorded and cyclic GMP was measured by radioimmunoassay (RIA). Two bradykinin binding sites were detected, suggesting the presence of two subtypes of B2 kinin receptors. Bradykinin increased [Ca2+]i, and this action was antagonized by the B2 kinin receptor antagonist Hoe 140 and the K channel inhibitor tetrabutylammonium (TBA). Hoe 140 competitively antagonized the relaxing effects of bradykinin, whereas a B1 antagonist was inactive. L-omega N-nitro-arginine (L-NNA) diminished one part of bradykinin-induced relaxation and abolished the increases in cyclic GMP; TBA inhibited another part of the relaxing effect and attenuated (but not significantly) increases in cyclic GMP, and Hoe 140 completely inhibited relaxation and increases in cyclic GMP. The results indicate that the bradykinin response is mediated by biosynthesis of EDRF, which is sensitive to L-NNA, and of EDHF, which is sensitive to TBA.

Topics: Animals; Arginine; Biological Factors; Bradykinin; Bradykinin Receptor Antagonists; Cattle; Cells, Cultured; Coronary Vessels; Cyclic GMP; Endothelium, Vascular; In Vitro Techniques; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide; Nitroarginine; Quaternary Ammonium Compounds; Receptors, Bradykinin; Swine

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiac function independent of their blood pressure (BP)-lowering actions. We investigated the effect of chronic subantihypertensive ACE inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRSP). Animals were treated in utero and subsequently to age 20 weeks with the ACE inhibitor perindopril (0.01 mg/kg/day). The contribution of endogenous bradykinin (BK) potentiation to the actions of the ACE inhibitor was assessed by cotreatment with the BK beta 2-receptor antagonist Hoe 140 (500 micrograms/kg/day subcutaneously, s.c.) from age 6 to 20 weeks and by measurement of myocardial prostacyclin and cyclic GMP concentrations. Chronic low-dose perindopril treatment had no effect on development of hypertension and left ventricular hypertrophy (LVH), but perindopril improved cardiac function, as demonstrated by increased LV pressure (LVP) (19.4%) and LVdp/dtmax (27.8%) but no change in heart rate (HR). The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactate concentrations in the coronary venous effluent were reduced by 39.3, 50, and 60.6%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and CK were increased by 16.3, 33.1, and 28.2%, respectively. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by concomitant chronic BK receptor blockade. Cardiac prostacyclin concentrations were threefold elevated in perindopril-treated animals whereas cardiac cyclic GMP concentration remained unchanged as compared with that of controls. Our data demonstrate that chronic low-dose ACE inhibitor treatment can improve cardiac function and metabolism by potentiating endogenous BK.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 6-Ketoprostaglandin F1 alpha; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Cerebrovascular Disorders; Coronary Circulation; Creatine Kinase; Cyclic GMP; Disease Models, Animal; Glycogen; Heart; Heart Rate; Hypertension; Hypertrophy, Left Ventricular; Indoles; L-Lactate Dehydrogenase; Myocardium; Perindopril; Rats; Rats, Inbred SHR

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

The activity of the renal kallikrein-kinin system is controlled by the concentration of intrarenal kinins. Neutral endopeptidase 24.11 (NEP) cleaves kinins as effectively as kininase I and kininase II. It is also well known that NEP metabolizes atrial natriuretic peptide (ANP). The present study evaluated the effects of NEP inhibitor on renal action by kinins, ANP and nitric oxide in Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats. In normotensive rats, we demonstrated that 1) inhibition of NEP potentiates the contribution of kinins to the renal water-sodium metabolism and overcomes the contribution of ANP to that metabolism, 2) nitric oxide participates in the action of kinins, and 3) changes in urinary cGMP excretion do not reflect the changes in plasma ANP, but the changes in nitric oxide, under these conditions. On the other hand, it was also suggested that augmented ANP may contribute mainly to renal water-sodium handling by NEP inhibitor in DOCA-salt rats. Therefore, the contributions of the two systems to the diuretic and natriuretic mechanisms of NEP inhibition may differ between Sprague-Dawley normotensive rats and DOCA-salt hypertensive rats.

Topics: Animals; Atrial Natriuretic Factor; Bradykinin; Cyclic GMP; Cyclohexanecarboxylic Acids; Diuresis; Kallikrein-Kinin System; Kidney; Kinins; Natriuresis; Neprilysin; Rats; Rats, Sprague-Dawley; Sodium

Dorsal root ganglion (DRG) neurons express receptors for bradykinin and capsaicin, both algesic substances. Administration of bradykinin or capsaicin to neurons cultured from embryonic rat DRG stimulated the production of cyclic GMP but did not affect the production of cyclic GMP in nonneuronal DRG cultures. Bradykinin-evoked cyclic GMP production was mediated by B2 receptors and was unaltered by indomethacin. Both bradykinin- and capsaicin-stimulated cyclic GMP production required Ca2+ and was inhibited by methylene blue. Furthermore, methylene blue attenuated basal cyclic GMP production in DRG neurons, suggesting tonic cyclic GMP production in these cells. L-NG-monomethyl arginine inhibited both bradykinin- and capsaicin-stimulated cyclic GMP production as well as basal cyclic GMP production. These findings suggest the involvement of a nitrosyl compound in bradykinin- and capsaicin-stimulated cyclic GMP production and in tonic cyclic GMP production in DRG neurons.

Topics: Animals; Arginine; Bradykinin; Bradykinin Receptor Antagonists; Calcium; Capsaicin; Cells, Cultured; Cyclic GMP; Ganglia, Spinal; Guanylate Cyclase; Methylene Blue; Neurons; Nitric Oxide; omega-N-Methylarginine; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Arginine; Bradykinin; Cattle; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Female; In Vitro Techniques; Male; Myocardial Ischemia; Nitric Oxide; Nitroarginine; Oligopeptides; Rats; Rats, Wistar; Receptors, Angiotensin

We investigated functional changes in aortic preparations of spontaneously hypertensive rats treated in utero and subsequently up to 20 weeks of age with the angiotensin converting enzyme (ACE) inhibitors ramipril (0.01 and 1 mg/kg per day) and perindopril (0.01 mg/kg per day). Early-onset treatment with the high dose of ramipril inhibited aortic ACE activity, prevented the development of hypertension, increased aortic vasodilator responses to acetylcholine (10(-8) to 10(-6) mol/L), decreased vasoconstrictor responses to norepinephrine (10(-8) mol/L), and increased aortic cyclic GMP content by 160%. Low-dose ramipril inhibited aortic ACE activity and attenuated the aortic vasoconstrictor response to norepinephrine but had no effect on blood pressure. Low-dose treatment with ramipril and perindopril resulted in a significant increase in aortic cyclic GMP content by 98% and 77%, respectively. Long-term coadministration of the bradykinin B2-receptor antagonist Hoe 140 abolished the ACE inhibitor-induced increase in aortic cyclic GMP. Our data demonstrate that long-term treatment with ACE inhibitors can alter vascular function of compliance vessels independently of the antihypertensive action. The increase in aortic cyclic GMP was due to bradykinin potentiating the action of the ACE inhibitors.

Topics: Aging; Analysis of Variance; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Bradykinin; Cyclic GMP; Dose-Response Relationship, Drug; Female; Hypertension; In Vitro Techniques; Indoles; Maternal-Fetal Exchange; Muscle Contraction; Muscle, Smooth, Vascular; Peptidyl-Dipeptidase A; Perindopril; Pregnancy; Ramipril; Rats; Rats, Inbred SHR; Reference Values; Systole

The angiotensin converting enzyme (ACE) inhibitors, moexiprilat and ramiprilat, relaxed preconstricted endothelium-intact bovine coronary artery rings and enhanced the relaxant response to bradykinin. The relaxation was observed in the presence of a cyclooxygenase inhibitor and without previous exposure to bradykinin. ACE inhibitor-dependent relaxation was attenuated by the selective B2-kinin receptor antagonist, Hoe 140, and completely abolished by removal of the endothelium. Bradykinin or moexiprilat also significantly increased the cyclic guanosine monophosphate (cGMP) content of these coronary segments, an effect which was abolished by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (NNA), or by removal of the endothelium. NNA also diminished the relaxant response to moexiprilat, but only partially inhibited that to bradykinin, suggesting that the ACE inhibitor-induced relaxation was predominantly mediated by endothelial NO release, whereas bradykinin acted in part by another endothelium-dependent mechanism. These findings indicate that ACE inhibitors can elicit endothelium-dependent relaxations presumably by facilitating the accumulation of endothelium-derived kinins in or at the vessel wall. This local mechanism may significantly contribute to the antihypertensive action of these compounds in vivo.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Cattle; Coronary Vessels; Cyclic GMP; Endothelium, Vascular; In Vitro Techniques; Isoquinolines; Nitric Oxide; Nitroarginine; Ramipril; Tetrahydroisoquinolines; Vasodilation

We have recently shown that cultured endothelial cells produce kinins that can stimulate endothelial nitric oxide (NO) production in an autocrine manner. Because both the kallikrein-kinin system and the L-arginine/NO pathway have been implicated in the pathogenesis of septic shock, we investigated the possible involvement of endothelium-derived kinins in the response of cultured endothelial cells to bacterial lipopolysaccharide (LPS). In primary cultures of human umbilical vein and porcine aortic endothelial cells, LPS (0.3 to 3 micrograms/ml) induced significant concentration-dependent increases in cyclic GMP and 6-keto-PGF1 alpha, both of which were abolished in the presence of the selective bradykinin B2-receptor antagonist HOE 140 (0.1 microM). These LPS-induced increases in cyclic GMP and 6-keto-PGF1 alpha were short lived, being maximal after 5 min but were not apparent after 60 min. In parallel with these effects, LPS (30 micrograms/ml) induced a distinct, HOE 140-sensitive increase in the intracellular calcium concentration of human endothelial cells loaded with indo-1. In summary, these data suggest that the release of endothelium-derived kinin and subsequent stimulation of endothelial cells, followed by the enhanced production of NO and prostacyclin (PGI2), are implicated in the immediate hypotension induced by LPS in vivo.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Aorta; Bradykinin; Calcium; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Humans; Kinins; Lipopolysaccharides; Nitric Oxide; Swine; Umbilical Veins

Like bradykinin the converting enzyme inhibitor ramiprilat concentration-dependently enhances the formation of nitric oxide and prostacyclin assessed by intracellular cyclic GMP accumulation and 6-keto prostaglandin F1. resp. Both ramiprilat-induced effects are completely suppressed by the specific kinin receptor antagonist Hoe 140. The ramiprilat-induced cyclic GMP increase is totally blocked by the stereospecific inhibitor of nitric oxide synthase, NG-nitro-L-arginine.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Arginine; Bradykinin; Captopril; Cattle; Cells, Cultured; Cyclic GMP; Endothelium, Vascular; Epoprostenol; Nitric Oxide; Nitroarginine; Ramipril