nitroarginine and icatibant

Experiments were designed to determine if salivary gland homogenates (SGH) of the sand fly Lutzomyia longipalpis, the vasodilatory peptides maxadilan and pituitary adenylate cyclase-activating peptide (PACAP-38) may cause plasma leakage and to what extent these effects could be due to PAC1 receptor stimulation.. Using FITC-dextran as a plasma marker, intravital microscopy of the hamster cheek pouch (HCP) and a digital camera were used to assess arteriolar diameter and fluorescence of a selected area (5 mm(2)) representative of the HCP microcirculation.. Cheek pouches prepared for intravital microscopy and exposed to topical application of SGH, maxadilan or PACAP-38 developed maximal dilation of arterioles in the range of 20-60 mum within 10 min, and this effect lasted for 30-90 min. The increase in fluorescence intensity induced by each of these compounds was due to plasma leakage from postcapillary venules. The mutant peptide of maxadilan (M-65), a PAC1 receptor antagonist, inhibited both dilation and plasma leakage induced by SGH or maxadilan. Plasma leakage induced by SGH was modestly inhibited by the bradykinin B(2) receptor antagonist HOE-140, but not by the antihistamine mepyramine or the nitric oxide synthase inhibitor L-NA.. SGH of L. longipalpis and its vasodilatory peptide maxadilan caused long-lasting arteriolar dilation and plasma leakage in the cheek pouch via PAC1 receptor activation.

Topics: Adrenergic beta-Antagonists; Animals; Arterioles; Bradykinin; Cricetinae; Enzyme Inhibitors; Female; Histamine H1 Antagonists; Insect Proteins; Male; Microscopy, Fluorescence; Nitroarginine; Pituitary Adenylate Cyclase-Activating Polypeptide; Plasma; Psychodidae; Pyrilamine; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I; Salivary Glands; Vasodilation; Vasodilator Agents; Venules

The influence of an irreversible inhibitor of constitutive NO synthase (L-NOArg; 1.0 mg/kg ip), a relatively selective inhibitor of inducible NO synthase (L-NIL; 1.0 mg/kg ip) and a relatively specific inhibitor of neuronal NO synthase (7-NI; 0.1 mg/kg ip), on antihyperalgesic action of selective antagonists of B2 and B1 receptors: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8] bradykinin (HOE 140; 70 nmol/kg ip) or des Arg10 HOE 140 (70 nmol/kg ip) respectively, in model of diabetic (streptozotocin-induced) and toxic (vincristine-induced) neuropathy was investigated.. The changes in pain thresholds were determined using mechanical stimuli--the modification of the classic paw withdrawal test described by Randall-Selitto.. The results of this paper confirm that inhibition of bradykinin receptors and inducible NO synthase but not neuronal NO synthase activity reduces diabetic hyperalgesia. Pretreatment with L-NOArg and L-NIL but not 7-NI, significantly increases antihyperalgesic activity both HOE 140 and des Arg10 HOE 140. It was also shown that both products of inducible NO synthase and neuronal NO synthase activation as well as bradykinin are involved in hyperalgesia produced by vincristine. Moreover, L-NOArg and 7-NI but not L-NIL intensify antihyperalgesic activity of HOE 140 or des-Arg10HOE 140 in toxic neuropathy.. Results of these studies suggest that B1 and B2 receptors are engaged in transmission of nociceptive stimuli in both diabetic and toxic neuropathy. In streptozotocin-induced hyperalgesia, inducible NO synthase participates in pronociceptive activity of bradykinin, whereas in vincristine-induced hyperalgesia bradykinin seemed to activate neuronal NO synthase pathway. Therefore, concomitant administration of small doses of bradykinin receptor antagonists and NO synthase inhibitors can be effective in alleviation of neuropathic pain, even in hospital care.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Drug Evaluation, Preclinical; Enzyme Inhibitors; Hyperalgesia; Hypoglycemic Agents; Indazoles; Lysine; Male; Nitric Oxide Synthase; Nitroarginine; Pain Measurement; Rats; Rats, Wistar; Receptors, Bradykinin; Streptozocin; Tetrahydroisoquinolines; Vincristine

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

Taking into consideration that mechanisms involved in the vasodilatator actions of angiotensin II have not yet been completely elucidated, the present study was undertaken in order to examine the mechanisms underlying the angiotensin II-induced relaxation of rat renal artery (RRA). Angiotensin II produced concentration-dependent and endothelium-independent relaxation of isolated RRA. Angiotensin II-induced relaxation was partially reduced by inhibitors of nitric oxide synthase and guanylyl cyclase. The remaining dilatation was inhibited by a potassium channel blocker, charybdotoxin. Precontraction of RRA with high concentration of K(+) partially reduced angiotensin II-evoked relaxation, while indomethacin, glibenclamide, apamin and barium did not alter the angiotensin II concentration-response curve. Losartan had no effect on angiotensin II effect. Oppositely, HOE 140 and PD123319, separately or in combination, partially antagonized vasorelaxation induced by angiotensin II. Complete blockade of RRA response was obtained after simultaneous incubation of all three receptor antagonists HOE-140, PD123319, and losartan; L-NOARG plus HOE-140; or PD123319 plus charybdotoxin. These results indicate that angiotensin II produces endothelium-independent relaxation of RRA, which is most probably mediated by the interaction of the NO-cGMP pathway and K(+) channels. Moreover, we can assume that AT(1), AT(2), and B(2) receptors are involved in the vasorelaxant effect of angiotensin II.

Topics: Angiotensin II; Animals; Bradykinin; Imidazoles; In Vitro Techniques; Male; Nitroarginine; Pyridines; Rats; Rats, Wistar; Renal Artery; Vasodilation

It has been reported that endothelium-dependent relaxations are preserved in isolated coronary arteries of endothelial nitric oxide synthase-deficient (eNOS-/-) mice with a possible involvement of nNOS. However, it remains to be examined whether nNOS compensates coronary flow response in a beating heart of eNOS-/- mice and if so, whether and where nNOS is up-regulated. Coronary flow response to bradykinin was examined in Langendorff-perfused hearts from WT and eNOS-/- mice. Bradykinin-induced coronary flow was greater in eNOS-/- mice than in WT mice, and indomethacin had no inhibitory effect on it. Bradykinin receptor antagonist HOE-140 abolished the bradykinin response in both strains. Non-selective NOSs inhibitor L-NNA inhibited the bradykinin-induced coronary flow in both strains, whereas specific inhibitors of nNOS, SMTC, and 7-NI, significantly attenuated the coronary flow response only in eNOS-/- mice. A guanylate cyclase inhibitor ODQ also attenuated the bradykinin response in eNOS-/- mice. Immunohistochemistry revealed the presence of nNOS mainly in coronary vascular smooth muscle cells (VSMCs) in both strains and Western blot analysis demonstrated a marked increase in cardiac nNOS expression in eNOS-/- mice. These results indicate that nNOS compensates coronary flow response to bradykinin in eNOS-/- mice, for which up-regulation of nNOS in VSMCs may be involved.

Topics: Animals; Bradykinin; Citrulline; Coronary Circulation; Coronary Vessels; Enzyme Inhibitors; Female; Immunohistochemistry; In Vitro Techniques; Indomethacin; Male; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurons; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Nitroarginine; Oxadiazoles; Thiourea; Up-Regulation; Vasodilation

We examined effects of bradykinin on antidiuresis and norepinephrine overflow induced by renal nerve stimulation (RNS) in anesthetized dogs, with or without blockade of the B2 receptor by Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) or the endogenous nitric oxide generation by N(G)nitro-L-arginine (NOARG), a nitric oxide synthase inhibitor. RNS (0.5-2.0 Hz) produced significant decreases in urine flow, urinary and fractional excretions of sodium, and increases in norepinephrine secretion rate (NESR), without affecting systemic and renal hemodynamics. Intrarenal arterial infusion of bradykinin (5 ng/kg per minute) significantly suppressed the RNS-induced antidiuresis and increase in NESR. Hoe 140 (100 ng/kg per minute) did not affect the RNS-induced renal actions, but in the presence of Hoe 140, bradykinin-induced suppressive actions on reductions in urine formation and increases in NESR in response to RNS were abolished. RNS during intrarenal arterial infusion of NOARG (40 microg/kg per minute) led to potent reductions in urine formation and decreased renal blood flow and glomerular filtration rate. Simultaneously, NESR was markedly increased. During NOARG infusion, bradykinin-induced decreases in renal actions elicited by RNS were markedly attenuated. These findings suggest that bradykinin suppresses the RNS-induced norepinephrine overflow and renal actions via nitric oxide production mediated by activation of B2 receptor. Renal noradrenergic neurotransmission may be inhibited by bradykinin at the prejunctional level, when its local production in the kidney is enhanced.

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Antagonists; Animals; Bradykinin; Bradykinin Receptor Antagonists; Dogs; Electric Stimulation; Enzyme Inhibitors; Female; Hemodynamics; Kidney; Male; Natriuresis; Nitroarginine; Norepinephrine; Renal Circulation; Urine

This study was conducted to determine potentially differential effects between an angiotensin II type 1 (AT(1)) receptor antagonist and an ACE inhibitor on systemic, renal, and glomerular hemodynamics and pathological changes in spontaneously hypertensive rats (SHR) with N(omega)-nitro-L>-arginine methyl ester (L-NAME)-exacerbated nephrosclerosis. The hemodynamic, renal micropuncture, and pathological studies were performed in 9 groups of 17-week-old male SHR treated as follows: group 1, controls (n=16); group 2, candesartan (10 mg/kg per day for 3 weeks) (n=7); group 3, enalapril (30 mg/kg per day for 3 weeks) (n=8); group 4, candesartan (5 mg/kg per day) plus enalapril (15 mg/kg per day for 3 weeks) (n=9); group 5, L-NAME (50 mg/L in drinking water for 3 weeks) (n=17); group 6, L-NAME (50 mg/L) plus candesartan (10 mg/kg per day for 3 weeks) (n=7); group 7, L-NAME (50 mg/L) for 3 weeks followed by candesartan (10 mg/kg per day) for another 3 weeks (n=8); group 8, L-NAME (50 mg/L) plus enalapril (30 mg/kg per day for 3 weeks) (n=7); and group 9, L-NAME (50 mg/L) plus enalapril (30 mg/kg per day) and the bradykinin antagonist icatibant (500 microg/kg SC per day via osmotic minipump for 3 weeks) (n=7). Both candesartan and enalapril similarly reduced mean arterial pressure and total peripheral resistance index. These changes were associated with significant decreases in afferent and efferent glomerular arteriolar resistances as well as glomerular capillary pressure. Histopathologically, the glomerular and arterial injury scores were decreased significantly, and left ventricular and aortic masses also were diminished significantly in all treated groups. L-NAME-induced urinary protein excretion was prevented by both candesartan and enalapril. Thus, both AT(1) receptor and ACE inhibition prevented and reversed the pathophysiological alterations of L-NAME-exacerbated nephrosclerosis in SHR. Itatibant only blunted the antihypertensive effects of enalapril but did not attenuate the beneficial effects of ACE inhibition on the L-NAME-induced nephrosclerosis. Thus, the AT(1) receptor antagonism and ACE inhibition have similar renal preventive effects, which most likely were achieved through reduction in the effects of angiotensin II, and ACE inhibition of bradykinin degradation demonstrated little evidence of renoprotection.

Topics: Adrenergic beta-Antagonists; Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Body Weight; Bradykinin; Enzyme Inhibitors; Male; NG-Nitroarginine Methyl Ester; Nitroarginine; Organ Size; Protective Agents; Rats; Rats, Inbred SHR; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2

In the present study the role of brain AT(2) receptor in the cardiovascular response to stress was investigated in conscious rats. Footshock-stress increased mean arterial pressure (MAP) and heart rate (p < 0.0001). Intracerebroventricular (i.c.v.) administration of losartan (100 microg/5 microl), a specific angiotensin AT(1) receptor antagonist, not only attenuated the pressor response to footshocks, but also resulted in a consistent vasodepressor response (-10 mmHg, p < 0.02). Meanwhile, heart rate response was not altered. Given alone, PD 123319 (3 microg/5 microl, i.c.v.), a specific angiotensin AT(2) receptor antagonist, did not alter the hemodynamic response to footshocks. However, simultaneous block of brain AT(1) and AT(2) receptors by combined administration of losartan and PD 12319, eliminated the vasodepressor response unmasked after footshocks in rats i.c.v.-pretreated with losartan alone. In addition, we studied the role of brain kinins and nitric oxide (NO) in the vasodepressor response observed after footshocks in losartan i.c.v.-treated rats. Intracerebroventricular administration of icatibant (20 pmol/5 microl), a selective B(2) receptor antagonist, or N(G)-nitro-L-arginine methyl ester (100 microg/5 microl), a selective NO-synthase inhibitor, abolished the vasodepressor response to footshocks in losartan-treated rats. Our data suggest that the vasodepressor response to footshocks in the presence of AT(1) antagonist is triggered by activation of AT(2) receptor. Brain NO and kinins appear to contribute in this effect.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Brain; Electroshock; Enzyme Inhibitors; Extremities; Heart Rate; Imidazoles; Injections, Intraventricular; Losartan; Male; Nitric Oxide Synthase; Nitroarginine; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Receptors, Angiotensin

1. Systemic infusion of angiotensin II (AII) increased papillary blood perfusion (PBP) measured by laser-Doppler flowmetry in rats, aged about 5 weeks. 2. The mechanisms involved in this response were determined by infusion of AII in the presence of systemic doses of losartan (a type 1 AII receptor antagonist), HOE-140 (a bradykinin B2 receptor antagonist), and an inhibitor of NO production - Nomega-nitro-L-arginine (NOLA). 3. Mean arterial blood pressure (MAP) and PBP increased in a dose-dependent manner in response to intravenous infusions of AII. Infusion of losartan abolished these responses to AII but HOE-140 was without effect. Infusion of NOLA abolished the increase in PBP but did not affect the pressor response to AII. Systemic infusion of sodium nitroprusside restored the response to AII in experiments with NOLA infusion. 4. The results indicate that the increase in PBP caused by AII is mediated via angiotensin AT1 receptors and does not involve bradykinin B2 receptors. The AII-induced increase in PBP is dependent upon the presence of NO, thus providing a mechanism for maintenance of papillary perfusion in the face of generalized renal vasoconstriction due to AII.

Topics: Angiotensin II; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Kidney Medulla; Laser-Doppler Flowmetry; Losartan; Nitroarginine; Nitroprusside; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Regional Blood Flow; Renal Circulation; Ultrasonography

1. Effects of bradykinin (BK) on renal haemodynamics and urine formation were examined in anaesthetized dogs. 2. Renal arterial infusion of BK at doses of 5 or 50 ng/kg per min produced dose-dependent increases in renal blood flow (RBF), without affecting systemic arterial pressure or glomerular filtration rate. There were also significant and dose-dependent increases in urine flow (UF), urinary excretion of sodium (UNaV) and fractional excretion of sodium (FENa) and decreases in urine osmolality during BK infusion. 3. Renal haemodynamic and excretory responses to the BK infusion were completely abolished by the simultaneous administration of Hoe 140 (icatibant, 100 ng/kg per min intrarenally), a selective BK B2-receptor antagonist. 4. In the presence of NG-nitro-L-arginine (NOARG; 40 micrograms/kg per min intrarenally), a nitric oxide (NO) synthase inhibitor, BK-induced renal vasodilative and natriuretic effects were markedly attenuated, although responses of UF and urine osmolality to BK remained unchanged. The water diuretic effect of BK was abolished in dogs given both NOARG and ibuprofen (12.5 mg/kg bolus injection plus 12.5 mg/kg per h of sustained infusion intravenously), a cyclooxygenase inhibitor. 5. These results clearly indicate that renal haemodynamic and excretory responses to BK were mediated exclusively by the B2-receptor. Renal vasodilative and natriuretic responses are mainly linked to NO generation, while both NO and prostaglandin biosynthesis are involved in the BK-induced water diuresis.

Topics: Adrenergic beta-Antagonists; Anesthesia; Animals; Bradykinin; Dogs; Drug Interactions; Enzyme Inhibitors; Female; Hemodynamics; Ibuprofen; Kidney; Male; Nitroarginine; Urination

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

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

The effects of intravenous (iv) bolus administrations of bradykinin (0.1-1 microgram.kg-1) on large and small coronary arteries were investigated in seven chronically instrumented conscious dogs. Bradykinin dose-dependently increased heart rate, left ventricular dP/dt max, coronary blood flow and coronary artery diameter and decreased aortic pressure. Subchronic inhibition of the nitric oxide synthase (NOS) pathway (N omega-nitro-L-arginine, 20 mg.kg-1.d-1 during 7 days) attenuated the systemic and coronary effects of bradykinin. HOE 140, a specific bradykinin B2 receptor antagonist, administered at a dose (30 micrograms/kg) sufficient to completely inhibit the systemic and coronary effects of exogenous bradykinin (1 microgram/kg, iv bolus), had no effect on baseline systemic and coronary hemodynamic parameters. HOE 140 had also no effect on the flow-dependent increase in large coronary artery diameter and on the relationship between flow debt and flow repayment volumes observed during myocardial reactive hyperemia. This lack of effect of HOE 140 persisted when experiments were repeated after NOS inhibition. We conclude that (a) exogenous bradykinin dilates large and small coronary arteries through a partially NO-mediated mechanism, and (b) endogenous bradykinin plays no role in the control of arterial pressure, heart rate, LV dP/dt max, basal and flow-stimulated coronary hemodynamics, both in control conditions and after subchronic inhibition of NOS in the conscious dog.

Topics: Acetylcholine; Animals; Blood Volume; Bradykinin; Bradykinin Receptor Antagonists; Coronary Circulation; Dogs; Heart Rate; Hyperemia; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Nitroglycerin; Vasodilation; Vasodilator Agents

To examine whether the bradykinin-nitric oxide (NO) pathway directly participates in the antihypertrophic property of angiotensin-converting enzyme (ACE) inhibitors in congestive heart failure, the effects of bradykinin were studied in rat cultured heart cells. Bradykinin (0.1, 1 nM) prevented the phenylephrine-induced increase in protein/DNA content, an index of hypertrophy of heart cells, and amplified the nitrite/nitrate content in the medium. Perindoprilat (1 microM), an ACE inhibitor, also restrained the progression of cardiac hypertrophy and augmented NO release. These effects of perindoprilat were abolished by HOE-140 (kinin B2 antagonist), N omega-nitro-L-arginine (NO synthase inhibitor), and methylene blue (guanylate cyclase inhibitor). Furthermore, there was a significant correlation between protein/DNA content and nitrite/nitrate content. These results indicate that bradykinin inhibits the progression of cardiac hypertrophy due to the increase in NO release and that perindoprilat produces beneficial effects on cardiac hypertrophy by stimulating the bradykinin-NO pathway.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Animals, Newborn; Bradykinin; Bradykinin Receptor Antagonists; Cardiomegaly; Cells, Cultured; Heart; Indoles; Myocardium; Nitrates; Nitric Oxide; Nitrites; Nitroarginine; Phenylephrine; Rats; Rats, Sprague-Dawley; Receptors, Bradykinin; Regression Analysis

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

1. The objective of this study in the hamster cheek pouch was to investigate the role of nitric oxide in bradykinin-induced microvascular leakage. The cheek pouch microcirculatory bed of the anaesthetized hamster was directly observed under microscope and vascular leakage was evidenced by dextranfluorescein isothiocyanate (FITC-dextran) extravasation. 2. Bradykinin superfusion (but not [des-Arg9]-bradykinin up to 3 x 10(-6) M) induced an increase in microvascular permeability (log EC50: -6.5 +/- 0.4) which was exclusively located on the post-capillary venule. Plasma extravasation was blocked by intravenous pretreatment with Hoe 140, a bradykinin B2 receptor antagonist (estimated log ID50: -9.5 +/- 0.2). 3. The effects of bradykinin (3 x 10(-7) M) superfusion were partially but significantly inhibited by indomethacin (10(-5) M, P < 0.05) and abolished by pretreatment with L-nitro-arginine (L-NOARG; 10(-5) M). 4. Acetylcholine (10(-6) M, which releases endothelial nitric oxide (NO), and sodium nitroprusside (10(-6) M, a nitrovasodilator) superfusion did not induce any changes in permeability, per se. Cromakalim (10(-5) M, a potassium channel opener) superfusion induced a moderate but significant plasma extravasation. 5. The effects of bradykinin, blocked by L-NOARG pretreatment, were restored by the co-perfusion of either sodium nitroprusside or cromakalim. Conversely vasoconstriction, produced by a stable analogue of thromboxane A2 (U46619, 3 x 10(-7) M), inhibited the increase in permeability produced by bradykinin. 6. The measurement of arteriolar diameter showed that bradykinin induced a vasodilatation which was blocked by L-NOARG. L-NOARG in itself was a powerful vasoconstrictor. Sodium nitroprusside and cromakalim, in the presence of L-NOARG, were able to restore the inhibited vasodilator response to bradykinin. 7. These results suggest: (1) bradykinin-induced microvascular leakage is mediated by bradykinin B2 receptor activation; (2) the increase in permeability is due to two different independent phenomena, i.e. post-capillary venular endothelial gap formation and arteriolar vasodilatation which increases the post-capillary venular transmural pressure: (3) NO is only involved in the arteriolar dilatation component of the bradykinin-induced increase in microvascular permeability.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Capillaries; Capillary Permeability; Cheek; Cricetinae; Cyclooxygenase Inhibitors; Endothelium, Vascular; Enzyme Inhibitors; Male; Mesocricetus; Mouth Mucosa; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Receptors, Bradykinin; Vasoconstriction; Vasodilator Agents

Ring segments of rat middle cerebral artery (MCA) were prepared for measurement of isometric force and precontracted with 10(-4) M uridine triphosphate (UTP). Concentration-effect curves (CEC) were constructed for bradykinin (BK, 10(-8)(-10)(-1) M) in segments with functionally intact (E+) or denuded (E-) endothelium. E- segments did not dilate to BK. The BK receptor was characterized by application of specific B1 or B2 antagonists [des-Arg4-Leu8] BK (10(-5) M) and [D-Arg4-Hyp3-Thi5-D-Tic7-Oic8] BK (HOE140, 3 x 10(-7) M), respectively, or B2 agonist [des-Arg9] BK (10(-8)-10(-4) M). Involvement of nitric oxide (NO) was tested with NG-nitro-L-arginine (LNNA, 10(-4) M). BK induced concentration-dependent relaxation with a maximal effect (Emax) of 40.86 +/- 1.50% at 10(-4) M and a pD2 (-log10 EC50) of 6.818 +/- 0.044. This relaxation could be prevented with HOE140 or LNNA, but was not influenced by [des-Arg(9)-Leu] BK. [des-Arg9] BK did not induce any effect. These results demonstrate that BK induced relaxation via endothelial B2 receptors and release of NO in isolated rat MCA.

Topics: Animals; Bradykinin; Bradykinin Receptor Antagonists; Cerebral Arteries; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; In Vitro Techniques; Male; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; Rats; Rats, Inbred WKY; Receptor, Bradykinin B2; Receptors, Bradykinin; Vasodilation

This study was undertaken to investigate the role of nitric oxide (NO), cyclooxygenase products and bradykinin (Bk) receptors in the Bk evoked responses of canine renal arteries and perfused kidneys. Rings of isolated canine renal arteries were mounted in organ chambers for measurement of isometric force. The isolated canine kidneys were perfused with Krebs-solution (constant flow) and the perfusion pressure was continuously recorded. The influence of the cyclooxygenase inhibitor indomethacin and the nitric oxide (NO) synthase inhibitor N omega-nitro-L-arginin (L-NOARG) on the vasocontractile responses to phenylephrine (PE) were examined in both preparations. Furthermore, the effects of Bk on the tone of canine isolated renal arteries and on the vasopressor responses of isolated buffer-perfused kidneys of dogs were tested in the absence and presence of enzyme inhibitors and the B2 kinin receptor antagonist HOE-140. It was found that indomethacin enhanced the contractile responses of large renal arteries to PE by 77 +/- 10%. In intact artery rings L-NOARG (0.1 mM) caused an additional potentiation of the PE-induced contractions in the presence of indomethacin (from 11.5 +/- 1.2 mN to 21.6 +/- 1.7 mN). However, L-NOARG failed to affect contractile responses to PE in endothelium-denuded rings. Bk produced a concentration-dependent relaxation of the precontracted endothelium-intact renal arteries. The IC50 value for Bk was 11.2 +/- 3.7 nM. The relaxant activity of the peptide in renal artery rings was not affected by indomethacin (3 microM). However, in the presence of L-NOARG a significantly higher concentration (IC50 = 860 +/- 300 nM) of Bk was required to relax renal arteries. The Bk receptor antagonist HOE-140 (10 nM for 40 min) attenuated the relaxant effect of Bk in renal artery rings (from an IC50 of 14.2 +/- 2.5 nM to 216 +/- 37 nM). Indomethacin (3 microM for 20 min) did not significantly alter the arteriolar vasoconstriction (from 45 +/- 4 mm Hg to 48 +/- 5 mm Hg, n = 5) evoked by PE. By contrast, L-NOARG (0.1 mM) potentiated (from 56 +/- 7 mm Hg to 94 +/- 11 mm Hg) the PE-induced vasopressor responses in perfused kidneys. Bk reduced the size of the pressor responses at relatively low concentrations (2-60 nM) but the dose-response curve was flat and the maximum inhibitory effect hardly exceeded 50 percent. Indomethacin (3 microM) did not modify the inhibitory effect of Bk in perfused kidney. In the presence of L-NOARG, Bk depressed the PE induced va

Topics: Adrenergic beta-Antagonists; Animals; Bradykinin; Buffers; Cyclooxygenase Inhibitors; Dogs; Enzyme Inhibitors; Female; In Vitro Techniques; Indomethacin; Male; Muscle Tonus; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitroarginine; Perfusion; Phenylephrine; Renal Artery; Renal Circulation; Vasoconstrictor Agents; Vasodilator Agents

Collagenase (100 micrograms) induced a large plasma extravasation, during the first 15 min after its injection in rat paw, associated with the rapid development of oedema which subsided after 6 h. The extent of the oedema was similar in normal and kininogen-deficient rats. The swelling induced in normal rats was reduced by HOE 140 (D-Arg[Hyp3,Thi5,D-Tic7,Oic8]bradykinin), a bradykinin B2 receptor antagonist, and by three serine protease inhibitors, soybean trypsin inhibitor (SBTI), Leucaena leucocephala trypsin inhibitor 1 (LLTI-1) and Leucaena leucocephala trypsin inhibitor 2 (LLTI-2). These agents had no effect on the oedema induced in kininogen-deficient rats. The swelling was also reduced by methysergide, indomethacin, ketoprofen and methylprednisolone. It was increased by heparin, but it was not modified by mepyramine, WEB 2086 (3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo- [4,3-a][1,4]-diazepine-2-yl]-1-(4-morpholinyl)-1-propanone) and NG-nitro-L-arginine. In vitro, collagenase did not release kinins from rat plasma or from purified T-kininogen. LLTI-1 and LLTI-2 did not inhibit collagenase activity for one of its specific substrates. Kinins are thus involved in the development of collagenase oedema in normal rats. Their generation would be indirect following changes in matrix proteins in extravascular spaces. Nevertheless, kinins are not the decisive mediators of the swelling. Serotonin, possibly released from platelets, and prostanoids participate in the inflammatory process.

Topics: Animals; Arginine; Azepines; Bradykinin; Collagenases; Edema; Female; Heparin; Hindlimb; Indomethacin; Kallikrein-Kinin System; Ketoprofen; Kininogens; Male; Methysergide; Nitroarginine; Platelet Aggregation Inhibitors; Pyrilamine; Rats; Rats, Wistar; Serine Proteinase Inhibitors; Triazoles

1. Rings of bovine left anterior descending coronary artery (LAD) were contracted with the thromboxane A2-mimetic, U46619 (1-30 nM), to approximately 40% of their maximum contraction to 125 mM KCl Krebs solution (KPSSmax) for comparison of responses to the B1 and B2 kinin receptor agonists, des-Arg9-bradykinin (des-Arg9-BK) and bradykinin (BK), respectively. Relaxation responses were normalized as percentages of the initial U46619-induced contraction level, while contractile responses were expressed as percentages of KPSSmax. 2. After 6 h of in vitro incubation in Krebs solution at 37 degrees C, des-Arg9-BK (pEC50, 8.00 +/- 0.08; maximum response (Rmax), 93.9 +/- 1.9%) and BK (pEC50, 9.75 +/- 0.07; Rmax, 100.1 +/- 0.7%) caused endothelium-dependent relaxations in precontracted rings of bovine LAD which were competitively and selectively antagonized by the B1 receptor antagonist, des-Arg9-[Leu8]-BK (pA2, 6.27 +/- 0.11) and the B2 receptor antagonist Hoc-140 (pA2, 9.63 +/- 0.14), respectively. 3. At 3 h of in vitro incubation, the sensitivity (pEC50, 7.45 +/- 0.10) and Rmax (84.6 +/- 3.3%) to des-Arg9-BK were significantly less than those obtained in the same tissues at 6 h (pEC50, 7.94 +/- 0.06; Rmax, 91.4 +/- 2.5%), whereas endothelium-dependent relaxations to BK and ACh were unaffected by incubation time. 4. Relaxation responses to des-ARg9-BK, but not BK, at both 3 h and 6 h were significantly attenuated by the protein synthesis inhibitors, cycloheximide (30 and 100 microM) and actinomycin D (2 microM). 5. At 6 h, the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (L-NOARG, 100 microM), caused a significant 2 fold decrease in pEC50 (9.58 +/- 0.03) but had no effect on Rmax for BK. For des-Arg9-BK, L-NOARG (100 microM) caused a marked and significant decrease in both the pEC50 and Rmax and revealed contractions to low concentrations of des-Arg9-BK. In both cases, L-NOARG inhibition was reversed in the presence of L-arginine (10 mM). 6. At 6 h removal of the endothelium abolished relaxation responses to des-Arg9-BK and BK, and for des-Arg9-BK, but not BK, unmasked concentration-dependent contractions (pEC50, 7.57 +/- 0.09; Rmax, 83.4 +/- 9.1%). The sensitivity of contractions to des-Arg9-BK increased slightly from 3 h (pEC50, 7.37 +/- 0.08) to 6 h (pEC50, 7.62 +/- 0.12) of in vitro incubation; however, there was a small but significant depression in the maximum response over this time (Rmax, 126.8 +/- 8.5% and 103.3 +/- 8.6% for 3 h and 6 h of

Topics: Acetylcholine; Animals; Anti-Inflammatory Agents, Non-Steroidal; Arginine; Bradykinin; Bradykinin Receptor Antagonists; Cattle; Coronary Vessels; Endothelium, Vascular; Enzyme Inhibitors; In Vitro Techniques; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitroarginine; Protein Synthesis Inhibitors

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

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

1. During heat exposure, rats secrete large amounts of saliva. Salivation started when body temperature exceeded 39 degrees C and was reduced by kininogen deficiency or by HOE 140, a bradykinin antagonist. This secretory response was associated with a partial depletion of glandular kallikrein from the submaxillary glands. The depletion was abolished by simultaneous treatment of the animals with an alpha- and a beta-adrenergic antagonist. During heat exposure, plasma levels of kininogens were reduced. 2. Pilocarpine and substance P induced a similar flow of saliva in normal and kininogen-deficient rats and released low amounts of kallikrein from salivary glands. Phenylephrine and isoproterenol induced a larger flow of saliva in normal rats than in kininogen-deficient rats. Both agents released large amounts of kallikrein in saliva but isoproterenol was only active at large doses. 3. During heat exposure, the blood content of submaxillary glands in normal as well as in kininogen-deficient rats increased as a function of the ambient temperature. This increase was suppressed by atropine and NG-nitro-L-arginine, a NO-synthase inhibitor, but was not modified by HOE 140. Simultaneously, a swelling of the glands and of the surrounding soft tissues occurred in normal but not in kininogen-deficient rats. Kallikrein was present in the edema fluid. 4. The kallikrein-kinin system would thus participate in heat-induced salivary secretion and kinins may be a factor responsible for electrolyte and water exchanges in the glands.

Topics: Adrenergic alpha-Antagonists; Adrenergic beta-Antagonists; Animals; Arginine; Atropine; Bradykinin; Hot Temperature; Kallikrein-Kinin System; Kallikreins; Kininogens; Male; Nitroarginine; Pilocarpine; Rats; Rats, Inbred BN; Rats, Wistar; Saliva; Stress, Physiological; Submandibular Gland; Substance P

To delineate the cardioprotective actions of bradykinin (BK) and the contribution of endogenous kinins to the cardiac effects of the ACE inhibitor ramipril, we used the specific B2 kinin receptor antagonist icatibant (HOE 140) during myocardial ischemia and left ventricular hypertrophy (LVH). In isolated working rat hearts, perfusion with ramiprilat (10 nM to 10 microM) reduced the incidence and duration of ventricular fibrillation, and improved cardiodynamics and myocardial metabolism. BK perfusion (0.1 nM to 10 nM) induced comparable cardioprotective effects. In addition, perfusion with ramiprilat (0.1 microM) markedly increased kinin outflow measured by RIA. The beneficial effects of ramiprilat and BK were abolished by the addition of the specific NO synthase inhibitor NG-nitro-L-arginine (L-NNA 1 microM) or icatibant (1 nM). Similar results were obtained in dogs, rabbits and rats with myocardial infarction induced by ligation of the left descending coronary artery. The influence of the icatibant on the antihypertrophic effect of ramipril and BK in the LVH was investigated in rats made hypertensive by aortic banding. Ramipril at the antihypertensive dose of 1 mg kg-1 day-1 for 6 weeks prevented the increase in blood pressure and the development of LVH. The lower non-antihypertensive dose of ramipril (10 micrograms kg-1 day-1 for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity but also prevented LVH after aortic banding. The antihypertrophic effect of the higher and the lower dose of ramipril as well as the antihypertensive action of the higher dose of ramipril were abolished by coadministration of the icatibant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arginine; Bradykinin; Dogs; Endothelium, Vascular; Humans; Hypertrophy, Left Ventricular; Myocardial Ischemia; Nitroarginine; Ramipril; Rats

The angiotensin I (AI) metabolite, A(1-7), elicited a concentration-dependent dilator response (ED50 > or = 2 microM) in porcine coronary artery rings which was markedly attenuated by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine, and abolished after removal of the endothelium. This effect of the heptapeptide was not mimicked by AII, AIII or A(3-8) at comparable concentrations. The A(1-7)-induced relaxation was not affected by AT1 or AT2 receptor blockade or cyclo-oxygenase inhibition, but was attenuated by the B2 receptor antagonist, Hoe 140, and augmented by the angiotensin-converting enzyme (ACE) inhibitor, quinaprilat. These findings suggest that the relaxation to A(1-7) was mediated by the release of NO from the coronary endothelium through activation of an, as yet unidentified, AT receptor, the occupation of which also seems to stimulate the release of vasoactive kinins. Since A(1-7) accumulates during ACE inhibition, this mechanism may contribute to the coronary dilator effect of ACE inhibitors in vivo.

Topics: Amino Acid Sequence; Angiotensin I; Angiotensin II; Animals; Arginine; Bradykinin; Coronary Vessels; Endothelium, Vascular; In Vitro Techniques; Isoquinolines; Molecular Sequence Data; Muscle Relaxation; Nitric Oxide; Nitroarginine; Peptide Fragments; Receptors, Angiotensin; Swine; Tetrahydroisoquinolines; Vasodilator Agents

Topics: Amino Acid Oxidoreductases; Animals; Arginine; Blood Pressure; Bradykinin; Hypertension; Hypertrophy, Left Ventricular; Male; Nitric Oxide Synthase; Nitroarginine; Organ Size; Rats; Rats, Sprague-Dawley

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

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

The interaction of angiotensin-converting enzyme (ACE) inhibitors and bradykinin was investigated in isolated bovine and human coronary arteries. Rings with and without endothelium were mounted in organ chambers for measurement of isometric force. The effects of the ACE inhibitors lisinopril, enalaprilat, fosinoprilat, ramiprilat, and captopril were determined during submaximal stimulation with bradykinin or other vasodilators. Lisinopril and captopril alone did not affect vascular tone; however, in rings with endothelium partially relaxed with bradykinin (> or = 10(-10) M), all ACE inhibitors caused further relaxations. Lisinopril did not affect bradykinin concentrations in the incubation medium. Mechanical removal of the endothelium or incubation with nitro-L-arginine or the bradykinin2-receptor antagonist Hoe 140 prevented the relaxations to bradykinin and lisinopril. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium-dependent relaxations to lisinopril were also observed in human coronary arteries treated with bradykinin (> or = 10(-7) M). Thus, ACE inhibitors potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries. This local mechanism occurs regardless of elevated bradykinin concentrations in the blood and reduced angiotensin II generation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Bradykinin; Captopril; Cattle; Coronary Vessels; Dipeptides; Enalaprilat; Endothelium, Vascular; Fosinopril; Humans; In Vitro Techniques; Lisinopril; Muscle Relaxation; Muscle, Smooth, Vascular; Nitroarginine; Ramipril; Receptors, Bradykinin; Receptors, Neurotransmitter; Vasodilation; Vasodilator Agents

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

Bradykinin perfusion (BK 1 x 10(-12) to 1 x 10(-8) mol/l) of isolated working rat hearts with postischemic reperfusion arrhythmias induced a reduction of the incidence as well as duration of ventricular fibrillation, improvement of cardiodynamics via increased left ventricular pressure, contractility, and coronary flow without changes in heart rate. These beneficial effects were accompanied by reduced activities of the cytosolic enzymes lactate dehydrogenase and creatine kinase as well as lactate output. In the myocardial tissue lactate content was reduced and the energy rich phosphates increased compared to saline perfused control hearts. Glycogen stores were also preserved. These beneficial effects of BK were concentration-dependently abolished by perfusion of the B2 kinin receptor antagonist HOE 140 and the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA). These results suggest that improved cardiac function during and after myocardial ischemia as well as increased energy rich phophates and glycogen stores are mediated by BK and the subsequent release of NO, shifting myocardial metabolism during ischemia and reperfusion to the glucose pathway which leads to changes indicative for cardioprotection.

Topics: Adenosine Triphosphate; Animals; Arginine; Bradykinin; Female; Glycogen; Heart; Heart Rate; In Vitro Techniques; Lactates; Male; Myocardium; Nitroarginine; Perfusion; Phosphocreatine; Rats; Rats, Wistar