Novel compounds possessing potent cAMP and cGMP phosphodiesterase inhibitory activity. Synthesis and cardiovascular effects of a series of imidazo[1,2-a]quinoxalinones and imidazo[1,5-a]quinoxalinones and their aza analogues.

A series of novel imidazoquinoxalinones and their aza analogues were prepared by the cyclization of o-amino(1H-imidazol-1-yl)aryls and heteroaryls with carbonyldiimidazole. The compounds were screened for inhibition of Type I and Type IV phosphodiesterases (PDE's) and evaluated for their vasorelaxant and positive inotropic activities in vitro. In general, compounds having potent PDE inhibitory activity also possessed good inotropic and vasodilator activity, although linear correlations between these activities could not be established.

Cardiotonic agents. 6. Histamine analogues as potential cardiovascular selective H2 agonists.

Twenty-six alkyl and aralkyl histamine analogues were prepared as potential cardiotonic agents. Compounds were designed to allow interaction with a putative secondary aryl binding site at the H2 receptor, the presence of which was inferred from the structure of cyprohepatadine, which is known to have H2-antagonist properties. The compounds were examined for inotropic activity in ferret papillary muscle. Potent inotropic activity was generally found in N-alkyl- and N,N-dialkylimidazole-4-ethanamines, whereas N-(amidoalkyl)imidazole-4-ethanamines and N-alkylimidazole-4-propanamines were at best weakly active. Five compounds were examined in screens designed to assess hemodynamic effects and gastric acid secretion in vivo. Two of these compounds, alpha-(3-phenyl-2-transpropenyl)-1H-imidazole-4-ethanamine and N-heptyl-1H-imidazole-4-ethanamine, showed positive inotropic activity with minimal effects on heart rate and mean arterial pressure in vivo; however, both compounds were found to stimulate gastric acid secretion. These results demonstrate that selectivity between various H2-receptor-mediated activities can be obtained with substituted histamine analogues.

Endothelium-derived and intraneuronal nitric oxide-dependent inhibition of norepinephrine efflux from sympathetic nerves by bradykinin.

Evidence is presented that bradykinin inhibits norepinephrine efflux from sympathetic nerves innervating canine mesenteric and pulmonary arteries, in part, by releasing endothelium-derived relaxing factor (EDRF) from the vascular endothelium. Moreover, in the absence of vascular endothelium, bradykinin also inhibits norepinephrine efflux from the sympathetic nerve terminals innervating these blood vessels. This inhibition is attenuated by canavanine and LNMMA, which inhibit the conversion of arginine to nitric oxide, and is enhanced after overnight incubation of blood vessels with arginine. In endothelium-rubbed blood vessels the inhibitory effect of bradykinin on norepinephrine efflux is enhanced by increasing extracellular calcium ion ([Ca2+]o) and attenuated by nitrendipine. We propose that bradykinin inhibits norepinephrine efflux by stimulating intraneuronal nitric oxide from arginine.

Release of norepinephrine from adrenergic nerve endings of blood vessels is modulated by endothelium-derived relaxing factor.

The release of norepinephrine from adrenergic nerve endings is inhibited by substances which raise cyclic 3',5'-guanosine monophosphate (cGMP) in neural tissue. Endothelium-derived relaxing factor (EDRF) elevates cGMP in vascular smooth muscle. Thus, EDRF may also modulate the release of norepinephrine (NE) from adrenergic nerves. We tested this postulate in isolated canine pulmonary arteries and veins using the technique of superfusion and measurement of the efflux of radiolabeled NE during transmural nerve stimulation at 1, 2, 4, 8, 16 and 32 Hz for 10 min. In segments of artery and vein with intact endothelium the contractile responses to low frequency nerve stimulation were decreased when compared to endothelium rubbed blood vessels. Electrical stimulation of arteries and veins with intact endothelium for 10 min released less 2-[14C]-NE than rubbed blood vessels, especially at the lower frequencies of 1, 2 and 4 Hz, with lesser effects at frequencies of 16 and 32 Hz. Using the technique of bioassay, EDRF from porcine thoracic aorta inhibited the efflux of 2-[14C]-NE from the pulmonary artery and vein. The findings support the conclusion that the endothelium can inhibit release of NE from sympathetic nerve innervating canine pulmonary artery and vein. The endothelium, in part through EDRF, can act as an endogenous inhibitor or sympathetic neurotransmitter release.

Coronary vasodilator responses to bradykinin in euglycemic and diabetic rats.

Diabetes mellitus is associated with endothelial dysfunction that is believed to result in impaired release of vasoconstrictor and vasodilator substances from the endothelium and thereby diminished reactivity of many vascular beds. This study was designed to characterize bradykinin (BK)-induced coronary vasodilation in normal and diabetic rats. Bradykinin-stimulated vasodilation of the rat coronary vasculature is mediated by a cytochrome P450-1A (CYP-1A)- inhibitable metabolite that activates KCa, but not KATP, channels on the coronary vascular smooth muscle. Although BK stimulates the release of nitric oxide from the vascular endothelium, the released nitric oxide and its ability to stimulate guanylate cyclase only modulates the duration of, rather than the magnitude of, BK-induced coronary vasodilation. Twelve weeks of streptozotocin-induced diabetes did not affect the coronary vascular responses to BK or the components that mediate BK-induced vasodilation (ie, K-channel activation, nitric oxide-guanylate cyclase). The data support the conclusions that the coronary vasodilator response of the rat to BK is CYP-1A and KCa-channel mediated, that coreleased nitric oxide only modulates the duration of BK-induced vasodilation, and that these mechanisms are unaffected by moderate diabetes.

Cyclic GMP modulates release of norepinephrine from adrenergic nerves innervating canine arteries.

Evidence is presented that compounds which stimulate the soluble form of the enzyme guanylate cyclase or which inhibit the enzyme cGMP phosphodiesterase (PDE), responsible for the degradation of cGMP (including endothelium-derived relaxing factor) are inhibitors of sympathetic neurotransmission to vascular smooth muscle and inhibit the efflux of norepinephrine from sympathetic nerves. Moreover, prostacyclin, papaverine, iloprost, and forskolin, compounds which stimulate the enzyme adenylate cyclase, and rolipram (neural specific) and milrinone, enoximone, and piroximone (muscle specific) inhibitors of Type III cAMP PDE and degradation of cAMP, do not inhibit nerve stimulation to most blood vessels. The data support the concept that cGMP may act as a negative feedback modulator of physiologic frequencies of sympathetic nerve activity to blood vessels. cAMP does not appear to modulate adrenergic neurotransmission to vascular smooth muscle at physiologic frequencies of neural stimulation.

Inhibition of sympathetic neurotransmitter release by modulators of cyclic GMP in canine vascular smooth muscle.

The contractile response to neurally released norepinephrine (NE) from sympathetic nerve endings innervating vascular smooth muscle are inhibited by substances which raise either cyclic AMP and cyclic GMP concentrations in smooth muscle. However, cyclic AMP is believed to facilitate NE release from sympathetic nerves whereas the role of cyclic GMP in this process is undefined. We examined the effects of presumed modulation of the intraneuronal concentration of cyclic AMP and cyclic GMP on sympathetic neurotransmission to isolated canine mesenteric artery by measurement of the efflux of [2-14C]NE during transmural nerve stimulation (calcium dependent release of NE) and administration of tyramine (calcium independent release of NE) and measurement of the contractions to exogenous NE and tyramine. Stimulation of adenylate cyclase with forskolin, prostacyclin and iloprost, a stable prostacyclin analog, and inhibition of Type III cyclic AMP phosphodiesterase with neural specific rolipram, 'non-specific pelrinone and milrinone and isobutylmethylxanthine did not enhance the efflux of [2-14C]NE from sympathetic nerves innervating the blood vessels. Isoproterenol enhanced the efflux of [2-14C]NE. The effect was inhibited by propranolol but not affected by milrinone, amrinone or rolipram. Activators of guanylate cyclase (SIN-1a an active metabolic of molsidomine, nitroglycerin and sodium nitroprusside) and inhibitors of Type II cyclic GMP phosphodiesterase (M&B-22948 and verofyllin) inhibited the efflux of NE released by transmural nerve stimulation but not by tyramine. These data support the conclusion that cyclic GMP may be an inhibitory modulator of calcium and depolarization dependent NE release from sympathetic nerves, whereas neuronal cyclic AMP may not be a primary modulator of neurotransmission to vascular smooth muscle.

The effect of thromboxane on contraction of canine mesenteric and lingual arteries.

Thromboxane A2 (TXA2), a potent vasoconstrictor agent, is released from platelets and smooth muscle during inflammation and trauma. TXA2 may cause lingual artery (LA) contraction, leading to lingual paresthesia. The effects of U-46619, a TxA2 mimetic, on isolated rings of canine LA and mesenteric artery (MA) were examined. U-46619 (1 nmol/L to 1 mumol/L) caused a triphasic contraction of LA and MA; a rapid, phasic contraction; a slow, sustained contraction; and, upon washout of U-46619, a maintained contraction. The MA relaxed slowly, but the LA remained contracted for at least three h after washout. Decreasing extracellular calcium ion (Ca2+o) to less than 0.1 mumol/L with 2 mmol/L EGTA relaxed MA, but not LA. EGTA (4 mmol/L) partially relaxed the maintained contraction of LA. Inhibition of protein kinase C with amphotericin B or staurosporine inhibited the phasic and sustained contractions of LA, but did not affect the maintained contraction in the presence or absence of EGTA. Thus, CA2+o was required for the initial contraction of the LA by U-46619, but did not appear to be required for the maintained contraction following washout of U-46619. The data support the conclusion that following a brief exposure to U-46619, maintained contraction of LA persists by a unique mechanism that may be independent of Ca2+ and protein kinase C. Sustained LA contraction after exposure to endogenous TXA2 during inflammation and trauma may contribute to impaired lingual blood flow and orofacial tissue injury.

Simultaneous pressure and 19F NMR pH measurements of smooth muscle cells of intact hog carotid arteries at rest and during contractions with norepinephrine.

Using 19F NMR we have measured the intracellular pH of the vascular smooth muscle cells of hog carotid arteries at rest and during contractions induced with norepinephrine. Experiments were performed on single, intact arteries closed at both ends, superfused from the lumen and loaded with the 19F NMR pH indicator alpha-difluoromethylalanine. At rest, luminal pressure was maintained at 100 +/- 2 mm Hg and intracellular pH was 7.12 +/- 0.04. Contractions elicited with 10(-5) M norepinephrine were associated with a pressure increase of 18 +/- 6 mm Hg and a decrease in pH of 0.04 +/- 0.02 units.

Nitro containing L-arginine analogs interfere with assays for nitrate and nitrite.

We evaluated the effect of in vivo and in vitro administration of nitro-containing and nitro-deficient L-arginine-derived nitric oxide (NO) synthase inhibitors on the measurement of NO in plasma, urine and HEPES buffered physiologic salt solution (PSS) by ozone chemiluminescence and by the modified Griess reaction. In vivo administration of 1, 5, 25, 40 or 50 mg/kg of NG-nitro-L-or D-arginine methyl ester (LNAME, DNAME), NG-nitro-L-arginine (LNA) or aminoguanidine (AG) to rats and mice increased NO in urine and plasma as determined by chemiluminescence using 2.3% vanadium chloride in 2N HCI at 100 degrees C as the redox reagent. In vivo administration of 1 and 10 mg/kg/day of NG-imino-ethyl-L-ornithine (LNIO) or 3 amino-1,2,4 triazine (AT) reduced plasma and urine NO. Addition of LNAME, DNAME and LNA (100 nM to 1 mM) to the redox solution produced a concentration response curve for NO in the chemiluminescence assay similar to that produced by standard solutions of sodium nitrite and nitrate. LNMMA produced a small NO signal but only at concentrations equal to or exceeding 0.1 mM. LNIO, AT and AG did not give any NO signal even at concentrations exceeding 1 mM. Conversion of plasma or urine nitrate to nitrite with cadmium gave elevated values of plasma nitrite by the Greiss assay when LNAME or LNA was the NO synthase inhibitor. We conclude that in vivo and in vitro use of LNAME and LNA and in vivo use of high doses of aminoguanidine interfere with the assay of NO2- and NO3- with the modified Griess reaction and with chemiluminescence. We suggest that LNAME and LNA not be used in vivo or in vitro when total RNI is measured with these assays.

A biomechanical evaluation of magnetic resonance imaging-compatible wire in cervical spine fixation.

In a bovine cervical spine model, the ultimate and fatigue strengths as well as relative magnetic resonance imaging artifact produced by titanium, cobalt chrome, and stainless-steel wires in various gauges were assessed. Single-cycle and fatigue strength of wire constructs were measured. Although larger wires generally had greater static strength, fatigue strength was mixed. Sixteen-gauge titanium, and all stainless-steel models (22-gauge braided, 18-gauge, and Songer cable) withstood 10,000 cycles without failure, whereas all other constructs rarely could withstand a similar 10,000 cycles. Magnetic resonance imaging was performed on calf cervical spines instrumented with the various materials. Titanium exhibited the least artifact, stainless-steel showed the greatest artifact, and cobalt chrome an intermediate amount. Although titanium wire produces the least amount of magnetic resonance imaging artifact, it remains a poor choice for implant fixation because its notch sensitivity reduces its fatigue resistance compared with stainless steel, which remains the more dependable choice.

Penetration of glycopeptide antibiotics in nucleus pulposus.

The penetration of the glycopeptide antibiotics vancomycin and teicoplanin into the nucleus pulposus of rabbits was studied. Blood samples were obtained at 0.5, 1, 4, 8, and 24 hours after intravenous administration of 30 mg/kg vancomycin or 16 mg/kg teicoplanin. Concentrations of antibiotics were determined in tissue specimens and serum samples by fluorescence polarization immunoassays. Antimicrobial activity in the nucleus pulposus was determined with an agar diffusion method using a strain of Micrococcus luteus as the indicator organism. A peak concentration of vancomycin in the nucleus pulposus was attained 8 hours after drug administration. Teicoplanin reached its maximum level and plateaued 1 and 2 hours, respectively, after injection, and it remained unchanged for the rest of the study. This microbiologic analysis showed that the nucleus pulposus contained an antimicrobial level of glycopeptide antibiotics after administration. Because rabbit nucleus pulposus is similar anatomically to that of humans, these results may have implications regarding the timing and choice of antibiotic administration.

Ouabain enhances basal release of nitric oxide from carotid artery.

The authors tested the postulate that ouabain releases nitric oxide (NO) from the vascular endothelium of porcine carotid arteries (PCAs) with the technique of perfusion-superfusion bioassay, in which the perfused PCA with endothelium served as the source of NO and superfused left circumflex coronary artery (CMFX) rings with rubbed endothelium served as the bioassay tissue. Selective exposure of the PCA to ouabain (10 microM) enhanced the basal release of NO but did not affect bradykinin-stimulated (BK; 0.1-100 picomoles) release of NO. The effect of ouabain on basal release of NO from PCA persisted after pretreatment of either PCA or circumflex coronary artery with propranolol (1 microM); ibuprofen (1 microM); and hydrocortisone (10 microM). Finally, selective pretreatment of the PCA with L-NG-monomethylarginine (LNMMA; 100 microM) to inhibit 1-arginine-derived NO synthesis inhibited the relaxation of the circumflex coronary artery to basal, BK, and ouabain-stimulated effluent. Since a nonspecific increase in intracellular calcium ion will enhance both basal and agonist-induced release of NO, the authors conclude that a ouabain-sensitive ATPase is involved in basal release of NO from the endothelium of the PCA. Alternatively, ouabain may act on an isozyme of NO synthase in the vascular endothelium. Speculatively, ouabain-induced stimulation of NO release from vascular endothelium may contribute to the beneficial effect of ouabain in congestive heart failure.

Ethanol metabolism is not required for inhibition of LPS-stimulated transcription of inducible nitric oxide synthase.

We examined the effect of inhibition of ethanol metabolism on ethanol-mediated suppression of Escherichia coli endotoxin (LPS-induced upregulation of transcription and release of inducible nitric oxide synthase (iNOS) and tumor necrosis factor alpha (TNFalpha) from rat alveolar macrophages (AM) in vivo. Ethanol (3.45 and 5.5 g/kg/IP) and t-butanol (3.7 g/kg, IP), given 30 min before intratracheal administration of LPS (1.0 mg/kg), inhibited the upregulation of iNOS mRNA and protein, determined by competitor equalized RT-PCR and Western immunoblot, respectively, but not TNFalpha mRNA in AM obtained 2 h after LPS administration by bronchoalveolar lavage (BAL). However, ethanol and t-butanol inhibited LPS-stimulated nitrate and nitrite (RNI) and TNFalpha protein in BAL fluid. Pretreatment of rats with 4-methylpyrazole (100 mg/kg, IP) 2 h before, or disulfiram 30 min before, administration of ethanol (3.45 g/kg, IP) failed to attenuate the inhibitory effect on iNOS mRNA or protein. t-Butyl hydroperoxide (100 mg/kg, IP) given to rats 30 min before administration of LPS enhanced LPS-mediated upregulation of iNOS mRNA and TNFalpha protein in AM and BAL fluid. The inhibitory effect of ethanol on iNOS mRNA was not mediated by an interaction with elevated levels of circulating corticosterone because pretreatment of rats with RU-38486 (100 mg/kg, IM), which inhibited prednisolone (50 mg/kg, IM), induced suppression of LPS-stimulated iNOS mRNA, and failed to attenuate ethanol-mediated inhibition of LPS-stimulated iNOS mRNA in AM. We conclude that metabolism of ethanol to acetaldehyde via alcohol dehydrogenase is not required for ethanol-mediated suppression of LPS-induced iNOS transcription and TNFalpha synthesis/release in AM. Moreover, an interaction of ethanol or acetaldehyde with circulating corticosterone is not involved in ethanol-mediated attenuation of LPS-stimulated iNOS mRNA or protein or TNFalpha protein in the lung. Speculatively, because oxidation of t-butanol to t-butylhydroperoxide results in activation, rather than inhibition, of iNOS and TNF-alpha, the reported ethanol-mediated enhancement of iNOS mRNA may result from the action of the hydroxyethyl radical.

Role of PKC and tyrosine kinase in ethanol-mediated inhibition of LPS-inducible nitric oxide synthase.

Ethanol increases human and animal susceptibility to opportunistic lung infections in part by suppression of endotoxin (LPS) and bacteria-mediated upregulation of inducible nitric oxide synthase (iNOS) in alveolar macrophages (AM). LPS and cytokine-induced NOS mRNA are dependent on NF-kappaB/Rel (NFkappaB) and Activator Protein-1 (AP-1), which are regulated in turn by protein kinase C and tyrosine kinase-dependent phosphorylation. ETOH does not directly inhibit NFkappaB or AP-1, in vivo, but rather inhibits LPS-induced activation of the MEKK/MAP kinase system and inhibition of inhibitory protein IkappaBalpha required for formation of AP-1 and NFkappaB, respectively. in AM. Both transcription factors are involved iNOS mRNA transcription. LPS-induced upregulation of MEKK/MAP tyrosine kinase upregulates NADPH oxidase activity and oxygen free radical formation required for activation of NFkappaB and AP-1 and phosphorylation of IkappaBalpha. LPS downregulates endogenous calcium-sensitive PKC isozymes (PKCdelta), which repress iNOS mRNA expression. ETOH inhibits LPS-induced upregulation of iNOS mRNA by preventing its ability to decrease PKCdelta and upregulate tyrosine kinase-mediated phosphorylation. This effect of ETOH is prevented by inhibitors of PKC and tyrosine kinase. The data support the hypothesis that ETOH inhibits LPS-induced upregulation of iNOS mRNA by interfering with the phosphorylation processes involved in activation of the nuclear transcription factors NFkappaB and AP-1.

Ethanol suppresses LPS-induced mRNA for nitric oxide synthase II in alveolar macrophages in vivo and in vitro.

Alcohol abuse increases the incidence and severity of opportunistic lung infections and pneumonias. Inducible nitric oxide (NO) synthase (iNOS II) and NO may be a pivotal system in the intracellular bactericidal activity of macrophages. We tested the hypothesis that acute administration of ethanol (ETOH) suppressed Escherichia coli endotoxin lipopolysaccharide (LPS) mediated upregulation of the iNOS II system in the lung of the rat, in vivo. We also tested the effect of ETOH on alveolar macrophage (AM) production of free NO using microelectrodes. Male Sprague-Dawley rats were given ETOH (5.5 g/kg, IP) 30 min. before giving intratracheal sterile phosphate buffered saline solution (PBS, 0.5 ml) or LPS (1 mg/kg in a total volume of 0.5 ml PBS). The isolated lungs were subjected to bronchoalveolar lavage (BAL) 3.5 hr. later. Aliquots of the BAL fluid were assayed for tumor necrosis factor alpha TNF alpha and reactive nitrogen intermediates (nitrate and nitrite) (RNI) with chemiluminescence. Aliquots of AM were incubated 1 hr ex vivo for spontaneous production of RNI or frozen and assayed for iNOS II mRNA with competitor exchange reverse transcriptase polymerase chain reaction (cERT-PCR). The lung was homogenized and assayed for RNI. LPS increased BAL fluid TNF alpha and RNI, lung RNI, and the spontaneous production of RNI by AM, ex vivo. These effects were inhibited by in vivo administration of inhibitors of iNOS II. LPS increased iNOS mRNA in AM. This was unaffected by iNOS inhibitors. ETOH suppressed LPS-induced BAL fluid TNF, iNOS mRNA and RNI production by AM and the lung.(ABSTRACT TRUNCATED AT 250 WORDS)

Escherichia coli-induced inhibition of endothelium-dependent relaxation and gene expression and release of nitric oxide is attenuated by chronic alcohol ingestion.

We examined the effect of chronic administration of ETOH on Escherichia coli-mediated suppression of relaxation and nitric oxide (NO) production by the rat thoracic aorta (RTA) and gene expression for constitutive NO synthase (cNOS) by the adrenal gland. Chronic alcoholic rats ("alcoholic") were fed a diet containing ETOH as 36% of the caloric intake for 8-10 weeks. Nonalcoholic control rats ("control") were fed an isocaloric equivalent diet containing 36% dextrin. Alcoholic rats were given an injection of approximately approximately 10(10) live E. coli through a dorsal SC catheter 24 and 19 h before experimentation ("alcoholic-septic"), and control rats were treated in an identical manner ("septic"). The next day the rats were anesthetized with ketamine-xylazine (0.1 ml/100 g rat) and rings of RTA were mounted in muscle chambers for isometric recording of force development. Rings of RTA were precontracted with an EC50 concentration of phenylephrine, and relaxation to acetylcholine (ACh), A23187, and nitroglycerin were obtained. A23187- and ACh-induced relaxation was attenuated in RTA obtained from septic rats, whereas the relaxation to nitroglycerin was slightly enhanced. Chronic administration of ETOH attenuated the effects of E. coli on endothelium-dependent relaxation in alcoholic-septic rats. NO was measured with ozone chemiluminescence. Basal and stimulated NO production was attenuated in RTA obtained from septic rats and unaffected in RTA obtained from alcoholic or alcoholic-septic rats. cNOS was unmeasurable in adrenals from septic rats. ETOH increased mRNA for cNOS, an effect amplified in alcoholic-septic rats. Thus, E. coli inhibits endothelium-dependent relaxation and NO production, and ETOH attenuates these effects of E. coli on the endothelium-NO system, possibly by upregulating gene expression for cNOS.

Ethanol relaxes pulmonary artery by release of prostaglandin and nitric oxide.

Acute-intake of ethanol is associated with vasodilation of vascular smooth muscle (VSM). Relaxation of VSM is dependent, in part, on the actions of nitric oxide (NO) and prostaglandin (PG) produced by endothelial cells (EC) lining the VSM. We examined the effects of endothelium rubbing and inhibition of EC synthesis of NO and PG on ethanol-induced relaxation of bovine pulmonary artery (BPA) and pulmonary vein (BPV) in vitro. Rings of isolated BPA and BPV were mounted in muscle chambers for the isometric recording of force development. Blood vessels were precontracted with an EC50 concentration of the thromboxane receptor mimetic U46619. Ethanol (0.01, 0.02, 0.04, 0.08, 0.16, 0.32, 0.64, and 1.28% (w/v) produced concentration-dependent relaxation of BPA and BPV. Ethanol-induced relaxation was attenuated in BPA with rubbed EC and by the NO synthase inhibitors, L-NG monomethylarginine (LNMMA, 50 microM) and L-nitroarginine (NOLA, 10 microM), and the prostaglandin cyclooxygenase inhibitor, ibuprofen (10 microM). In contrast, ethanol-induced relaxation of BPV was not affected by endothelium rubbing or by NOLA or LNMMA, but was partially attenuated by ibuprofen. Nitric oxide was measured with the chemiluminescence technique. Ethanol increased the content of NO released under basal conditions by the BPA but did not effect basal NO release from BPV. However, ethanol enhanced bradykinin-induced release of NO from BPA and BPV and, at low concentrations, augmented bradykinin-induced relaxation of both BPA and BPV.(ABSTRACT TRUNCATED AT 250 WORDS)