Vasorelaxant Agents Research Articles

Growth hormone replacement reduces C‐reactive protein and large‐artery stiffness but does not alter endothelial function in patients with adult growth hormone deficiency

Hypopituitary patients have an increased risk of vascular mortality that may relate to growth hormone deficiency (GHD). We investigated the effects of 6 months of GH therapy on large- and small-artery function and high-sensitivity C-reactive protein (hsCRP) in a cohort of GH-deficient patients. Sixteen hypopituitary patients were randomized to 6 months of GH therapy or no treatment, then vice versa. hsCRP, 24-h blood pressure (BP) and pulse wave velocity (PWV) were measured and resistance arteries were used to construct concentration-response curves to endothelium-dependent and -independent agents. GH therapy increased IGF-1 from 60 +/- 7.2 to 167 +/- 16.2 microg/l [confidence interval (CI) 94.9, 138.8, P < 0.001]. hsCRP declined after 6 months of GH from 3.8 +/- 0.88 to 2.0 +/- 0.49 mg/l (CI 0.73, 3.57, P = 0.006). Mean arterial BP fell from 91.7 +/- 1.5 to 89.3 +/- 1.2 mmHg (CI 0.81, 4.07, P = 0.005), as did PWV (8.1 +/- 0.4 to 6.7 +/- 0.5 m/s). The decline in PWV correlated with the decline in hsCRP (r = 0.68, P = 0.01). Resistance artery function was unchanged after GH therapy. GH replacement may lead to differentially altered production of vasorelaxant agents from the endothelium of large and small arteries. Reduction in vascular inflammation may be associated with reduced vascular risk.

A Phenoxazine Compound, 2-Amino-4,4.ALPHA.-dihydro-4.ALPHA.-7-dimethyl-3H-phenoxazine-3-one Reverses the Phenylephrine or High-K+ Induced Contraction of Smooth Muscles in Rat Aorta and Guinea Pig Tenia Cecum

2-Amino-4,4alpha-dihydro-4alpha-7-dimethyl-3H-phenoxazine-3-one (Phx-1) reversed concentration dependently the contraction of both rat aorta and guinea pig tenia cecum induced by phenylephrine or high-K(+). Since Phx-1 suppresses the responses of human mononuclear cells to phytohemagglutinin, (Akazawa et al. Tohoku J. Exp. Med., 196, 185-192, 2002), Phx-1 may be useful for developing new vasorelaxing agents with immunosuppressive action.

Synthesis and biological evaluation of flavonoids as vasorelaxant agents

Several 5,7-dihydroxyflavone and quercetin 3- O-glycosides have been synthesized and evaluated for vasorelaxant activity. A log P–activity relationship amongst flavonoids was suggested.

Gramine: a vasorelaxing alkaloid acting on 5-HT(2A) receptors.

The vascular effects of gramine on resistance vessels were evaluated, in particular as regards the 5-hydroxytryptamine (5-HT) system. We compared the action of gramine with that of ketanserin, a 5-HT (2A) antagonist; both compounds induced concentration-dependent relaxation in precontracted arterial rings. Also, the 5-HT concentration-effect curve shifted to the right in the presence of gramine, like ketanserin. These results suggest that gramine is a vasorelaxing agent acting mainly by antagonism at 5-HT (2A) receptors.

Cardiovascular hybrid drugs: new benzazepinone derivatives as bradycardic agents endowed with selective β1-Non-competitive antagonism

The synthesis and pharmacological profile of some hybrid compounds bearing both the benzazepinone moiety present in Zatebradine and typical β-blocker aryloxypropanolamine groups are described. The new compounds proved to be endowed with negative chronotropic and inotropic activity and are weak vasorelaxant agents. The cardiodepressant action is probably due to selective β1-noncompetitive reversible antagonism. Both enantiomers of the most active compound 5c were synthesized and they showed a different cardiovascular profile, that is (+)-(R)-enantiomer displays affinity for cardiac β1-adrenoceptors, while (−)-(S)-enantiomer shows specificity for vessel smooth muscle.

Cardiovascular effects of the essential oil of Alpinia zerumbet leaves and its main constituent, Terpinen-4-ol, in rats: role of the autonomic nervous system.

Cardiovascular effects of intravenous ( i. v.) treatment with the essential oil of Alpinia zerumbet (EOAZ) were investigated in rats. Additionally this study examined (I) whether the autonomic nervous system is involved in the mediation of EOAZ-induced changes in mean aortic pressure (MAP) and heart rate (HR), and (II) whether these changes could be, at least in part, attributed to the actions of terpinen-4-ol (Trp-4-ol), the major constituent of EOAZ. In both pentobarbitone-anaesthetised and conscious rats, i. v. bolus injections of EOAZ (1 to 20 mg/kg) elicited immediate and dose-dependent decreases in MAP. In anaesthetised rats, EOAZ decreased HR only at higher doses (10 and 20 mg/kg), while changes of this parameter were not uniform in conscious rats. Hypotensive responses to EOAZ were of the same order of magnitude or duration, irrespective of whether the animal was under general anaesthesia. Pretreatment of anaesthetised rats with bilateral vagotomy did not modify significantly the hypotensive and bradycardic responses to EOAZ. In conscious rats, i. v. injections of bolus doses (1 to 10 mg/kg) of Trp-4-ol also elicited immediate and dose-dependent decreases in MAP. However, these hypotensive effects were significantly greater than those evoked by the same doses of EOAZ (1 to 10 mg/kg). Intravenous pretreatment of conscious rats with either methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) had no significant effects on the EOAZ-induced hypotension. These data show that i. v. treatment with the EOAZ in either anaesthetised or conscious rats induced an immediate and significant hypotension, an effect that could be partially attributed to the actions of Trp-4-ol. The hypotension appears independent of the presence of an operational sympathetic nervous system, suggesting that the EOAZ may be a direct vasorelaxant agent.

CGS 34226, a thiol-based dual inhibitor of endothelin converting enzyme-1 and neutral endopeptidase 24.11.

Endothelins (ETs) are potent vasoconstrictors and have been implicated in the pathogenesis of various cardiovascular and renal diseases. In contrast, atrial natriuretic peptide (ANP) is a potent vasorelaxant and diuretic agent, which is mainly degraded by neutral endopeptidase 24.11 (NEP) in vivo. Thus, compounds that can suppress the biosynthesis of ETs by inhibiting endothelin converting enzymes (ECEs), which catalyse the final step of post-translational processing of the vasoconstrictors, while simultaneously potentiating the levels of ANP by inhibiting NEP may have novel therapeutic utility. Through targeted screening of our compound library and subsequent optimization, CGS 34226 was identified as a potent, dual inhibitor of ECE-1 and NEP, inhibiting the enzymes with respective IC(50) values of 11 and 4.6 nM. In vivo, CGS 34226 suppressed the big endothelin-1 (big ET-1)-induced pressor response dose-dependently. At 15 and 90 min after an intravenous dose of 30 mg/kg in anaesthetized rats, this compound inhibited the big ET-1-induced effect by 79% and 65% respectively. In addition, CGS 34226 increased plasma ANP immunoreactivity by 120% up to 4 h after an intravenous dose of 10 mg/kg in conscious rats infused with ANP at a rate of 450 ng/kg per min, intravenously. These results show that CGS 34226 is a potent dual inhibitor of ECE-1 and NEP in vitro and in vivo and that the compound may represent a novel agent for the treatment of cardiovascular and renal dysfunction.

Mannich bases of 3 H-pyrrolo[3,2- f]quinoline having vasorelaxing activity

Mannich bases obtained by aminoalkylation of 3 H-pyrrolo[3,2- f]quinoline were designed and prepared as potential vasorelaxing agents. Compounds Ia– Va were characterised by IR, 1H-NMR, mass spectral data and elemental analysis; IIb, c– Vb, c were also confirmed by 1H-NMR spectra of reaction mixtures. To estimate their vascular activity, prototypes 1-( N, N-dimethylaminomethyl)- ( Ia) and 1-(4-phenyl-piperazin-1-ylmethyl)- ( IVa) 3 H-pyrrolo[3,2- f]quinoline derivatives were studied in rat-tail arteries. In tissues precontracted with 0.5 μM 5-hydroxytryptamine (5-HT), 3 μM phenylephrine or 80 mM KCl, Ia and IVa showed endothelium-independent relaxing action. In a preliminary study on the cellular mechanisms of Ia, the influence of propranolol, a β-receptor antagonist, and ketanserin, a 5-HT 2A-receptor antagonist, was checked. In the presence of phenylephrine, the vasorelaxing effect of Ia was not affected by these inhibitors.

Impaired Response to Insulin Associated with Protein Kinase C in Chronic Fructose-induced Hypertension

A fructose-enriched diet induces an increase in blood pressure associated with metabolic alterations in rats. Our hypothesis was that an increase in protein kinase C (PKC) activation, reported in the acute period of fructose overload, and an impaired vessel's response to vasoactive substances contribute to maintain elevated blood pressure levels in the chronic period. The aims of this study were to investigate in this animal model of hypertension: (1) if the increase in PKC activation was also found in the chronic stage; (2) the involvement of nitric oxide and insulin in the vessel's response; and plasma atrial natriuretic factor and nitrites/nitrates (nitric oxide metabolites) behavior. We evaluated the effects of: PKCstimulator 12,13-phorbol dibutyrate, phenylephrine, insulin, nitric oxide synthase-inhibitor N G -nitro- L arginine methyl esther (L-NAME) and PKC-inhibitor Calphostin C on aortic rings responses of Sprague- Dawley rats: fructose-fed and control. The fructose-fed group showed higher contractility to 12,13- phorbol dibutyrate than the control group in aortic rings pre-incubated with insulin, and this difference disappeared with L-NAME. The response to phenylephrine in rings pre-incubated with Calphostin C was decreased in the fructose-fed group and increased with Calphostin C plus L-NAME. Fructose-fed rats showed higher levels of plasma atrial natriuretic factor and nitrites/nitrates than controls. In conclusion, chronic fructose feeding seems to develop an impaired response to insulin, dependent on nitric oxide, suggesting a PKC alteration. Vasorelaxant agents, such as atrial natriuretic factor and nitric oxide, would behave as compensatory mechanisms in response to high blood pressure.

Cocaine toxic effect on endothelium-dependent vasorelaxation: an in vitro study on rabbit aorta

Effects of cocaine on vascular endothelium relaxing properties and the related mechanism were investigated in vitro in rabbit aorta. Several vasorelaxing agents with different mechanisms, i.e. acetylcholine, substance P, calcium ionophore A23187, 2,5-di- tert-butylhydroquinone, or sodium nitroprusside, were employed. Cocaine effects on the vascular response to relaxing agents in cumulative (acetylcholine, substance P, or A23187) or single dose (2,5-di- tert-butyl-hydroquinone) were performed in endothelium-intact aortic rings precontracted with phenylephrine. Relaxing activity of cumulative doses of sodium nitroprusside was evaluated in endothelium-denuded aortic rings, in the presence of cocaine. Cocaine significantly reduced endothelium-dependent relaxations induced by acetylcholine, or substance P. By contrast A23187 endothelium-mediated relaxation as well as endothelium-independent relaxation by sodium nitroprusside were unaffected by cocaine. Furthermore, cocaine significantly increased endothelium-dependent relaxation response to 2,5-di- tert-butylhydroquinone, a sarcoplasmic Ca 2+-ATPase pump inhibitor, in the aortic rings. These findings indicate that cocaine reduces nitric oxide release from vascular endothelium apparently through the inhibiting action of Ca 2+-ATPase pump.

Essential oil of Croton nepetaefolius decreases blood pressure through an action upon vascular smooth muscle: studies in DOCA-salt hypertensive rats.

Experiments tested the hypothesis that hypotensive effects of intravenous (i.v.) treatment with the essential oil of Croton nepetaefolius (EOCN) result from its vasodilatory effects directly upon vascular smooth muscle. In both deoxycorticosterone-acetate (DOCA)-salt hypertensive and uninephrectomised control, conscious rats, i.v. bolus injections of EOCN (1 to 50 mg/kg) decreased mean aortic pressure (MAP) and heart rate (HR) in a dose-related manner. Treatment with DOCA-salt significantly enhanced EOCN-induced decreases in MAP without affecting bradycardia. Likewise, both maximal percent and absolute decreases in MAP elicited by i.v. hexamethonium (30 mg/kg), a ganglion blocker, were significantly greater in DOCA-salt hypertensive than in control rats. In DOCA-salt hypertensive rats, i.v. pretreatment with hexamethonium (30 mg/kg) reduced the bradycardia elicited by EOCN (50 mg/kg) without affecting the enhancement of EOCN-induced hypotension. In isolated thoracic aorta preparations from DOCA-salt hypertensive rats, EOCN (1-300 micrograms/ml) induced a concentration-dependent reduction of phenylephrine-induced contraction. Arteries from DOCA rats showed increased sensitivity to EOCN, as evidenced by the significant decrease in the IC50 for EOCN-induced reduction of phenylephrine-induced contraction (16.4 +/- 3.6 vs. 112.9 +/- 23.4 micrograms/ml in uninephrectomized controls). These results show that i.v. treatment with EOCN dose-dependently decreases blood pressure in conscious DOCA-salt hypertensive rats, and this action is enhanced when compared with uninephrectomized controls. This enhancement appears to be related mainly to an increase in EOCN-induced vascular smooth muscle relaxation rather than to enhanced sympathetic nervous system activity in this hypertensive model. Thus, the hypothesis that EOCN may be a direct vasorelaxant agent is supported by the results of the present study.

REPEATED PGE1 TREATMENT ENHANCES NITRIC OXIDE AND ERECTION RESPONSES TO NERVE STIMULATION IN THE RAT PENIS BY UPREGULATING CONSTITUTIVE NOS ISOFORMS

To assess whether intracavernosal injections of prostaglandin E1 (PGE1) can influence nitric oxide (NO) release in the corpora in a rat model of penile erection. The extracellular levels of NO were monitored at 100 seconds intervals in the corpus cavernosum of anesthetized rats by using differential normal pulse voltammetry with porphyrin-Nafion coated carbon fiber microelectrodes. The intracavernosal pressure (ICP) was simultaneously recorded. PGE1 was given either as a single dose (ranging from 0.2 to 15 microg.) or as repeated 2 microg. injections in alternate days for two weeks. The NO and ICP responses to electrostimulation of the cavernosal nerve (SCN) was studied in the animals in the repeated treatment schedule at 1, 7, 15 and 30 days after its termination. The levels of the three NO synthase (NOS) isoforms in the cavernous tissue were measured by immunoblotting. Acute PGE1 treatment dose-relatedly increased NO levels in the corpora, with a concomitant ICP increase with the highest dose. Repeated 2 microg. PGE1 injections increased the NO and ICP responses to SCN as compared with intact or vehicle-injected animals. This treatment also increased the penile content of the neuronal and endothelial NOS proteins. The inducible NOS isoform remained unchanged after either vehicle or PGE1 injections. The effects of the repeated PGE1 treatment were greater in the group studied 24 hours after the last injection and decreased progressively thereafter. Stimulation of NO release can contribute to the erectogenic effect of intracavernous PGE1 injections. The increased levels of constitutive NOS isoforms in the corpora could contribute to the improvement of the erectile function reported by some patients following repeated treatment with vasorelaxant agents.

PF9404C, a new slow NO donor with beta receptor blocking properties.

1. PF9404C is the S-S diesteroisomer of a novel blocker of beta adrenergic receptors with vasodilatory properties. It causes a concentration-dependent relaxation of rat aorta helical strips pre-contracted with 10(-6) M noradrenaline (NA; IC(50) 33 nM). It was equipotent to nitroglycerin (NTG; IC(50) 49 nM), but much more potent than isosorbide dinitrate (ISD; IC(50) 15,000 nM). 2. Oxyhaemoglobin (10 microM) shifted to the right the concentration-response curve for the relaxation induced by PF9404C (IC(50) 530 nM) or NTG (IC(50) 61 nM). 3. Either methylene blue (MB) or ODQ (1 microM each) largely prevented the vasorelaxing responses to increasing concentrations of PF9404C or NTG. 4. In rat aorta smooth muscle cells, PF9404C increased the formation of cyclic GMP from 3 pmol mg(-1) protein in basal conditions, to 53 pmol mg(-1) protein in 10 microM PF9404C. Neither metoprolol nor carvedilol enhanced cyclic GMP. 5. In the electrically driven guinea-pig left atrium, PF9404C blocked the inotropic effects of isoprenaline in a concentration-dependent manner. Its IC(50) (30 nM) was similar to that for S-propranolol (22.4 nM) and lower than the IC(50)s for metoprolol (120 nM) and atenolol (192 nM). The beta-adrenergic ligand (-)-[(3)H]-CGP12177 (0.2 nM) was displaced from its binding to rat brain membranes with K(i) of 7 nM, 17 nM, 170 nM and 1.2 microM respectively for PF9404C, S-(-)propranolol, metoprolol, and atenolol. 6. The data are consistent with the idea that the S-S diesteroisomer PF9404C, is a potent vasorelaxing agent, as well as a blocker of cardiac beta adrenergic receptors. The mechanism of its vasorelaxing effects involves the slow generation of NO. This molecule can, therefore, exhibit antihypertensive and cardioprotective actions through a double mechanism, NO donation and beta blockade.

Cardiovascular effects of the essential oil of Croton nepetaefolius in rats: role of the autonomic nervous system.

Cardiovascular effects of intravenous (i.v.) treatment with the essential oil of Croton nepetaefolius (EOCN) were investigated in rats. Additionally, this study examined the importance of the autonomic nervous system in mediation of the EOCN-induced changes in mean aortic pressure (MAP) and heart rate (HR). In both pentobarbitone-anaesthetised and conscious rats, i.v. bolus injections of EOCN (1 to 50 mg/kg) elicited dose-dependent decreases in MAP and HR. Both decreases were of the same order of magnitude or duration, irrespective of whether the animal was under general anaesthesia. Pretreatment of anaesthetised rats with bilateral vagotomy reduced the magnitude of EOCN-induced bradycardia without affecting hypotension. Likewise, i.v. pretreatment of conscious rats with either methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) significantly decreased the bradycardic effects of EOCN by the same order of magnitude. Neither compound influenced the hypotensive effects elicited by EOCN. This is the first physiological evidence that i.v. treatment with EOCN in either anaesthetised or conscious rats elicits hypotension and bradycardia. EOCN-induced bradycardia appears dependent upon the presence of an intact and functional parasympathetic nerve drive to the heart. However, EOCN-induced hypotension appears independent of the presence of an operational sympathetic nervous system. This suggests that EOCN may be a direct vasorelaxant agent.

Influence of depolarization on vasorelaxant potency and efficacy of Ca2+ entry blockers, K+ channel openers, nitrate derivatives, salbutamol and papaverine in rat aortic rings.

We examined the effects of various KCl concentrations on the actions of some vasodilators belonging to different pharmacological classes in rat aortic rings. In some experiments, tissues were precontracted with noradrenaline after blocking voltage-dependent channels to assess the effects of depolarisation unaccompanied by the entry of extracellular Ca2+ into the cytosol. Concentration/response curves for the vasorelaxant effect of calcium entry blockers (e.g. diltiazem), K+ channel openers (e.g. aprikalim), nitrate derivatives (e.g. nitroglycerin), a beta2-adrenergic agonist (salbutamol) and papaverine were obtained by using endothelium-denuded rat aortic rings precontracted with KC1 (20-60 mM) to determine the potencies and efficacies of the drugs. The efficacies and potencies of calcium entry inhibitors were virtually independent of the [KCl]. A reduction in the potency (up to 18-fold) of papaverine occurred without changes in efficacy when the [KCl] was raised from 20 to 60 mM. The decline in potency was even greater for nitrate-like compounds. The potency of K+ channel openers in aortic rings precontracted with 30 mM KCI decreased by three- to sixfold compared with those precontracted with 20 mM KCl. With the exception of pinacidil, the efficacy of these agents already started to decline in preparations precontracted with 25 mM KCI and was virtually zero in preparations precontracted with 60 mM KCI. In contrast to other K+ channel openers, the vasorelaxant action of pinacidil was relatively resistant to glibenclamide. Salbutamol produced only a slight relaxation even in preparations precontracted with 20 mM KCl. In nitrendipine-pretreated, noradrenaline-precontracted aortic rings, the vasorelaxant effects of aprikalim, but not those of linsidomine or papaverine, declined when the [KCl] of the bathing medium was increased. In conclusion, the vasorelaxant potency and efficacy of calcium entry blockers is independent of the [KCI] used to precontract rat aortic rings, and thus, of the degree of membrane depolarisation. In contrast, increasing the [KCl] strongly reduces the potency and the efficacy of K+ channel openers not only in this preparation but also in noradrenaline-precontracted rings in which the entry of extracellular Ca2+ was prevented with nitrendipine. This indicates that, with the exception of pinacidil, the vasorelaxant activity of K+ channel openers depends on the degree of membrane depolarisation. Finally, the vasorelaxant potency and efficacy of nitrate-like compounds and papaverine are independent of depolarisation per se but they are markedly affected by the influx of Ca2+ accompanying elevated [KCI]. Thus, the degree of vessel depolarisation should be taken into consideration when attempting to compare potencies and efficacies among vasorelaxant agents.

Renal and vascular actions of equol in the rat.

The urinary isoflavonoid equol inhibits membrane Na-K-Cl cotransporters at similar concentrations to those at which furosemide inhibits them, but the significance of this action is not known. To investigate the potential salidiuretic and vascular actions of equol in the rat. Renal functioning was assessed in vitro in the isolated perfused kidney and in vivo in conscious rats. The vascular contractility of isolated aorta was assessed. In the isolated perfused kidney equol was concentrated 50- to 70-fold in the urinary fluid, it was 3-4 times less potent than furosemide at increasing diuresis, natriuresis and kaliuresis (the difference was due to its higher protein-binding affinity), and it induced a modest but significant increase in glomerular filtration rate. In vivo, orally administered equol was a modest natriuretic agent, about 8-fold less potent than orally administered furosemide (in molar terms). In isolated aortic rings precontracted by administration of phenylephrine, administration of equol relaxed the contracted aorta at 10-fold lower concentrations (concentration for half-maximal activity 58.9 +/- 16 micromol/l, n = 3) than did furosemide (concentration for half-maximal activity 633 +/- 145 micromol/l, n = 3). Equol is a modest natriuretic and vasorelaxant agent in the rat. Further studies are required in order to investigate the potential natriuretic and perhaps hypotensive actions of dietary equol precursors (daidzein).

Differential effects of acetylcholine and bradykinin on prostanoid release from the rat mesenteric bed: role of endothelium and of nitric oxide

The roles of nitric oxide and of endothelium in the effects of the vasorelaxing agents acetylcholine and bradykinin on the production of prostanoids was studied in the isolated and perfused mesenteric vascular bed of the rat. Prostanoids were measured in the perfusate by high-performance liquid chromatography (HPLC). In the intact vascular bed, 1 μM bradykinin increased the release of 6-keto-prostaglandinF 1α (stable metabolite of prostacyclin) and of prostaglandin E 2 and 10 μM acetylcholine stimulated the efflux of prostacyclin only. In the de-endothelialized vascular bed, bradykinin increased the release of prostacyclin whereas acetylcholine increased the efflux of thromboxane. The inhibition of nitric oxide synthesis with 100 μM N G-nitro- l-arginine methyl ester prevented the effect of bradykinin but did not modify the effects of acetylcholine on prostanoid release. In addition, 100 μM l-arginine reversed the inhibitory effect of N G-nitro l-arginine methyl ester on bradykinin-stimulated prostaglandin production. It is concluded that acetylcholine and bradykinin stimulate prostanoid release in the rat mesenteric vascular bed with different patterns and through different mechanisms.

Evidence for endothelium-derived relaxing factor/nitric oxide in equine digital arteries

Abstract Objective To test the hypothesis that endothelium-derived nitric oxide modulates vasomotor reactivity in equine digital arteries. Design Digital arteries were isolated from adult horses, and their vasodilator properties were examined in an in vitro controlled environment. Animals Five adult horses (1 gelding, 4 mares) without evidence of hoof or vascular disease were studied. Procedure Arterial rings with or without endothelium were exposed to endothelium-dependent vasodilator drugs in the presence or absence of a pharmacologic inhibitor of the enzyme nitric oxide synthase. Results Vasodilator effects of 3 endothelium-dependent vasorelaxant agents were significantly greater in endothelium-intact vessels than in endothelium-denuded vessels. Moreover, a nitric oxide synthase inhibitor reduced vasodilator responses to endothelium-dependent vasodilators in endothelium-intact arteries, but had no discernable effects in endothelium-denuded arteries. Conclusions These findings indicate the presence of endothelium-derived relaxing factor/nitric oxide in blood vessels of horses, and identify vascular endothelium as an endogenous modulator of vasomotor tone in the digital arteries of this species.

Comparative pharmacology of nitric oxide and nitric oxide generators on cardiac contractility in mammalian species

Nitric oxide (NO) is a potent vasorelaxing agent at nanomolar concentrations. At low nanomolar concentrations, NO also inhibits platelet aggregation, attenuates leukocyte adherence to the vascular endothelium, and quenches superoxide radicals. At high nanomolar concentrations, NO attenuates smooth muscle cells growth and stimulates proliferation of vascular endothelial cells. However, even at micromolar concentrations, NO fails to significantly alter cardiac contractility in isolated rat or cat cardiac muscle. Moreover, l-arginine, even at millimolar concentrations, fails to exert a decrease in cardiac contractility significantly greater than that produced by d-arginine.

Prevention and therapy of the adult respiratory distress syndrome.

The complex pathophysiology of adult respiratory distress syndrome (ARDS) makes preventive and therapeutic concepts difficult. Ample experimental evidence indicates that ARDS can be prevented by blocking systemic inflammatory agents. Clinically, only heparin, for inhibition of coagulation phenomena, is presently used among this array of approaches. Corticosteroids have not proven to be beneficial in ARDS. Alternative antiinflammatory agents are being proposed and are under current clinical investigation (e.g. indomethacin, acetylcysteine, alpha 1-proteinase inhibitor, antitumor necrosis factor, interleukin 1 receptor antagonist, platelet-activating factor antagonists). Symptomatic therapeutic strategies in early ARDS include selective pulmonary vasodilation (preferably by inhaled vasorelaxant agents) and optimal fluid balance. Transbronchial surfactant application, presently tested in pilot studies, may be available for ARDS patients in the near future and may have acute beneficial effects on gas exchange, pulmonary mechanics, and lung hemodynamics; its impact on survival cannot be predicted at the present time. Strong efforts should be taken to reduce secondary nosocomial pneumonia in ARDS patients and thus avoid the vicious circle of pneumonia, sepsis from lung infection, and perpetuation of multiple organ dysfunction syndrome. Optimal respirator therapy should be directed to ameliorate gas-exchange conditions acutely but at the same time should aim at minimizing potentially aggravating side effects of artificial ventilation (barotrauma, O2 toxicity). Several new techniques of mechanical ventilation and the concept of permissive hypercapnia address these aspects. Approaches with extracorporeal CO2 removal and oxygenation are being used in specialized centers.