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W Gonzalez

Publications and source records attributed to W Gonzalez.

At least 19 recordsLinked to original sources
PubMed2001

Mechanisms of L-type Ca(2+) current downregulation in rat atrial myocytes during heart failure.

Downregulation of the L-type Ca(2+) current (I(Ca)) is an important determinant of the electrical remodeling of diseased atria. Using a rat model of heart failure (HF) due to ischemic cardiopathy, we studied I(Ca) in isolated left atrial myocytes with the whole-cell patch-clamp technique and biochemical assays. I(Ca) density was markedly reduced (1.7+/-0.1 pA/pF) compared with sham-operated rats (S) (4.1+/-0.2 pA/pF), but its gating properties were unchanged. Calcium channel alpha(1C)-subunit quantities were not significantly different between S and HF. The beta-adrenergic agonist isoproterenol (1 micromol/L) had far greater stimulatory effects on I(Ca) in HF than in S (2.5- versus 1-fold), thereby suppressing the difference in current density. Dialyzing cells with 100 micromol/L cAMP or pretreating them with the phosphatase inhibitor okadaic acid also increased I(Ca) and suppressed the difference in density between S and HF. Intracellular cAMP content was reduced more in HF than in S. The phosphodiesterase inhibitor 3-isobutyl-1-methyl-xanthine had a greater effect on I(Ca) in HF than in S (76.0+/-11.2% versus 15.8+/-21.2%), whereas the inhibitory effect of atrial natriuretic peptide on I(Ca) was more important in S than in HF (54.1+/-4.8% versus 24.3+/-8.8%). Cyclic GMP extruded from HF myocytes was enhanced compared with S (55.8+/-8.0 versus 6.2+/-4.0 pmol. mL(-1)). Thus, I(Ca) downregulation in atrial myocytes from rats with heart failure is caused by changes in basal cAMP-dependent regulation of the current and is associated with increased response to catecholamines.

1-Methyl-3-isobutylxanthine↗
PubMed2001

Endothelium-independent conversion of angiotensin I by vascular smooth muscle cells.

The conversion of angiotensin I (AT-I) to angiotensin II (AT-II) by angiotensin I-converting enzyme (ACE) is a key step in the action of angiotensins. ACE is constitutively expressed in endothelial cells, but can also be detected at low levels in smooth muscle cells (SMC). Furthermore, in rats the ACE activity can be induced in SMC in vivo by experimental hypertension or vascular injury and in vivo by corticoid treatment. This study was therefore undertaken to evaluate the conversion of AT-I and its subsequent effects in SMC in basal conditions and after stimulation by dexamethasone. Using rat and human SMC, showed that dexamethasone induced ACE expression and that this enzyme was functional, leading to AT-II-dependent intracellular signaling. A fourfold increase in phospholipase C activity in response to AT-I was observed in dexamethasone-activated SMC compared with quiescent SMC. This effect of dexamethasone on signal transduction is dependent on ACE activity, whereas AT-II receptor parameters remain unchanged. The action of AT-I was blocked by an AT1 receptor antagonist, suggesting that it was mediated by AT-II. Similarly, dexamethasone-induced ACE expression was present in human SMC, and calcium signaling was mobilized in response to AT-I in activated human cells. Experiments performed with cocultures of endothelial cells and SMC in a Transwell system showed that the response to AT-I was limited to the compartment where AT-I was localized, suggesting that AT-I does not pass through the endothelial cell barrier to interact with underlying SMC. Our data suggest that in rat, as in human SMC, the conversion of AT-I into AT-II and the signal transduction in response to AT-I are ACE expression-dependent. In addition, the present findings show that this SMC response to AT-I is endothelium-independent, supporting the idea of a local generation of AT-II in the vascular wall.

Angiotensin I↗
PubMed2001

Transforming growth factor-beta regulation of endothelin expression in rat vascular cell and organ cultures.

Transforming growth factor (TGF)-beta increases the production of the vasoactive peptide endothelin (ET) in cultures of vascular endothelial cells (EC) and vascular smooth muscle cells (VSMC), but the physiologic or pathologic significance of this regulation has not been determined. The present studies test the hypothesis that when EC and VSMC are in direct contact or close proximity, ET expression is, at least in part, dependent on TGF-beta. The effects of TGF-beta on ET-1 mRNA (Northern analysis and reverse transcription polymerase chain reaction) and peptide (radioimmunoassay) levels were assessed in rat EC and VSMC and vascular organ cultures. TGF-beta2 (1 ng/ml) increased ET-1 mRNA in VSMC and EC plus VSMC cultures and increased ET-1 peptide in EC, VSMC, and EC plus VSMC cultures. TGF-beta2 also increased ET-1 mRNA and peptide in vascular organ cultures. Antibodies that neutralized the activities of TGF-beta1 and TGF-beta2 decreased ET-1 mRNA in EC plus VSMC cultures and in vascular organ cultures. These data indicate that when EC and VSMC are in direct contact or close proximity, TGF-beta increases ET expression and active TGF-beta is present and promotes ET expression. These data suggest that TGF-beta is a determinant of vascular ET expression in vivo, and that TGF-beta regulation of ET expression would affect cardiovascular function in health and disease.

Animals↗
PubMed2000

Shear stress induces iNOS expression in cultured smooth muscle cells: role of oxidative stress.

After deendothelialization, the most luminal smooth muscle cells of the neointima are in contact with blood flow and express inducible nitric oxide synthase (iNOS) in vivo. We hypothesized that shear stress may be a stimulus for this iNOS overexpression. We have thus submitted smooth muscle cells to laminar shear and measured the iNOS expression. Shear stress (20 dyn/cm(2)) induced iNOS mRNA and protein expression, whereas brain NOS mRNA expression was decreased. Conversely, nitrite production was increased. This production was blocked by a selective iNOS inhibitor. Pyrrolidine dithiocarbamate, an antioxidant molecule, and BXT-51072, a gluthation peroxidase mimic, both inhibited the shear-induced iNOS expression. Shear stress also increased the expression of both membrane subunits of NADPH oxidase p22(phox) and Mox-1. Shear stress activated the redox-sensitive nuclear translocation of the transcription nuclear factor-kappaB (NF-kappaB) and stimulated the degradation of both cytosolic inhibitors kappaB alpha and beta. These results show that shear stress can induce iNOS expression and nitrite production in smooth muscle cells and suggest that this regulation is probably mediated by oxidative stress-induced NF-kappaB activation.

Animals↗
PubMed2000

Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress.

The recruitment of monocytes via the endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) is a key step in the formation of the initial lesion in atherosclerosis. Because angiotensin (Ang) II may be involved in this process, we investigated its role on the signaling cascade leading to VCAM-1 expression in endothelial cells. Ang II stimulates mRNA and protein expression of VCAM-1 in these cells via the AT(1) receptor. This effect was enhanced by N(G)-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, and blocked by pyrrolidinedithiocarbamate, an antioxidant molecule. Ang II activated the redox-sensitive transcription factor nuclear factor-kappaB and stimulated the degradation of both inhibitor of kappaB (IkappaB)alpha and IkappaBbeta with different kinetics. The degradation of IkappaBs induced by Ang II was not modified by incubation with exogenous superoxide dismutase and catalase, suggesting that this effect was not mediated by the extracellular production of O(2)(-). In contrast, rotenone and antimycin, 2 inhibitors of the mitochondrial respiratory chain, inhibited the Ang II-induced IkappaB degradation, showing that generation of reactive oxygen species in the mitochondria is involved on Ang II action. BXT-51702, a glutathione peroxidase mimic, inhibited the effect of Ang II, and aminotriazole, an inhibitor of catalase, enhanced it, suggesting a role for H(2)O(2) in IkappaB degradation. This is confirmed by experiments showing that Ang II stimulates the intracellular production of H(2)O(2) in endothelial cells. These results demonstrate that Ang II induced an intracellular oxidative stress in endothelial cells, which stimulates IkappaB degradation and nuclear factor-kappaB activation. This activation enhances the expression of VCAM-1 and probably other genes involved in the early stages of atherosclerosis.

Angiotensin II↗
PubMed2000

Molecular plasticity of vascular wall during N(G)-nitro-L-arginine methyl ester-induced hypertension: modulation of proinflammatory signals.

It has previously been reported that hypertension induced by the chronic blockade of NO production is characterized by a proinflammatory phenotype of the arterial wall associated with a periarterial accumulation of inflammatory cells. In the present study, the cellular and molecular mechanisms involved in the luminal and perivascular accumulation of inflammatory cells were evaluated in the aortas of N(G)-nitro-L-arginine methyl ester (L-NAME)-treated rats. Because the medial layer remains intact, putative markers of the resistance of the vascular wall to cell migration and to oxidative stress were also explored. For this purpose, monocyte adhesion, cytokine expression, superoxide anion production, and nuclear factor-kappa B (NF-kappa B) activation were assessed in the aortas of L-NAME-treated rats. Expressions of tissue inhibitor of metalloproteinases-1 (TIMP-1) and heme oxygenase-1 (HO-1) in the aortic wall were also studied as possible markers of such resistance. Chronic blockade of NO production increased ex vivo monocyte adhesion to the endothelium, increased the production of superoxide anions, and activated the NF-kappa B system. In concert with this modification of the redox state of the vascular wall in L-NAME-treated rats, the expression of proinflammatory cytokines interleukin-6, monocyte chemoattractant protein-1, and macrophage colony-stimulating factor was increased. In parallel, expressions of both TIMP-1 and HO-1 were increased. All these changes were prevented by treatment with an angiotensin-converting enzyme inhibitor (Zofenopril). Hypertension associated with a proinflammatory phenotype of the vascular wall induced by blockade of NO production could be due to an increase in oxidative stress, which, in turn, activates the NF-kappa B system and increases gene expression. In parallel, the arterial wall overexpresses factors such as TIMP-1 and HO-1, which could participate in the resistance to cell migration and oxidative stress.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

[Functional compartmentation of the endocrine action of cardiac natriuretic peptides].

The endocrine function of the heart is to secrete Atrial and Brain natriuretic -peptides (ANP and BNP). These peptides are biologically active via particulate guanylate cyclases which generate cyclic GMP, the second intracellular messenger. A polysaccharide antagonist, HS-142-1 has been recently described by a Japanese Group. Cyclic GMP is partly secreted from the target cells into the extra cellular medium in which its accumulation is proportional to the concentration of the natriuretic peptide. Neutral Endopeptidase (NEP) is a zinc ectoenzyme involved in the catabolism of natriuretic peptides. NEP is absent in plasma but present on the surface of endothelial and smooth muscle cells. NEP is mainly expressed at the apical pole of the epithelial cells of the proximal tubule in the nephron. Chronic increase in volume and pressure within the cardiac cavities is associated with the oversecretion of natriuretic peptides. This chronic phenomenon involves the recruitment of all the cardiac myocytes to express natriuretic peptide genes. The clinical application of this hyperplasic phenomenon is congestive heart failure, in which the plasma levels of natriuretic peptides correlate with the level of the -hemodynamic stress. Therefore the plasma levels of natriuretic peptides are good pronostic markers in both experimental and human heart failure. The degree of congestive heart failure as well as the plasma levels of ANP and BNP are also -correlated with the plasma and urinary levels of cyclic GMP. The plasma level of -cyclic GMP is correlated with the endothelial concentration of cyclic GMP but not with the cyclic GMP concentration in smooth muscle cells. From these experimental data, we can conclude that plasma cyclic GMP originates from endothelial cells and is related to particulate guanylate cyclase activity. In contrast natriuretic peptides do not modulate vascular wall cyclic GMP content. The natriuretic action of ANP is probably due to the interaction of the filtered peptide with the particulate guanylate cyclase at the apical pole of the epithelial cells. The apparition of peptiduria associated with natriuresis during NEP inhibition provides evidence of the action of the peptide in the urinary compartment. It is also by a urinary pathway via the macula densa that ANP, and its potentiation by NEP inhibition, decreases renin secretion. The fact that plasma levels of ANP and plasma and urine levels of cyclic GMP correlate with the degree of salt retention in congestive heart failure, provides evidence for chronic desensitization of the system. An up-regulation of Na(+), K(+), 2Cl(-) expression associated with experimental congestive heart failure has recently been shown. Similarly, a modulation of the different sodium transporter systems along the nephron could be one of the counter-regulations leading to desensitization to natriuretic peptides. In conclusion, natriuretic peptides are true endocrine peptides, secreted by the heart, transported in the plasma, filtered by the glomeruli and active at the nephron level. The molecular effector of ANP and cyclic GMP in the epithelial cells is probably the G-kinase II, isoform phosphorylating the cystic fibrosis transmembrane conductance regulator (CFTR). The exact mechanism of desensitization remains to be elucidated.

Atrial Natriuretic Factor↗
PubMed1996

Design of orally active dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme with long duration of action.

Mercaptoacyl dipeptides, containing a glycine linked to a C-terminal 5-phenylproline, have been synthesized in order to obtain new highly efficient dual inhibitors of the two zinc metallopeptidases, neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), which are involved in the control of blood pressure and fluid homeostasis. These compounds have been designed (i) to fit optimally the ACE pharmacophore previously described (Fournié-Zaluski, M. C.; et al. J. Med. Chem. 1994, 37, 1070-1083), through interaction with the S1, S1', and S2' subsites of this enzyme, (ii) and to interact with the S1' and S2' subsites of NEP with the 5-phenylproline moiety outside the catalytic domain (Coric, P.; et al. J. Med. Chem. 1996, 39, 1210-1219). Replacement of Gly by Ala in these mercaptoacyl dipeptides induced an about 100-fold decrease in ACE inhibition. This shows that, in agreement with molecular modeling studies, a steric constraint as weak as a methyl group hinders optimal ACE active site recognition. Among these compounds, the dual inhibitor 26 (RB 106) (Ki, ACE = 0.35 nM; NEP = 1.6 nM) showed excellent pharmacokinetic properties with an almost complete in vivo inhibition of NEP and ACE for more than 4 h after oral administration in mice of a low dose (2.6 x 10(-5) mol/kg) of the inhibitor. Moreover, RB 106 remained active 12 h after oral administration. In spontaneous hypertensive rats, a chronic treatment of orally administered RB 106 (25 mg/kg/day) induced a prolonged hypotensive effect (-28 mmHg) still significant 2 days after the end of the treatment. In DOCA salt rats, a hypotensive response and a significant natriuresis were observed after i.v. administration. RB 106, which is one of the most potent dual inhibitors described to date, could have interesting clinical applications in long term treatment of congestive heart failure and myocardial ischemia.

Administration, Oral↗
PubMed1996

Effects of angiotensin-converting enzyme and neutral endopeptidase inhibitors: influence of bradykinin.

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

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Endothelin antagonists in salt-dependent hypertension associated with renal insufficiency.

Bosentan is a nonspecific antagonist for endothelin (ET) receptors, and BQ123 is a specific inhibitor for ET-A receptors. We compared the effects of bosentan (10 mg/kg intravenously, i.v.) and BQ123 (10 mg/kg/h i.v.) on blood pressure and renal function in deoxycorticosterone acetate (DOCA)-salt rats, Dahl salt-sensitive (Dahl-S) rats, and normotensive Wistar rats. In normotensive Wistar rats, bosentan and BQ123 decreased blood pressure. Only BQ123 decreased glomerular filtration rate (GFR) and filtration fraction. These results indicate that ET-A receptors play a role in glomerular function. In DOCA-salt rats, bosentan and BQ123 caused a decrease in blood pressure to normal range and a decrease in renal vascular resistances. Bosentan decreased filtration fraction. Paradoxically, BQ123 caused a decrease in GFR. In Dahl-S rats, bosentan and BQ123 decreased blood pressure, but blood pressure did not reach normal ranges. Bosentan did not modify renal function, but BQ123 caused a decrease in the GFR and filtration fraction. Our results confirm the importance of specific and nonspecific ET antagonists in decreasing blood pressure in models of salt-dependent hypertension. However nonspecific inhibition of ET action did not improve renal function and specific inhibition of ET-A receptors by BQ123 temporarily worsened renal function.

Animals↗
PubMed1996

Inhibition of both angiotensin-converting enzyme and neutral endopeptidase by S21402 (RB105) in rats with experimental myocardial infarction.

The vasoconstrictor angiotensin II and atrial natriuretic peptide (ANP) are oppositely involved in the development of heart failure, as modeled by myocardial infarction (MI) in rats. MI is a model also characterized by sodium retention despite the elevated plasma ANP levels, showing a desensitization of responses to ANP. S21402 (RB105) {N-[2S,3R-(2-mercaptom-ethyl-1-oxo-3-phenylbutyl) L-alanine]} is a dual inhibitor that inhibits both neutral endopeptidase (Ki = 1.7 +/- 0.3 nM) and angiotensin-converting enzyme (Ki = 4.2 +/- 0.5 nM). Inhibition of neutral endopeptidase protects endogenous ANP, and inhibition of angiotensin-converting enzyme blocks angiotensin II production, whereas inhibition of both peptidases is required to protect endogenous bradykinin (BK). Induction of MI in rats, by ligation of the left coronary artery, increased the base-line plasma ANP, cyclic GMP (cGMP) and renin concentrations, which were related to the degree of MI (moderate and severe MI rats). Urinary excretion of ANP, cGMP and BK was also increased in MI rats and was linked to the infarction size. S21402 (RB105) (25 mg/kg bolus plus 25 mg/kg/hr i.v.) decreased the mean blood pressure and increased natriuresis in MI rats whatever the degree of MI. S21402 (RB105) induced an increase in plasma renin in MI rats despite the elevated base-line levels. S21402 (RB105) did not alter the plasma in ANP in MI rats. However, plasma cGMP was increased by the dual inhibitor, as a function of the infarction severity. Urinary excretion of ANP, cGMP and BK was also increased by S21402 (RB105), proportionally to the infarction size. Whatever the degree of MI, S21402 (RB105) was able to induce natriuresis, characterized by a desensitization of ANP-induced renal responses. Inhibition of both angiotensin-converting enzyme and neutral endopeptidase by potentiating endogenous ANP and BK and blocking angiotensin II production could be an interesting therapeutic approach in heart failure.

Alanine↗
PubMed1994

Dual inhibition of angiotensin-converting enzyme and neutral endopeptidase by the orally active inhibitor mixanpril: a potential therapeutic approach in hypertension.

In the treatment of cardiovascular disease, it could be of therapeutic interest to associate the hypotensive effects due to the inhibition of angiotensin II formation with the diuretic and natriuretic responses induced by the protection of the endogenous atrial natriuretic peptide (ANP). Investigation of this hypothesis requires an orally active compound able to simultaneously inhibit angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP), which is involved in renal ANP metabolism. Such compounds have been rationally designed by taking into account the structural characteristics of the active site of both peptidases. Among them, RB 105, N-[(2S,3R)-2-mercaptomethyl-1-oxo-3-phenylbutyl]-(S)-alanine, inhibited NEP and ACE with Ki values of 1.7 +/- 0.3 nM and 4.2 +/- 0.5 nM, respectively. Intravenous infusion of RB 105 in conscious spontaneously hypertensive rats prevented the pressor response to exogenous angiotensin I and potentiated the natriuretic response to ANP. Infusion of RB 105, at 2.5, 5, 10, 25, and 50 mg/kg per hr decreased blood pressure dose-dependently in conscious catheterized spontaneously hypertensive rats and increased diuresis and natriuresis. Infusion of RB 105 as a bolus of 25 mg/kg followed by 25 mg/kg per hr similarly decreased blood pressure and increased natriuresis in three different models of hypertension (renovascular, deoxycorticosterone acetate-salt, and spontaneously hypertensive rats). Mixanpril, a lipophilic prodrug of RB 105 (ED50 values when given orally to mice, 0.7 mg/kg for NEP; 7 mg/kg for ACE), elicited dose-dependent hypotensive effects of long duration in spontaneously hypertensive rats after oral administration [-37 mmHg for 50 mg/kg twice a day (1 mmHg = 133 Pa) and is therefore the first dual NEP/ACE inhibitor potentially useful for clinical investigations.

Administration, Oral↗
PubMed1994

New dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme: rational design, bioavailability, and pharmacological responses in experimental hypertension.

In the treatment of cardiovascular diseases, it could be of therapeutic interest to associate the hypotensive effects resulting from the inhibition of angiotensin II formation, ensured by endothelial angiotensin-converting enzyme (ACE), with the diuretic and natriuretic responses due to the protection of the endogenous atrial natriuretic peptide (ANP) from inactivation by epithelial neutral endopeptidase (NEP). However, an investigation of this hypothesis requires an orally active compound able to jointly inhibit ACE and NEP. Dual inhibitors have therefore been designed by a rational approach, based on the characteristics of the active sites of both enzymes, which belong to the same family of zinc metallopeptidases, and on the structures of their most potent and selective inhibitors. As both NEP and ACE contain a large S'1-S'2 domain able to accommodate aromatic residues, the cyclic ACE inhibitor 3-(mercaptomethyl)-3,4,5,6-tetrahydro-2-oxo-1H-1-benzazocine-1-ace tic acid was selected as a template. Various aliphatic constraints were introduced on the benzyl moiety of the potent NEP inhibitor N-[2-(mercaptomethyl)-3-phenylpropanoyl]-L-tyrosine (IC50 NEP = 2 nM, IC50 ACE = 25 nM) to improve the fit between the computed most stable conformers of these molecules and the ACE template. New dual inhibitors, of general formula, N-[2(R,S)-(mercaptomethyl)-3(R,S)-phenylbutanoyl]-L-amino acid with IC50 values in the nanomolar range for both enzymes were generated by this approach. The separation of the four stereoisomers using chiral amines and the stereoselective synthesis of the 2-(mercaptomethyl)-3-phenylbutanoyl moiety showed that inhibitors with the 2S,3R configuration are the most potent on both NEP and ACE. The "in vivo" potency of various prodrugs of these inhibitors to inhibit ACE activity in lung and NEP activity in kidney was measured after oral administration in mice. From this pharmacokinetical study the most potent dual inhibitor RB 105 (N-[(2S,3R)-2-(mercaptomethyl)-3-phenylbutanoyl-L-alanine (compound 44c) (KI NEP 1.7 nM, KI ACE 4.5 nM) and its most efficient in vivo prodrug mixanpril, [N-[(2S,3R)-2-[(benzoylthio)methyl]-3-phenylbutanoyl]-L-alan ine (compound 18) (ED50 NEP approximately 1 mg/kg, ED50 ACE approximately 7 mg/kg) were selected. Competition experiments with a tritiated inhibitor of ACE or NEP bound to mouse lung and kidney membranes respectively showed that mixanpril has a long duration of action (> 8 h). As expected, after i.v. administration in the spontaneously hypertensive rat (SHR), RB 105 decreased blood pressure and increased diuresis and natriuresis.(ABSTRACT TRUNCATED AT 400 WORDS)

Alanine↗
PubMed1994

Insulin secretion in rats with chronic nitric oxide synthase blockade.

Nitric oxide, which is produced from L-ar-ginine by a nitric oxide-synthase enzyme, has been shown to be a ubiquitous messenger molecule. Recently, it has been suggested that nitric oxide might influence insulin secretion by activating the soluble guanylate cyclase and generating cyclic guanosine monophosphate (cGMP). We have investigated the role of the nitric oxide pathway in insulin secretion by evaluating the insulin response to several secretagogues in rats in which nitric oxide-synthase was chronically inhibited by oral administration of the L-arginine analogue, NG-nitro-L-arginine methyl ester (L-NAME). Blood pressure and aortic wall cGMP content were used as indices of nitric oxide-synthase blockade. Insulin secretion was evaluated after an intravenous bolus of D-glucose, L-arginine or D-arginine. Chronic L-NAME administration induced a 30% increase in blood pressure and a seven-fold drop in arterial cGMP content. Body weight, fasting plasma glucose and insulin were not influenced by L-NAME administration. First-phase insulin secretion (1 + 3 min) in response to glucose was not significantly different in L-NAME and control rats. The areas under the insulin curve were similar in both groups. Insulin secretion in response to D-arginine or L-arginine in L-NAME-treated and control rats were also similar. In conclusion, chronic nitric oxide-synthase blockade increases blood pressure and decreases aortic cGMP content, but does not alter insulin secretion in response to several secretagogues. Chronic oral administration of L-NAME in the rat provides an adequate animal model for studying the L-arginine nitric oxide-pathway.

Amino Acid Oxidoreductases↗
PubMed1993

Unusual complication of retrograde coronary sinus perfusion with pulmonary artery catheter.

A balloon-tipped catheter placed in the coronary sinus is used during cardiac surgery for retrograde cardioplegia and is secured by a purse string suture placed proximal to the atrioventricular groove in the lower right atrium. We report a complication of this procedure where a pulmonary artery catheter was sutured to the wall of the right atrium by the purse string suture in a patient scheduled for aortocoronary bypass grafting. Pulsatile resistance was noted when we attempted to withdraw the catheter indicating an attachment to the heart. The pulmonary artery catheter within the vascular space after atrial cannulation should be checked since the sheath-protected cannula will enable free mobility.

Aged↗
PubMed1993

Effects of converting enzyme inhibitor and neutral endopeptidase inhibitor on blood pressure and renal function in experimental hypertension.

Angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP) are implicated in the metabolism of several peptides involved in blood pressure and sodium homeostasis control, such as angiotensins, atrial natriuretic factor (ANF), bradykinin and endothelin. The effects of a highly selective NEP inhibitor (NEPI), retrothiorphan, of a converting enzyme inhibitor (CEI), enalaprilat, and of the combination, CEI + NEPI, were assessed in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, spontaneously hypertensive rats (SHRs) and renovascular hypertensive rats. NEPI increased diuresis, natriuresis and urinary cyclic GMP (cGMP), ANF and bradykinin in the three models. NEPI decreased blood pressure in DOCA-salt hypertensive rats only, whereas CEI decreased blood pressure in SHRs and renovascular hypertensive rats only and increased plasma renin. CEI had no effect on urinary aldosterone or bradykinin in any of the three models. CEI + NEPI increased diuresis and natriuresis in DOCA-salt hypertensive rats and SHRs, and increased urinary cGMP, ANF and bradykinin and plasma renin levels. CEI and NEPI interacted significantly to decrease blood pressure and to increase urinary cGMP in SHRs only. Hence, NEPI increases diuresis, natriuresis and urinary cGMP, ANF and bradykinin in experimental hypertension, whereas CEI acts on blood pressure and increases in plasma renin in SHRs and renovascular hypertensive rats. The significant interaction between CEI and NEPI to decrease blood pressure in SHRs indicates that simultaneous blockade of the two metallopeptidases results in potentiation of the hypotensive effect and that the SHRs appear to be a good model for studying NEP and ACE coinhibition. Finally, NEP rather than ACE appears to be involved in bradykinin renal catabolism in experimental hypertension.

Angiotensin-Converting Enzyme Inhibitors↗