Biomedical subjects

G J Dusting

Publications and source records attributed to G J Dusting.

At least 19 recordsLinked to original sources

PubMed2004

Activation of IP prostanoid receptors prevents cardiomyocyte hypertrophy via cAMP-dependent signaling.

The antihypertrophic action of angiotensin-converting enzyme inhibitors in the heart results partly from local potentiation of bradykinin. We have demonstrated that the antihypertrophic action of bradykinin is mediated by the release of nitric oxide from endothelium and elevation of cardiomyocyte cGMP. Whether other paracrine factors derived from the coronary endothelium, such as prostacyclin (PGI2), may act to prevent hypertrophy has not been explored. In the vasculature, activation by PGI2 of IP and EP1 prostanoid receptors elicits vasodilatation (via cAMP-dependent signaling) and vasoconstriction, respectively. The present objective was to determine whether IP prostanoid receptor activation has antihypertrophic actions in adult rat cardiomyocytes (ARCM). The selective IP agonist cicaprost (1 microM) virtually abolished the increase in [3H]phenylalanine incorporation (a marker of hypertrophy) induced either by endothelin-1 (ET-1; 60 nM, n = 10, P < 0.005) or by angiotensin II (1 microM, n = 6, P < 0.005). Cicaprost also inhibited ET-1 induction of c-fos mRNA expression, an additional marker of hypertrophy in ARCM (n = 5, P < 0.005). In the absence of hypertrophic stimuli, cicaprost alone did not significantly influence either marker. The antihypertrophic actions of cicaprost were mimicked by the dual IP/EP1 agonist iloprost (1 microM) in the presence of the EP1 antagonist AH-6809 (3 microM). Furthermore, cicaprost modestly but significantly increased cardiomyocyte cAMP content by 13 +/- 6% (P < 0.05, n = 4), and the antihypertrophic effect of cicaprost was lost in the presence of the cAMP-dependent protein kinase inhibitor H-89 (1 microM, n = 5, P < 0.05). However, ET-1 also induced increases in the activity of the intracellular growth signals ERK1 (by 3-fold) and ERK2 (by 5-fold) in ARCM, and these were not inhibited by cicaprost (P < 0.01, n = 5). Activation of IP receptors thus represents a novel approach to prevention of hypertrophy, and this effect is linked to cAMP-dependent signaling.

Angiotensin II↗

PubMed2001

Endothelial dysfunction induced by oxidized low-density lipoproteins in isolated mouse aorta: a comparison with apolipoprotein-E deficient mice.

We characterized the acute effects of oxidized low-density lipoproteins (oxidized-LDL) on vascular reactivity in isolated aorta from wild-type C57BL/6J mice, and compared these with the chronic alterations in vascular function observed in apolipoprotein-E gene knockout [ApoE(-/-)] mice fed a high-fat diet, which results in hyperlipidemia and atherosclerosis. In the abdominal (but not thoracic) aorta, oxidized-LDL (100 microg/ml) reduced relaxations induced by acetylcholine (10(-9) M-10(-5) M), which are mediated entirely by nitric oxide (NO). The relaxations induced by the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 10(-8) M-10(-4) M), the cyclic GMP analogue 8-bromo cyclic GMP (100 microM) and the nonspecific vasodilator papaverine (100 microM) were not changed by oxidized-LDL. Native LDL had no effect on vasorelaxations. The attenuation of endothelium-dependent relaxations caused by oxidized-LDL mimicked the endothelial dysfunction found in ApoE(-/-) mice. These results are consistent with the suggestion that oxidized-LDL has an important role in the pathogenesis of endothelial NO dysfunction associated with hyperlipidemia and atherosclerosis in these mice.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed2001

Endothelium-dependent vasorelaxation independent of nitric oxide and K(+) release in isolated renal arteries of rats.

1. We investigated whether K(+) can act as an endothelium-derived hyperpolarizing factor (EDHF) in isolated small renal arteries of Wistar-Kyoto rats. 2. Acetylcholine (0.001 - 3 microM) caused relaxations that were abolished by removal of the endothelium. However, acetylcholine-induced relaxations were not affected by the nitric oxide (NO) synthase inhibitor N:(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM), by L-NAME plus the soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ, 1 microM) or by L-NAME plus the cyclo-oxygenase inhibitor indomethacin (10 microM). In rings precontracted with high-K(+)(60 mM) physiological salt solution in the presence of L-NAME, acetylcholine-induced relaxations were abolished. 3. L-NAME-resistant relaxations were abolished by the large-conductance Ca(2+)-activated K(+) channel inhibitor charybdotoxin plus the small-conductance Ca(2+)-activated K(+) channel inhibitor apamin, while the inward rectifier K(+) channel inhibitor Ba(2+) or the gap junction inhibitor 18alpha-glycyrrhetinic acid had no effect. Acetylcholine-induced relaxation was unchanged by ouabain (10 microM) but was partially inhibited by a higher concentration (100 microM). 4. In half of the tissues tested, K(+)(10 mM) itself produced L-NAME-resistant relaxations that were blocked by ouabain (10 microM) and partially reduced by charybdotoxin plus apamin, but not affected by 18alpha-glycyrrhetinic acid or Ba(2+). However, K(+) did not induce relaxations in endothelium-denuded tissues. 5. In conclusion, acetylcholine-induced relaxations in this tissue are largely dependent upon hyperpolarization mechanisms that are initiated in the endothelium but do not depend upon NO release. K(+) release cannot account for endothelium-dependent relaxation and cannot be an EDHF in this artery. However, K(+) itself can initiate endothelium-dependent relaxations via a different pathway from acetylcholine, but the mechanisms of K(+)-induced relaxations remain to be clarified.

Acetylcholine↗

PubMed2000

Endothelial dysfunction limits the antihypertrophic action of bradykinin in rat cardiomyocytes.

We have previously demonstrated that bradykinin blocks hypertrophy of isolated cardiomyocytes: this is dependent on the release of nitric oxide from endothelial cells. In the present study, we investigated the influence of endothelial dysfunction on the antihypertrophic action of bradykinin. Angiotensin II (1 microM) induced a 34 +/- 2% increase in [3H]phenylalanine incorporation (P<0.001), an in vitro marker of hypertrophy, in adult rat cardiomyocytes co-cultured with bovine aortic endothelial cells. This response was blocked by bradykinin (10 microM), but restored by the nitric oxide synthase inhibitor. N(omega)-monomethyl-L-arginine (100 microM). However, the antihypertrophic effect of bradykinin in co-culture was abolished by 24 h pretreatment of endothelial cells with high glucose (25 mM, to mimic hyperglycemia) and attenuated by hydrogen peroxide (100 microM, to mimic oxidative stress). Pretreatment with oxidized low-density lipoprotein (100 microg/ml for 24 h, to mimic hyperlipidemia) was without effect. The hypertrophic response to angiotensin II was not modified by endothelial cell pretreatment. Furthermore, the ability of bradykinin to elevate cGMP (a marker for nitric oxide) in cardiomyocytes co-cultured with endothelial cells was attenuated by pretreatment with either high glucose or hydrogen peroxide. In conclusion, loss of the cardioprotective action of bradykinin against angiotensin II-induced hypertrophy was associated with impaired nitric oxide release from dysfunctional endothelial cells.

Angiotensin II↗

PubMed2000

Type-C natriuretic peptide prevents development of experimental atherosclerosis in rabbits.

1. We investigated the effect of local administration of type-C natriuretic peptide (CNP) on the endothelial dysfunction and development of an atheroma-like neointima induced by a peri-arterial collar in rabbits. 2. Peri-arterial collars were placed on both common carotid arteries allowing local treatment of the collared region with either CNP (10 micromol/L) or saline. After 7 days, uncollared (control) and collared sections were taken from both arteries for pharmacological and morphological analysis. 3. Application of the collar markedly attenuated (P < 0.05) endothelium-dependent vasorelaxation induced by acetylcholine (ACh); inhibition of 5-hydroxytryptamine contraction was 80+/-5% in control sections compared with 44+/-4% in collared sections from the same arteries. Local infusion of CNP (10 micromol/L) into the collar restored ACh-induced vasorelaxation (74+/-3% from collared arteries + CNP vs 77+/-2% from control sections from the same arteries). 4. Type-C natriuretic peptide treatment also reduced (P < 0.05) intimal thickening compared with contralateral collared arteries (intima/media ratio 0.06+/-0.01 vs 0.16+/-0.01). 5. These results provide evidence that locally administered CNP is effective in preventing the endothelial dysfunction and development of a neointima in this model.

Acetylcholine↗

PubMed1999

Cyclosporin A and tacrolimus (FK506) suppress expression of inducible nitric oxide synthase in vitro by different mechanisms.

1 The effects of the immunosuppressant drugs cyclosporin A and tacrolimus (FK506) on nitric oxide synthesis were examined in a murine macrophage cell line (J774) and rat vascular smooth muscle cells (VSMC) in culture for 24 and 48 h, respectively. 2 Cyclosporin A (0.01-10 microM) inhibited by up to 90% accumulation of nitrite induced by lipopolysaccharide (LPS) in both cell lines, but FK506 (0.01-10 microM) had a weaker effect on nitrite accumulation in these cells. Cyclosporin A and FK506 (at 1 microM) also significantly inhibited nitrite production induced by recombinant murine interferon-gamma (rIFNgamma) and recombinant murine interleukin-1beta (rIL-1beta) in J774 and VSMC, respectively. 3 In J774 cells, cyclosporin A (but not FK506) at 1 microM was inhibitory when co-incubated with the inducing agents but not when the cells were treated with the immunosuppressant before or after the inducer. In VSMC, nitrite production was inhibited by co-incubation of cyclosporin A or FK506 with the inducer, or when the immunosuppressants were pre-incubated with cells. In contrast, N-monomethyl L-arginine (NMMA) abolished nitrite production when incubated with either cell type during or after addition of inducing agent, but not if cells were preincubated with NMMA. 4 RNA extracted from treated J774 and VSMC was subjected to reverse transcription-polymerase chain reaction (RT-PCR). Cyclosporin A, but not FK506, suppressed expression of mRNA for NOS2 in a concentration-dependent manner when co-incubated with LPS. 5 The fact that the potency difference between cyclosporin A and FK506 for NO suppression is the opposite to that for inhibition of interleukin-2 generation suggests that the immunosuppressants act in J774 macrophages and VSMC through intracellular mechanisms that differ from those elucidated in T-cells. Cyclosporin A suppresses NOS2 gene transcription, but FK506 acts post-transcriptionally to suppress NO generation in VSMC. 6 Taken together the present data suggest that therapeutic concentrations of cyclosporin A, but not FK506, might well suppress NO production, but FK506 would not have this effect. Suppression of NO might contribute to the side effects of hypertension and nephrotoxicity associated with long-term use of cyclosporin A to prevent transplant rejection.

Animals↗

PubMed1999

Lipocortin-1 preserves myocardial responsiveness to beta-adrenergic stimulation in rat papillary muscle.

1. During septic shock, myocardial contractile dysfunction is accompanied by the release of cytokines and enhanced production of nitric oxide, and the contractile dysfunction is prevented by glucocorticoids. 2. Myocardial dysfunction was induced in vitro by incubation of rat papillary muscle for 15 h with endotoxin (lipopolysaccharide, LPS) and interferon-gamma (IFN-gamma). 3. Both baseline contractile function and inotropic responsiveness to isoprenaline were markedly reduced by the combination of LPS plus IFN-gamma. 4. Lipocortin-1 (LC-1) is induced by glucocorticoids, and LC-1(2-26), its N-terminal fragment, protected the papillary muscle inotropic responsiveness to isoprenaline, but did not affect the decline in baseline contractile function induced by LPS plus IFN-gamma. 5. The mechanisms of this protective action need to be explored further, but LC-1 may prove to be a novel cardioprotective agent for the management of septic shock.

Adrenergic beta-Agonists↗

PubMed1999

Hyperglycaemia abolishes the antihypertrophic efficacy of bradykinin in rat ventricular myocytes.

1. Bradykinin inhibits hypertrophy of rat ventricular myocytes, but only in the presence of endothelial cells. 2. The influence of hyperglycaemia on the ability of bradykinin to prevent hypertrophy was investigated in adult rat ventricular myocytes cocultured with bovine aortic endothelial cells (BAEC). 3. In myocytes cocultured with normal BAEC, angiotensin II (AngII; 1 mumol/L) significantly increased [3H]-phenylalanine incorporation (an in vitro marker of hypertrophy) by 32 +/- 2%. This was abolished by bradykinin (10 mumol/L). 4. Pretreatment of BAEC with high glucose (25 mmol/L for 24 h) prior to coculture with myocytes reduced the antihypertrophic effect of bradykinin, but did not modulate the hypertrophic effect of AngII. 5. Pretreatment of BAEC with hyperglycaemia abolishes the antihypertrophic efficacy of bradykinin in rat ventricular myocytes cocultured with BAEC. This has implications for the action of angiotensin-converting enzyme inhibitors.

Angiotensin II↗

PubMed1998

Cardiodepressant effects of interferon-gamma and endotoxin reversed by inhibition of NO synthase 2 in rat myocardium.

Endogenous nitric oxide (NO) signalling pathways within the myocardium depress myocardial contractile function in septic shock and some cardiomyopathies. We have explored the role of NO synthases (NOSs) in mediating the cardiodepressant actions of interferon-gamma (IFN-gamma) and lipopolysaccaride (LPS) in rat papillary muscle. Muscles from the right ventricle were electrically stimulated (0.2 Hz) at 30 degrees C and isometric contraction monitored. Exposure to IFN-gamma and LPS for 15 h in vitro significantly decreased the peak tension (PT for IFN-gamma + LPS, from 0.13 +/- 0.03 to 0.07 +/- 0.02 g) and rate of tension development (dT/dt for IFN-gamma + LPS, from 1.78 +/- 0.36 to 1.17 +/- 0.28 g/s) compared to untreated controls, and this was prevented by dexamethasone (1 microM) and partly reversed by a non-specific NOS inhibitor, NG-nitro-L-arginine (NOLA, 30 microM). Likewise, the maximum inotropic response of the papillary muscles to isoprenaline (0.001-10 microM) decreased significantly after 15 h treatment with IFN-gamma and LPS (PT from 83 +/- 18 to 28 +/- 6%; +dT/dt from 83 +/- 12 to 31 +/- 7%; -dT/dt from 83 +/- 12 to 38 +/- 6%). Again, the depressant effects of IFN-gamma and LPS on inotropic responsiveness to isoprenaline were completely prevented by pretreatment with dexamethasone (1 microM), by a specific inhibitor of NOS2, mercaptoethylguanidine (MEG, 30 microM) and by NOLA. Whereas dexamethasone and NOLA protected against the attenuation of baseline contractions induced by LPS and IFN-gamma, MEG did not. Western blot analysis of cardiac myocytes showed that there was no constitutive expression of NOS2, but IFN-gamma and LPS induced expression of NOS2, and this was prevented by dexamethasone. Thus IFN-gamma, in the presence of LPS, reduced papillary muscle contraction and decreased responsiveness to beta-adrenoceptor stimulation through induction of NOS2 in the muscle. Increased NO production may contribute to the cardiac depression during septic shock and anti-cancer therapy with cytokines, and perhaps in heart failure.

Adrenergic beta-Agonists↗

PubMed1998

CGRP and nitric oxide of neuronal origin and their involvement in neurogenic vasodilatation in rat skin microvasculature.

1. Sensory nerves are important for the initiation of neurogenic inflammation and tissue repair. Both calcitonin gene-related peptide (CGRP) and nitric oxide (NO) have been implicated in neurogenic vasodilatation and inflammatory responses. 2. A blister model in the rat hind footpad was used as a site to induce neurogenic vasodilatation in response to antidromic electrical stimulation of the sciatic nerve. Blood flux was monitored with a laser Doppler flow monitor. 3. The quantitative contributions of CGRP and NO to vasodilatation were examined by use of the CGRP receptor antagonist CGRP8-37 and NO synthase inhibitors 7-nitroindazole (7-NI), 3-bromo 7-NI and N(G)-nitro L-arginine methyl ester (L-NAME). The potential modulatory role of endothelin was examined by use of the ET(A) receptor antagonist BQ-123. 4. CGRP8-37 (10 microM) was perfused over the blister base before nerve stimulation and continuously throughout the post-stimulation period, resulting in a significant reduction (41%) in the blood flux vascular response. 5. Pretreatment with the specific neuronal NO synthase inhibitors, 7-NI and 3-bromo 7-NI (10 mg kg(-1), i.v.), and of the non-specific L-NAME (100 microM), resulted in significant inhibition of the blood flux response (36%, 72% and 57% decrease, respectively). In contrast, 7-NI treatment in young rats pretreated with capsaicin had no further effect on the vascular response, suggesting that the source of NO is the sensory nerves. 6. BQ-123 (10 microM) significantly enhanced the stimulation-induced blood flux response (61% increase). When 7-NI was co-administered with either CGRP8-37 or BQ-123, the drug actions were additive, suggesting that there was no interaction between NO and CGRP or endothelin. 7. These data suggest that both NO and CGRP participate in neurogenic vasodilatation in rat skin microvasculature and that this response is modulated by endogenous endothelin.

Animals↗

PubMed1998

Nitric oxide in atherosclerosis: vascular protector or villain?

1. Nitric oxide (NO) has important roles in physiological vasodilatation, cytotoxicity and vascular disease. Nitric oxide and prostacyclin (PGI2), both released from the endothelium, act synergistically to inhibit platelet aggregation and adhesion. These autacoids also inhibit the adhesion and migration of leucocytes and, in some arteries, they synergize in terms of vasodilation. 2. The development of atherosclerosis and hyperlipaemia per se is accompanied by impairment of endothelium-dependent vasodilation. 3. Atherosclerosis is associated with marked changes in the activity of isoforms of NO synthase (NOS) in the artery wall, including increased expression of the NOS2 (inducible) isoform in complex human lesions as well as in the neointima of experimental animal models. 4. Failure of NO release from the endothelium with normal physiological stimuli, which has been attributed to a defect in the operation of the endothelial NOS (NOS3), provides conditions propitious for leucocyte adhesion, vasospasm, thrombosis and, in addition, may promote increased proliferation of intimal cells. 5. Nitric oxide and superoxide anions generated by inflammatory cells in atherosclerosis react to form cytodestructive peroxynitrite radicals, potentially causing injury to the endothelium and myocytes, and this may be a factor in apoptosis of cells leading to plaque rupture. 6. We have been able to reverse these NO defects with therapeutic agents, including angiotensin-converting enzyme inhibitors, antagonists of platelet-activating factor and NO donor compounds, all offering promise in protecting against some manifestations of vascular disease.

Animals↗

PubMed1997

Depression of the inotropic action of isoprenaline by nitric oxide synthase induction in rat isolated hearts.

The mechanisms involved in myocardial dysfunction during septic shock are not well understood. We have investigated the effects of endotoxin and the role of nitric oxide (NO) in the beta-adrenoceptor responsiveness of rat isolated, ejecting hearts perfused at 60 mmHg of head pressure. In vivo pretreatment with endotoxin (4 mg/kg, i.p., 3 h before heart isolation) significantly attenuated the inotropic response (increase in left ventricular developed pressure, LVP) to isoprenaline (0.15 microgram) after 30 min equilibration and after a further 90 min of perfusion. The peak rate of LVP development (dP/dtmax) in response to isoprenaline was reduced by endotoxin pretreatment, as was the increase of coronary flow. The depression of ventricular contraction was prevented by pretreatment with dexamethasone (1 mg/kg, i.p., 30 min before endotoxin), and was also restored by perfusion with NG-nitro-L-arginine (L-NA, 10 microM) for 60 min, but not by NG-nitro-D-arginine (D-NA, 10 microM). Mercaptoethylguanidine (MEG, 30 microM), a selective inhibitor of the inducible NO synthase (isoform 2), also reversed the depression of the isoprenaline response caused by endotoxin pretreatment. However, treatment with endotoxin, dexamethasone, L-NA, D-NA or MEG had minimal effects on the baseline parameters of LVP, dP/dtmax and coronary flow, which all tended to decline over the 2 h perfusion period. Western blot analysis using an antibody to NO synthase (isoform 2, but not to isoform 3) revealed the induction of a protein corresponding to NO synthase 2 in the endotoxin-treated hearts but not in control hearts or those treated with dexamethasone or MEG. In summary, these results indicate the endotoxin depresses myocardial contractile function and reduces inotropic responsiveness to beta-adrenoceptor activation. The effect of endotoxin on the inotropic response is mediated, at least in part, by products of an endogenous NO synthase that is suppressed by dexamethasone and a specific inhibitor of NO synthase (isoform 2).

Adrenergic beta-Agonists↗

PubMed1997

A nitric oxide donor (spermine-NONOate) prevents the formation of neointima in rabbit carotid artery.

1. In the present study we investigated the effect of spermine diazeniumdiolate (spermine-NONOate), a nitric oxide donor, on the early development of atheroma-like lesions induced by a peri-arterial collar in rabbits. 2. Spermine-NONOate was given locally by incorporating the compound (1 mg/mL) into a silastic collar, which was applied on one common carotid artery of rabbit while the other carotid artery had a placebo collar (without compound) applied. 3. Fourteen days postimplantation, both carotid arteries were dissected free for histological study (n = 6). 4. After 14 days with collars, treatment with spermine-NONOate had significantly reduced (by 74%) the thickness of the neointima in comparison with the contralateral collared artery without compound. Blood pressure did not change during treatment. Nitric oxide, detected as nitrite, was still released from spermine-NONOate silastic collars after 14 days implantation. 5. These results suggest that locally administered spermine-NONOate is effective in slowing the development of neointima in this model.

Administration, Topical↗

PubMed1997

Induction of nitric oxide synthase in the neointima induced by a periarterial collar in rabbits.

A Silastic collar placed around the common carotid artery of rabbits causes the formation, within 7 days, of an atheroma-like neointima containing cells with the appearance of synthetic-phenotype smooth muscle cells. Using immunohisto-chemistry, we detected the appearance of the cytokine-inducible form of nitric oxide synthase (iNOS, or isoform II) in the neointima of rabbits that had the collar in place for 7 or 14 days. This iNOS immunofluorescence collocalized with anti-smooth muscle myosin in the intima, indicating that it is expressed in smooth muscle cells, and iNOS was also present in a few endothelial cells in collared sections. There was no evidence of iNOS expression in the arterial wall before the neointima was apparent, that is, after only 2 days with the collar. The expression of endothelial NOS (eNOS, or isoform III) immunofluorescence was confined to the endothelial cells in control sections, as it was in collared sections with neointima at 7 and 14 days. Specific immunofluorescence for neuronal NOS (nNOS, or isoform I) was not observed in any sections. Our results suggest that nitric oxide is produced by the inducible isoform of NOS in modified smooth muscle cells of the developing neointima. Activity of iNOS might deprive the endothelium of substrate for nitric oxide production and might explain the compromised endothelium-dependent vasodilatation observed both in this model of atherosclerosis and in human coronary artery disease.

Animals↗

PubMed1996

Perindopril treatment prevents the loss of endothelial nitric oxide function and development of neo-intima in rabbits.

An atheroma-like neo-intima was produced by positioning a flexible collar around the common carotid arteries of normocholesterolaemic rabbits. Vessel segments taken from the mid-region of the collared and control region of the same artery were studied 7 days after surgery. Placebo rabbits were provided ab libitum with regular tap water, and treated animals were supplied with water containing perindopril (0.3 mg/kg/day) for 14 days. Perindopril treatment reduced plasma angiotensin converting enzyme (ACE) activity by 88%, but did not significantly alter arterial blood pressure or heart rate. In control rings from placebo rabbits perindoprilat in vitro (0.1-1.0 microM) reduced the sensitivity to angiotension I up to 20-fold but did not affect that of angiotensin II. In placebo rabbits, the collared arterial segments were approximately five-fold more sensitive to the vasoconstrictor action of 5-HT (P < 0.05) than the corresponding control segments. Perindopril treatment did not prevent the supersensitivity of the collared vessels to 5-HT. Development of the lesion in placebo or perindopril-treated rabbits did not alter the vascular sensitivity to either angiotensin I (10(-9)-10(-5)M) or angiotensin II (10(-10)-10(-6)M). The vasorelaxant action of sodium nitroprusside was similar in collared and control rings, whereas the maximum endothelium-dependent vasorelaxant response to acetylcholine was reduced from 68 +/- 5% in control rings, to 44 +/- 8% (mean +/- S.E.M., n = 9, P < 0.05) in collared rings of placebo-treated rabbits. In the perindopril-treated animals, this impairment of relaxation was restored in collared vessels and was no longer significantly different from the control sections. In contrast, perindoprilat in vitro (1.0 microM) did not alter the vasorelaxant response to acetylcholine in control or collared rings in a separate series of placebo rabbits. Morphologically, vessel segments taken from the centre of the collared artery of all placebo rabbits showed a thickened intima filled with cells that had the appearance of synthetic-state smooth muscle. The intimal/medial cross-sectional area ratio was reduced from 0.11 +/- 0.02 (n = 10) in placebo rabbits to 0.05 +/- 0.01 (n = 9) in perindopril-treated rabbits, whereas cross-sectional area of media of the collared vessels was similar in the two groups. Thus ACE may have important roles in the initiation and progression of atheroma-like lesions. Inhibition of ACE with perindopril reduces intimal thickening and restores the defective vasodilatation induced by the endothelial-dependent vasodilator, acetylcholine.

Angiotensin II↗

PubMed1996

Nitric oxide in coronary artery disease: roles in atherosclerosis, myocardial reperfusion and heart failure.

Nitric oxide (NO), derived from the vascular endothelium or other cells of the cardiovascular system, has an important role in physiological regulation of blood flow and has pathophysiological functions in cardiovascular disease. The mechanisms and enzymes involved in the biosynthesis of NO and biological actions of NO, including vasodilatation, cytotoxicity and inflammation, are briefly reviewed. These reactions involving NO cause pathological disturbances of arterial function, coronary blood flow regulation, and may contribute to cardiac myocyte dysfunction. NO and prostacyclin (PGI2), which is also released from the endothelium, act synergistically to inhibit platelet aggregation and adhesion, and in some arteries these mediators also synergise in terms of vasodilatation. In addition, NO is capable of hyperpolarizing vascular smooth muscle, but activation of the endothelium may cause hyperpolarization and may thus promote vasodilatation by an additional mechanism. After myocardial ischemia and reperfusion, production of NO and superoxide radicals represent important mechanisms of cytotoxicity, causing injury to the coronary endothelium and myocytes and compromising ventricular contractile function. Moreover, upon reperfusion endothelium-dependent vasodilatation is impaired and the coronary arteries constrict, leading to irregular myocardial perfusion. This is a consequence of the accumulation of activated leucocytes that we found to generate endogenous inhibitors of NO. These factors have yet to be fully characterised, but clearly they may have a role in irregularities of myocardial reperfusion and cellular injury. Chronic heart failure is associated both with impairment of endothelium-dependent vasodilatation and with excess production of NO via the inducible NO synthase (iNOS), although it is unclear whether the latter assists or compromises ventricular contractile performance under these conditions. Disturbances in the activity of isoforms of NO synthase in the artery wall also accompany the development of atherosclerosis, providing conditions propitious for vasospasm and thrombosis, and perhaps contributing to cell proliferation. Reversing these NO defects with therapeutic agents including angiotensin converting enzyme (ACE) inhibitors offers promise in protecting against some manifestations of vascular disease.

Angioplasty↗

PubMed1995

Angiotensin-converting enzyme inhibitors reduce neointimal thickening and maintain endothelial nitric oxide function in rabbit carotid arteries.

Application of periarterial collars induced atheroma-like lesions in the carotid arteries of normocholesterolemic rabbits. Vessel segments taken from the mid-region of the collar (cuffed region) and control regions of the same artery were studied at 7 days after surgery. A group of placebo rabbits was provided ad libitum with regular tap water, and treated animals were supplied for 14 days (beginning 7 days before collar application) with water containing perindopril (daily intake of approximately 0.3 mg/kg). Perindopril treatment reduced plasma angiotensin-converting enzyme (ACE) activity by 88% but did not significantly alter arterial blood pressure or heart rate. The sensitivity of arterial rings to angiotensins I and II did not differ between control and cuffed arteries in either placebo or perindopril-treated rabbits, but in rings from both groups of rabbits the sensitivity to the vasoconstrictor action of serotonin was higher in the cuffed segments, as in previous studies. In addition, in placebo rabbits the endothelium-dependent vasorelaxant response to acetylcholine (which results from the release of nitric oxide) was weaker in cuffed arteries than in controls, whereas in the perindopril-treated animals, this impairment of relaxation was restored to the extent that, in cuffed vessels, it was no longer significantly different from the controls. Similar results were obtained in rabbits treated with another ACE inhibitor (ramipril). In contrast, acute treatment with the metabolite, perindoprilat, in vitro (1.0 microM) did not alter the response to acetylcholine in control or cuffed rings from placebo rabbits. Morphologically, vessel segments taken from the center of the cuffed artery of placebo rabbits showed a thickened intima with marked smooth muscle cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

Role of nitric oxide in the actions of substance P and other mediators of inflammation in rat skin microvasculature.

The role of nitric oxide in inflammatory responses to substance P and other mediators of inflammation was examined in rat skin microvasculature in a blister base raised on the hind footpad. Superfusion of substance P (1 microM) over the blister base caused an increase in plasma extravasation and a vasodilator response which was not maintained. N(G)-Nitro-L-arginine (100 microM), an inhibitor of nitric oxide biosynthesis, attenuated vasodilatation and plasma extravasation due to substance P. The inactive isomer N(G)-nitro-D-arginine was without effect. Neurokinin A (1 microM), 5-hydroxytryptamine (1 microM), ATP (50 microM) and vasoactive intestinal polypeptide (1 microM) elicited vasodilation, which for vasoactive intestinal polypeptide was maintained even after washout. 5-Hydroxytryptamine and neurokinin A, but not ATP or vasoactive intestinal polypeptide, significantly increased plasma extravasation. Vasodilatation to neurokinin A, 5-hydroxytryptamine and ATP, and the increase in plasma extravasation due to neurokinin A and 5-hydroxytryptamine were unaffected by N(G)-nitro-L-arginine (100 microM), whereas vasodilation due to vasoactive intestinal polypeptide was significantly attenuated. These findings suggest that in rat skin microvasculature in vivo, nitric oxide is involved in vasodilator responses due to substance P and vasoactive intestinal polypeptide, and plasma extravasation due to substance P, but does not contribute significantly to vasodilatation induced by neurokinin A, 5-hydroxytryptamine or ATP, or the plasma extravasation induced by neurokinin A or 5-hydroxytryptamine.

Adenosine Triphosphate↗