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M R MacLean

Publications and source records attributed to M R MacLean.

At least 19 recordsLinked to original sources
PubMed2003

5-HT moduline: an endogenous inhibitor of 5-HT(1B/1D)-mediated contraction in pulmonary arteries.

(1) 5-HT moduline (5-HTm) is tetrapeptide (Leu-Ser-Ala-Leu) previously shown to act as a specific endogenous antagonist to central 5-HT(1B/1D) receptors. Its effects were investigated in rat and rabbit pulmonary arteries (PAs). (2) In rabbit PAs, contractile responses to the 5-HT(1B/1D) receptor agonist 5-carboxamidotryptamine (5-CT) were inhibited by 1 and 10 micro M 5-HTm in a non-competitive fashion with the maximum contractile response (E(max), per cent of response to 50 mM KCl) being reduced from 65.6+/-7% (n=6) to 39.7+/-6.5% (n=6) and 25.2+/-7.9 (n=4), respectively. The ability of 5-HTm to inhibit responses to 5-CT was increased by the aminopeptidase inhibitor bestatin (10 micro M). (3) In the rabbit PAs, the nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine methylester (L-NAME) potentiated responses to 5-CT (E(max): 106+/-22.5 (n=4)) and this response was also inhibited by 10 micro M 5-HTm (E(max): 38+/-13% (n=8)). (4) 5-HTm (10 micro M) inhibited responses to 5-CT in rat PAs, the E(max) being reduced from 24.8+/-4.1% (n=7) to 15.5+/-3.7% (n=9). 5-HTm induced relaxation of 5-CT-pre-constricted rat PAs with a pIC(50) of 9.0+/-0.6 (n=9). (5) In PAs from chronic hypoxic, pulmonary hypertensive rats, the maximum response to 5-CT was increased to 80+/-8.5% (n=11). 5-HTm reduced this response to 34.4+/-6.3% (n=12). L-NAME markedly inhibited the ability of 5-HTm to inhibit responses to 5-CT (E(max) before 5-HTm: 100.5+/-16% (n=5), E(max) after 5-HTm: 107+/-11.3% (n=4)). (6) In conclusion we show here for the first time that 5-HTm is a non-competitive inhibitor of 5-HT(1B/1D) receptor-mediated constriction in PAs. In rat PAs, L-NAME can inhibit this effect of 5-HTm.

Animals↗
PubMed2001

Contribution of the 5-HT(1B) receptor to hypoxia-induced pulmonary hypertension: converging evidence using 5-HT(1B)-receptor knockout mice and the 5-HT(1B/1D)-receptor antagonist GR127935.

5-Hydroxytryptamine (5-HT)(1B) receptors mediate contraction in human pulmonary arteries, and 5-HT(1B) receptor-mediated contraction is enhanced in pulmonary arteries from hypoxic rats. Here we further examine the role of this receptor in the development of pulmonary hypertension (PHT) by examining (1) the effects of a 5-HT(1B/1D)-receptor antagonist (GR127935) on hypoxia-induced PHT (CHPHT) in rats and (2) CHPHT in 5-HT(1B)-receptor knockout mice. In rats, hypoxia increased right ventricular pressure and right ventricular hypertrophy and induced pulmonary vascular remodeling associated with an increase in pulmonary arterial wall thickness. GR127935 (3 mg. kg(-1). d(-1)) reduced all of these indices. 5-HT(1)-mediated contraction was enhanced in pulmonary arteries of the CHPHT rats. The effects of GR127935 on PHT indices were associated with an attenuation of the enhanced contractile responses to 5-HT and the 5-HT(1)-receptor agonist, 5-carboxamidotryptamine (5-CT), in isolated pulmonary arteries. In wild-type mice, hypoxia increased right ventricular hypertrophy, which was absent in 5-HT(1B)-receptor knockout mice. Hypoxia increased pulmonary vascular remodeling in wild-type mice, and this was reduced in the 5-HT(1B)-receptor knockout mice. Hypoxia increased 5-HT(1)-mediated contraction in pulmonary arteries from the wild-type mice and this was attenuated in the 5-HT(1B)-receptor knockout mice. In conclusion, the 5-HT(1B) receptor plays a role in the development of CHPHT. One possible mechanism may be via enhanced 5-HT(1) receptor-mediated contraction of the pulmonary arterial circulation.

Animals↗
PubMed2001

Increased contractile response to 5-hydroxytryptamine1-receptor stimulation in pulmonary arteries from chronic hypoxic rats: role of pharmacological synergy.

1. 5-Hydroxytryptamine (5-HT)(1)-receptor-induced contraction is enhanced, or uncovered, by elevated vascular tone in many arteries including pulmonary arteries. In hypoxia-induced pulmonary hypertension, the endogenous tone of pulmonary arteries is elevated and this may contribute to increased 5-HT(1)-receptor-induced contraction. Here we investigate the influence of vascular tone induced by endothelin-1 (ET-1), neuropeptide Y (NPY), KCl, 4-aminopyridine (inactivator of K(v) channels, 4-AP) or the calcium ionophore A23187 on contractile responses to the 5-HT(1)-receptor agonist 5-carboxamidotryptamine (5-CT) in small muscular pulmonary arteries from control rats and rats exposed to chronic hypoxia. The influence of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME, 100 microM) was also studied. These conditions were chosen to mimic those that influence pulmonary vascular tone in hypoxia-induced pulmonary hypertension. 2. In control rat small pulmonary arteries, only high concentrations of 5-CT (>1 microM) induced vasoconstriction. Tone induced by NPY, 4-AP and A23187 had no effect on responses to 5-CT whilst responses to 5-CT were increased by ET-1- and KCl-induced tone. In the presence of L-NAME these responses to 5-CT were enhanced further. 3. Responses to 5-CT were enhanced 3 - 4 fold in small pulmonary arteries from hypoxia-exposed, pulmonary hypertensive rats and neither L-NAME nor increasing tone with NPY, 4-AP, A23187, ET-1 or KCl had any further effect on responses to 5-CT. 4. The results suggest that inhibition of nitric oxide synthase combined with KCl- or ET-1-induced vascular tone potentiates responses to 5-HT(1)-receptor-induced contraction in pulmonary arteries in a synergistic fashion and this mimics the effects of chronic hypoxic exposure.

Animals↗
PubMed2001

Potent vasodilator responses to human urotensin-II in human pulmonary and abdominal resistance arteries.

The peptide human urotensin-II (hUT-II) and its receptor have recently been cloned. The vascular function of this peptide in humans, however, has yet to be determined. Vasoconstrictor and vasodilator responses to hUT-II were investigated in human small muscular pulmonary arteries [approximately 70 microm internal diameter (ID)] and human abdominal resistance arteries (approximately 200 microm ID). Vasodilator responses were investigated in endothelin-1 (3 nM) precontracted vessels and, in the small pulmonary vessels, compared with the known vasodilators adrenomedullin, sodium nitroprusside, and acetylcholine. In human small pulmonary arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [-log M concentration causing 50% of the maximum vasodilator effect (pIC(50)) 10.4 +/- 0.5; percentage of reduction in tone (E(max)) 81 +/- 8% (vs. 23 +/- 11% in time controls), n = 5]. The order of potency for vasodilation was human urotensin-II = adrenomedullin (pIC(50) 10.1 +/- 0.4, n = 6) > sodium nitroprusside (pIC(50) 7.4 +/- 0.2, n = 6) = acetylcholine (pIC(50) 6.8 +/- 0.3, n = 6). In human abdominal arteries, hUT-II did not induce vasoconstriction but was a potent vasodilator [pIC(50) 10.3 +/- 0.7; E(max) 96 +/- 8% (vs. 43 +/- 16% in time controls), n = 4]. This is the first report that hUT-II is a potent vasodilator but not a vasoconstrictor of human small pulmonary arteries and systemic resistance arteries.

Abdomen↗
PubMed2001

Effect of adrenomedullin on the production of endothelin-1 and on its vasoconstrictor action in resistance arteries: evidence for a receptor-specific functional interaction in patients with heart failure.

Endothelin-1 (ET-1) and adrenomedullin (ADM) are both produced in the arterial wall, but have opposing biological actions. Evidence from experimental animals suggests a functional interaction between ET-1 and ADM. We have tested this in humans. Small resistance arteries were obtained from gluteal biopsies taken from patients with chronic heart failure (CHF) due to coronary heart disease (CHD), or with CHD and preserved ventricular function. The contractile responses to big ET-1 and to ET-1 in both sets of vessels were studied in the absence (control) and presence of ADM at 20 pmol/l (low ADM) or 200 pmol/l (high ADM), using wire myography. ADM did not affect the conversion of big ET-1 into ET-1 in vessels from patients with either CHD or CHF. Low ADM did not alter the contractile response to ET-1 in vessels from patients with CHF. Low ADM was not tested in vessels from patients with CHD, but high ADM did not affect this response in arteries from these patients. High ADM did, however, significantly reduce the vasoconstrictor effect of ET-1 in vessels from patients with CHF. The maximum response, as a percentage of the response to high potassium, was 199% (S.E.M. 25%) in the control experiments (n=14), 205% (27%) in the low-ADM (n=7) studies and 150% (17%) in the high-ADM (n=6) experiments (P<0.001). Furthermore, the Hill coefficient increased from 0.57+/-0.05 in the absence of ADM to 1.16+/-0.15 in the high-ADM experiments, indicating that ADM at 200 pmol/l specifically antagonized one receptor type in vessels from patients with CHF. We conclude that there is a one-site receptor interaction between ADM and ET-1 that is specific for vessels from patients with CHF. This functional interaction between ADM and ET-1 in resistance arteries may be of pathophysiological importance in CHF.

Adrenomedullin↗
PubMed2000

Accumulation of nitrotyrosine correlates with endothelial NO synthase in pulmonary resistance arteries during chronic hypoxia in the rat.

Nitrotyrosine and eNOS were detected immunocytochemically using specific antibodies in paraffin sections of lung from rats subjected to hypoxia for 2, 7, or 14 days. The staining intensity for eNOS was enhanced in the endothelium of both resistance and conduit pulmonary arteries at 2 days. Staining intensity for eNOS remained elevated at 7 and 14 days in conduit arteries, whereas it progressively increased further in resistance arteries. Nitrotyrosine staining was elevated to a similar degree in endothelium and adjacent vascular smooth muscle. In resistance pulmonary arteries, there was a progressive increase in nitrotyrosine, which matched the increase in eNOS. In conduit pulmonary arteries, nitrotyrosine increased only after 14 days of hypoxia. The results suggest that in chronic hypoxia the up-regulation of eNOS leads to the formation of peroxynitrite which has access to both endothelium and vascular smooth muscle.

Actins↗
PubMed2000

Relationship among antioxidant activity, vasodilation capacity, and phenolic content of red wines.

The relationship among antioxidant activity, based on the electron-spin resonance determination of the reduction of Fremy's radical, vasodilation activity, and phenolic content was investigated in 16 red wines. The wines were selected to provide a range of origins, grape varieties, and vinification methods. Sensitive and selective HPLC methods were used for the analysis of the major phenolics in red wine: free and conjugated myricetin, quercetin, kaempferol, and isorhamnetin; (+)-catechin, (-)-epicatechin, gallic acid, p-coumaric acid, caffeic acid, caftaric acid, trans-resveratrol, cis-resveratrol, and trans-resveratrol glucoside. Total anthocyanins were measured using a colorimetric assay. The total phenolic content of the wines was determined according to the Folin-Ciocalteu colorimetric assay and also by the cumulative measurements obtained by HPLC. The 16 wines exhibited a wide range in the values of all parameters investigated. However, the total phenol contents, measured both by HPLC and colorimetrically, correlated very strongly with the antioxidant activity and vasodilation activity. In addition, the antioxidant activity was associated with gallic acid, total resveratrol, and total catechin. In contrast, only the total anthocyanins were correlated with vasodilation activity. The results demonstrate that the different phenolic profiles of wines can produce varying antioxidant and vasodilatant activities, which opens up the possibility that some red wines may provide enhanced health benefits for the consumer.

Antioxidants↗
PubMed2000

Regional modulation of cyclic nucleotides by endothelin-1 in rat pulmonary arteries: direct activation of G(i)2-protein in the main pulmonary artery.

The ability of endothelin-1 (ET-1) to modulate the cyclic nucleotides, guanosine 3' 5' cyclic monophosphate (cyclic GMP) and adenosine 3' 5' cyclic monophosphate (cyclic AMP) was assessed in the main elastic pulmonary elastic artery (4 - 5 mm i.d.) and the small muscular pulmonary arteries (150 - 200 micrometer i.d.) of the rat. ET-1 caused an increase in cyclic GMP in the larger vessels but had no effect in the smaller arteries. The increase in cyclic GMP was not dependent on an intact endothelium and was inhibited by the ET(A)-receptor antagonist FR139137 (1 microM). ET-1 caused a decrease in cyclic AMP in the main pulmonary arteries, an effect that was partially blocked by FR139317 but not influenced by the ET(B)-receptor antagonist BQ-788 (1 microM) or removal of the vascular endothelium. In contrast, ET-1 caused an increase in cyclic AMP in the small vessels, an effect that was blocked by BQ-788 but unaffected by FR139317. In the main pulmonary arteries, ET-1 caused enhanced incorporation of radiolabelled ADP-ribose by cholera toxin into G(i)2 in the main pulmonary artery, an indicator of its receptor-mediated activation. In summary, we have shown that in the small muscular pulmonary artery of the rat, (where ET(B) mediated vasoconstriction prevails), there is an ET(B)-mediated increase in cyclic AMP with no net effect on cyclic GMP levels. In the large arteries, (where vasoconstriction is mediated via the ET(A) receptor), there is an ET(A)-mediated increase in cyclic GMP (endothelium independent) and an ET(A)-mediated (endothelium independent) decrease in cyclic AMP.

Adenosine Diphosphate Ribose↗
PubMed2000

Contractile responses to human urotensin-II in rat and human pulmonary arteries: effect of endothelial factors and chronic hypoxia in the rat.

Responses to human urotensin-II (hU-II) were investigated in human and rat pulmonary arteries. Rat pulmonary arteries: hU-II was a potent vasoconstrictor of main pulmonary arteries (2 - 3 mm i.d.) (pEC(50), 8.55+/-0.08, n=21) and was approximately 4 fold more potent than endothelin-1 [ET-1] (P<0.01), although its E(max) was considerably less (approximately 2.5 fold, P<0.001). The potency of hU-II increased 2.5 fold with endothelium removal (P<0.05) and after raising vascular tone with ET-1 (P<0.01). E(max) was enhanced approximately 1.5 fold in the presence of N(omega)-nitro-L-arginine methylester (L-NAME, 100 microM, P<0.01) and approximately 2 fold in vessels from pulmonary hypertensive rats exposed to 2 weeks chronic hypoxia (P<0.05). hU-II did not constrict smaller pulmonary arteries. Human pulmonary arteries ( approximately 250 microm i.d.): in the presence of L-NAME, 3 out of 10 vessels contracted to hU-II and this contraction was highly variable. hU-II is, therefore, a potent vasoconstrictor of rat main pulmonary arteries and this response is increased by endothelial factors, vascular tone and onset of pulmonary hypertension. Inhibition of nitric oxide synthase uncovers contractile responses to hU-II in human pulmonary arteries.

Animals↗
PubMed1999

Chronic exposure to hypoxia attenuates contractile responses in rat airways in vitro: a possible role for nitric oxide.

We investigated the effect of chronic hypoxia (10% O(2) for 14 days) on airway responsiveness in rats. Chronic hypoxia significantly (P<0. 05, P<0.01, P<0.01, respectively) attenuated contractions evoked by methacholine (10(-9)-3x10(-4) M), endothelin-1 (10(-10)-3x10(-7) M) and potassium chloride (10(-3)-7x10(-2) M) in rat isolated trachea. To investigate this attenuation, we studied the effect of epithelial removal, indomethacin (3x10(-6) M), and L-nitro arginine methyl ester (L-NAME, 10(-4) M), on contractile responses in control and chronically hypoxic rat trachea. Indomethacin did not alter contractions evoked by methacholine or endothelin-1 in control or hypoxic rats. In contrast, epithelial removal and L-NAME both significantly potentiated responses to methacholine and endothelin-1 in trachea from control and chronically hypoxic rats. In separate experiments, tracheal rings were first contracted with methacholine (10(-6) M) and then relaxed, either by the nitric oxide donor sodium nitroprusside or by the beta(2)-adrenoceptor agonist, salbutamol. Sodium nitroprusside was significantly (P<0.001) more effective at reversing induced tone in tracheal rings from chronically hypoxic than control rats. Salbutamol, however, was equally effective in chronically hypoxic and control rats. These results suggest that, in trachea from both control and chronically hypoxic rats, contractile responses to methacholine and endothelin-1 are inhibited by nitric oxide, probably released from the epithelium. The attenuation of contractile responses in airways from chronically hypoxic rats may be due to an enhanced guanylyl cyclase activity and hence, an increased response to nitric oxide.

Albuterol↗
PubMed1999

Endothelin B receptors are functionally important in mediating vasoconstriction in the systemic circulation in patients with left ventricular systolic dysfunction.

OBJECTIVES: This study was designed to assess the functional importance of endothelin (ET)B receptors in patients with left ventricular systolic dysfunction (LVSD) by comparing the hemodynamic effects of ET-1, a nonselective ET(A) and ET(B) agonist, with ET-3, a selective ET(B) receptor agonist. BACKGROUND: Knowledge of the functional importance of ET(B) receptors in mediating vasoconstriction in chronic heart failure will help determine whether antagonists at both ET(A) and ET(B) receptors are required to fully prevent vasoconstriction to endogenously produced ET-1. METHODS: We infused ET-1 (5 and 15 pmol/min) and ET-3 (5 and 15 pmol/min) into two separate groups of eight patients with LVSD with similar baseline hemodynamic indices. Hemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. RESULTS: Endothelin-1 infusion led to systemic vasoconstriction, with a rise in mean arterial pressure (mean +/- SEM 100 +/- 3 to 105 +/- 3 mm Hg, p < 0.02) and systemic vascular resistance (1,727 +/- 142 to 2,055 +/- 164 dyn/s/cm(-5), p < 0.001) and a fall in cardiac index (2.44 +/- 0.21 to 2.22 +/- 0.20 liters/min/m , p < 0.01). Endothelin-3 infusion also led to systemic vasoconstriction, with a rise in mean arterial pressure (99 +/- 6 to 105 +/- 6 mm Hg, p < 0.01) and systemic vascular resistance (1,639 +/- 210 to 1,918 +/- 245 dyn/s/cm(-5), p < 0.01) and a fall in cardiac index (2.66 +/- 0.28 to 2.42 +/- 0.24 liters/min/m2, p < 0.05). Pulmonary hemodynamic measurements did not change significantly in either group. CONCLUSIONS: Both ET-1 and ET-3 infusions led to systemic vasoconstriction; the hemodynamic changes observed were of a similar magnitude at the same molar concentration. This suggests that ET(B) receptors are functionally important in mediating vasoconstriction, at least in the systemic circulation, in patients with LVSD.

Aged↗
PubMed1999

The effect of chronic hypoxia on endothelin receptor subtype-mediated responses in rat isolated airways.

Contractile responses to endothelin-1 (ET-1) were investigated in isolated trachea from rats previously exposed to chronic hypoxia (10% O(2)) or room air for 14 days. Concentration-response curves were constructed to ET-1 (10(-11)-3x10(-7)m ) in the presence and absence of the ET(A)receptor antagonist FR 139317 (10(-8), 10(-7)and 10(-6)m ), the ET(B)receptor antagonist BQ 788 (10(-6)and 3x10(-6)m ), the non-selective ET receptor antagonist SB 209670 (10(-7)and 10(-6)m ) and a combination of FR 139317 (10(-6)m ) and BQ 788 (10(-6)m ). Concentration-response curves were also conducted to the ET(B)receptor agonist sarafotoxin S6c (10(-11)-3x10(-7)m ). In addition, responses to ET-1 (10(-11)-3x10(-7)m ) were examined in the presence and absence of the nitric oxide synthase inhibitor, L-NAME. In control rat trachea, both FR 139317 and BQ 788 failed to inhibit ET-1-induced contractions and, indeed, FR 139317 (10(-8)m ) and BQ 788 actually potentiated responses. In trachea from chronic hypoxic rats, FR 139317 did not alter ET-1 responses whereas BQ 788 again potentiated ET-1-induced contractions. The non-selective ET receptor antagonist SB 209670 attenuated ET-1-evoked contractions in trachea from control and chronically hypoxic rats. A combination of FR 139317 (10(-6)m ) and BQ 788 (10(-6)m ) also attenuated ET-1 responses in control rat trachea, but not trachea from chronically hypoxic rats. In trachea from both control and chronically hypoxic rats, L-NAME significantly potentiated responses to ET-1. To investigate ET receptor-mediated relaxation, tissues were preconstricted with methacholine and concentration-response curves were conducted to ET-1 (10(-13)-10(-8)m ) in the presence and absence of BQ 788 (10(-6)m ) and to the ET(B)receptor agonist sarafotoxin S6c (10(-13)-10(-8)m ). In trachea from control and chronic hypoxic rats, ET-1 and sarafotoxin S6c evoked only very small, non-reproducible relaxatory responses.

Animals↗
PubMed1999

Pulmonary hypertension, anorexigens and 5-HT: pharmacological synergism in action?

In pulmonary hypertension (PHT), pulmonary vascular resistance is elevated as a result of increased pulmonary vascular tone and pulmonary vascular remodelling. Certain diet pills, such as the fenfluramines, have been associated with the development of PHT. This class of drugs act as indirect 5-HT receptor agonists and can inhibit 5-HT reuptake and cause the release of 5-HT from platelets. Many pulmonary vasoconstrictors, including 5-HT, activate both Gi- and Gq-linked receptors. Increasing evidence suggests that Gq activation might amplify Gi-linked intracellular pathways to 'uncover' or potentiate vasoconstrictor responses - a phenomenon known as pharmacological synergism, which occurs in the pulmonary circulation. In this review the evidence that 5-HT plays a role in PHT and that pharmacological synergism might contribute to its pathology is discussed.

Appetite Depressants↗
PubMed1999

5-hydroxytryptamine receptors mediating contraction in human small muscular pulmonary arteries: importance of the 5-HT1B receptor.

1. The 5-hydroxytryptamine (5-HT) receptors mediating vasoconstriction in isolated human small muscular pulmonary arteries (SMPAs) were determined using techniques of wire myography and reverse transcription-polymerase chain reaction (RT - PCR). 2. The agonists 5-HT, 5-carboxamidotryptamine (5-CT, unselective for 5-HT1 receptors) and sumatriptan (selective for 5-HT1B/D receptors) all caused contraction and were equipotent (pEC50s: 7.0+/-0.2, 7.1+/-0.3 and 6.7+/-0.1, respectively) suggesting the presence of a 5-HT1 receptor. 3. Ketanserin (5-HT2A-selective antagonist, 0.1 microM) inhibited 5-HT-induced contractions only at non-physiological/pathological concentrations of 5-HT (>0.1 microM) whilst GR55562 (5-HT1B/1D-selective antagonist, 1 microM) inhibited 5-HT-induced contractions at all concentrations of 5-HT (estimated pKB=7.7+/-0.2). SB-224289 (5-HT1B-selective antagonist, 0.2 microM) inhibited sumatriptan-induced contractions (estimated pKB=8.4+/-0.1) whilst these were unaffected by the 5-HT1D-selective antagonist BRL15572 (0.5 microM) suggesting that the 5-HT1B receptor mediates vasoconstriction in this vessel. 4. RT - PCR confirmed the presence of substantial amounts of mRNA for the 5-HT2A and 5-HT1B receptor subtypes in these arteries whilst only trace amounts of 5-HT1D receptor message were evident. 5. These findings suggest that a heterogeneous population of 5-HT2A and 5-HT1B receptors co-exist in human small muscular pulmonary arteries but that the 5-HT1B receptor mediates 5-HT-induced vasoconstriction at physiological and pathophysiological concentrations of 5-HT. These results have important implications for the treatment of pulmonary hypertension in which the 5-HT1B receptor may provide a novel and potentially important therapeutic target.

Base Sequence↗
PubMed1998

Pulmonary responses to 5-hydroxytryptamine and endothelin-1 in a rabbit model of left ventricular dysfunction.

OBJECTIVE: To determine whether pulmonary hypertension developed in a coronary artery-ligated rabbit model of left ventricular dysfunction (LVD) and to examine the effects of i.v. 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) on pulmonary arterial pressure (PAP). METHODS: Eight weeks after experimental coronary artery ligation or sham operation, ejection fractions were assessed by echocardiography. The rabbits were later anaesthetised and pulmonary arterial pressure was measured via a catheter inserted into the pulmonary artery via the right external jugular vein. 5-HT (1-400 micrograms/kg) and ET-1 (0.001-4 nmol/kg) were administered i.v. RESULTS: Ejection fraction was significantly decreased from 76.6 +/- 1.4% in sham-operated to 42.2 +/- 1.3% in coronary artery-ligated rabbits (n = 9 in each group; P < 0.001), consistent with LVD. Baseline mean pulmonary arterial pressure was significantly increased in the coronary artery-ligated group compared to the shams, (16.5 +/- 0.5 vs. 11.5 +/- 0.8 mmHg; P < 0.001). A significant degree of right ventricular hypertrophy was found in the coronary artery-ligated rabbits (0.70 +/- 0.04 g/kg final body weight (f.b.wt.), n = 8 cf. 0.48 +/- 0.02 g/kg f.b.wt. in sham-operated controls, n = 8; P < 0.001). There was a significant increase in the percentage of muscularised pulmonary vessels adjacent to alveolar ducts and alveoli < 60 microns i.d. in the LVD rabbits compared with their sham-operated controls (8.5 +/- 0.4 cf. 20 +/- 0.5%; P < 0.0005). 5-HT produced a greater response in the coronary artery-ligated rabbits (a maximum increase of 8.7 +/- 1.0 mmHg in mean pulmonary artery pressure vs. 4.6 +/- 1.5 mmHg for sham-operated controls; P < 0.05). ET-1 did not have any effect on pulmonary arterial pressure in either group. CONCLUSION: In the rabbit, LVD secondary to coronary artery ligation, causes right ventricular hypertrophy, pulmonary vascular remodelling, and an increased PAP consistent with the onset of pulmonary hypertension (PHT). The greater PAP response to i.v. 5-HT in the PHT group supports the hypothesis that this substance could be involved in the development of PHT. A role for ET-1 cannot be excluded, despite its lack of effect on PAP when intravenously administered in either group.

Animals↗