Biomedical subjects

M R MacLean

Publications and source records attributed to M R MacLean.

At least 37 records · Page 2Linked to original sources

PubMed1998

Endothelin-1 has haemodynamic effects at pathophysiological concentrations in patients with left ventricular dysfunction.

OBJECTIVES: Plasma levels of immunoreactive endothelin-1 (ET-1) are raised in chronic heart failure. Whether plasma ET-1 contributes to the haemodynamic derangement found in chronic heart failure is not known. We investigated the effects of exogenous ET-1 on the pulmonary and systemic vasculature in patients with left ventricular systolic dysfunction (LVD), with or without overt heart failure. METHODS: ET-1 was infused at 1, 5 and 15 pmol/min into a distal pulmonary artery of ten patients with LVD to achieve plasma concentrations of ET-1 similar to those found in patients with heart failure and pulmonary hypertension. Haemodynamics were measured using a pulmonary thermodilution catheter and an arterial line. Intravascular Doppler and local pulmonary angiography were used to assess local pulmonary blood flow in the first four patients. RESULTS: Systemic haemodynamic changes occurred with ET-1 infusion: mean arterial pressure (100 +/- 3 [standard error of the mean]) to 107 +/- 3 mmHg; p < 0.01) and systemic vascular resistance (1699 +/- 118 to 2033 +/- 135 dynes s/cm5; p < 0.001) rose, while the cardiac index fell from 2.43 +/- 0.17 to 2.20 +/- 0.16 l/min/m2 (p < 0.002). Mean pulmonary artery pressure (21 +/- 2 mmHg) and pulmonary vascular resistance (151 +/- 14 to 147 +/- 14 dynes s/cm5) did not change however. CONCLUSIONS: Exogenous ET-1, when infused to achieve plasma concentrations similar to those in severe heart failure and pulmonary hypertension, causes systemic but not pulmonary vasoconstriction.

Aged↗

PubMed1998

Influence of applied tension and nitric oxide on responses to endothelins in rat pulmonary resistance arteries: effect of chronic hypoxia.

1. The effect of basal tension (transmural tensions 235 +/- 29 mg wt (low tension: equivalent to approximately 16 mmHg) and 305 +/- 34 mg wt (high tension: equivalent to 35 mmHg)) on rat pulmonary resistance artery responses to endothelin-1 (ET-1) and the selective ET(B)-receptor agonist sarafotoxin S6c (S6c) were studied. The effects of nitric oxide synthase inhibition with N(omega)-nitro-L-arginine methylester (L-NAME, 100 microM) on ET receptor-induced responses, as well as vasodilator responses to acetylcholine (ACh) and S6c, were also investigated. Changes with development of pulmonary hypertension, induced by two weeks of chronic hypoxia, were determined. 2. Control rat preparations showed greatest sensitivity for ET-1 when put under low tension (pEC50: 8.1 +/- 0.1) compared with at the higher tension (pEC50: 7.7 +/- 0.1) and there were significant increases in maximum contractile responses to S6c (approximately 80%) and noradrenaline (approximately 60%) when put under high tension. 3. In control pulmonary resistance arteries, both ET-1 and S6c produced potent vasoconstrictor responses. S6c was 12 fold more potent than ET-1 in vessels set at low tension (S6c pEC50: 9.2 +/- 0.1) and 200 fold more potent than ET-1 when the vessels were set at high tension (S6c pEC50: 9.0 +/- 0.1). Chronic hypoxia did not change the potencies of ET-1 and S6c but did significantly increase the maximum contractile response to ET-1 by 60% (at low tension) and 130% (at high tension). 4. In control rat vessels, L-NAME itself caused small increases in vascular tone (5-8 mg wt tension) in 33-56% of vessels. In the chronic hypoxic rats, in vessels set at high tension, L-NAME-induced tone was evident in 88% of vessels and had increased to 26.9 +/- 6.6 mg wt tension. Vasodilatation to sodium nitroprusside, in non-preconstricted vessels, was small in control rat vessels (2-6 mg wt tension) but increased significantly to 22.5 +/- 8.0 mg wt tension in chronic hypoxic vessels set at the higher tensions. Together, these results indicate an increase in endogenous tone in the vessels from the chronic hypoxic rats which is normally attenuated by nitric oxide production. 5. L-NAME increased the sensitivity to S6c 10 fold (low tension) and 6 fold (high tension) only in chronic hypoxic rat pulmonary resistance arteries. It had no effect on responses to ET-1 in any vessel studied. 6. Vasodilatation of pre-contracted vessels by ACh was markedly greater in the pulmonary resistance arteries from the chronic hypoxic rats (pIC50: 7.12 +/- 0.19, maximum: 72.1 +/- 0.2.0%) compared to their age-matched controls (pIC50: 5.77 +/- 0.15, maximum: 28.2 +/- 2.0%). There was also a 2.5 fold increase in maximum vasodilatation induced by ACh. 7. These results demonstrate that control rat preparations showed greatest sensitivity for ET-1 when set at the lower tension, equivalent to the pressure expected in vivo (approximately 16 mmHg). Pulmonary hypertension due to chronic hypoxia potentiated the maximum response to ET-1. Pulmonary resistance arteries from control animals exhibited little endogenous tone, but exposure to chronic hypoxia increased endogenous inherent tone which is normally attenuated by nitric oxide. Endogenous nitric oxide production may increase in pulmonary resistance arteries from chronic hypoxic rats and attenuate contractile responses to ET(B2) receptor stimulation. Relaxation to ACh was increased in pulmonary resistance arteries from chronic hypoxic rats.

Animals↗

PubMed1998

Endothelin receptors mediating contraction of rat and human pulmonary resistance arteries: effect of chronic hypoxia in the rat.

1. We examined the endothelin (ET) receptors mediating contractions to ET-1, ET-3 and sarafotoxin S6c (SX6c) in rat pulmonary resistance arteries by use of peptide and non-peptide ET receptor antagonists. Changes induced by pulmonary hypertension were examined in the chronically hypoxic rat. The effect of the mixed ET(A)/ET(B) receptor antagonist SB 209670 on endothelin-mediated contraction was also examined in human pulmonary resistance arteries. 2. In rat vessels, the order of potency for the endothelin agonists was SX6c = ET-3 > ET-1 (pEC50 values in control rats: 9.12+/-0.10, 8.76+/-0.14 and 8.12+/-0.04, respectively). Maximum contractions induced by ET-3 and ET-1 were increased in vessels from chronically hypoxic rats. 3. The ET(A) receptor antagonist FR 139317 (1 microM) had no effect on the potency of ET-1 in any vessel studied but abolished the increased response to ET-1 in the chronically hypoxic vessels. The ET(A) receptor antagonist BMS 182874 (1 microM) increased the potency of ET-1 in control rat vessels without effecting potency in the pulmonary hypertensive rat vessels. 4. Bosentan (non-peptide mixed ET(A)/ET(B) receptor antagonist) increased the potency of ET-1 in control rat vessels but was without effect in the pulmonary hypertensive rat vessels. Bosentan (1 microM) inhibited responses to SX6c in control and chronically hypoxic rat vessels with pKb values of 5.84 and 6.11, respectively. The ET(B) receptor antagonist BQ-788 (1 microM) did not inhibit responses to ET-1 in any vessel tested but did inhibit responses to both SX6c and ET-3 (pKb values in control and chronically hypoxic rat vessels respectively: SX6c 7.15 and 7.22; ET-3: 6.68 and 6.89). BQ-788 (1 microM) added with BMS 182874 (10 microM) did not inhibit responses to ET-1 in control vessels but caused a significant inhibition of responses to ET-1 in chronically hypoxic preparations. 5. SB 209670 inhibited responses to ET-1 in both control and chronically hypoxic vessels with pKb values of 7.36 and 7.39, respectively. SB 209670 (0.1 and 1 microM) virtually abolished responses to ET-1 in the human pulmonary resistance artery. 6. In conclusion, in rat pulmonary resistance arteries, vasoconstrictions induced by ET-1, SX6c and ET-3 are mediated predominantly by activation of an ET(B)-like receptor. However, lack of effect of some antagonists on ET-1 induced vasoconstriction suggests that ET-1 stimulates an atypical ET(B) receptor. The increase in potency of ET-1 in the presence of some antagonists suggests the presence of an inhibitory ET(A)-like receptor. The influence of this is reduced, or absent, in the chronically hypoxic rats. Increased responses to ET-1 are observed in the chronically hypoxic rat and may be mediated by increased activation of ET(A) receptors. SB 209670 is unique in its potency against responses to ET-1 in both control and chronically hypoxic rats, as well as human, isolated pulmonary resistance arteries.

Animals↗

PubMed1998

Development of endothelin receptors in perinatal rabbit pulmonary resistance arteries.

1. Contractile responses to endothelin-1 (ET-1) and sarafotoxin S6c (S6c) were studied in pulmonary resistance arteries (approximately 320 microm i.d.) from fetal, 0-24 h, 4 day and 7 day rabbits. The effects of the ET(A)-selective antagonist FR139317, the selective ET(B) receptor antagonist BQ-788 and the non-selective ET(A)/ ET(B) receptor antagonist SB 209670, on these responses, were determined. Acetylcholine-induced vasodilation and noradrenaline-evoked contractions were also examined. 2. ET-1 potency was in the following order (pEC50 values): fetal (8.7) = 0-24 h (8.8) = 4 day (8.6) > 7 day (8.0). The order of potency for S6c was 7 days (11.1) = 4 days (10.8) > 0-24 h (9.7) > fetal (8.6). Hence, S6c and ET-1 were equipotent in the fetus but S6c was increasingly more potent than ET-1 with increasing age, being some 1000 times more potent by 7 days. By 7 days, responses to ET-1 were also resistant to both FR139317 and BQ-788. FR139317 inhibited responses to ET-1 in vessels from 0-24 h and 4 day, but not fetal, rabbits (pKb: 6.4 in 4 day rabbits). BQ-788 inhibited responses to ET-1 at all age points except for 7 days (pKb: 6.7 at 0-24 h; 6.2 at 4 days). BQ-788 inhibited responses to S6c at all age points (pKb: 8.5 at 4 days). SB 209670 inhibited responses to ET-1 and S6c at 0-24 h and 4 days (pKb for ET-1: 8.3 and 8.0 respectively; pKb for S6c: 9.2 and 10.2 respectively). 3. Acetylcholine (1 microM) induced vasodilation at all age points (inhibited by 100 microM L-N(omega)-nitroarginine methylester) although the degree of vasodilation was significantly reduced (approximately 75%) at 0-24 h. Noradrenaline induced contraction at all age points except 7 days and its response was significantly enhanced at 0-24 h. 4. Over the first week of life, the potency of S6c increases whilst that to ET-1 decreases suggesting differential development of responses to ET-1 and S6c and heterogeneity of ET(A)- or 'ET(B)-like' receptor-mediated responses. There is no synergism between ET(A) and ET(B) receptors at birth but this is established by 7 days. Immediately after birth rabbit Pulmonary Resistance Arteries are hyperresponsive to ET-1 and noradrenaline but exhibit impaired nitric-oxide dependent vasodilation.

Acetylcholine↗

PubMed1998

Influence of chronic hypoxia on the contributions of non-inactivating and delayed rectifier K currents to the resting potential and tone of rat pulmonary artery smooth muscle.

Exposing rats to chronic hypoxia increased the 4-aminopyridine (4-AP) sensitivity of pulmonary arteries. 1 mM 4-AP caused smooth muscle cell depolarization and contraction in arteries from hypoxic rats, but had little effect in age-matched controls. Chronic hypoxia downregulated delayed rectifier K+ current (IK(V)), which was nearly 50% blocked by 1 mM 4-AP, and non-inactivating K+ current (IK(N)), which was little affected by 1 mM 4-AP. The results suggest that IK(N) determines resting potential in control rats and that its downregulation following hypoxia leads to depolarization, which activates IK(V) and increases its contribution to resting potential. The hypoxia-induced increase in 4-AP sensitivity thus reflects a switch in the major K+ current determining resting potential, from IK(N) to IK(V). This has important implications for the actions and specificity of pulmonary vasodilator drugs.

4-Aminopyridine↗

PubMed1998

5-hydroxytryptamine receptors mediating vasoconstriction and vasodilation in perinatal and adult rabbit small pulmonary arteries.

1. Vasoconstrictor responses to 5-HT, 5-carboxamidotryptamine (5-CT, 5-HT1 receptor agonist), alpha-methyl-5-HT (5-HT2 receptor agonist) and sumatriptan (5-HT1D/1B receptor agonist) were studied in fetal, 0-24 h, 4 day, 7 day and adult rabbit pulmonary resistance arteries (PRAs), alone and in the presence of the NO synthase inhibitor Nomega-nitro-L-arginine methylester (L-NAME). The effect of the selective 5-HT receptor antagonists ketanserin (5-HT2A receptor) and GR55562 (5-HT1B/1D receptor) on vasoconstrictor responses to 5-HT were studied in the presence of L-NAME. Vasodilator responses to 5-CT were also studied in pre-contracted PRAs. 3. 5-HT and alpha-methyl-5-HT were equipotent in causing contraction in the PRAs at each age (e.g. pEC50s for 5-HT and alpha-methyl-5-HT were 6.74+/-0.13 and 6.63+/-0.22 respectively in adult vessels). In the perinatal PRAs, sumatriptan and 5-CT produced negligible contractions, but in adult PRAs, 5-CT and sumatriptan were potent agonists with pEC50s of 6.05+/-0.3 and 5.70+/-0.20 respectively. 4. L-NAME markedly increased the maximum response to 5-HT in the 0-24 h, 4 day and 7 day vessels and increased 5-HT potency in the 4-, 7-day-old and adult rabbit vessels. 5. In perinatal vessels, responses to 5-HT, with L-NAME present, were antagonized by ketanserin (30 nM and 0.1 microM) but not GR55562 (1 microM). A small ketanserin-resistant, GR55562-sensitive component was observed at 0-24 h. In adult vessels, both ketanserin and GR55562 inhibited 5-HT-induced responses. 7. Vasodilator responses to 5-CT were observed in pre-contracted PRAs from 4- and 7-day-old rabbits but not in the fetus, 0-24 h old or adult rabbit vessels. At 4 days the vasodilator response was inhibited both by L-NAME and GR55562. At 7 days the response was only partly blocked by L-NAME and resistant to GR55562. The L-NAME resistant component was antagonized by the 5-HT7 receptor antagonist spiperone (1 microM). 8. The results suggest that 5-HT2A-receptors mediate vasoconstriction in perinatal vessels whilst the 5-HT1D or 5-HT1B receptor contributes in adult rabbit vessels. The 5-HT1D or 5-HT1B receptor mediates NO-dependent vasodilation in vessels from rabbits at 4 days of age whilst 5-HT7 receptors mediate NO-independent vasodilation by 7 days.

Animals↗

PubMed1998

Developmental changes in endothelium-dependent vasodilation and the influence of superoxide anions in perinatal rabbit pulmonary arteries.

ACh-induced vasodilation was investigated in pulmonary arteries from 8 and 2 day pre-term foetal, neonatal (0-12 h and 4 day old) and adult rabbits. The effects of superoxide anion generation [with hypoxanthine (HX, 0.1 mM)/xanthine oxidase (XO, 15 mu ml(-1))], endogenous superoxide dismutase (SOD) inhibition [with the Cu-Zn SOD inhibitor triethylenetetramine (TETA, 1 mM)], endogenous superoxide anion scavenging [by superoxide dismutase (SOD, 50 u ml(-1))] and inhibition of endothelial nitric oxide synthase (eNOS) [with, Nomega-nitro-L-arginine methylester (L-NAME, 0.1 mM)], on basal and ACh-induced NO activity were studied by examining phenylephrine-induced contraction and ACh-induced vasodilation respectively. L-NAME and endothelium removal abolished all ACh-induced vasodilation and 1 microM sodium nitroprusside fully dilated all vessels. ACh-induced vasodilation was absent in the 8 day pre-term foetus and 0-12 h neonate but present at all other ages. L-NAME itself contracted 2 day pre-term foetal vessels. At 0 12 h, SOD, but not the phosphodiesterase 5 inhibitor zaprinast (1 microM), uncovered ACh-induced vasodilation. At this age SOD reduced phenylephrine-induced contraction which was not influenced by TETA, L-NAME or HX/XO, and L-NAME itself did not cause contraction. This suggests both ACh-induced and basal NO activity are compromise in these vessels by endogenous superoxide anion production and deficiencies in endogenous SOD activity. In 4 day vessels, but not adult vessels, L-NAME, TETA and HX/XO augmented contractions to phenylephrine, and L-NAME itself induced vasoconstriction, suggesting that basal NO and SOD activities were present by 4 days but were not evident in the adult. ACh-induced NO activity, and the influence of endogenous SOD on this, were present in the adult (and 4 day) vessels as superoxide generation with HX/XO significantly reduced ACh-induced vasodilation and this effect was inhibited by SOD and augmented by TETA. Increased oxygen tensions > 500 mmHg attenuated ACh-induced vasodilation in the foetal but not neonatal rabbits. Raising the oxygen tension from approximately 20 to approximately 120 mmHg revealed ACh-induced vasodilation in the 8 day pre-term vessels. In summary, superoxide anion accumulation combined with deficiencies in SOD activity may transiently compromise basal and ACh-induced NO activity at birth. Experimental oxygen tensions markedly influence ACh-induced vasodilation in foetal rabbit pulmonary arteries.

Acetylcholine↗

PubMed1998

Heterogeneity of endothelin-B receptors in rabbit pulmonary resistance arteries.

We have previously shown that endothelin-B (ETB) receptors mediate contraction in human and rat pulmonary resistance arteries (PRAs). Here we characterize the endothelin (ET) receptors in rabbits PRAs. PRAs (approximately 150 microns i.d.) were studied using wire myography. Vasoconstrictor effects to ET-1, ET-3, and the ETB-selective agonist sarafotoxin S6c (S6c) were studied in the presence and absence of the ETA receptor antagonist FR139317, the ETB-selective antagonist BQ788, and the mixed ETA/ETB antagonist SB209670. The effect of SB209670 was also studied in human PRAs (approximately 250 microns i.d.). Competitive ET-1 binding studies were also carried out on rabbit small pulmonary artery homogenates. The potencies of the agonists were in the following order: S6c > ET-3 = ET-1. Concentration-response curves (CRCs) to ET-1 were biphasic, with a gradual slope up to approximately 1 nM and a steeper component at higher concentrations of ET-1. Neither FR139317 (1 microM) nor BQ788 (1 microM) inhibited responses to ET-1. BQ788 inhibited S6c- and ET-3 induced contractions with pKb values of 6.8 +/- 0.1 and 6.3 +/- 0.2, respectively. SB209670 inhibited responses to ET-1 in the higher concentration component of the CRC and inhibited responses to S6c in a competitive fashion. pKb values for ET-1 and S6c were 6.8 +/- 0.2 and 7.5 +/- 1, respectively. SB209670 (0.1-1 microM) totally abolished responses to ET-1 in human PRAs. The binding assay established two ET binding sites in rabbit PRAs, one low affinity (Ki = 480 pM) and one high affinity (Ki = 64 fM). The study provides evidence for a heterogeneous population of ETB-like receptors in pulmonary resistance arteries, including an atypical ETB receptor sensitive to SB209670.

Animals↗

PubMed1998

Pulmonary and systemic responses to exogenous endothelin-1 in patients with left ventricular dysfunction.

Plasma levels of immunoreactive endothelin-1 (ET-1) are elevated in chronic heart failure (CHF) and have been reported to correlate closely with pulmonary hemodynamic measurements. We investigated the effects of exogenous ET-1 on the pulmonary vasculature in patients with left ventricular systolic dysfunction (LVD), with or without overt heart failure. ET-1 was infused at 1, 5, and 15 pmol/min into a distal pulmonary artery of 10 patients with LVD. Hemodynamics were measured by a thermodilution catheter and arterial line. Intravascular Doppler and local pulmonary angiography were used to assess local pulmonary blood flow in the first four patients. Systemic hemodynamic changes occurred with ET-1 infusion in a dose-dependent fashion. Mean arterial pressure (100 +/- 8-107 +/- 11 mm Hg; p < 0.01) and systemic vascular resistance (1,699 +/- 375-2,033 +/- 427 dynes/s/cm-5; p < 0.001) rose, whereas the cardiac index fell from 2.43 +/- 0.53 to 2.20 +/- 0.491/min/m2 (p < 0.002). However, mean pulmonary artery pressure (21 +/- 7 mm Hg) and pulmonary vascular resistance (151 +/- 43-147 +/- 43 dynes/s/cm-5) did not change. Exogenous ET-1, when infused into patients with LVD, causes systemic but not pulmonary vasoconstriction.

Aged↗

PubMed1998

EndothelinB receptors in rabbit pulmonary resistance arteries: effect of left ventricular dysfunction.

The endothelin (ET) receptor that mediates vasoconstriction of the isolated rabbit pulmonary resistance artery was characterized using selective ET receptor agonists and antagonists. We also examined changes in ET-induced vasoconstriction brought about by left ventricular dysfunction using the rabbit coronary ligation model. The rank order of potency for contraction was sarafotoxin S6c (S6c) > ET-1 = ET-3, which is characteristic of an ETB-like receptor. The combined ETA/ETB receptor antagonist SB209670 (1 microM) antagonized responses to ET-1 and S6c with estimated pKb values of 6.8 +/- 0.2 and 7.8 +/- 0.2, respectively. BQ788 (1 microM) antagonized responses to S6c and ET-3 (but not ET-1) with estimated pKb values of 7.1 +/- 0.2 and 6.6 +/- 0.1, respectively. The ETA receptor antagonist FR139317 (1 microM), either alone or in combination with BQ788, did not inhibit responses to ET-1. The profile of the ET-1 response was not altered by left ventricular dysfunction. In control rabbits, the inhibitor of nitric oxide synthase N omega-nitro-L-arginine methyl ester (100 microM) had no significant effect on the potency of either ET-1 or S6c. In the coronary-ligated rabbits, however, it significantly increased the potency (10-15-fold) of both ET-1 and S6c. These results suggest that the ET receptor that mediates contraction in rabbit pulmonary resistance arteries has the characteristics of an ETB-like receptor. The responses to ET-1 are not altered by LVD but may be modified by increased release of nitric oxide.

Animals↗

PubMed1996

Hypoxic constrictor response in the isolated pulmonary artery from chronically hypoxic rats.

The aim of this study was to characterise the response to acute hypoxia in pulmonary artery rings isolated from rats exposed to chronic hypoxia for 2 weeks (CH) and following recovery in room air for 24 h (post hypoxic, PH). Large intrapulmonary artery (IPA) rings (internal diameter = 1.5 +/- 0.11 mm; n = 13) from CH and PH rats and age-matched controls were studied. These were precontracted with phenylephrine using standard organ bath procedures at an oxygen tension of 152 mmHg and subjected to an acute hypoxia stimulus (bubbling with 0% O2 giving Po2 = 7 mmHg or 2% O2 giving PO2 = 20 mmHg). Acute hypoxia-induced pulmonary vasoconstriction (HPV) consisted of a transient contraction, a relaxation and a sustained contraction over 30 min. Pulmonary vasoconstriction induced by 0% O2 was significantly reduced in IPA rings from the CH but not PH group compared with the response obtained from the control group. HPV induced by 2% O2 in IPA rings from CH and PH rats was not significantly different from that in control rats not subjected to chronic hypoxia. Mechanical removal of the endothelium or inhibition of nitric oxide (NO) synthase by L-NOARG (300 microM) reduced the contractile phases of HPV in IPA rings from control and CH rats. Carbachol-induced endothelium-dependent relaxation in phenylephrine precontracted IPA rings was significantly attenuated in the CH but not PH group. In conclusion, the present study demonstrates that HPV induced by 0% O2 in rat IPA rings was blunted in CH rats and restored following 24 h in room air, in parallel with changes in endothelium function.

Animals↗

PubMed1996

5-Hydroxytryptamine receptors mediating vasoconstriction in pulmonary arteries from control and pulmonary hypertensive rats.

1. We investigated 5-hydroxytryptamine (5-HT)-receptor mediated vasoconstriction in the main, first branch and resistance pulmonary arteries removed from control and pulmonary hypertensive rats. Contractile responses to 5-HT, 5-carboxamidotryptamine (5-CT, non-selective 5-HT1 agonist), and sumatriptan (5-HT1D-like receptor agonist) were studied. The effects of methiothepin (non-selective 5-HT1 + 2-receptor antagonist) and ketanserin (5-HT2A receptor antagonist) and GR55562 (a novel selective 5-HT1D receptor antagonist) on 5-HT-mediated responses were also studied. Basal levels of adenosine 3':5'-cyclic monophosphate ([cyclic AMP]i) and guanosine 3':5'-cyclic monophosphate ([cyclic GMP]i) were determined and we assessed the degree of inherent tone in the vessels under study. 2. 5-HT was most potent in the resistance arteries. pEC50 values were 5.6 +/- 0.1, 5.3 +/- 0.1, 5.0 +/- 0.2 in the resistance arteries, pulmonary branch and main pulmonary artery, respectively (n = at least 5 from 5 animals). The sensitivity to, and maximum response of, 5-HT was increased in all the arteries removed from the chronic hypoxic (CH) rats. In CH rats the pEC50 values were 5.9 +/- 0.2, 6.3 +/- 0.2, 6.4 +/- 0.2 and the increase in the maximum response was 35%, 51% and 41% in the resistance arteries, pulmonary branch and main pulmonary artery, respectively. Sumatriptan did not contract any vessel from the control rats whilst 5-CT did contract the resistance arteries. In the CH rats, however, they both contracted the resistance arteries (responses to sumatriptan were small) (pEC50: 5-CT; 5.4 +/- 0.2) and the pulmonary artery branches (pEC50: sumatriptan, 5.4 +/- 0.2; 5-CT, 5.4 +/- 0.2). 5-CT also caused a contraction in the main pulmonary artery (pEC50: 6.0 +/- 0.3). 3. Ketanserin (1 nM-1 microM) caused a competitive antagonism of the 5-HT response in all vessels tested. In control rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 8.3, 7.8 and 9.2, respectively. Methiothepin (1 nM-1 microM) inhibited responses to 5-HT in the first branch (estimated pKb value: 7.8) and main pulmonary artery. In CH rats, the estimated pKb values for ketanserin in resistance arteries, pulmonary branches and main pulmonary artery were 7.7, 8.3 and 9.6, respectively. Methiothepin also inhibited contractions to 5-HT in the pulmonary artery branch and main pulmonary artery with estimated pKb values of 7 and 9.5, respectively. In control animals, GR55562 had no effect on responses to 5-HT in any of the vessels tested. In the CH rats the estimated pKb values for GR55562 were 6.5, 7.8 and 7.0 in the pulmonary resistance arteries, first branch and main pulmonary artery, respectively. 4. Large pulmonary arteries from controls demonstrated inherent tone and this was increased three fold in the CH rats. The resistance arteries from controls demonstrated little inherent tone though this was enhanced in those from the CH rats. 5. [Cyclic AMP]i was 259 +/- 23 pmol mg-1 protein in the pulmonary artery branches removed from control rats and decreased to 192 +/- 11 pml mg-1 protein in the CH rats (P < 0.01, n = 8). [Cyclic GMP]i also decreased in the pulmonary artery branches (from 550 +/- 15, control to 462 +/- 31 pmol mg-1 protein in CH vessels, n = 8, P < 0.01) and in the main pulmonary arteries (from 566 +/- 33, control to 370 +/- 25 pmol mg-1 protein in CH vessels, n = 8, P < 0.001). No changes in either [cyclic AMP]i or [cyclic GMP]i were observed in the resistance arteries. 6. The results suggest that the increased vasoconstrictor response to 5-HT in CH rat pulmonary arteries is due to an increase in 5-HT2A-receptor mediated contraction combined with an increase in r5-HT1B-like receptor-mediated contraction. An increase in vascular tone and decreased levels of [cyclic GMP]i in the large pulmonary arteries may contribute to the observed increase in activity of r5-HT1B-like receptor

Animals↗

PubMed1996

Evidence for 5-HT1-like receptor-mediated vasoconstriction in human pulmonary artery.

1. The 5-hydroxytryptamine (5-HT) receptors mediating contraction of human isolated pulmonary artery rings were investigated. Responses to the agonists 5-carboximidotryptamine (5-CT, non-selective 5-HT1 agonist), sumatriptan (5-HT1D-like receptor agonist), 5-HT and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 5-HT1A receptor agonist) were studied. Responses to 5-HT and sumatriptan in the presence of the antagonists, methiothepin (non-selective 5-HT1+2-receptor antagonist), ketanserin (5-HT2A receptor antagonist) and the novel antagonist, GR55562 (5-HT1D receptor antagonist) were also studied. 2. All agonists contracted human pulmonary artery ring preparations in the following order of potency 5-CT > 5-HT = sumatriptan > 8-OH-DPAT. Maximum responses to 5-HT, 5-CT and sumatriptan were not significantly different. 3. Methiothepin 1 nM and 10 nM, but not 0.1 nM reduced the maximum contractile responses to 5-HT but did not alter tissue sensitivity to 5-HT. Methiothepin 0.1 nM, 1 nM and 10 nM had a similar effect on responses to sumatriptan. 4. The 5-HT2A receptor antagonist ketanserin (10 nM, 100 nM and 1 microM) also reduced the maximum contractile response to both 5-HT and sumatriptan without affecting tissue sensitivity to these agonists. 5. The novel 5-HT1D receptor antagonist, GR55562, inhibited responses to 5-HT and sumatriptan in a true competitive fashion. 6. The results suggest that the human pulmonary artery has a functional population of 5-HT1D-like receptors which are involved in the contractile response to 5-HT.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1996

EndothelinB receptor-mediated contraction in human pulmonary resistance arteries.

1. Using wire myography, we have examined the endothelin (ET) receptor subtypes mediating vasoconstriction to ET peptides in human pulmonary resistance arteries (150-200 microns, i.d.). 2. Cumulative concentration-response curves to ET-1, sarafotoxin 6c (SX6c) and ET-3 were constructed in the presence and absence of the selective antagonists FR 139317 (ETA-selective), BMS 182874 (ETA-selective) and BQ-788 (ETB-selective). 3. All agonists induced concentration-dependent contractions. However, the response curves to ET-1 were biphasic in nature. The first component demonstrated a shallow slope up to 1 nM ET-1. Above 1 nM ET-1 the response curve was markedly steeper. Maximum responses to ET-3 and SX6c were the same as those to 1 nM ET-1 and 30% of those to 0.1 microM ET-1. The order of potency, taking 0.3 microM as a maximum concentration was SX6c >> ET-3 > ET-1 (pEC50 values of: 10.75 +/- 0.27, 9.05 +/- 0.19, 8.32 +/- 0.08 respectively). Taking 1 nM ET-1 as a maximum, the EC50 for ET-1 was 10.08 +/- 0.13 and therefore ET-1 was equipotent to ET-3 and SX6c over the first component of the response curve. 4. Responses to ET-1 up to 1 nM were resistant to the effects of the ETA receptor antagonists, FR 139317 and BMS 182874 but were inhibited by the ETB receptor antagonist, BQ-788. Conversely, responses to ET-1 over 1 nM were inhibited by the ETA receptor antagonists, FR 139317 and BMS 182874 but unaffected by the ETB receptor antagonist, BQ-788. 5. The results suggest that at concentrations up to 1 nM, responses to ET-1 are mediated via the ETB receptor, whilst the responses to higher concentrations are mediated by ETA receptors.

Endothelins↗

PubMed1995

Contractile responses to sumatriptan in isolated bovine pulmonary artery rings: relationship to tone and cyclic nucleotide levels.

We examined responses to the 5-hydroxytryptamine 1D (5-HT1D)-receptor agonist sumatriptan in bovine pulmonary artery rings (2-3 mm ID). The effects of agonist-induced tone and agents that alter intracellular cyclic AMP [cyclic AMP]i or [cyclic GMP]i on responses to sumatriptan were investigated. At resting tension, responses to sumatriptan were slight or not evident. In the presence of tone induced by U46619, responses to sumatriptan (1 nM-30 mM) were greatly potentiated, as were responses to the alpha2-adrenoceptor agonist UK14304. Responses to the alpha 1-adrenoceptor agonist phenylephrine (PE) were potentiated only slightly. In the presence of U46619, addition of the adenylyl cyclase activator, forskolin (1 nM-0.1 microM or isoprenaline (ISO 1 microM) induced relaxations and increases in [cyclic AMP]i and resulted in further potentiation of the contractile response to sumatriptan. Addition of 0.1 microM sodium nitroprusside (SNP) inhibited sumatriptan-induced contractions. Whereas sumatriptan alone did not significantly affect [cyclic AMP]i, in the presence of U46619 it decreased [cyclic AMP]i. This effect of sumatriptan was further enhanced in the presence of forskolin. Sumatriptan increased [cyclic GMP]i. Using a nitric oxide (NO) synthase inhibitor and vessels denuded of endothelium, we showed that the increased [cyclic GMP]i in response to sumatriptan was endothelium-dependent and mediated by NO. This increase in [cyclic GMP]i was not observed in the presence of U46619. By measuring cyclic AMP and cyclic GMP phosphodiesterase (PDE) levels, we demonstrated that the point of "cross-talk" between cyclic nucleotides may not be at the level of total PDE activity. These results highlight the important role of [cyclic AMP], [cyclic GMP]i, and endothelium function in the control of 5-HT1D receptor-mediated vasoconstriction, which is dependent on a decrease in [cyclic AMP]i in the absence of an increase in [cyclic GMP]i.

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

PubMed1995

Effects of pulmonary hypertension on vasoconstrictor responses to endothelin-1 and sarafotoxin S6C and on inherent tone in rat pulmonary arteries.

Vasoconstrictor responses to endothelin-1 (ET-1) and the ETB receptor agonist sarafotoxin S6c (SXS6c) were investigated in the main pulmonary artery and pulmonary artery branch removed from rats previously exposed to 10% O2 [chronic hypoxic (CH) rats] or room air (control rats) for 2 weeks. The effects of nitric oxide synthase (NOS) inhibition with L-Nomega-nitroarginine methyl ester (L-NAME) (100 microM) on ET receptor-induced responses in these arteries were also investigated. In control rats, in rings of main pulmonary arteries and pulmonary artery branches. ET-1 induced vasoconstrictor responses. These responses were mediated by the ETA receptor as they were antagonized by the ETA receptor antagonist FR 139317 whereas SXS6c did not vasoconstrict. Chronic hypoxia had no effect on the sensitivity of the main pulmonary arteries to ET-1, whereas small vasoconstrictor responses to SCS6c were evident. ET-1 was more potent in the CH rat pulmonary artery branches than in controls. SXS6c also caused vasoconstriction with a maximum response 30% of that to ET-1 in both endothelium-intact and endothelium-denuded vessels. L-NAME increased the sensitivity to ET-1 in the CH rat main pulmonary arteries and increased the responses to low concentrations of ET-1 in the control rat main pulmonary arteries but did not affect any ET-1 responses in any other vessels. It did disclose responses to SXS6c in control rat main pulmonary arteries. L-NAME itself increased vascular tone to a greater extent in CH rat pulmonary arteries than in controls. In preconstricted pulmonary arteries, however, relaxations to acetylcholine (ACh) were diminished in the CH rats as compared with their controls. All pulmonary artery branches, denuded of their vascular endothelium, relaxed to sodium nitroprusside (SNP) and therefore exhibited endogenous vascular tone. This effect was greatest in the pulmonary artery branches from the CH rats. The results suggest that rat large pulmonary artery responses to ET-1 are normally mediated by ETA receptors. Pulmonary hypertension can potentiate ETA receptor-mediated vasoconstriction and facilitate ETB receptor-mediated vasoconstriction. Endogenous NO may normally suppress ETA receptor-mediated responses in rat main pulmonary arteries. Rat pulmonary arteries exhibit endogenous tone, which is increased by exposure to chronic hypoxia.

Animals↗

PubMed1995

The role of alpha 2-adrenoceptors in the vasculature of the rat tail.

1. The effects of alpha 2-adrenoceptor agonists and antagonists on rat tail skin temperature (tts), an indicator of local cutaneous blood flow, were studied in conscious and anaesthetized rats and in the isolated, Krebs perfused, vascular bed of the rat tail. 2. In conscious rats, at an ambient temperature of 18.5-20 degrees C, tts was 21.0 +/- 0.2 degrees C and core (rectal) temperature (tc) was 38.2 +/- 0.04 degrees C (n = 126). The alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197; 1 mg kg-1, s.c., n = 6), produced a rapid elevation in tts to 29.1 +/- 0.7 degrees C (P < 0.001 vs. saline-treated control group), attained 10 min after injection. tc fell slightly, by 1.0 +/- 0.1 degrees C. The tts response was dose-related over the dose-range tested (0.01-1 mg kg-1, s.c.), with an ED50 of 17 micrograms kg-1, s.c. (n = 6 per dose). 3. The maximum increases in tts in response to a dose of 1 mg kg-1, s.c. of alpha 2-adrenoceptor antagonists were as follows (n = 6 per drug): delequamine (+9.6 +/- 0.8 degrees C) > yohimbine (+9.0 +/- 1.0 degrees C) > WY-26703 (+7.9 +/- 1.3 degrees C) > piperoxan (+5.6 +/- 1.7 degrees C) > idazoxan (+4.6 +/- 1.3 degrees C) > imiloxan (+4.1 +/- 1.3 degrees C) > SKF 104078 (+2.0 +/- 1.9 degrees C) > BDF-6143 (+1.3 +/- 0.8 degrees C). 4. Prazosin (0.3 mg kg-1, s.c.), hydralazine (10 mg kg-1, s.c.) and nifedipine (3 mg kg-1, s.c.) did not increase tts, whereas propranolol (10 mg kg-1, s.c.) evoked a small increase in tts (+2.9 +/- 1.0 degrees C). Pentolinium (2-10 mg kg-1, s.c.) elicited a dose-related increase in tts, which was elevated by 4.4 +/- 1.3 degrees C after a dose of 10 mg kg-1; tc was reduced in a dose-related manner. Drug vehicles (1 ml kg-1, s.c.) had no effect on tts or tc. 5. In anaesthetized rats, idazoxan (300 microg, i.v.) produced a rapid increase in tts which was detectable 2 min after beginning the injection, reaching a peak after 7 min. When the same dose was administered i.c.v., tts also rose, but more slowly. The peak response (+ 3.6 +/- 0.70C, n = 5) was significantly smaller than when idazoxan was administered intravenously (+ 6.3 +/- 1.2 C, n = 5), which suggests that the increase in tts following systemic administration of M2-adrenoceptor antagonists is not due to a central effect. The change in tts was not secondary to changes in blood pressure.6. In the isolated, Krebs perfused, tail vascular bed of the rat, at an ambient temperature of 20-21C,under constant flow conditions (3.5-4.0 ml min-1; n = 4), baseline perfusion pressure was 57 +/- 4 mmHg.5-Hydroxytryptamine (5-HT; 70-150 nM) increased perfusion pressure by 56+/- 9 mmHg. The alpha2-adrenoceptor agonist, UK-14,304 (10 nmol), elicited a further increase in perfusion pressure by27.5 +/- 15 mmHg but had no effect in the absence of 5-HT; this response to UK-14,304 was abolished by rauwolscine (1 microM).7. Under constant pressure conditions (-100 mmHg; n = 9), baseline mean perfusion flow was 2.1 +/- 0.2 ml min-1, and mean tail skin temperature was 31.6 +/- 0.6C. 5-HT (119 +/- 28 nM) decreased tts.by 3.3 +/- 2.0 C and reduced flow by 1.2 +/- 0.3 ml min-1. UK-14,304 (10 nmol) further reduced tts by 3.0 +/- 0.3 C without significant effect on flow; this effect was also abolished by 1 microM rauwolscine.8. We conclude that post-junctional M2-adrenoceptors in the vasculature of the rat tail have a major vasoconstrictor role, controlling both the flow and distribution of blood within the tail and thereby thermoregulatory heat loss from its surface.

Adrenergic Antagonists↗

PubMed1995

EndothelinB receptor-mediated contraction of human and rat pulmonary resistance arteries and the effect of pulmonary hypertension on endothelin responses in the rat.

We investigated the endothelin (ET) receptor subtypes that mediate vasoconstriction in human and rat pulmonary resistance arteries and the effect of pulmonary hypertension on endothelin (ET)-induced contractile responses in rat vessels. In human vessels, sarafotoxin S6c (SXS6c) was more potent than ET-1, but its maximal contractile response was only 20-30% of that to ET-1. Responses to ET-1 were resistant to the ETA antagonist FR 139317, and another, BMS 182874, inhibited responses only to high concentrations of ET-1. In all rat vessels, ET-1, ET-3, and the ETB receptor agonist SXS6c showed the following order of potency: SXS6c = ET-3 > ET-1, and responses to SXS6c were inhibited by the ETB receptor antagonist BQ 788 (1 microM). Maximal responses to ET-1 were greatest in chronic hypoxic (CH) pulmonary-hypertensive rats. In control rats, responses to ET-1 were unaffected by FR 139317 (1 microM) and were potentiated by BMS 182874 (1 microM) and by the mixed ETA/ETB receptor antagonist bosentan (1 microM). A combination of BMS 182874 (10 microM) and the ETB receptor antagonist BQ 788 (1 microM) had no effect on responses to ET-1. In the CH rats, responses to ET-1 were unaffected by FR 139317, BMS 182874, or bosentan. The results suggest the presence of an inhibitory ETA receptor in these vessels that may inhibit ET-1 activation of ETB receptors, and also suggest that the influence of this inhibitory ETA receptor is reduced in CH rat vessels. The results indicate a role for ETB receptors in ET-1-mediated vasoconstriction in both human and rat pulmonary resistance arteries.

Animals↗