The effect of ischaemia on endothelium-dependent vasodilatation and adrenoceptor-mediated vasoconstriction in rat isolated hearts (original) (raw)
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Naunyn-Schmiedeberg’s Archives of Pharmacology, 1994
We investigated the relative contribution of basal and agonist stimulated EDRF/NO release to the adjustment of coronary tone and myocardial perfusion in conscious dogs by inhibiting coronary endothelial NO formation with NG-nitro-L-arginine methyl ester (L-NAME). Chronically instrumented conscious dogs (n = 9) were prepared for measurement of mean arterial blood pressure (MAP), heart rate (HR), coronary blood flow (CF) and diameter of the left circumflex (CDLc) and left anterior descending (CDLAD) coronary artery, respectively. Intracoronary infusions of L-NAME (30.3 mM; 0.25 ml x min-1) caused significant increases in MAP and decreases in HR. CDLc decreased by 3.8°70 from 3.01_+0.04 to 2.90+0.04 mm and CF decreases by 30% from 12.9_+0.2 to 9.1 +0.2 (aU). Peak reactive hyperemia (CFmax) evoked by 20-s-lasting occlusions of the left circumflex coronary artery decreased from 29.9+0.8 to 25.8_+ 1.0 aU and maximal flow-dependent coronary dilation were reduced from 2.04_+0.08 to 0.91 _+0.12% after inhibition of NO-synthesis. Intracoronary infusions of acetylcholine (ACh), adenosine (Ado), bradykinin (Bk), and papaverine (Pap) caused dose-dependent increases in CDLc and CE Infusion of L-NAME nearly abolished the dilator effect of Ado on CDLc and reduced those to ACh, Bk and Pap. Increases in CF to ACh, Ado and Bk but not to Pap were reduced by L-NAME. Subsequent intracoronary infusions of L-arginine (303 mM; 0.25 ml x min-1) reduced L-NAME-induced CF-changes partly, but did not reverse coronary constriction. These results suggest that inhibition of the continuous release of nitric oxide markedly reduces myocardial perfusion in vivo. Endogenous dilator mechanisms are likewise impaired. Thus, in the heart, nitric oxide deficiency probably cannot be fully compensated for by counterregulating mechanisms.
Minimal ?1- and ?2-adrenoceptor-mediated coronary vasoconstriction in the anaesthetized swine
Naunyn-Schmiedeberg's Archives of Pharmacology, 1990
e-Adrenoceptor-mediated coronary vasoconstriction contributes to the initiation and aggravation of experimental and clinical myocardial ischaemia. However, the extent of e ~-and ~2-adrenoceptor-mediated constriction has not been characterized in the porcine coronary circulation despite the frequent use of this experimental model.
Archiv für Experimentelle Pathologie und Pharmakologie
1. Coronary vasoconstriction was examined in response to the neuronal release of noradrenaline produced by bilateral carotid occlusion and the infusion of tyramine (5-50 gg/kg/min i. v.) in anaesthetized dogs which had been vagotomized and treated with the ]~-adrenoceptor antagonist propranolol (1.0 mg/kg i.v.). These responses were compared to those produced by the infusion of noradrenaline (0.1-0.5 gg/kg/min i.v.). 2. Similar increases in late diastolic coronary resistance were produced by bilateral carotid occlusion (0.70 + 0.25 mmHg min/ml), and intravenous infusions of tyramine, 20~tg/kg/min (0.70+0.12 mmHg min/ml) and noradrenaline, 0.5 gg/kg/min (0.59 _+ 0.11 mm Hg min/ml). 3. Selective antagonism at eladrenoceptors with prazosin (0.5 mg/kg i.v.) attenuated the coronary constrictor response to bilateral carotid occlusion (0.36 + 0.09 mm Hg min/ml), tyramine (0.12 __% 0.06 mm Hg min/ml) and noradrenaline (0.18 + 0.07 mmHg min/ml). Antagonism at c~2-adrenoceptors with idazoxan (1 mg/kg i.v.) attenuated the coronary vasoconstriction produced by bilateral carotid occlusion (0.30 + 0.06 mmHg min/ml), tyramine (0.17 + 0.08 mm Hg min/ml) and noradrenaline (0.12 _+ 0.03 mm Hg min/ml). Combined antagonism at both cq-and e2-adrenoceptors with prazosin and idazoxan abolished the responses to bilateral carotid occlusion, tyramine and noradrenaline. 4. These results show that coronary vasoconstriction produced by either neuronally released or exogenous noradrenaline is mediated by both cqand c~2-adrenoceptors. It appears that in the coronary resistance vessels of the dog postjunctional al-and c~2adrenoceptors are both innervated by sympathetic nerves.
1. Coronary vasoconstriction was examined in response to the neuronal release of noradrenaline produced by bilateral carotid occlusion and the infusion of tyramine (5-50 gg/kg/min i. v.) in anaesthetized dogs which had been vagotomized and treated with the ]~-adrenoceptor antagonist propranolol (1.0 mg/kg i.v.). These responses were compared to those produced by the infusion of noradrenaline (0.1-0.5 gg/kg/min i.v.). 2. Similar increases in late diastolic coronary resistance were produced by bilateral carotid occlusion (0.70 + 0.25 mmHg min/ml), and intravenous infusions of tyramine, 20~tg/kg/min (0.70+0.12 mmHg min/ml) and noradrenaline, 0.5 gg/kg/min (0.59 _+ 0.11 mm Hg min/ml). 3. Selective antagonism at eladrenoceptors with prazosin (0.5 mg/kg i.v.) attenuated the coronary constrictor response to bilateral carotid occlusion (0.36 + 0.09 mm Hg min/ml), tyramine (0.12 __% 0.06 mm Hg min/ml) and noradrenaline (0.18 + 0.07 mmHg min/ml). Antagonism at c~2-adrenoceptors with idazoxan (1 mg/kg i.v.) attenuated the coronary vasoconstriction produced by bilateral carotid occlusion (0.30 + 0.06 mmHg min/ml), tyramine (0.17 + 0.08 mm Hg min/ml) and noradrenaline (0.12 _+ 0.03 mm Hg min/ml). Combined antagonism at both cq-and e2-adrenoceptors with prazosin and idazoxan abolished the responses to bilateral carotid occlusion, tyramine and noradrenaline. 4. These results show that coronary vasoconstriction produced by either neuronally released or exogenous noradrenaline is mediated by both cqand c~2-adrenoceptors. It appears that in the coronary resistance vessels of the dog postjunctional al-and c~2adrenoceptors are both innervated by sympathetic nerves.
British Journal of Pharmacology, 1994
1 Coronary vascular responses to bilateral carotid occlusion (BCO) and the intravenous infusion of tyramine (Tyr, 20fLg kg-' min-) and noradrenaline (NA, 0.5 Lg kg-min-') were examined after bilateral vagotomy and antagonism of P-adrenoceptors. BCO, Tyr and NA decreased large coronary artery diameter and increased mean coronary resistance and systemic arterial pressure without affecting heart rate. 2 Inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA, 5 and 15 mg kg-') significantly increased mean arterial pressure and decreased heart rate and large coronary artery diameter. Mean coronary resistance was unaffected by either dose of L-NNA. L-NNA significantly reduced depressor and coronary vasodilator responses to the endothelium-dependent vasodilator acetylcholine (ACh, 0 tg kg-', i.v.). Systemic and coronary vasodilator responses to sodium nitroprusside (SNP, 5 ftg kg-') were unaffected by L-NNA with the exception that the dilatation of the large coronary artery was significantly enhanced by the higher dose. 3 L-NNA significantly enhanced constriction of the large coronary arteries caused by BCO, Tyr and NA but did not affect the increases in mean coronary resistance or systemic arterial pressure. 4 Inhibition of NO synthesis enhances adrenergic constriction of large coronary arteries caused by both neuronally released and exogenous noradrenaline. In contrast, L-NNA did not affect adrenergic constriction of coronary or systemic resistance vessels. Endothelium-derived NO may play an important role in the modulation of noradrenergic vasoconstriction in coronary conductance arteries.
Journal of Pharmacy and Pharmacology, 2002
The hypothesis that the coronary vasodilator effects of adenosine receptor agonists are independent of the vascular endothelium or mediators derived therefrom was examined in guinea-pig isolated working hearts. Adenosine receptor agonists, 5« -(N-ethylcarboxamido)adenosine (NECA; two-fold selective for A 2 over A 1 receptors), 2-[p-(2-carboxyethyl)phenylethylamino]-5« -N-ethylcarboxamidoadenosine (CGS21680; A 2A selective), N 6 -cyclopentyl-adenosine (CPA; A 1 selective) and N 6 -(3-iodobenzyl)adenosine-5« -N-methyluronamide (IB-MECA; A 3 selective), were infused (3¬ 10 7 M) after endothelium removal by passing oxygen through the coronary circulation. In spontaneously beating hearts, CGS21680 and NECA increased, while CPA decreased, coronary ow. NECA and CPA reduced heart rate, left ventricular pressure and aortic output. The nitric oxide synthase (NOS) inhibitor, N G -nitro-L-arginine (L-NOARG ; 3¬ 10 5 M) abolished the vasodilatation by NECA but not CGS21680, indicating that nitric oxide (NO) of a non-endothelial source mediated the NECA response. Coronary vasodilatation by CGS21680 was inhibited by the A 2A receptor antagonist, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo [2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM241385). Indometacin (10 6 M) attenuated the coronary vasodilatation to CGS21680, suggesting a partial role for cyclooxygenase products. IB-
British Journal of Pharmacology, 1998
1 The functional role of the nitric oxide (NO)/guanosine 3':5'-cyclic monophosphate (cyclic GMP) pathway in experimental myocardial ischaemia and reperfusion was studied in rat isolated hearts. 2 Rat isolated hearts were perfused at constant pressure with Krebs-Henseleit buer for 25 min (baseline), then made ischaemic by reducing coronary¯ow to 0.2 ml min 71 for 25 or 40 min, and reperfused at constant pressure for 25 min. Drugs inhibiting or stimulating the NO/cyclic GMP pathway were infused during the ischaemic phase only. Ischaemic contracture, myocardial cyclic GMP and cyclic AMP levels during ischaemia, and recovery of reperfusion mechanical function were monitored.