The effect of ischaemia on endothelium-dependent vasodilatation and adrenoceptor-mediated vasoconstriction in rat isolated hearts (original) (raw)
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.
Clinical Physiology - CLIN PHYSIOL, 1989
The effects of selective a,-adrenergic blockade with doxazosin on regional myocardial tissue blood flow was studied in anaesthetized cats with acute coronary artery occlusion. Reflex tachycardia was prevented by selective f3 ,-adrenergic blockade with atenolol and coronary perfusion pressure was kept constant by partial stenosis of the descending aorta. Administration of atenolol reduced cardiac mechanical work-load by its negative inotropic and chronotropic effects, and reduced myocardial tissue blood flow in normally perfused myocardium. This reduction was most pronounced in the endocardial half-layer of the myocardium adjacent t o the ischaemic region. Administration of doxazosin in this situation clearly reduced peak systolic and coronary perfusion pressure. But when coronary perfusion pressure was raised to pre-administration values, measurements of regional blood flow revealed no changes either in ischaemic or non-ischaemic myocardium. Also, there was no sign of redistribution of blood flow between endocardial and epicardial tissue in any area. This study, therefore, indicates that a,-adrenoceptors play a minor role in the regulation of coronary blood flow in normal myocardium as well as ischaemic myocardium.
The nitroxyl anion (HNO) is a potent dilator of rat coronary vasculature
Cardiovascular Research, 2007
Objective: The nitroxyl anion (HNO) is the one-electron reduction product of NO U. This redox variant has been shown to be endogenously produced and to have effects that are pharmacologically distinct from NO U. This study investigates the vasodilator and chronotropic effects of HNO in the rat isolated coronary vasculature. Methods: Sprague-Dawley rat hearts were retrogradely perfused with Krebs' solution (8 ml/min) using the Langendorff technique. Perfusion pressure was raised using a combination of infusion of phenylephrine and bolus additions of the thromboxane mimetic U46619 to attain a baseline perfusion pressure of 100-120 mm Hg. The vasodilator effects of a nitroxyl anion donor, Angeli's salt, were examined in the absence and presence of HNO and NO U scavengers, K + channel inhibition, and soluble guanylate cyclase (sGC) inhibition. In addition, the inotropic and chronotropic effects of Angeli's salt were examined in hearts at resting perfusion pressure (50-60 mm Hg) and compared to responses evoked by acetylcholine and isoprenaline. Results: Angeli's salt causes a potent and reproducible vasodilatation in isolated perfused rat hearts. This response is unaffected by the NO U scavenger hydroxocobalamin (0.1 mM) but is significantly inhibited by the HNO scavenger N-acetyl-L-cysteine (4 mM), suggesting that HNO is the mediator of the observed responses. Vasodilatation responses to Angeli's salt were virtually abolished in the presence of the sGC inhibitor ODQ (10 μM). The magnitude of the vasodilatation response to Angeli's salt was significantly reduced in the presence of 30 mM K + , 10 μM glibenclamide and in the presence of the calcitonin gene-related peptide (CGRP) antagonist CGRP (8-37) (0.1 μM). Angeli's salt had little effect on heart rate or force of contraction, whilst isoprenaline and acetylcholine elicited significant positive and negative cardiotropic effects, respectively. Conclusions: The HNO donor Angeli's salt elicits a potent and reproducible vasodilatation response. The results suggest that the response is elicited by HNO through sGC-mediated CGRP release and K ATP channel activation.
Adrenergic mechanism in the control of endothelial function
There is considerable evidence that many disease are associated with endothelial dysfunction and reduced nitric oxide production such as hypertension, obesity, dyslipidemias, diabetes, heart failure, atherosclerosis. Notably these conditions are also characterized by alteration in the adrenergic tone.
Vasomotor response to different endothelium-dependent vasodilators in an animal model
The Journal of invasive cardiology, 2012
Incomplete re-endothelialization of stents can be revealed as paradoxical vasoconstriction with endothelium-dependent vasodilators. As no consensus exists about the best method or agent, our objective is to analyze the response to different drugs in a coronary swine model. Twenty-seven stents were implanted in 9 domestic swine. The vessel diameter of proximal and distal segments (≥5 mm) was assessed immediately post implantation. Different endothelium-dependent vasodilators were used: intracoronary (IC) acetylcholine, 20 μg (A2) and 40 μg (A4), IC serotonin (S), 100 μg, and isoproterenol (I), intravenous infusion. The results are presented as constriction (%) compared with maximal vasodilation with IC nitroglycerin (N, 200 μg). In 10 vessels (37%), A4 provoked an occlusive spasm. Acetylcholine induced a higher degree of vasoconstriction (A4, 42 ± 39%; A2, 16 ± 14%) than the rest of the agonists (S, 6 ± 12%; I, 6 ± 11%; P<.01). The constriction rate was not related to the induced ...
European Journal of Pharmacology, 1996
The possible modulation by the endothelium of the contractile responses to sympathetic nerve stimulation was examined in isolated superfused human saphenous vein. Contractile response curves for transmural nerve stimulation and noradrenaline were higher in endothelium-denuded than in intact human saphenous vein rings. In vessels with endothelium, transmural nerve stimulation-and noradrenaline-induced contractions were unaffected by the cyclooxygenase inhibitor, indomethacin (10 txM), but were potentiated by the nitric oxide (NO) synthase inhibitor, L-N°'-nitro-L-arginine (L-NNA, 3 ~M) even when combined with o-arginine (0.3 mM), but not with L-arginine (0.3 mM). As in the case of noradrenaline, contractile responses to 5-HT, but not to KC1, were enhanced by endothelium removal, L-NNA or L-NNA Flus D-arginine, but were unaffected by L-NNA plus L-arginine. The guanylyl cyclase inhibitor, methylene blue (10 ~M), potentiated both transmural nerve stimulation-and noradrenaline-induced contractions in endothelium intact rings, whereas it enhanced, although to a lesser degree, only the neurally evoked contractions in endothelium-denuded human saphenous vein. In the vessels without endothelium L-NNA failed to affect the vasoconstriction induced by both transmural nerve stimulation and noradrenaline. Our results suggest that at least two inhibitory factors are involved in modulating the sympathetic vasoconstriction in the human saphenous vein: (1) at a postjunctional level, NO, the release of which from endothelial cells is probably stimulated by the activation of specific receptors, and (2) at a prejunctional level, an unidentified vasodilator agent, which is unmasked by the removal of the endothelium layer and which is probably co-released along with noradrenaline, and which acts through the guanylyl cyclase pathway.
British Journal of Pharmacology, 1977
I The effects of noradrenaline upon the cardiovascular system of the rat, anaesthetized with pentobarbitone, have been investigated. 2 Noradrenaline produces a dose-dependent increase in mean arterial blood pressure (MABP) which is due entirely to an increase in cardiac output; total peripheral vascular resistance (TPR) remains unchanged. 3 Following P-adrenoceptor blockade the pressor response to infused noradrenaline is enhanced and is now due mainly to an increase in TPR; the increment in cardiac output is reduced. 4 After a-adrenoceptor blockade the pressor response is greatly reduced; the residual increase in MABP is due solely to an increase in cardiac output. 5 After ganglion blockade resting cardiac output and TPR both fall, resulting in a reduction in MABP. The pressor response to noradrenaline is enhanced and is now due to increases in both TPR and in cardiac output. 6 The cardiovascular response of the anaesthetized rat to noradrenaline can be explained in terms of classical a-and /J-adrenoceptor stimulation by the amine; the unusual form of the response may be due to an effective predominance of/-adrenoceptor-mediated effects in this species. 7 It is suggested that the failure of exogenous noradrenaline to produce a rise in TPR results from a balance between the a-adrenoceptor-mediated increase and fl-adrenoceptor-mediated decrease in this variable. However, this proposed balance is lost if resting vasoconstrictor tone is reduced by ganglion blockade.
British Journal of Pharmacology, 1992
on vasodilatation induced by ATP, substance P, 5-hydroxytryptamine (5-HT), bradykinin and sodium nitroprusside (SNP) were examined in the guinea-pig coronary bed, by use of a Langendorff technique. The effects of these inhibitors of nitric oxide synthesis were assessed on their ability to inhibit both the amplitude and the area of the vasodilator response. 2 The vasodilator responses evoked by low doses of 5-HT (5 x 10`-'°5 x 10 mol) were almost abolished by L-NAME and L-NOARG (both at 10-5, 3 x 10-5 and 1O-4M), although L-NOARG (3 x 10-s M) was significantly less potent than L-NAME (3 x 10-5 M) as an inhibitor of vasodilator responses to 5-HT (5 x 10-8 mol). 3 The vasodilator responses evoked by substance P (5 x 102-5 X I0-mol) were reduced in the presence of L-NAME and L-NOARG (both at 10-5 and 3 x 10-5 M). The response to substance P was almost abolished by L-NAME and L-NOARG (both at 10-4 M). 4 The amplitude of the vasodilator responses to ATP (5 x 10-" and 5 x 10-9-5 x 10-mol) was little affected by either L-NAME or L-NOARG (both at 10-5, 3 x 10-5 and 10-4 M). However, the area of the response to ATP (5 x 10-`o-5 x 10-7 mol) was inhibited by L-NAME (10-5, 3 x 10-5 and 10-4M) and to a lesser extent by L-NOARG (10-5 and 10-M). 5 The amplitude and area of the vasodilator responses to bradykinin (5 x 10-12-5 x 10-11 mol) were reduced, but not abolished, by L-NOARG and L-NAME. 6 Neither the amplitude nor area of the responses to sodium nitroprusside (5 x 10-'°-5 x 10-7 mol) were inhibited by either L-NAME or L-NOARG (both at 10-5 and 3 x 10-5 M). 7 It is concluded that in the guinea-pig coronary vasculature, the vasodilatation evoked by substance P and low doses of 5-HT is mediated almost exclusively via nitric oxide, whereas the vasodilatations evoked by ATP and bradykinin appear to involve other mechanisms in addition to the release of nitric oxide. L-NAME was a more effective agent than L-NOARG in inhibiting the vasodilator actions of 5-HT and ATP in this preparation.