The effect of ischaemia on endothelium‐dependent vasodilatation and adrenoceptor‐mediated vasoconstriction in rat isolated hearts

Abstract

1 The aim of this study was to investigate whether global ischaemia and reperfusion in rat isolated hearts affects endothelium-dependent vasodilatation and adrenoceptor-mediated vasoconstriction. In addition, it was first determined whether inhibition of the actions of nitric oxide (NO) influenced the responses to a-adrenoceptor agonists in the rat coronary vasculature.2 In rat isolated, Langendorff perfused hearts, inhibition of NO with haemoglobin (Hb, 6 gM) significantly inhibited the vasodilator responses to the endothelium-dependent vasodilators, acetylcholine (ACh, 3-100 pmol), carbachol (CCh, 10-300 pmol), bradykinin (Bk, 1-30 pmol) and histamine (0.3-10 nmol) but did not affect responses to the endothelium-independent vasodilator, sodium nitroprusside (SNP, 0.01-1 nmol). 3 Inhibition of the action of NO by Hb significantly enhanced the vasoconstrictor response to the nonselective a-adrenoceptor agonist, noradrenaline (NA, 0.1-1O nmol) and the a2-adrenoceptor agonist, B-HT 920 (0.001 -1 imol) but had no effect on the vascular response to the ac-adrenoceptor agonist, methoxamine (MTX, 10-300 nmol). 4 In the perfused hearts ischaemia, induced by 30 min perfusion at 5% of the normal rate of flow, followed by 15 min of reperfusion (ischaemia/reperfusion) selectively impaired the vasodilator responses to ACh and CCh which act by muscarinic receptor stimulation but did not affect responses to the other endothelium-dependent vasodilators Bk and histamine or to the endothelium-independent dilator SNP. 5 After ischaemia/reperfusion the coronary vasoconstrictor responses to B-HT 920 were slightly but significantly enhanced whereas the responses to NA and MTX were unaffected. 6 Thus, in the rat isolated heart, low flow induced-ischaemia and reperfusion causes a selective impairment of muscarinic receptor-mediated vasodilatation but does not impair responses to all endothelium-dependent vasodilators. Enhanced constrictor responses to noradrenaline and B-HT 920 in the presence of Hb indicates that endogenous NO modulates the constriction of coronary resistance vessels in response to stimulation of a2-adrenoceptors. Ischaemia and reperfusion in this isolated vascular bed caused only a small increase in the coronary vasoconstrictor response to cx2-adrenoceptor stimulation. It appears that in the rat isolated heart the degree of endothelial dysfunction caused by ischaemia/reperfusion is insufficient to cause a functionally significant change in a-adrenoceptormediated constriction.

Adenosine receptor-mediated coronary vascular protection in post-ischemic mouse heart

“…Data verify selective endothelial dysfunction following I/R in a blood-cell free model, confirming the importance of neutrophil-independent processes in vascular injury (Tsao and Lefer, 1990;Pannangpetch and Woodman, 1996;Baxter, 2002;Flood et al, 2002). Importantly, findings reveal exogenous A 3 AR and endogenous A 1 AR activation significantly limit this vascular dysfunction, with protection impacting on the functional status of the coronary vascular (improving intrinsic hyperemic responses).…”

“…Ischemia -reperfusion in the presence of blood leads to generalized loss of vasodilator reserve together with impaired basal flow (no reflow), and likely involves leukocyte-dependent oxidative injury and vascular plugging (Mehta et al, 1989;Jordan et al, 1999;Woodman, 1999;Kurzelewski et al, 2002). However, the individual role/importance of neutrophils has been challenged in recent years (Baxter, 2002), and it is clear that selective coronary endothelial dysfunction also occurs independently of blood cells via poorly defined processes (Tsao and Lefer, 1990;Pannangpetch and Woodman, 1996;Baxter, 2002;Flood et al, 2002). We have focussed on the endothelial component of injury, crucial to cardiovascular outcomes and cardiovascular risk (Granger, 1999;Schachinger et al, 2000), employing a blood-free model of the intact coronary vasculature.…”

“…We therefore chose to identify processes involved in generating injury, and which may therefore represent targets of A 3 AR (and intrinsic A 1 AR) agonism. Oxidative stress is considered a key mediator of vascular dysfunction, reducing NO availability (Tomasian et al, 2000;Indik et al, 2001), and occurring both in the absence (Tsao and Lefer, 1990;Pannangpetch and Woodman, 1996) and presence (Indik et al, 2001) of blood-borne elements. Adenosine can protect against oxidant generation and injury in cardiac tissue (Pisarenko et al, 1997;Vanden Hoek et al, 2000;Narayan et al, 2001), and there is evidence A 3 ARs may enhance anti-oxidant status in endothelial, Fig.…”

“…Importantly, multiple processes contribute to post-ischemic vascular injury, including both blood-cell (e.g. neutrophil) dependent Woodman, 1999;Kurzelewski et al, 2002) and independent (Tsao and Lefer, 1990;Pannangpetch and Woodman, 1996;Baxter, 2002;Flood et al, 2002) mechanisms. While adenosine has been shown to modify neutrophildependent damage (Jordan et al, 1997VintenJohansen et al, 1999), very little is known regarding the ability of ARs to modify other aspects of the vascular injury process (which themselves remain poorly understood).…”

Protease-Activated Receptor-2 Activation Causes EDHF-Like Coronary Vasodilation

“…38 -41 Reduced responses to endothelium-dependent dilators, including thrombin, 38 acetylcholine, 42 and serotonin, 43 have been demonstrated following I/R injury. Unlike these ischemia-sensitive vasodilators, we demonstrate that PAR2 responses are resistant to I/R injury, and this may be the property on which the protection afforded by SLIGRL in I/R injury is dependent.…”