Paradoxical coronary microcirculatory constriction during ischemia: a synergic function for nitric oxide and endothelin

Abstract

. Paradoxical coronary microcirculatory constriction during ischemia: a synergic function for nitric oxide and endothelin. Am J Physiol Heart Circ Physiol 291: H1814 -H1821, 2006. First published April 28, 2006 doi:10.1152/ajpheart.00220.2006.-A paradoxical microcirculatory constriction has been observed in hearts of patients with ischemia, secondary to coronary stenosis. Here, using the isolated mouse heart (Langendorff), we examined the mechanism of this response, assuming involvement of nitric oxide (NO) and endothelin-1 (ET-1) systems. Perfusion pressure was maintained at 65 mmHg for 70 min (protocol 1), or it was reduced to 30 mmHg over two intervals, between the 20-and 40-min marks (protocol 2) or from the 20-min mark onward (protocol 3). In protocol 1, coronary resistance (CR) remained steady in untreated heart, whereas it progressively increased during treatment with the NO synthesis inhibitor N G -nitro-L-arginine methyl ester (L-NAME) (2.7-fold) or the ETA antagonist BQ-610 (2.8 fold). The ETB antagonist BQ-788 had instead no effect by itself but curtailed vasoconstriction to BQ-610. In protocol 2, hypotension raised CR by 2.2-fold. This response was blunted by reactive oxygen species (ROS) scavengers (mannitol and superoxide dismutase plus catalase) and was converted into vasodilation by L-NAME, BQ-610, or BQ-788. Restoration of normal pressure was followed by vasodilation and vasoconstriction, respectively, in untreated and treated preparations. In protocol 3, CR progressively increased with hypotension in the absence but not presence of L-NAME or BQ-610. We conclude that the coronary vasculature is normally relaxed by two concerted processes, a direct action of NO and ET-1 curtailing an ETB2-mediated tonic vasoconstriction through ETA activation. The negative feedback mechanism on ETB2 subsides during hypotension, and the ensuing vasoconstriction is ascribed to ET-1 activating ETA and ETB2 and reactive nitrogen oxide species originating from ROS-NO interaction. coronary circulation; reactive oxygen species; vasomotor tone CORONARY AUTOREGULATION REFLECTS the intrinsic capability of coronary microvessels to dilate in response to a reduction in pressure so as to maintain a flow constant within certain limits (7). Below this autoregulatory break point, flow decreases and becomes pressure dependent, while vasodilation is maximal (4). However, this conventional model of coronary blood flow control has been challenged by studies (24,30,32,34) in patients presenting severe microcirculatory vasoconstriction rather than vasodilation during spontaneous or demand-induced ischemia. Because of the concomitant coronary artery disease, it has been hypothesized that this paradoxical response results from reduced nitric oxide (NO) bioavailability (20,25) and/or increased endothelin (ET) release (20), because both such events are characteristic of coronary atherosclerosis. However, microcirculatory vasoconstriction, or submaximal vasodilation, has also been observed in the normal animal during severe ischemia or cor...

Up-regulation of heme oxygenase-1 after infarct initiation reduces mortality, infarct size and left ventricular remodeling: experimental evidence and proof of concept

“…The finding of increased basal microvascular resistance is in agreement with the documented hypo-perfusion of the remote viable region in patients with chronic myocardial infarction [51,52]. In previous ex-vivo experiments, we found a similar increase in coronary resistance in control hearts following L-NAME [30] suggesting impaired endothelial function and reduced NO bioavailability in the surviving myocardium. However, the mechanism(s) underlying the further increase in resistance during hypotension (paradoxical vasoconstriction) in the remote zone of infarcted heart remains to be elucidated, especially in relation to the observed significant increase of circulating ET-1 in MI as opposed to PGE 2 .…”

Beneficial effect of heme oxygenase-1 expression on myocardial ischemia-reperfusion involves an increase in adiponectin in mildly diabetic rats

“…Thus, in spite of the documented ischemia, coronary microvascular tone increased, challenging the traditional view of maximal vasodilation during restricted flow and justifying the term "paradoxical vasoconstriction" to define such a phenomenon. This is the expression of an active increase in vascular tone as previously shown by the prompt reversal via papaverine or adenosine and by manipulation with eNOS inhibitors, endothelin blockade, and antioxidants (26).…”

“…Recently, both clinical and experimental studies (26,48) have demonstrated a "paradoxical" coronary microvascular constriction during severe reduction in perfusion pressure and myocardial ischemia. It is not known whether this may be a naturally occurring response to severe hypotension and ischemia, possibly intended to preserve capillary pressure, or whether it may be caused or enhanced by the presence of endothelial dysfunction, hence, aggravating myocardial ischemia.…”

“…In the isolated mouse model, "paradoxical coronary vasoconstriction" has been reproduced by perfusion at low pressure and the endothelium appears to play a pivotal role in this vascular response, which involves the cooperative vasoconstrictive actions of the nitric oxide (NO) and endothelin systems (26). In particular, nitric oxygen synthase (NOS) inhibition or the administration of reactive oxygen species (ROS) scavengers has been able to antagonize the paradoxical vasoconstrictive response to low pressure.…”

Effect of Endothelin on Sodium/Hydrogen Exchanger Activity of Human Monocytes and Atherosclerosis‐Related Functions

“…Apart from NHE1, a number of signaling molecules, such as protein kinase C (PKC), reactive oxygen species (ROS), NO, mitogen‐activated protein kinase (MAPK), phosphatidylinositol 3‐kinase (PI3K) are associated with ET‐1 16–20 . In particular, it is reported that ET‐1 causes the induction of the superoxide production originated from the activation of NADPH oxidase and uncoupled NO synthesis 21 .…”