Impaired vascular sensitivity to nitric oxide in the coronary microvasculature after endotoxaemia

Abstract

1 The eects of endotoxaemia on coronary vasodilator responses to bradykinin (BK), sodium nitroprusside (SNP) and nicardipine were investigated in the rat isolated heart perfused at constant ow ex vivo. 2 Dose-dependent reductions in coronary perfusion pressure reaching a maximum of 56+3 and 57+5 mmHg were observed for BK and SNP respectively. The BK response was biphasic, consisting of a rapid dilator response that was insensitive to N G nitro-L-arginine methyl ester (L-NAME, 0.1 mM) and a second slower component whose duration was attenuated by L-NAME. 3 Hearts obtained from rats treated with endotoxin (2.5 mg kg 71 , i.p.) for 2 or 6 h had increased basal coronary perfusion pressure and reduced vasodilator responses to BK or SNP. Dilator responses to nicardipine were not aected by endotoxin treatment. In vitro perfusion of hearts from endotoxin-treated rats with L-NAME (0.1 mM) restored SNP responses to control values. 4 Treatment with dexamethasone (1 mg kg 71), 1 h before endotoxin did not alter the endotoxininduced impairment of dilator responses to BK or SNP. 5 These results show that coronary microvascular responses are altered following endotoxin exposure. Endotoxin results in increased coronary microvascular tone despite induction of NO synthase and inhibits the dilator response to BK and SNP, vasodilators that act via the release of NO. Responses to SNP in endotoxin-treated hearts were restored to control values in the presence of L-NAME suggesting that enhanced endogenous NO synthesis might saturate guanylate cyclase resulting in reduced response to NO donors. The reduced response to vasodilators and increased coronary resistance might be important in determining the response of the coronary circulation to systemic in¯ammation and infection.

Oroxylin A, but Not Vasopressin, Ameliorates Cardiac Dysfunction of Endotoxemic Rats

“…Similar results have been reported by others [24, 33–35]. This coronary vasoconstriction has been suggested to involve release of vasoconstrictors including endothelin-1 (ET-1, a potent vasoconstrictor and proinflammatory peptide) [36] from the coronary and endocardial endothelial cells and/or impaired vasodilator responses of NO [33]. Therefore, the increased coronary resistance in early-stage endotoxemic hearts may lead to loss of local regulatory mechanism and an increased propensity for coronary vasospasm, myocardial ischemia and coronary dysfunction [37].…”

Myocardial Dysfunction and Potential Cardiac Hypoxia in Rats Induced by Carbon Monoxide Inhalation

“…The reason why CO exposure may increase myofilament calcium sensitivity is not readily apparent. Calcium sensitivity of the contractile apparatus, however, is known to be modulated under various conditions, such as acidosis, accumulation of intracellular inorganic phosphate, and cGMP/cAMP-dependent phosphorylation of cardiac sarcomeric proteins (22,23,38,39). It can be thus hypothesized that, in our study, changes in cGMP/ cAMP ratio induced by CO may have influenced, at least in part, calcium myofilament responsiveness.…”

“…After 10 min of perfusion with Krebs solution (in mM: NaCl, 118; KCl, 4.5; CaCl 2 , 1.4; NaHCO 3 , 25; MgSO 4 , 1.2; NaH 2 PO 4 , 1.4; glucose, 11), hearts were perfused with Krebs solution containing 3.2 mM KCl to increase coronary vascular tone, thus allowing vasodilator responses to be observed, as previously described (22). Hearts were perfused at a constant 10-ml/min flow and coronary perfusion pressure monitored by a pressure transducer.…”

Extracellular L‐arginine is required for optimal NO synthesis by eNOS and iNOS in the rat mesenteric artery wall

“…Administration of antioxidants has been found to reduce organ dysfunction following endotoxin shock (Zacharowski et al ., 2000) and to protect the aorta against hyporeactivity and endothelium dysfunction (Zingarelli et al ., 1997). In endotoxaemia, the attenuated response to the NO donor sodium nitroprusside was normalised by the NO synthase inhibitor L ‐NAME (Tsuchida et al ., 1994; Bogle et al ., 2000). LPS can upregulate other enzymes that are capable of generating superoxide, such as NADPH oxidase (Brandes et al ., 1999), and this could contribute to superoxide formation following LPS administration.…”