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Objective: To examine the effect of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide synthase, on coronary artery endothelial function in hypercholesterolaemic patients. Design: Quantitative coronary angiography and Doppler flowmetry were used to examine the effects of intracoronary infusion of BH4 on vascular response to acetylcholine (ACh). Setting: Tertiary cardiology centre. Patients: 18 patients with angiographically normal coronary arteries, of whom nine had hypercholesterolaemia and nine had noromocholesterolaemia. Interventions: ACh (3 and 30 µg/min) was infused for two minutes into the left coronary ostium. ACh was then simultaneously infused with BH4 (1 mg/min) before and after infusion of L-N G -monomethyl-Larginine (L-NMMA) (40 µmol/min for five minutes). Main outcome measures: Diameter of the epicardial coronary arteries and coronary blood flow. Results: In hypercholesterolaemic patients, BH4 attenuated the ACh induced decrease in coronary diameter (p < 0.05) and restored the ACh induced increase in coronary blood flow (p < 0.05). In normocholesterolaemic patients, BH4 did not affect the ACh induced changes in coronary diameter or coronary blood flow. In both groups, L-NMMA decreased the baseline coronary diameter (p < 0.05) and baseline coronary blood flow (p < 0.05). In hypercholesterolaemic patients, L-NMMA inhibited both the BH4 mediated attenuation of the ACh induced decrease in coronary diameter (p < 0.05) and the BH4 mediated enhancement of the ACh induced increase in coronary blood flow (p < 0.01). Conclusions: Intracoronary infusion of BH4 restores coronary endothelial function by improving the bioavailability of endothelium derived nitric oxide in hypercholesterolaemic patients. P atients with various coronary risk factors, such as hypercholesterolaemia, have been shown to have impaired coronary artery endothelium dependent vasodilatation in response to acetylcholine (ACh), which is characterised by reduced endothelium derived nitric oxide bioavailability.1-5 It has been reported that tetrahydrobiopterin (BH4) serves as an essential cofactor for endothelial nitric oxide synthase 6 7 and that reduced bioavailability of BH4 during activation of nitric oxide synthase decreases nitric oxide production, while simultaneously increasing formation of oxygen derived free radicals. [8][9][10] In addition, a recent study suggested that BH4 may serve as a scavenger of oxygen derived free radicals. 11Therefore, intracellular BH4 concentrations in endothelial cells may be decreased in patients with impaired endothelial function. In support of this hypothesis, recent studies have shown that supplementation of BH4 improves impaired endothelial function under various pathological states in vivo, including hypercholesterolaemia and smoking.12 13 In addition, Maier and colleagues 14 reported that BH4 improves impaired coronary vascular responses to ACh in the coronary arteries of patients with coronary artery disease. However, most of the patients involved in these studies had multiple coron...

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The observation that organic Ca2+ channel blockers are more effective in lowering blood pressure and peripheral resistance in hypertensive compared to normotensive subjects suggests that there is a greater contribution from voltage-gated Ca2+ channels (CaL) to vascular force maintenance in hypertensive arteries. This study tests this hypothesis by comparing the effects of Bay k 8644 and nisoldipine on basal force development, contractile responses to norepinephrine and serotonin, and Ca2+ currents (ICa) in mesenteric artery (MA) from Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). MA rings were used to record isometric contractions at Lmax. Single cells were isolated by collagenase plus elastase for measurement of CaL properties by patch-clamp methods. Contractile responses to Bay k 8644 were larger and more sensitive in SHR than WKY, and were larger in endothelium-denuded compared to intact rings. In SHR, the addition of 10 nmol/L Bay k 8644 increased contractile sensitivity to norepinephrine (NE) and serotonin (5HT), and increased maximum response to 5HT. In WKY, 10 nmol/L Bay k 8644 produced a small increase in 5HT sensitivity with no effect on maximum response, and had no effect on NE responses. In the presence of 1 mumol/L nisoldipine, the maximum response and the sensitivity to both NE and 5HT were decreased in both WKY and SHR with the inhibitory effects of nisoldipine being larger in SHR than WKY. Peak ICa was larger in SHR, and current-voltage curves were shifted toward more negative voltages compared to WKY. Bay k 8644 increased ICa in both WKY and SHR myocytes with no apparent difference in the magnitude of its effect when expressed as a percent of control ICa. These results suggest that CaL contribute significantly to tonic force maintenance as well as to agonist responses in MA from both WKY and SHR, but with a much larger contribution in SHR. Differences in the sensitivity of CaL to Bay k 8644 were not responsible for the differences in contractile responses to this agonist.