The Doppler guide wire measures phasic flow velocity patterns and linearly tracks changes in flow rate in small, straight coronary arteries. It should facilitate measurement of phasic coronary flow velocity during coronary angiography and angioplasty.

Background-Recent studies in vitro have demonstrated that endothelium-derived hydrogen peroxide (H 2 O 2 ) is an endothelium-derived hyperpolarizing factor (EDHF) in animals and humans. The aim of this study was to evaluate our hypothesis that endothelium-derived H 2 O 2 is an EDHF in vivo and plays an important role in coronary autoregulation. Methods and Results-To test this hypothesis, we evaluated vasodilator responses of canine (nϭ41) subepicardial small coronary arteries (Ն100 m) and arterioles (Ͻ100 m) with an intravital microscope in response to acetylcholine and to a stepwise reduction in coronary perfusion pressure (from 100 to 30 mm Hg) before and after inhibition of NO synthesis with N G -monomethyl-L-arginine (L-NMMA). After L-NMMA, the coronary vasodilator responses were attenuated primarily in small arteries, whereas combined infusion of L-NMMA plus catalase (an enzyme that selectively dismutates H 2 O 2 into water and oxygen) or tetraethylammonium (TEA, an inhibitor of large-conductance K Ca channels) attenuated the vasodilator responses of coronary arteries of both sizes. Residual arteriolar dilation after L-NMMA plus catalase or TEA was largely attenuated by 8-sulfophenyltheophylline, an adenosine receptor inhibitor. Conclusions-These results suggest that H 2 O 2 is an endogenous EDHF in vivo and plays an important role in coronary autoregulation in cooperation with NO and adenosine.

We developed a portable needle-probe videomicroscope with a charge-coupled device (CCD) camera to visualize the subendocardial microcirculation. In 12 open-chest anesthetized pigs, the sheathed needle probe with a doughnut-shaped balloon and a microtube for flushing away the intervening blood was introduced into the left ventricle through an incision in the left atrial appendage via the mitral valve. Images of the subendocardial microcirculation of the beating heart magnified by 200 or 400 on a 15-in. monitor were obtained. The phasic diameter change in subendocardial arterioles during cardiac cycle was from 114±46 ,um (mean+SD) in end diastole to 84±26 ,um in end systole (p<0.001, n=13, ratio of change=24%) and that in venules from 134±60 ,m to 109±45 ,um (p<0.001, n=15, ratio of change=17%). In contrast, the diameter of subepicardial arterioles was almost unchanged (2% decrease, n=5, p<0.01), and the venular diameter increased by 19%1 (n=8, p<0.001) from end diastole to end systole. Partial kinking and/or pinching of vessels was observed in some segments of subendocardial arterioles and venules. The percentage of systolic decrease in the diameter from diastole in the larger (>100 ,um) subendocardial arterioles and venules was greater than smaller (50-100 ,m) vessels (both p<0.05). In conclusion, using a newly developed microscope system, we were able to observe the subendocardial vessels in diastole and systole. The vascular compression by cardiac contraction decreased the diameters of subendocardial arterioles and venules by about 20o, whereas subepicardial arterial diameter changed very little during the cardiac cycle and subepicardial venules increased in diameter during systole. (Circulation Research 1993;72:939-946) KEY WORDS * subendocardial microcirculation heart * needle-probe videomicroscope he phasic flows in the left coronary artery and T vein are unlike those of other organs; the arterial inflow is greatest during diastole, whereas the venous outflow is greatest during systole.1-6 This unique pattern of coronary arterial and venous flow was inferred in 1695 by Scaramucci,7 who is considered the founder of coronary physiology. He hypothesized that the myocardial vessels are squeezed by the contraction of the muscle fibers around them, which

Abstract-We investigated whether aliskiren, a direct renin inhibitor, improves NO bioavailability and protects against spontaneous atherosclerotic changes. We also examined the effects of cotreatment with aliskiren and valsartan, an angiotensin II receptor blocker, on the above-mentioned outcomes. Watanabe heritable hyperlipidemic rabbits were treated with vehicle (control), aliskiren, valsartan, or aliskiren plus valsartan for 8 weeks. Then, acetylcholine-induced NO production was measured as a surrogate index of endothelium protective function, and both superoxide and vascular peroxynitrite were measured. Tetrahydrobiopterin in aortic segments was assessed by high-performance liquid chromatography with fluorescence detection. Plaque area was quantified by histology. Increase in plasma NO concentration in response to intra-aortic acetylcholine infusion was significantly greater in all of the test groups than in controls. Aliskirenϩvalsartan cotreatment increased acetylcholine-induced NO by 6.2 nmol/L, which was significantly higher than that with either aliskiren or valsartan alone. Vascular superoxide and peroxynitrite levels were both significantly higher in controls and significantly lower in the aliskirenϩvalsartan group than in the aliskiren or valsartan group. The highest tetrahydrobiopterin levels were observed after aliskirenϩvalsartan cotreatment. Histology of the thoracic aorta revealed that the plaque area was significantly decreased with combination therapy compared with monotherapy. Treatment with a direct renin inhibitor has protective effects on endothelial function and atherosclerotic changes. Furthermore, cotreatment with a direct renin inhibitor and an angiotensin II receptor blocker has additive protective effects on both. T he renin-angiotensin system (RAS) activity may be a key factor in the pathophysiology and development of hypertension, atherosclerosis, heart failure, and renal disease in a substantial number of patients. 1,2 However, it remains unclear whether angiotensin-converting enzyme (ACE) inhibitors and angiotensin (Ang) II receptor blockers (ARBs) have fully delivered the expected reduction in cardiovascular risk. In fact, optimized RAS suppression is difficult to achieve with currently available antihypertensive agents, partly because ACE inhibitors and ARBs both activate compensatory feedback mechanisms that result in renin release and increase plasma renin activity (PRA). [3][4][5] In contrast, renin inhibitors neutralize any compensatory increase in PRA and prevent the formation of both Ang I and Ang II. 6 Aliskiren, the first in a new class of orally effective renin inhibitors for the treatment of hypertension, is a potent and specific inhibitor of human renin in vitro with an IC 50 value in the low nanomolar range. 7,8 Studies in healthy volunteers have shown that aliskiren treatment leads to dose-dependent reductions in PRA and Ang II levels. 9 Early clinical trials in hypertensive patients showed that this drug provided antihypertensive efficacy comparable to those of th...

Background-The phase difference of coronary arterial and venous flows indicates the importance of intramyocardial capacitance vessels in storing diastolic flow and in discharging volume in systole. However, the anatomic and functional characteristics of the capacitance vessels are unclear. We aimed to clarify those characteristics with their transmural difference by 3D visualization of transmural microvessels under diastole and systole. Methods and Results-We performed complete intracoronary filling of a contrast medium into Langendorff's Wistar rat hearts under (1) St Thomas-perfused diastolic arrest (D-mode) and (2) BaCl 2 -induced systolic arrest (S-mode). Precise transmural 3D architectures of capillaries and of pre-and post-capillary microvessels (ie, microvessels larger than capillaries) were visualized clearly with a confocal laser scanning microscope and x-ray microcomputed tomography (microCT), respectively. Vascular volume fraction (VF) and systolic-induced VF reduction rate from D-to S-mode were analyzed. The net capillary VF in D-mode (20.4Ϯ0.9%) was 10 times that of larger microvessels and was reduced in S-mode by 32% without capillary collapse. Systolic-induced VF reduction rate was smaller in capillaries than in larger microvessels (48%; PϽ0.05). The larger microvessel VF in D-mode (2.2Ϯ0.2%) was reduced in S-mode, accompanied by complicated 3D deformation. Conclusions-Capillaries were relatively resistant to the systolic extravascular compression compared with pre-and post-capillary microvessels, conveniently beneficial for the myocardial oxygen delivery throughout a cardiac cycle. Nevertheless, a larger change in the absolute volume of capillaries may function as effective capacitance. On one hand, the pre-and post-capillary microvessels showed a larger phasic change in resistance, which may function to maintain the capillary patency during systole. (Circulation. 2002;105:621-626.)

Objective-When the availability of tetrahydrobiopterin (BH4) is deficient, endothelial nitric oxide synthase (eNOS) produces superoxide rather than NO (uncoupled eNOS). We have shown that the atherosclerotic lesion size was augmented in apolipoprotein E-deficient (ApoE-KO) mice overexpressing eNOS because of the enhanced superoxide production. In this study, we addressed the specific importance of uncoupled eNOS in atherosclerosis, and the potential mechanistic role for specific versus nonspecific antioxidant strategies in restoring eNOS coupling. Methods and Results-We crossed mice overexpressing eNOS in the endothelium (eNOS-Tg) with mice overexpressing GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 synthesis, to generate ApoE-KO/eNOS-Tg/GCH-Tg mice. As a comparison, ApoE-KO/eNOS-Tg mice were treated with vitamin C. Atherosclerotic lesion formation was increased in ApoE-KO/eNOS-Tg mice compared with ApoE-KO mice. GCH overexpression in ApoE-KO/eNOS-Tg/ GCH-Tg mice increased vascular BH4 levels and reduced plaque area. This reduction was associated with decreased superoxide production from uncoupled eNOS. Vitamin C treatment failed to reduce atherosclerotic lesion size in ApoE-KO/eNOS-Tg mice, despite reducing overall vascular superoxide production. Conclusion-In contrast to vitamin C treatment, augmenting BH4 levels in the endothelium by GCH overexpression reduced the accelerated atherosclerotic lesion formation in ApoE-KO/eNOS-Tg mice, associated with a reduction of superoxide production from uncoupled eNOS. Key Words: eNOS uncoupling Ⅲ tetrahydrobiopterin Ⅲ vitamin C Ⅲ atherosclerosis Ⅲ apolipoprotein E-deficient mice N itric oxide (NO) derived from endothelial NO synthase (eNOS) is a critical signaling molecule in the vasculature and has a range of antiatherogenic effects. 1 In eNOS/ apolipoprotein E (ApoE) double-knockout mice, atherosclerosis is increased, suggesting a protective effect of eNOSderived NO. 2,3 However, certain vascular diseased states are associated with an increase rather than a decrease in the expression of eNOS. 4,5 We have shown that endotheliumtargeted overexpression of eNOS in ApoE-KO (ApoE-KO/ eNOS-Tg) mice surprisingly resulted in decreased endothelial NO availability, increased vascular superoxide production, and accelerated atherosclerosis. 6 See page 1493These observations could be explained by a relative deficiency of the cofactor tetrahydrobiopterin (BH4) causing eNOS uncoupling, 7 where the enzymatic reduction of molecular oxygen by eNOS is no longer coupled to L-arginine oxidation, resulting in production of superoxide rather than NO. In ApoE-KO/eNOS-Tg mice, dietary BH4 supplementation reduced superoxide production and increased NO availability, although it was unclear whether this was a general antioxidant effect of BH4 or a specific effect on eNOS coupling. 6 Indeed, dietary supplementation with the antioxidant vitamin C can also reduce vascular oxidative stress, increase BH4 levels, and was sufficient to improve the depressed endothelium-dependent relaxatio...

Background-Because coronary blood flow is impeded during systole, the duration of diastole is an important determinant of myocardial perfusion. The aim of this study was to show that coronary flow modulates the duration of diastole at constant heart rate. The increase in DTF at low pressure may be explained by a decrease in interstitial volume at low pressure, which either decreases the preload of the myocytes or reduces the buffer capacity for ions determining repolarization, thereby causing an earlier onset of relaxation. Conclusions-Because the largest increase in DTF occurs at pressures below the autoregulatory range when blood flow to the subendocardium is closely related to DTF, modulation of DTF by coronary blood flow can provide an important regulatory mechanism to match supply and demand of the myocardium when vasodilatory reserve is exhausted. (Circulation. 1999;100:75-81.) Methods and Results-In

We have recently demonstrated that endogenous H2O2 plays an important role in coronary autoregulation in vivo. However, the role of H2O2 during coronary ischemia-reperfusion (I/R) injury remains to be examined. In this study, we examined whether endogenous H2O2 also plays a protective role in coronary I/R injury in dogs in vivo. Canine subepicardial small coronary arteries (>or=100 microm) and arterioles (<100 microm) were continuously observed by an intravital microscope during coronary I/R (90/60 min) under cyclooxygenase blockade (n=50). Coronary vascular responses to endothelium-dependent vasodilators (ACh) were examined before and after I/R under the following seven conditions: control, nitric oxide (NO) synthase (NOS) inhibitor NG-monomethyl-L-arginine (L-NMMA), catalase (a decomposer of H2O2), 8-sulfophenyltheophylline (8-SPT, an adenosine receptor blocker), L-NMMA+catalase, L-NMMA+tetraethylammonium (TEA, an inhibitor of large-conductance Ca2+-sensitive potassium channels), and L-NMMA+catalase+8-SPT. Coronary I/R significantly impaired the coronary vasodilatation to ACh in both sized arteries (both P<0.01); L-NMMA reduced the small arterial vasodilatation (both P<0.01), whereas it increased (P<0.05) the ACh-induced coronary arteriolar vasodilatation associated with fluorescent H2O2 production after I/R. Catalase increased the small arterial vasodilatation (P<0.01) associated with fluorescent NO production and increased endothelial NOS expression, whereas it decreased the arteriolar response after I/R (P<0.01). L-NMMA+catalase, L-NMMA+TEA, or L-NMMA+catalase+8-SPT further decreased the coronary vasodilatation in both sized arteries (both, P<0.01). L-NMMA+catalase, L-NMMA+TEA, and L-NMMA+catalase+8-SPT significantly increased myocardial infarct area compared with the other four groups (control, L-NMMA, catalase, and 8-SPT; all, P<0.01). These results indicate that endogenous H2O2, in cooperation with NO, plays an important cardioprotective role in coronary I/R injury in vivo.