Adenosine-induced Coronary Vasodilation Research Articles

Early Hyperdynamic Sepsis Alters Coronary Blood Flow Regulation in Porcine Fecal Peritonitis.

Background: Sepsis is a common condition known to impair blood flow regulation and microcirculation, which can ultimately lead to organ dysfunction but such contribution of the coronary circulation remains to be clarified. We investigated coronary blood flow regulatory mechanisms, including autoregulation, metabolic regulation, and endothelial vasodilatory response, in an experimental porcine model of early hyperdynamic sepsis.Methods: Fourteen pigs were randomized to sham (n = 7) or fecal peritonitis-induced sepsis (n = 7) procedures. At baseline, 6 and 12 h after peritonitis induction, the animals underwent general and coronary hemodynamic evaluation, including determination of autoregulatory breakpoint pressure and adenosine-induced maximal coronary vasodilation for coronary flow reserve and hyperemic microvascular resistance calculation. Endothelial-derived vasodilatory response was assessed both in vivo and ex vivo using bradykinin. Coronary arteries were sampled for pathobiological evaluation.Results: Sepsis resulted in a right shift of the autoregulatory breakpoint pressure, decreased coronary blood flow reserve and increased hyperemic microvascular resistance from the 6th h after peritonitis induction. In vivo and ex vivo endothelial vasomotor function was preserved. Sepsis increased coronary arteries expressions of nitric oxide synthases, prostaglandin I2 receptor, and prostaglandin F2α receptor.Conclusion: Autoregulation and metabolic blood flow regulation were both impaired in the coronary circulation during experimental hyperdynamic sepsis, although endothelial vasodilatory response was preserved.

Interactions between A2A adenosine receptors, hydrogen peroxide, and KATP channels in coronary reactive hyperemia

Myocardial metabolites such as adenosine mediate reactive hyperemia, in part, by activating ATP-dependent K(+) (K(ATP)) channels in coronary smooth muscle. In this study, we investigated the role of adenosine A(2A) and A(2B) receptors and their signaling mechanisms in reactive hyperemia. We hypothesized that coronary reactive hyperemia involves A(2A) receptors, hydrogen peroxide (H(2)O(2)), and KATP channels. We used A(2A) and A(2B) knockout (KO) and A(2A/2B) double KO (DKO) mouse hearts for Langendorff experiments. Flow debt for a 15-s occlusion was repaid 128 ± 8% in hearts from wild-type (WT) mice; this was reduced in hearts from A(2A) KO and A(2A)/(2B) DKO mice (98 ± 9 and 105 ± 6%; P < 0.05), but not A(2B) KO mice (123 ± 13%). Patch-clamp experiments demonstrated that adenosine activated glibenclamide-sensitive KATP current in smooth muscle cells from WT and A(2B) KO mice (90 ± 23% of WT) but not A(2A) KO or A(2A)/A(2B) DKO mice (30 ± 4 and 35 ± 8% of WT; P < 0.05). Additionally, H(2)O(2) activated KATP current in smooth muscle cells (358 ± 99%; P < 0.05). Catalase, an enzyme that breaks down H(2)O(2), attenuated adenosine-induced coronary vasodilation, reducing the percent increase in flow from 284 ± 53 to 89 ± 13% (P < 0.05). Catalase reduced the repayment of flow debt in hearts from WT mice (84 ± 9%; P < 0.05) but had no effect on the already diminished repayment in hearts from A(2A) KO mice (98 ± 7%). Our findings suggest that adenosine A(2A) receptors are coupled to smooth muscle KATP channels in reactive hyperemia via the production of H(2)O(2) as a signaling intermediate.

A2A adenosine receptor-mediated increase in coronary flow in hyperlipidemic APOE&amp;ndash;knockout mice

Adenosine-induced coronary vasodilation is predominantly A2A adenosine receptor (AR)-mediated, whereas A1 AR is known to negatively modulate the coronary flow (CF). However, the coronary responses to adenosine in hyperlipidemia and atherosclerosis are not well understood. Using hyperlipidemic/atherosclerotic apolipoprotein E (APOE)–knockout mice, CF responses to nonspecific adenosine agonist (5′-N-ethylcarboxamide adenosine, NECA) and specific adenosine agonists (2-chloro-N6-cyclopentyl-adenosine [CCPA, A1 AR-specific] and CGS-21680, A2A AR-specific) were assessed using isolated Langendorff hearts. Western blot analysis was performed in the aorta from APOE and their wild-type (WT) control (C57BL/6J). Baseline CF (expressed as mL/min/g heart weight) was not different among WT (13.23 ± 3.58), APOE (13.22 ± 2.78), and APOE on high-fat diet (HFD) for 12 weeks (APOE-HFD, 12.37 ± 4.76). Concentration response curves induced by CGS-21680 were significantly shifted to the left in APOE and APOE-HFD when compared with WT. CCPA induced an increase in CF only at 10−6 M in all groups and the effect was reversed by the addition of a selective A2A AR antagonist, SCH-58261 (10−6 M), and a significant decrease in CF from baseline was observed. Western blot analysis showed a significant upregulation of A2A AR in the aorta from APOE and APOE-HFD. This study provides the first evidence that CF responses to A2A AR stimulation were upregulated in hyperlipidemic/atherosclerotic animals. The speculation is that the use of A2A AR-specific agonist for myocardial perfusion imaging (such as regadenoson) could overestimate the coronary reserve in coronary artery disease patients.

A2A Adenosine Receptor‐Mediated Coronary Flow Increase Is Enhanced in Hyperlipidemic Mice

Adenosine-induced coronary vasodilation is predominantly A2A AR-mediated; while A1 AR is known to negatively modulate vasodilation. However, the coronary responses to adenosine in hyperlipidemia and atherosclerosis are not clear. Using hyperlipidemic/atherosclerotic apolipoprotein E knockout mice (APOE-KO) model, coronary flow responses to non-specific (NECA) and specific adenosine agonists (CCPA, A1 AR specific, and CGS-21680, A2A AR specific) were assessed by Langendorff experiments. Western blots for A1 AR and A2A AR were performed in the aorta from APOE-KO and their wild type control (C57BL/6J). All mice were 20–23 weeks old. Baseline CF (expressed as ml/min/gram heart weight) was not different between C57BL/6J (12.52±4), APOE-KO (11.95±1.71), and APOE-KO on high fat diet for 12 weeks (APOE-KO-HFD, 12.18±4.75). NECA- and CGS-21680-induced increases in CF were both shifted to the left in APOE-KO and APOE-KO-HFD when compared to C57BL/6 (Figs. 1 and 2). CCPA also induced increase in CF at 10−6M in all groups and the effect was reversed by the addition of selective A2A AR antagonist, SCh-58261 (SCh, Fig. 3), and a significant decrease in CF from baseline was observed. Western blot analysis also demonstrated significant up-regulation of A2A AR in the aorta from APOE-KO and APOE-KO-HFD (Fig. 4). Therefore, CF responses to A2A AR stimulation were up-regulated in hyperlipidemic/atherosclerotic animals. Based on this, we can speculate that the use of adenosine or A2A AR specific agonist (such as Lexican® from CVTherapeutics) may be over estimating the coronary reserve in hyperlipidemic/atherosclerotic patients. Supported by NIH HL 027339 and HL094447. Figure 1Open in figure viewerPowerPoint Figure 2Open in figure viewerPowerPoint Figure 3Open in figure viewerPowerPoint Figure 4Open in figure viewerPowerPoint

A 2A Adenosine Receptor‐Mediated Nitric Oxide Release Was Blunted in Knockout Mouse Heart

Adenosine-induced coronary vasodilation is believed to be mediated mostly by A2A and/or A2B adenosine receptors (A2AAR and A2BAR). The roles of A2A/A2B AR in coronary vasodilation and its relationship to NO release are unclear. In this study, isolated heart experiments from A2AAR knockout (A2AKO) and wild type mice (A2AWT) were used to identify the role of A2AAR in response to activation by a non-selective adenosine analogue, NECA, and A2A selective agonist, CGS-21680. RT-PCR using isolated coronary arteries from A2AWT and KO were studied for AR expression. L-NAME did not affect baseline coronary flow (CF) until the concentration reached 10 μM in A2AWT (84.27 ± 8.37% from baseline, n=5). In A2AKO, the CF was significantly decreased by L- NAME only at a higher concentration (100 μM, 93.32 ± 5.8% from baseline, n=5). Further experiments demonstrated that CF increase by 100 μM NECA was significantly blunted by 10 μM L-NAME (377.08 ± 25.23% to 305.41 ± 30.73%, n=9) in A2AWT but not in A2AKO (153.66 ± 22.7% to 143.88 ± 36.65%, n=5). Similar results were also found using 50 nM of CGS-21680 instead of NECA in A2AWT (346±22.85 to 277±31.39, n=6). No change in CF to CGS-21680 was noted in A2AAKO. A2B AR expression was 4.5 fold higher in A2AKO compared to WT, suggesting a compensatory role for A2B AR. In conclusion, our data demonstrate a functional role for A2AAR in NO release upon stimulation by NECA and support the role for A2AAR in the regulation of basal coronary tone through the release of NO. Supported by HL 027339.

Endogenous nitric oxide modulates myocardial oxygen consumption in canine right ventricle.

The role of endogenous nitric oxide (NO) in modulating myocardial oxygen consumption (MVO2) is unclear, in part because of systemic and coronary hemodynamic effects of blocking NO release. This study evaluated the effect of NO on right ventricular MVO2 under controlled hemodynamic conditions. In 12 open-chest dogs, N(omega)-nitro-L-arginine methyl ester (L-NAME, 150 microg/min), a NO synthase (NOS) blocker, was infused into the right coronary artery. Heart rate and mean aortic pressure were constant. Right coronary blood flow and right ventricular MVO2 were measured at normal and elevated right coronary perfusion pressures (RCP) before and after L-NAME. To avoid effects of NO synthesis blockade on right coronary blood flow, which might have altered right ventricular MVO2, experiments, were conducted during adenosine-induced maximal coronary vasodilation. L-NAME did not affect right coronary blood flow (P = 0.51). However, L-NAME significantly increased right ventricular MVO2 (6% at RCP 100 mmHg, and 21% at RCP 180 mmHg). Right coronary blood flow varied with perfusion pressure (P < 0.02), and the elevation of MVO2 produced by L-NAME increased at higher flows (P < 0.04), consistent with the greater shear stress-mediated release of NO. These findings indicate that endogenous NO limits right ventricular MVO2.

Reduced coronary NO production in conscious dogs after the development of alloxan-induced diabetes

The role of nitric oxide (NO) in the control of coronary blood flow (CBF) during the development of diabetes is unknown. To study this, mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and CBF. With heart rate controlled (150 beats/min), veratrine (1-10 micrograms/kg) caused dose-dependent increases in CBF; e.g., 5 mirograms/kg of veratrine increased CBF by 57 +/- 7% from 41 +/- 1.3 ml/min (P < 0.05). The dogs developed diabetes 4-5 wk after injection of alloxan (40-60 mg/kg iv, blood glucose levels were 384 +/- 18 mg/dl). After diabetes the same doses of veratrine caused smaller increases in CBF; i.e., 5 micrograms/kg of veratrine increased CBF by 32 +/- 2% (P < 0.05 compared with control) from 28 +/- 4 ml/min. ACh- and adenosine-induced coronary vasodilation were reduced after diabetes as well. In anesthetized dogs after diabetes, vagal stimulation caused smaller increases in CBF. ACh and bradykinin caused smaller increases in NO(-)(2) production in coronary microvessels from diabetic dogs. Furthermore, despite the fact that mRNA for endothelial cell NO synthase from the aorta was increased twofold with the use of Northern blotting, the protein for aortic endothelial constitutive NO synthase was reduced by 66% after diabetes, as determined by Western blotting. Our results indicate that the NO-dependent coronary vasodilation by the Bezold-Jarisch reflex is impaired in conscious dogs after diabetes. The mechanism responsible for the impaired endothelium-dependent coronary vasodilation is most likely the decreased release of NO from the endothelium.

Significance of ST segment depression during adenosine-induced coronary hyperemia in angina pectoris and correlation with angiographic, scintigraphic, hemodynamic, and echocardiographic variables

Factors determining myocardial ischemia during adenosine-induced coronary vasodilation in patients with angina pectoris are not well defined. To evaluate the angiographic, scintigraphic, hemodynamic, and echocardiographic determinants of ST segment depression during adenosine infusion, 40 patients with angina pectoris underwent technetium-99m sestamibi single photon emission computed tomography and simultaneous two-dimensional echocardiography. Ischemic ST depression occurred in 18 patients (45%). Coronary angiography was performed in all patients and a coronary artery jeopardy score was determined. The sensitivity, specificity, and the predictive accuracy of adenosineinduced ST segment depression in detecting significant coronary artery disease were 53%, 100%, and 60%, respectively, while the corresponding results for detecting reversible perfusion defects were 61%, 92%, and 70%, respectively. Univariate predictors of ST segment depression included the coronary artery jeopardy score, the presence and the extent of reversible perfusion defects, the presence of three-vessel and/or left main coronary artery disease, and diastolic blood pressure at peak adenosine infusion. There was a trend ( P = 0.06) to a higher incidence of collateral vessels in patients developing ST segment depression. The coronary artery jeopardy score was found to be the only significant independent predictor of ST segment depression by stepwise multivariate logistic regression analysis. Thus, in patients with angina pectoris, the coronary artery jeopardy score, representing the extent of significant coronary artery disease, is the most important independent predictor of adenosine-induced ST segment depression. ST depression is unusual in the absence of reversible perfusion defects and is also associated with more extensive reversible defects.

Muscular and cardiac adenosine-induced pain is mediated by A1receptors

Objectives. This study attempted to establish whether bamiphylline, a selective antagonist of A1adenosine receptors, prevents the algogenic effects of adenosine in humans.Background. Experimental findings indicate that the sympathoexcitatory response elicited by adenosine is mediated by A1receptors.Methods. An intrailiac infusion of increasing doses (from 125 to 2,000 μg/min) of adenosine was given to 20 patients. Adenosine infusion was then repeated after intrailiac infusion of either bamiphylline or saline solution. In 14 other patients with angina, increasing doses of adenosine (from 108 to 1,728 μg/min) were infused into the left coronary artery. Adenosine infusion was then repeated after the intravenous infusion of either bamiphylline or placebo. Coronary blood flow velocity was monitored by a Doppler catheter. Data relative to pain severity are expressed as median and all other data as mean value ± 1 SD.Results. Bamiphylline prolonged the time to pain onset caused by the intrailiac adenosine infusion from 444 ± 96 to 749 ± 120 s (p < 0.001) and reduced pain severity from 45 to 24 mm (p < 0.01). After placebo infusion, the time to pain onset and pain severity were similar to that of baseline (428 ± 112 vs. 430 ± 104 s, p = 0.87 and 44 vs. 43 mm, p = 0.67, respectively). Bamiphylline prolonged the time to pain onset caused by intracoronary adenosine infusion from 519 ± 128 to 603 ± 146 s (p < 0.01) and reduced pain severity from 58 to 28 mm (p < 0.02). After placebo infusion, the time to pain onset and pain severity were similar to that at baseline (542 ± 87 vs. 551 ± 79 s, p = 0.14 and 55 vs. 50 mm, p = 0.61). Maximal coronary blood flow velocities before and after bamiphylline administration were similar (47 ± 22 vs. 49 ± 24 cm/s, p = 0.36) as well as before and after placebo administration (40 ± 20 vs. 41 ± 20 cm/s, p = 0.07).Conclusions. Bamiphylline reduces adenosine-induced muscular and cardiac pain but does not affect adenosine-induced coronary vasodilation. These findings indicate that at the dose used in this study, bamiphylline does not detectably block vascular A2-receptor-mediated adenosine effects in humans, which suggests that the muscular and cardiac algogenic effects of adenosine are mediated mainly by A1receptors.

Inhibition of adenosine-induced coronary vasodilation by block of large-conductance Ca(2+)-activated K+ channels

The aim of the present study was to investigate the contribution of large-conductance calcium-activated potassium (large-conductance KCa) channels to adenosine (Ado)- and nitroprusside-mediated relaxation in small coronary arteries. Canine subepicardial arteries (170 +/- 23 microns at 120 mmHg) were studied as in vitro pressurized vessels. Pressure-diameter experiments showed myogenic tone over a physiological range of pressures. Tone was increased with the thromboxane A2 analogue 9,11-dideoxy-11 alpha,9 alpha-epoxy-methanoprostaglandin F2 alpha (U-46619). Tetraethylammonium (TEA+; 1 mM) significantly inhibited Ado-induced [and by implication, adenosine 3',5'-cyclic monophosphate (cAMP)-induced] relaxations at Ado concentrations ranging from 0.1 to 10 microM with maximal inhibition (61 +/- 8%) at 1 microM Ado. The large-conductance KCa-channel blocker iberiotoxin (IbTX; 0.01-0.1 microM) inhibited Ado-mediated relaxation in a concentration-dependent manner. Inhibition by IbTX increased with increasing vessel pressure (i.e., 45 +/- 12% at 40 mmHg and 83 +/- 20% at 120 mmHg). TEA+ had a minimal effect (8 +/- 3%) on relaxation induced by nitroprusside. Similar results were found with acetylcholine and bradykinin. These results suggest that (in dog coronary arteries with diameter < 200 microns) large-conductance KCa-channel modulation may play a major role in cAMP-mediated relaxation but is not significant in guanosine 3',5'-cyclic monophosphate-mediated relaxation.

Infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of 5'-nucleotidase activity and attenuation of adenosine release.

We have previously reported that ischemic preconditioning increases 5'-nucleotidase activity and adenosine release during ischemia and reperfusion. However, its direct cause-and-effect relation has not been proven. To test the idea that the infarct size-limiting effect of ischemic preconditioning is blunted by inhibition of ectosolic 5'-nucleotidase activity, we assessed 5'-nucleotidase activity, adenosine release, and infarct size caused by sustained ischemia with and without an exposure to alpha,beta,-methylene adenosine 5'-diphosphate (AOPCP) in the ischemia-preconditioned myocardium. In 67 open-chest dogs, the left anterior descending coronary artery was cannulated and perfused with an extracorporeal bypass tube from the carotid artery. After hemodynamic stabilization, the coronary artery was occluded four times for 5 minutes separated by 5 minutes of reperfusion (ischemic preconditioning, n = 10). After this procedure, the coronary artery was occluded for 90 minutes followed by 6 hours of reperfusion. Infarct size normalized by the risk area was smaller than the control group (n = 8, 41.0 +/- 2.6% versus 6.8 +/- 1.9%), although there were no significant differences in the endomyocardial collateral flow measured at 80 minutes of ischemia (8.5 +/- 1.1 versus 9.4 +/- 1.0 mL/100 g per minute). Ectosolic and cytosolic 5'-nucleotidase activity and adenosine release were increased during reperfusion in the ischemic preconditioning group compared with the control group, and the activity of ectosolic 5'-nucleotidase was markedly reduced by AOPCP (n = 10). AOPCP affected neither adenosine-induced coronary vasodilation nor increases in myocardial oxygen consumption during an intracoronary infusion of isoproterenol (n = 10). To test whether the increase in 5'-nucleotidase activity decreases infarct size, we infused AOPCP 10 minutes before the ischemic preconditioning procedure and continued for 60 minutes after the onset of reperfusion (n = 8). AOPCP blunted the infarct size-limiting effect (infarct size, 38.8 +/- 4.9%). AOPCP without ischemic preconditioning did not increase infarct size (n = 9). Furthermore, when AOPCP was infused during the ischemic preconditioning procedure (n = 6) or during 60 minutes of reperfusion (n = 6), the infarct size-limiting effect was partially blunted (infarct size, 21.3 +/- 2.5% and 19.5 +/- 2.4%, respectively). Increases in ectosolic 5'-nucleotidase activity and adenosine release are primarily responsible for the infarct size-limiting effect of ischemic preconditioning. Exposures to adenosine during the ischemic preconditioning procedure and enhanced release of adenosine during reperfusion synergistically contribute to the infarct size-limiting effects.

Assessment of left ventricular wall motion in angina pectoris by two-dimensional echocardiography and myocardial perfusion by technetium-99m sestamibi tomography during adenosine-induced coronary vasodilation and comparison with coronary angiography

Myocardial perfusion and regional wall motion during adenosine-induced coronary vasodilation were assessed in 40 patients with angina pectoris by technetium-99m sestamibi single-photon emission computed tomography (SPECT) and simultaneous 2-dimensional echocardiography. Adenosine was infused intravenously at a dose of 140 μg/kg body weight per minute for 6 minutes, and technetium-99m sestamibi was injected at 3 minutes. Adenosine caused a significant decrease in systolic and diastolic blood pressure and a significant increase in heart rate and the heart rate-blood pressure product. Adverse effects were mild and transient and no patient required aminophylline. Completely or partially reversible defects on SPECT were present in 28 patients, a fixed defect was seen in 4 patients, and no defect was seen in 8 patients. Two-dimensional echocardiography revealed a new or worsening wall motion abnormality in 21 patients, a fixed abnormality in 4 patients and no abnormality in 15. Transient perfusion defects were associated with transient wall motion abnormalities in 71% of cases. The overall sensitivity, specificity and predictive accuracy of adenosine echocardiography in detecting significant coronary artery disease (>50% diameter stenosis) were 74,100 and 78%, respectively, whereas those of adenosine SPECT were 94, 100 and 95%, respectively (p <0.05, NS, and <0.05, respectively). Thus adenosine technetium-99m ses tamibi SPECT has a higher sensitivity and predictive accuracy than adenosine echocardiography, suggesting that adenosine-induced perfusion defects are not always associated with wall motion abnormality. Although the principal underlying mechanism of myocardial ischemia during adenosine infusion is a “coronary steal” phenomenon, the ischemia is also due to an enhanced myocardial oxygen demand, as indicated by an increased rate-pressure product.

Myocardial washout of sonicated iopamidol does not reflect the transmural distribution of coronary blood flow.

It has been shown in previous studies that myocardial contrast echocardiography provides quantitative information on coronary blood flow. However, the ability of contrast echo to assess the transmural (endo/epicardial) distribution of blood flow is still debated. To test this hypothesis, the left circumflex coronary arteries of six anaesthetized open-chested dogs were cannulated and perfused with blood from the femoral artery. At different rates of coronary blood flow, during adenosine-induced coronary vasodilation, sonicated iopamidol and radionuclide labelled microspheres were injected into the coronary cannula, immediately proximal to a mixing chamber. Two-D echo images were digitized and myocardial time-intensity curves were obtained for the endocardial, mid- and epicardial layers. A good correlation existed between contrast washout of the entire ventricular wall and coronary flow (r = 0.85). However, the washout rate from the endo-, mid- and epicardial layers showed weak correlations with corresponding regional blood flows measured by microspheres (r = 0.56, 0.71 and 0.58, respectively). No significant relationship was found between the endo/epicardial washout ratio and the corresponding flow ratio by microspheres. Thus, measurement of the transmural distribution of coronary blood flow by myocardial contrast echocardiography remains an elusive goal.

Beneficial effects of alpha 2-adrenoceptor activity on ischemic myocardium during coronary hypoperfusion in dogs.

We have previously reported that alpha 2-adrenoceptor stimulation enhances adenosine-induced coronary vasodilation. In the present study, we tested the hypothesis that alpha 2-adrenoceptor activity exerts beneficial effects on myocardial ischemia through augmentation of vasodilatory effects of released adenosine. In open-chest dogs, the left anterior descending coronary artery was perfused through an extracorporeal bypass tube from the carotid artery. Propranolol was infused into the bypass tube to exclude the metabolic effects of norepinephrine. When clonidine (0.24 micrograms/kg/min i.c.) was infused for 10 minutes after reduction of coronary blood flow by partial occlusion of the bypass tube, coronary blood flow was increased by 43% from 27 +/- 1 ml/100 g/min despite no changes in coronary perfusion pressure (38 +/- 5 mm Hg) and a slight decrease in adenosine release. Both fractional shortening and lactate extraction ratio of the perfused area were significantly improved (fractional shortening, 1.8 +/- 1.0 to 10.9 +/- 1.5%, p less than 0.001; lactate extraction ratio, -57.8 +/- 6.5 to -31.9 +/- 2.4%, p less than 0.005). Identical results were observed in the denervated hearts, indicating that the beneficial effect of clonidine is not attributed to the prevention of norepinephrine release from the sympathetic nerve terminals. The beneficial effects of clonidine were prevented by yohimbine, an alpha 2-adrenoceptor blocking agent. An adenosine receptor antagonist, 8-phenyltheophylline, also prevented the beneficial effects of clonidine, indicating that these beneficial effects are mediated by effects of adenosine. Furthermore, the extent of augmentation of coronary flow in the ischemic heart was coincided with that of augmentation of exogenous adenosine-induced hyperemic flow (40%) by clonidine. Production of cyclic AMP in the coronary artery during myocardial ischemia was augmented by clonidine. In 12 other dogs, myocardial ischemia was produced by intracoronary embolization of microspheres (15 microns in diameter). Clonidine enhanced (39%) the hyperemic coronary flow and improved both fractional shortening and lactate extraction ratio. Thus, we conclude that alpha 2-adrenoceptor stimulation can ameliorate myocardial ischemia mainly due to enhancement of vasodilatory effects of adenosine released from the ischemic myocardium.

Alpha 2-adrenoceptor stimulation can augment coronary vasodilation maximally induced by adenosine in dogs

To determine whether alpha 2-adrenoceptor stimulation can augment adenosine-induced coronary vasodilation, 34 open-chest dogs were studied. When a small dose of clonidine (up to 0.24 micrograms.kg-1.min-1 ic) was administered under beta-adrenoceptor blockade, coronary blood flow [312 +/- 16 (SE) ml.100 g-1.min-1] maximally induced by intracoronary infusion of adenosine was further increased (P less than 0.05) by 66 +/- 16 ml.100 g-1.min-1, despite no significant changes in coronary perfusion pressure, myocardial oxygen consumption, and coronary venous adenosine concentration. However, when a larger dose of clonidine (0.36-0.60 micrograms.kg-1.min-1) was infused, adenosine-induced flow progressively decreased. This biphasic action of the alpha 2-adrenoceptor activity was also observed when the dose of norepinephrine was increased during alpha 1-adrenoceptor blockade with prazosin. Norepinephrine up to 0.24 micrograms.kg-1.min-1 (ic) further increased adenosine-induced coronary blood flow by 24 +/- 5% (P less than 0.001), whereas hyperemic flow was decreased by a larger dose of norepinephrine. In contrast to the alpha 2-adrenoceptor stimulation, the alpha 1-adrenoceptor stimulation (norepinephrine with yohimbine) progressively decreased coronary blood flow. Furthermore, with a small dose of clonidine, reactive hyperemic flow significantly increased compared with that without clonidine (303 +/- 13 vs. 355 +/- 13 ml.100 g-1.min-1, P less than 0.001), but a larger dose of clonidine adversely reduced reactive flow (254 +/- 18 ml.100 g-1.min-1, P less than 0.001). Adenosine release during reactive hyperemia with and without intracoronary infusions of clonidine were not altered significantly.(ABSTRACT TRUNCATED AT 250 WORDS)

The dopamine-induced coronary vasoconstrictor response is potentiated by adenosine administration in the dog heart.

The ineffectiveness of beta-adrenergic blockade in abolishing adenosine-induced coronary vasodilation was utilized to demonstrate that dopamine (DA) is capable of eliciting very strong coronary vasoconstrictor actions in vivo. In 2 separate groups of dogs anesthetized with pentobarbital, responses to DA were assessed either by flowmeter recordings or by computer-aided infrared thermography, which senses coronary blood flow-dependent heat emission from the epicardium. In untreated controls, submaximal DA infusions (16 micrograms.kg-1.min-1 iv) elicited a coronary vasodilator response. The thermographic equivalent of this hemodynamic action was an increased epicardial temperature. Pretreatment with oxprenolol (0.5 mg.kg-1 iv) preserved both basic heart activity and cardiac heat emission at levels which were comparable to the control state, but prevented DA mediated excitation of cardiac and coronary beta-adrenoceptors. In this state, DA infusion constricted the coronary arteries and tended to decrease heart emission. However, both types of effects were moderate, and only the hemodynamic effect was statistically significant. If DA was given after the coronary bed had been dilated submaximally by adenosine (30 micrograms.kg-1.min-1 infused into the left heart), the flow-reducing effect of DA became a dramatic phenomenon, and the DA-induced epicardial cooling was significantly potentiated. The results show that after eliminating conventional beta-effects, DA affects the coronary arteries through vasoconstrictor mechanisms. This finding suggests that the DA-induced constriction is limited in undilated coronary arteries by the metabolic autoregulatory capacity of the vessels.

Alpha 2-adrenoceptor activity exerts dual control of coronary blood flow in canine coronary artery.

To test the hypothesis that alpha 2-adrenoceptor activity exerts a dual control of coronary blood flow, i.e., vasoconstriction and augmentation of the vasodilatory effect of adenosine, four doses of adenosine were infused into left anterior descending coronary artery before and during alpha 2-adrenoceptor stimulation or attenuation in anesthetized open-chest dogs. During a moderate alpha 2-adrenoceptor attenuation (yohimbine or rauwolscine, ic), which did not alter coronary blood flow (CBF) at the base-line condition, the hyperemic response of CBF to infused adenosine was markedly reduced, whereas during the potent attenuation both base-line CBF and adenosine-induced hyperemic CBF were significantly increased. Inversely, the moderate alpha 2-stimulation (0.03 microgram.kg-1.min-1 norepinephrine with prazosin, ic, or 0.04 microgram.kg-1.min-1 clonidine ic, under propranolol pretreatment) augmented the adenosine-induced coronary vasodilation, but the potent alpha 2-stimulation (0.3 microgram.kg-1.min-1 norepinephrine with prazosin ic, or 0.3 microgram.kg-1.min-1 clonidine ic) reduced both base-line CBF hyperemic CBF. In contrast, alpha 2-adrenoceptor activity did not affect papaverine-induced coronary vasodilation. Moreover, the reactive hyperemic flow after a brief coronary occlusion was reduced significantly during the moderate alpha 2-adrenergic attenuation, but it was augmented during the potent one. These results indicate that the moderate activation of the alpha 2-adrenoceptor augments the hyperemic response of CBF to both exogenous and endogenous adenosine, whereas the potent alpha 2-activation may mask this vasodilatory effect through the coronary vasoconstrictive effect.

Role of adenosine in coronary vasodilation during exercise.

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 +/- 7 to 39 +/- 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5-20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 +/- 6 to 62 +/- 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increase of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.

Coronary reactive hyperaemia and coronary dilator action of adenosine during intracoronary infusion of angiotensin II.

Investigations were carried out in chloralose-anesthetized, thoracotomized dogs. The effects of an intracoronary infusion of angiotensin II (3 ng/ml coronary blood) on reactive hyperaemic blood flow and adenosine-induced coronary vasodilation were established. Coronary artery occlusions were performed over periods of 5, 10 and 25 heart beats and adenosine was injected intracoronarily at dosages of 2, 4, and 8 microgram/kg body weight. The vasodilator effect of adenosine and reactive hyperaemia after 10 and 25 heart beats were both significantly diminished by angiotensin II. By contrast, reactive hyperaemia after coronary artery occlusion lasting 5 heart beats remained unchanged. The present results obtained with angiotensin II further confirm that adenosine is only partially involved in mediating reactive hyperaemia and that this involvement takes place only after sufficiently long periods of coronary artery occlusion.

The influence of dihydroergotamine on adenosine-induced and reactive coronary vasodilation. Interaction of dihydroergotamine and coronary vasodilation.

The influence of dihydroergotamine on adenosine-induced and reactive vasodilation after long and short periods of coronary artery occlusion was investigated in thoracotomized dogs. Adenosine-induced vasodilation (intracoronary administration) and vasodilation after long periods of coronary artery occlusion (25-35 beats) were similarly influenced, i.e. decreased by the i.v. administration of 10 mug/kg dihydroergotamine. By contrast vasodilation after short periods of coronary artery occlusion (4-7 beats) tended to be increased. This difference in response is thought to arise from two distinct mechanisms of coronary vasodilation after coronary artery occlusion depending on the duration of the occlusion period. The vasodilation after short periods of coronary artery occlusion possibly corresponds to physiological autoregulation. With longer periods of coronary artery occlusion an additional, consecutive mechanism is called into action.