Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise

A pivotal role for adenosine in the regulation of coronary blood flow is still controversial. Consequently, we investigated its role in the regulation of coronary vasomotor tone in swine at rest and during graded treadmill exercise. During exercise, myocardial O2 consumption increased from 167 +/- 18 micromol/min at rest to 399 +/- 27 micromol/min at 5 km/h (P </= 0.05), which was paralleled by an increase in O2 delivery, so that myocardial O2 extraction (76 +/- 1 and 78 +/- 1% at rest and 5 km/h, respectively) and coronary venous PO2 (24.5 +/- 1.0 and 22.8 +/- 0.3 mmHg at rest and 5 km/h, respectively) remained unchanged. After adenosine receptor blockade with 8-phenyltheophylline (5 mg/kg iv), the relation between myocardial O2 consumption and coronary vascular resistance was shifted toward higher resistance, whereas myocardial O2 extraction rose to 81 +/- 1 and 83 +/- 1% at rest and 5 km/h and coronary venous PO2 fell to 19.2 +/- 0.8 and 18.9 +/- 0.8 mmHg at rest and 5 km/h, respectively (all P </= 0.05). Thus, although adenosine is not mandatory for the exercise-induced coronary vasodilation, it exerts a vasodilator influence on the coronary resistance vessels in swine at rest and during exercise

Does effective diastolic coronary venous retroperfusion depend on arterial-like blood pressure in the coronary sinus

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The selective bradycardic effects of zatebradine (UL-FS 49) do not adversely affect left ventricular function in conscious pigs with chronic coronary artery occlusion

Summary This study was designed to test whether the selective bradycardic effects of zatebradine (UL-FS 49) were altered in the setting of chronic mild left ventricular dysfunction secondary to a myocardial infarction. We therefore administered four doses of UL-FS 49 at 15-min intervals (cumulative doses of 10, 30, 100, and 300 μg/kg) to eight normal conscious pigs and to seven pigs in which the left circumflex coronary artery was occluded 3 weeks previously. Left ventricular dysfunction in this second group of animals was manifested by an increase in left ventricular end-diastolic pressure (LVEDP 11±2 mmHg vs. 7±1 mmHg, respectively; p<0.05) and a decrease in LVdP/dtmax (3020±210 mmHg vs. 3720±210 mmHg, respectively; p<0.05). The results showed that UL-FS 49 was equally effective in reducing heart rate in both groups of animals [from 126±4 to 95±2 beats/min and from 140±5 to 98±6 beats/min for the normal animals and for the animals with a chronic myocardial infarction (MI), respectively]. The duration of left ventricular systole was not affected, but the duration of diastole was prolonged from 290±10 msec to 420±20 msec in the normal animals and from 250±10 msec to 430±30 msec in the animals with MI (both p<0.05). Up to 100 μg/kg UL-FS 49 did not affect arterial blood pressure, whereas LVdP/dtmax and cardiac output decreased by less than 10% in either group. With the highest dose there were decreases in cardiac output (20%) and LVdP/dtmax (15%) and a 5–6 mmHg increase in left ventricular end-diastolic pressure in both groups. The data suggest that UL-FS 49 in doses up to 100 μg/kg may also, in the setting of chronic mild left ventricular dysfunction, be an attractive agent when heart rate has to be reduced selectively

Phosphorylation by protein kinase C and the responsiveness of Mg2+-ATPase to Ca2+ of myofibrils isolated from stunned and non-stunned porcine myocardinm

Previously we showed in an in situ porcine model that the thiadiazinone derivative [+]EMD 60263, a Ca2+ sensitizer without phosphodiesterase III inhibitory properties, increased contractility more profoundly in stunned than in non-stunned myocardium. This finding was consistent with the observed leftward shifts of the pCa2+/Mg2+-ATPase curves of isolated myofibrils induced by [+]EMD 60263. The aim of the present investigation was to study the possible involvement of protein kinase C in the mechanism of reduced Ca2+ responsiveness of myofilaments during stunning. No differences were observed in the maximal activity of the Ca2+-stimulated Mg2+-ATPase and in the pCa50 of myofibrils isolated from non-stunned and stunned myocardium. After phosphorylation with [gamma-32P]-ATP and excess of purified rat brain protein kinase C, the myofibrils were separated on sodiumdodecylsulphate-polyacrylamide gelectrophoresis and the 32P incorporation counted by the Molecular Imager. Ca2+/ phosphatidylserine/sn-1,2 diolein-dependent 32P incorporation catalyzed by excess of purified rat brain protein kinase C in C-protein, TnT and TnI subunits did not show any differences between myofibrils from non-stunned and stunned myocardium. However, protein kinase C-induced phosphorylation of myofibrils isolated from ventricular myocardium of sham-operated pigs resulted in a marked leftward shift of the PCa50 from 6.03 ± 0.04 to 6.44 ± 0.06 (p < 0.05), while porcine heart cyclic AMP-dependent protein kinase-induced phosphorylation resulted in an expected small rightward shift to 5.97, although statistical significance was not reached. Protein kinase C-induced phosphorylation also stimulated (80%) the maximal myofibrillar Mg2+-ATPase activity. [+]EMD 60263 (3 μM) produced a leftward shift of the myofibrillar pCa2+/Mg2+-ATPase curve which was unaffected by prior protein kinase C-induced phosphorylation. In conclusion, the findings with isolated myofibrils from myocardium of anaesthetized open-chest pigs indicate that protein kinase C might be involved in the mechanism of reduced Ca2+ responsiveness of myofilaments in stunned myocardium. However, at this stage no differences could be found between the maximal activity of the Ca2+-stimulated Mg2+ -ATPase, the pCa50 and the degree of phosphorylation of myofibrils isolated from stunned and non-stunned myocardium

Efficiency of energy transfer, but not external work, is maximized in stunned myocardium

There is no evidence regarding the effect of stunning on maximization of regional myocardial external work (EW) or efficiency of energy transfer (EET) in relation to regional afterload (end-systolic stress, sigma(es)). To that end, we studied these relationships in both the left anterior descending coronary artery (LADCA) and left circumflex coronary artery regions in anesthetized, open-chest pigs before and after LADCA stunning. In normal myocardium, EET vs. sigma(es) was maximal at 75.4 (69.7-81.0)%, whereas EW vs. sigma(es) was submaximal at 12.0 (6.61-17.3) x 10(2) J/m(3). Increasing sigma(es) increased EW by 18 (10-27)%. Regional myocardial stunning decreased EET (27%) and EW (36%) and caused the myocardium to operate both at maximal EW (EW(max)) and at maximal EET (EET(max)). EET and EW became also more sensitive to changes in sigma(es). In the nonstunned region the situation remained unchanged. Combining the data from before and after stunning, both EW(max) and EET(max) displayed a positive relationship with contractility. In conclusion, the normal regional myocardium operated at maximal EET rather than at maximal EW. Therefore, additional EW could be recruited by increasing regional afterload. After myocardial stunning, the myocardium operated at both maximal EW and maximal EET, at the cost of increased afterload sensitivity. Contractility was a major determinant of this shift

Coronary vasodilatory action after a single dose of nicorandil

Coronary hemodynamics and vasodilatory effects on major epicardial arteries were investigated after a single dose of nicorandil in 22 patients undergoing cardiac catheterization for suspected coronary artery disease. Nicorandil, 20 mg, was administered sublingually to 11 consecutive patients and 40 mg to 11 others. Systemic blood pressure decreased significantly without affecting the heart rate. Coronary sinus blood flow did not change significantly. As the mean aortic pressure decreased significantly by 13% after 20 mg and 21% after 40 mg of nicorandil, the calculated coronary vascular resistance decreased but did not reach statistical significance. There was a decrease in myocardial oxygen consumption (-14% and -22%, respectively), and this was consistent with a significant decrease in the calculated pressure-rate product of 19% and 24%, respectively. A total of 103 selected coronary segments, including 17 stenotic segments, were analyzed quantitatively using a computer-assisted coronary angiography analysis system. After 20 or 40 mg of nicorandil, a significant increase of the mean diameter was observed in the proximal (+9% and +7%), midportion (+10% and +11%) and distal (+15% and +13%) parts of the left anterior descending coronary artery. Corresponding values for the proximal (+13% and +10%) and distal (+10% and +15%) segments of the circumflex artery were observed. An increase in the obstruction diameter was also observed in all but 3 of the analyzed stenotic segments. The results demonstrate that nicorandil, in the route and doses used, causes a significant vasodilation in the major epicardial coronary segments, including most stenotic segments, and decreases the myocardial oxygen demand with little effect on the resistance vessels