Shoichi Satoh

Modification of myogenic intrinsic tone and [Ca2+]i of rat isolated arterioles by ryanodine and cyclopiazonic acid.

The role of the sarcoplasmic reticulum (SR) in regulating myogenic tone and [Ca2+]i was examined with ryanodine and cyclopiazonic acid (CPA) in the rat skeletal muscle arteriole (A(sk)) and mesenteric arteriole (Ams). Arterioles were cannulated at both ends to control luminal pressure in a tissue bath. Luminal diameter was measured with a video-monitored microscopic system. Fura 2-AM was loaded to measure [Ca2+]i using the fluorescence intensity ratio at excitation wavelengths of 340 to 380 nm (F340/380). The myogenic response (luminal pressure was increased from 40 to 100 mm Hg) and the intrinsic tone at 40 mm Hg were observed in A(sk) but not in Ams. Ryanodine (10(-5) M decreased the steady-state diameter of A(sk) from 138 +/- 8 to 85 +/- 9 microns (P < .05) and increased the F340/380 ratio; these effects were reversed by nifedipine or Ca(2+)-free solution. Ryanodine shifted the [Ca2+]o-contraction response curve upward. CPA (10(-5) M) also decreased the steady-state diameter of A(sk) from 131 +/- 7 to 98 +/- 11 microns (P < .05). In contrast, Ams responded to neither ryanodine nor CPA. Caffeine-induced contractions were significantly reduced by either ryanodine or CPA in both arterioles. These results indicate that SR dysfunction increased the susceptibility of the arteriolar tone to [Ca2+]o and enhanced the tone of A(sk). In conclusion, the SR function may play a critical role in regulating [Ca2+]i and the intrinsic tone of A(sk) that was myogenically active at physiological luminal pressure.

Influences of pressure surrounding the heart and intracardiac pressure on the diastolic coronary pressure-flow relation in excised canine heart.

We investigated the change in the instantaneous diastolic left coronary pressure-flow relation (DPFR) when the pressure surrounding the heart (SHP), right heart pressure (RHP), and left heart pressure (LHP) were systematically varied. Eight excised and maximally vasodilated canine hearts placed in an air-tight chamber were used. To obtain a capacitance-free DPFR, coronary perfusion pressure was slowly decreased (about 2 mm Hg/sec) during a prolonged diastole. The zero-flow pressure (Pf = 0) and the slope of the DPFR were analyzed. The mean values of the slope did not change significantly throughout the interventions. The mean value of Pf=0 in the control state (SHP = RHP = LHP = 0 mm Hg) was 6.0 ± 2.0 mm Hg (mean ± SD, n = 8), significantly higher than the venous outflow pressure, RHP (p<0.001), and the other two pressures (p<0.001). When SHP was raised to 15 and 30 mm Hg, while the other pressures remained at 0 mm Hg, the mean values of Pf=0 increased to 20.9 ± 2.4 and 35.6 ± 3.1 mm Hg (p<0.001 and p<0.0005, respectively, vs. control). The mean values of Pf =0 when only RHP was elevated to 15 and 30 mm Hg were 16.0 ± 1.5 and 29.3 ± 1.5 mm Hg (p<0.001 and p<0.0005 vs. control). On elevation of LHP to 15 and 30 mm Hg, the mean values of Pf = 0 were 12.0 ± 2.8 and 17.3 ± 3.6 mm Hg (p<0.01 and p<0.01 vs. control). When both SHP and LHP were almost evenly elevated to about 15 and 30 mm Hg, the mean values of Pf = 0 were raised to 22.0 ± 2.9 and 35.3 ± 3.2 mm Hg, respectively. These mean values were not significantly different from those when only SHP was elevated to the comparable levels. The observation that Pf = 0 exceeded RHP in the control state and that RHP, which was elevated above the preceding Pf=0, was identical with the present Pf=0 supports the vascular waterfall mechanism when RHP is low. Furthermore, the evidence that the degree of DPFR shift was almost linearly dependent on the SHP level rather than on the LHP level indicates that the pressure on the epicardial side is one of the factors that determines the pressure at the top of the vascular waterfall.

Effects of the pericardium on the diastolic left coronary pressure-flow relationship in the isolated dog heart.

We studied the effects of the pericardium on diastolic left coronary pressure-flow relationships in heart-blocked and isolated canine preparations. In these preparations, the left and right coronary arteries were dilated with adenosine and perfused by means of a pressurized arterial reservoir. The diastolic left heart pressure (LHP) was controlled by the height of a reservoir connected to the left atrium and left ventricle. The right atrial and ventricular pressure i.e., coronary outflow pressure, was kept constant at 0 mm Hg. Before and after pericardiectomy, diastolic coronary pressure-flow relationships were obtained at three values of LHP (0, 15, and 30 mm Hg) with driving pressure decreasing (2 mm Hg/sec or less) from approximately 60 mm Hg to the actual zero-flow pressure (Pf = 0) during a single long diastole induced by cessation of ventricular pacing. The slopes of the coronary pressure-flow relationships were approximated by a linear regression analysis in which the correlation coefficients were greater than .98 in all cases. Before pericardiectomy, with LHP increasing from 0 to 15 and 30 mm Hg, the value of Pf = 0 significantly increased from 7 +/- 1 to 16 +/- 1 (p less than .01) and 28 +/- 2 mm Hg (p less than .01), respectively. After pericardiectomy, it increased from 7 +/- 1 to 14 +/- 1 (p less than .01) and 17 +/- 2 mm Hg (p less than .01), respectively. When LHP was at 0 and 15 mm Hg, the pericardiectomy had no effect on the value of Pf = 0.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of graded coronary flow reduction in the left anterior descending and septal arteries on left ventricular function in the canine heart.

We quantitatively analyzed the effect of graded left anterior descending and septal coronary flow (LAD + septal flow) reduction on left ventricular function with a left ventricular end-diastolic pressure (LVEDP) of 6 mm Hg and 12 mm Hg. We used an isolated, ejecting, canine heart preparation (n = 8), the coronary flow of which could be controlled independently of the aortic pressure. We kept the other hemodynamic variables — heart rate, left circumflex coronary flow, right coronary flow and aortic input impedance — constant within their normal physiologic range. We considered this reduction in LAD + septal flow to be analogous to that of the most frequent lesion in ischemic heart disease. There was no plateau in the left ventricular work caused by this reduction of the regional coronary flow. Therefore, the plateau commonly reported in previous studies may be partially a result of the compensatory elevation of LVEDP, which is necessary to maintain the left ventricular work.

Effects of OPC-8212, a new positive inotropic agent, and dobutamine on left ventricular global and ischemic regional functions and coronary hemodynamics under coronary artery stenosis

Summary: We have investigated the effects of OPC-8212, a new positive inotropic agent, and dobutamine, a known cardioselective inotropic agent, on global left ventricular (LV) and ischemic regional functions in 14 excised canine hearts with a flow-limiting stenosis of the left circumflex coronary artery (LCX) (i.e., 20–25% of control flow). OPC-8212 infusion (n = 7) under LCX stenosis improved cardiac depression [i.e., peak LV dP/dt increased from 1,295 ± 143 mm Hg/s to 2,669 ± 266 mm Hg/s (mean ± SEM) (p < 0.001)], while myocardial ischemic injury, assessed by myocardial CO2-tension and electrocardiogram (ECG)-ST changes, improved (i.e., ΔCO2-tension and ECG-ST deviation decreased from 21.1 ± 3.6 mm Hg and 3.8 ± 0.6 mV to 13.3 ± 2.8 mm Hg (p < 0.01) and 2.0 ± 0.7 mV (p < 0.05), respectively). On the other hand, dobutamine infusion (n = 7) further increased myocardial CO2-tension and ECG-ST deviation [i.e., ΔCO2-tension and ECG-ST deviation increased from 14.4 ± 4.2 mm Hg and 2.5 ± 1.2 mV to 29.0 ± 6.0 mm Hg (p < 0.01) and 4.9 ± 1.0 mV (p < 0.01), respectively]. At the same time, peak LV dP/dt clearly improved, but to a lesser degree; from 1,425 ± 153 mm Hg/s to 2,393 ± 245 mm Hg/s (p < 0.001). There was also an increase in percent systolic segment shortening of each corresponding area as with OPC-8212. As a result, the two inotropic drugs had different effects on ΔCO2-tension (p < 0.0001) and ECG-ST deviation (p < 0.0006) in the ischemic region. Thus, this new drug, OPC-8212, seems to be potentially useful in the management of heart failure induced or accompanied by ischemic heart disease.

Pressure-length loop in the ischemic segment during left circumflex coronary artery stenosis and its modification by afterload reducing in excised perfused canine hearts

SummaryBy using excised perfused heart preparations, we investigated the regional myocardial functions in the presence of a flow-limiting coronary stenosis of the left circumflex coronary artery (LCX) (approximately a 50% flow reduction of pre-ischemic control), as well as global cardiac functions during afterload reducing, while keeping left ventricular end-diastolic pressure (LVEDP) and heart rate constant. After inducing the LCX stenosis, cardiac output (CO), peak left ventricular pressure (peak LVP) and stroke work (SW) decreased from pre-ischemic control values, i.e., 81.1±3.2%, p<0.005, 88.1±3.8%, p<0.02 and 72.2±5.7%, p<0.005, respectively (n=7), whereas pressure-length (P-L) loop areas changed as follows; ischemic control values of the left anterior descending coronary artery (LAD) and LCX regions were 96.6±6.0%, n.s. and 72.6±9.0% of pre-ischemic control, p<0.02, respectively.Following afterload reducing with LCX stenosis, CO increased gradually, while the ischemic regional function started to further aggravate, and the initial point of further ischemic aggravation obtained in this experiment occurred at 63.5±6.9 mm Hg of mean aortic pressure (AoP). These results suggested that the increase of total cardiac function such as CO following afterload reducing was probably induced at the expense of aggravated regional ischemia. Therefore it was concluded that the treatment of ischemic myocardium by reducing afterload pressure should be done very carefully.

Effects of afterload elevation on the ischemic myocardium in isolated, paced canine heart with partial coronary stenosis

The effect of afterload elevation on the ischemic myocardium was examined in an isolated, paced canine heart with a partial coronary stenosis. The coronary blood flow of the left circumflex coronary artery was reduced to approximately one-third of the values before stenosis. The left circumflex coronary stenosis produced a decrease in global ventricular function, a decrease in systolic shortening and deviation of the ST-segment of the epicardial electrocardiogram and an increase in myocardial carbon dioxide (CO2) tension of the ischemic region. Then, afterload elevation with constant preload decreased the myocardial CO2 tension and improved the ST-segment deviation of the ischemic myocardium. Mechanical function, estimated by the relation between mean aortic pressure and systolic shortening, also improved with elevation of mean aortic pressure. In contrast, afterload elevation combined with preload elevation did not improve ischemic injury, as estimated by myocardial CO2 tension, and did not improve ST-segment deviation or mechanical function despite an increase in left circumflex coronary flow. These results suggest that the elevation of afterload pressure under constant preload improves ischemia produced by a partial coronary stenosis due to increased coronary blood supply; however, the preload elevation counterbalances the beneficial effects of afterload elevation.

Variations of Blood Pooling in Coronary Vascular Beds

The myocardium is highly vascular, consisting of 10% — 15% of blood at diastolic volume. Thereby coronary blood volume (CBV) affects both coronary hemodynamics and myocardial properties. The aims of this study were to assess: (a) variations of CBV in beating hearts with heart rate (HR) changes and (b) the effects of coronary venous pressure (VP) on diastolic myocardial properties. (a) To assess CBV, we measured myocardial volume in LV-isovolumically beating and vasodilated dog hearts mounted in a newly-developed pressure type plethysmography system. HR varied from 60 to 180 bpm when perfusion pressure (PP) was maintained constant at approximately either 70 or 40 mmHg. Mean CBV decreased linearly with reduced RR intervals at both PP, the decrease being significantly larger at a PP of 70, i.e., CBV = 3.5 × RR — 1.8 (PP = 70) vs CBV = 2.1 × RR — 1.0 (PP = 40), P < 0.005. These results suggest that HR and PP play important interdependent roles in determining CBV. (b) To assess the effect of CBV on diastolic myocardial distensibility, we studied excised, LV isovolumic dog hearts in which VP and right ventricular pressure (RVP) were manipulated separately. LV wall volume was determined by subepicardial segment length at end-diastole. Both VP and RVP were increased, from 0 to 30 mmHg, over a range of LV volumes. Left ventricular end-diastolic pressure (LVEDP) (mmHg) data are shown in the Table.

Coronary Circulation and Cardiac Function

In this article, the close link between coronary circulation and cardiac function is reviewed from several points of view. Cardiac function is greatly determined by the loading condition, and on the contrary, the latter definitely regulates coronary blood supply through myocardial oxygen demand. Since many other variables also affect both coronary circulation and cardiac function simultaneously, it is difficult to establish in the in situ heart how the relation between the two factors is modified by loading change alone. From the clinical point of view, this problem is serious in respect to how to change loading in order to manage myocardial ischemic injury with coronary stenosis. In that matter, our experimental model using an excised, perfused heart preparation has given some valuable insight. Although many questions remain unanswered and controversies remain, our results support the concept that preload elevation leads to aggravation of ischemic injury while alleviating it in afterload elevation. Effects of loading on coronary circulation are, in particular, discussed. We stress the important role of the pericardium and also of the surrounding heart pressure on determining Pf = 0.