Abstract 2406: Coronary Microvascular Function as a Target for Prevention of Systolic Heart Failure in Chronic Valvular Heart Disease: Aortic Regurgitation versus Mitral Regurgitation
Hideki OkuiShuichi HamasakiSanemasa IshidaMasakazu OgawaKeishi SaiharaKoji OriharaTakuro ShinsatoTakuro KubozonoSo KuwahataYuichi NinomiyaShouji FujitaTakuro TakumiAkiko YoshikawaYasuhisa IrikiChuwa Tei
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Background: The coronary microvascular vasodilating function is an important determinant of patient outcomes in a number of clinical settings, including coronary artery disease, hypertensive heart disease, or cardiomyopathy. However, the characteristics or the implication of coronary microcirculation in valvular heart disease has not been fully elucidated. The present study was designed to assess coronary vasodilating function and its effects on systolic function in patients with aortic regurgitation (AR) and mitral regurgitation (MR). Methods: Forty-four consecutive patients (66 yrs) with moderate to severe AR and 45 consecutive patients with moderate to severe MR (64 yrs) were enrolled for this study. All patients were free of coronary artery stenosis. Fifty-one age-matched patients without underlying cardiovascular disease served as controls. Endothelium-dependent and endothelium-independent vasodilating function of resistance coronary artery were assessed by coronary blood flow (CBF) response to acetylcholine and papaverine, respectively. Left ventricular ejection fraction (LVEF) was determined by echocardiography as an indicator of systolic function. Results: In patients with AR, both %change in CBF response to acetylcholine and papaverine were significantly lower than controls (32 ± 61 vs 64 ± 84, 172 ± 87 vs 268 ± 105, p < 0.05, p < 0.01, respectively). Further, %change in CBF response to acetylcholine positively correlated with LVEF (r = 0.45, p < 0.01). In patients with MR, %change in CBF response to papaverine was significantly lower than controls (221 ± 123 vs 268 ± 105, p < 0.05), but %change in CBF response to acetylcholine was comparable with controls. Moreover, neither %change in CBF response to acetylcholine nor CBF response to papaverine had significant correlation with LVEF. Conclusion: In patients with AR, both endothelium-dependent and endothelium-independent vasodilating function of resistance coronary artery were deteriorated. Further, endothelium-dependent vasodilating function may be associated with left ventricular systolic function. Our findings indicate coronary microvascular endothelial dysfunction as a potential target for prevention of systolic heart failure in patients with AR.Keywords:
valvular heart disease
The ethyl analogue of papaverine (ethaverine) is on the average equal to papaverine in peak potency as a coronary vasodilator in the surviving rabbit heart, when injected quickly. Its action is more durable at suprathreshold dosage so that in total effect summed over time it is more effective.
Coronary vasodilator
Vasodilator agents
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Objective: To analyze two techniques of papaverine application, topical spray on the harvested left internal mammary artery (LIMA) and perivascular injection, to find out their ability to improve LIMA flow.Methods: Forty patients were randomized into two groups.In Group 1, papaverine was sprayed on the harvested pedunculated LIMA.In Group 2, papaverine was delivered into the perivascular plane.Drug dosage was the same for both groups.LIMA flow was measured 20 minutes after applying papaverine.Blood flow was recorded for 20 seconds and flow per minute was calculated.The systemic mean pressures were maintained at 70 mmHg during blood collection.The data collected was statistically evaluated and interpreted. Results:The LIMA blood flow before papaverine application in the Group 1 was 51.9±13.40ml/min and in Group 2 it was 55.1±15.70 ml/min.Statistically, LIMA flows were identical in both groups before papaverine application.The LIMA blood flow, post papaverine application, in Group 1 was 87.20±13.46ml/min and in Group 2 it was 104.7±20.19ml/min.The Group 2 flows were statistically higher than Group 1 flows.Conclusion: Papaverine delivery to LIMA by the perivascular injection method provided statistically significant higher flows when compared to the topical spray method.Hence, the perivascular delivery of papaverine is more efficient than the spray method in improving LIMA blood flow.
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The objective of this work was to thoroughly examine the smooth muscle relaxing properties of cinnamedrine, compared with papaverine, in vitro, using rat uterus. Cinnamedrine and papaverine both exhibited dose-related spasmolytic activity in the isolated spontaneously contracting rat uterus and in uterine tissue pretreated with oxytocin to augment spasms. The IC50's for cinnamedrine and papaverine were 36.2 and 7.7 microM respectively; the IC50's after oxytocin pretreatment were 25.7 microM for cinnamedrine and 10.0 microM for papaverine. Neither hormonal status of the rats, with respect to their estrus cycle, nor oxytocin pretreatment of the isolated tissues noticeably affected the activity of either cinnamedrine or papaverine.
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Summary. . The isotope washout method has been widely used to study characteristics of the microcirculation in localized vascular beds. Some of these studies have used local injections of vasodilating agents to maximally dilate the vascular bed. This study was undertaken to determine the agent most effective in producing this critical vasodilation. A rabbit model was constructed that allowed the study of the subcutaneous blood flow by either 133 Xe and 131 I‐antipyrine washout. Dose‐response curves were constructed for five agents. The agents used and the doses that produced the maximum washout rate, were histamine (100 μ g ), verapamil (0–5 mg), prostaglandin El (6 μ g ), papaverine (5 mg) and nitroprusside (60 μ g. ) The five agents at these doses were compared with each other, and nitroprusside produced a greater washout rate than papaverine (P<0005), histamine ( P <0–001) and verapamil (P<0–005). There was no difference between nitroprusside and prostaglandin El ( P >0–01) The effect of three of the agents in producing tissue oedema was examined by comparing the washout rates values obtained with the two isotopes. Both nitroprusside and papaverine produced large oedema whereas histamine resulted in little oedema formation. Nitroprusside, therefore, appears to be the most suitable vasodilating agent for use in studies which require maximum vasodilation of localized vascular beds.
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In patients with severe peripheral vascular disease (mean arterial flow of 40 ml/min), a suspension of papaverine in a soft gelatin capsule produced plasma levels almost three times higher than those following treatment with a sustained- release tablet formulation. The higher plasma levels resulted in significantly greater vasodilation with increased distal arterial flow. The onset of peak pulsatile flow with the soft gelatin form came sooner than with the sustained- release form. However the durations of vasodilation were similar with both papaverine preparations. The vasodilatory activity of papaverine appeared to be greater in the sympathectomized leg. The soft gelatin formulation of papaverine may be an orally active vasodila tor, maintaining a distal runoff after reconstruction of a large artery, and may be effective in sustaining a longer vasodilatory effect in patients with small vessel disease, when surgical procedures may not be applicable.
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Abstract Topical vasodilating agents maximize blood flow and prevent vasospasm in microvascular tissuetransfer procedures. Two commonly used agents are papaverine and lidocaine. Although these drugs have vasodilating properties, no studies have directly compared their vasodilating abilities in a controlled, in vivo model. We used videomicroscopy and direct microscopic measurements to compare the vasodilating capacity of papaverine, 1% lidocaine, and saline solution in the femoral artery of Sprague‐Dawley rats. Degree of maximum dilation, ability to sustain dilation, average dilation over a 10‐minute period, and time to achieve maximum dilation were considered. Both papaverine and lidocaine were found to be superior to saline solution as vasodilating agents. Papaverine was found to sustain vasodilation longer than lidocaine, suggesting that it is a superior vasodilating agent in microvascular anastomoses.
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Intracavernous administration of papaverine is now commonly employed for diagnosis and therapy of impotence. To assess the pharmacokinetics of papaverine, we recorded its concentration in peripheral blood and also in cavernous blood after intravenous and intracavernous injection of 40mg of papaverine. Peripheral blood was sampled serially after injection. Plasma was immediately extracted and then kept at at -40°C until analysis. High pressure liquid chromatography was used to record the concentration of papaverine.The maximum serum concentration of papaverine measured after intracavernous injection was 7.7ng/ml, which was considerably lower than the average serum concentration of 24.0ng/ml after intravenous injection. Peak serum concentration was reached 1min after intravenous injection and 10min after intracavernous injection. It is clear that the corpus cavernosum constitutes a separate pharmacokinetic compartment. Therefore there was no significant difference between the papaverine concentration in peripheral blood of patients who showed full erection after intracavernous injection and that of patients who did not achieve erection. The concentration of papaverine in the intracavernous blood of a fully erected penis was only about 1 microgram/ml after 20min. This concentration is similar to that in cavernous blood of those who showed excessively persistent erection.Our results imply that papaverine administered into the cavernous space relaxes smooth muscle, and is then washed out to general circulation, and the concentration in the cavernous space reaches a low level of about 1 microgram/ml. The low concentration level is maintained for several hours during erection. Therefore, we presume that papaverine acts on both the inflow system and smooth muscle of cavernous tissue in the phase of producing erections. However, in the phase of maintaining erection, papaverine acts on the smooth muscle of cavernous tissue to reduce the outflow. We can not evaluate the inflow function or corporeal veno-occlusive function of the penis by the papaverine test a lone.
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