Takahiro Narishige

Basis for Increased Microtubules in Pressure-Hypertrophied Cardiocytes

BACKGROUND We have shown the levels of the sarcomere and the cardiocyte that a persistent increase in microtubule density accounts to a remarkable degree for the contractile dysfunction seen in pressure-overload right ventricular hypertrophy. In the present study, we have asked whether these linked phenotypic and contractile abnormalities are an immediate and direct effect of load input into the cardiocyte or instead a concomitant of hypertrophic growth in response to pressure overloading. METHODS AND RESULTS The feline right ventricle was pressure-overloaded by pulmonary artery banding. The quantity of microtubules was estimated from immunoblots and immunofluorescent micrographs, and their mechanical effects were assessed by measuring sarcomere motion during microtubule depolymerization. The biogenesis of microtubules was estimated from Northern and Western blot analyses of tubulin mRNAs and proteins. These measurements were made in control cats and in operated cats during and after the completion of right ventricular hypertrophy; the left ventricle from each heart served as a normally loaded same-animal control. We have shown that the alterations in microtubule density and sarcomere mechanics are not an immediate consequence of pressure overloading but instead appear in parallel with the load-induced increase in cardiac mass. Of potential mechanistic importance, both these changes and increases in tubulin poly A+ mRNA and protein coexist indefinitely after a new, higher steady state of right ventricular mass is reached. CONCLUSIONS Because we find persistent increases both in microtubules and in their biosynthetic precursors in pressure-hypertrophied myocardium, the mechanisms for this cytoskeletal abnormality must be sought through studies of the control both of microtubule stability and of tubulin synthesis.

Glibenclamide, a putative ATP-sensitive K+ channel blocker, inhibits coronary autoregulation in anesthetized dogs.

We tested the hypothesis that ATP-sensitive K+ channels are involved in the mechanism mediating coronary autoregulation in open-chest dogs. We perfused the left anterior descending coronary artery with arterial blood from an extracorporeal circuit and measured steady-state coronary blood flow (CBF) with stepwise changes in coronary perfusion pressure (CPP) between 50 and 150 mm Hg during an intracoronary infusion of vehicle or glibenclamide (a putative blocker of ATP-sensitive K+ channels). CBF was relatively stable over CPP between 50 and 110 mm Hg during vehicle infusion, indicating the presence of autoregulation at the CPP range. During glibenclamide infusion (10 micrograms.min-1 x kg-1), CBF progressively decreased with reduction in CPP below 110 mm Hg, whereas the CPP-CBF relation at CPP above 110 mm Hg was not altered by glibenclamide. The autoregulation index [1-(delta F/F)/(delta P/P), where F indicates CBF and P indicates CPP] was greater than 0 over the CPP range between 50 and 100 mm Hg during vehicle infusion and was less than 0 during glibenclamide infusion. Glibenclamide did not alter systemic arterial pressure, heart rate, left ventricular pressure, and changes in regional myocardial oxygen consumption associated with changes in CPP. In the absence of glibenclamide, the CPP-CBF relation was reproducible in the repeated studies for time control. These results suggest that ATP-sensitive K+ channels play an important role in mediating coronary autoregulation at the lower range of CPP in the blood-perfused dog heart.

Glibenclamide, a Selective Inhibitor of ATP-Sensitive K+ Channels, Attenuates Metabolic Coronary Vasodilatation Induced by Pacing Tachycardia in Dogs

BACKGROUND We previously reported that glibenclamide (a selective inhibitor of ATP-sensitive K+ channels [K+ATP channels]) inhibited metabolic coronary vasodilatation induced by beta 1-adrenoceptor stimulation. However, the role of K+ATP channels in metabolic coronary vasodilatation induced by tachycardia is still unknown. This study aimed to determine whether glibenclamide attenuates metabolic coronary vasodilatation induced by pacing-induced tachycardia. METHODS AND RESULTS In anesthetized dogs, increasing heart rate from 103 +/- 1 to 160 beats per minute with atrial pacing increased coronary blood flow without altering arterial pressure and left ventricular pressure. Intracoronary infusion of glibenclamide at 1.5 and 5.0 micrograms.kg-1.min-1 did not alter basal coronary blood flow but significantly attenuated (P < .01) the tachycardia-induced coronary vasodilatation without altering the tachycardia-induced increase in myocardial oxygen consumption (MVO2). In conscious dogs, intracoronary glibenclamide at 5.0 micrograms.kg-1.min-1 attenuated (P < .05) coronary vasodilatation induced by ventricular pacing from 85 +/- 6 to 150 beats per minute. Glibenclamide markedly attenuated coronary vasodilation evoked with the K+ATP channel opener pinacidil. CONCLUSIONS These data indicate that blockade of coronary vascular K+ATP channels with glibenclamide inhibited metabolic coronary vasodilatation induced by pacing tachycardia in dogs, suggesting that K+ATP channels are involved in the mechanism mediating metabolic coronary vasodilatation associated with pacing tachycardia.

Endothelium-derived nitric oxide does not modulate metabolic coronary vasodilation induced by tachycardia in dogs

Summary: Endothelium-derived nitric oxide (EDNO) has been implicated in the modulation of coronary arterial tone. The aim of this study was to determine if metabolic coronary vasodilation induced by pacing tachycardia is altered by the inhibition of EDNO synthesis. Before and after the intracoronary infusion of an inhibitor of EDNO synthesis (Nω-nitro-L-arginine-methyl-ester, L-NAME), changes in coronary blood flow (CBF), regional myocardial blood flow (MBF), and myocardial oxygen consumption (MVo2) were measured in anesthetized dogs in response to atrial pacing tachycardia. Increasing the heart rate from 109 × 10 to 160 beats/min by pacing produced significant increases in CBF (p < 0.05), MVo2 (p < 0.05), and MBF in each sublayer of the myocardium (p < 0.05). L-NAME did not alter the pacing-induced increases in CBF, MVo2, or regional MBF. In addition, the ratio of the tachycardia-induced increase in CBF to the increase in MVo2 was not changed by L-NAME. The coronary vasodilation evoked by acetylcholine was attenuated by L-NAME (p < 0.05). However, the response to sodium nitroprusside was not altered. These results suggest that EDNO does not play a primary role in the mechanism mediating metabolic coronary vasodilation induced by pacing tachycardia in dogs.

Effects of a new calcium antagonist, CD-832, on coronary and systemic hemodynamics in conscious dogs

The effects of a new calcium antagonist, CD-832, on coronary and systemic hemodynamics were compared with those of nifedipine in conscious dogs. A pair of 10-MHz piezoelectric crystals and an electromagnetic flow probe were placed on the left circumflex coronary artery (LCX) under sterile conditions to measure epicardial coronary artery diameter (CoD) and coronary blood flow (CBF), respectively. CD-832 (30, 100, and 300 micrograms/kg) and nifedipine (3, 10, and 30 micrograms/kg) produced dose-related increases in large epicardial CoD and in CBF. At doses of CD-832 (100 micrograms/kg) and nifedipine (30 micrograms/kg), producing the same increases in CoD and CBF, the duration of increases in CoD and in CBF was markedly longer after CD-832 than after nifedipine. CD-832 and nifedipine produced dose-related decreases in aortic blood pressure (AoP) and reflex increases in heart rate (HR). However, nifedipine produced significantly (p < 0.01) greater tachycardia than CD-832 in equieffective hypotensive doses. These results demonstrate that CD-832 produces sustained dilation of both large epicardial coronary arteries and small resistance vessels and that the degree of tachycardia after CD-832 is significantly less than that after nifedipine.

Effects of iomeprol, a new nonionic contrast medium, vis a vis iopamidol and nitroglycerin, on coronary diameter and blood flow in chronically instrumented dogs

The effects of an intracoronary administration of iomeprol, a new nonionic tri-iodinated water-soluble contrast medium, on coronary circulation were compared to those of iopamidol and those of nitroglycerin in 6 chronically instrumented conscious dogs. A pair of 10 MHz piezoelectric crystals and an electromagnetic flow probe were placed on the left circumflex coronary artery (LCCA) to measure the epicardial coronary diameter (CD) and coronary blood flow (CBF). Polyethylene tubing for drug administration was inserted into the LCCA proximal to the sonomicrometers. Iomeprol at the dose of 1 ml and 3 ml/min for 1 min significantly increased CD by 0.6±0.1% and 1.4±0.3%, respectively and CBF by 44.5±9% and 70±10%, respectively. Iopamidol at the same rates also significantly increased CD by 0.8±0.1% and 1.5±0.3% and CBF by 50±11% and 82±14%, respectively. There was no statistically significant difference between iomeprol-and iopamidol-induced increases in CD and CBF. However, the duration of the increase in CD was significantly shorter (p<0.05) after iomeprol than after iopamidol. Nitroglycerin (10 μg/kg) significantly increased CD by 4.5±1% and CBF by 105±10%. The increases in CD and CBF in response to iopamidol and iomeprol were significantly smaller (p<0.01) than to nitroglycerin. We conclude that vasodilating effects of iomeprol and iopamidol on the large epicardial coronary artery and coronary blood flow are comparable in conscious dogs and significantly lower than after nitroglycerin in the doses used by us.