Eric Messina

Caffeine attenuates the duration of coronary vasodilation and changes in hemodynamics induced by regadenoson (CVT-3146), a novel adenosine A2A receptor agonist.

Effects of caffeine on regadenoson-induced coronary vasodilation and changes in hemodynamics were examined in conscious dogs. Sixteen dogs were chronically instrumented for measurements of coronary blood flow (CBF), mean arterial pressure (MAP), and heart rate (HR). Regadenoson (5 μg/kg, IV) increased CBF from 34 ± 2 to 191 ± 7 mL/min. The duration of the 2-fold increase in CBF was 515 ± 71 seconds. Regadenoson decreased MAP by 15 ± 2% and increased HR by 114 ± 14%. Regadenoson-induced maximum increases in CBF were not significantly lower in the presence of caffeine at 1, 2, 4, and 10 mg/kg (2 ± 3, 0.7 ± 3, 16 ± 5, and 13 ± 8%, respectively; all P > 0.05). Caffeine at 1, 2, 4, and 10 mg/kg significantly decreased the duration of the 2-fold increase in CBF induced by regadenoson by 17% ± 4%, 48% ± 8%, 62% ± 5%, and 82% ± 5%, respectively (all P < 0.05). Caffeine at 4 and 10 mg/kg significantly attenuated the effects of regadenoson on MAP and HR. The results indicate that 1 to 10 mg/kg caffeine dose-dependently reduced the duration, but not the peak increase of CBF caused by 5 μg/kg regadenoson.

Role of Nitric Oxide in the Control of Cardiac Oxygen Consumption in B2-Kinin Receptor Knockout Mice

Abstract —The aim of this study was to determine whether bradykinin, the angiotensin-converting enzyme inhibitor ramiprilat, and the calcium-channel antagonist amlodipine reduce myocardial oxygen consumption (MVo 2 ) via a B 2 -kinin receptor/nitric oxide–dependent mechanism. Left ventricular free wall and septum were isolated from normal and B 2 -kinin receptor knockout (B 2 −/−) mice. Myocardial tissue oxygen consumption was measured in an airtight chamber with a Clark-type oxygen electrode. Baseline MVo 2 was not significantly different between normal (239±13 nmol of O 2 · min −1 · g −1 ) and B 2 −/− (263±24 nmol of O 2 · min −1 · g −1 ) mice. S-nitroso-n-acetyl-penicillamine (10 −7 to 10 −4 mol/L) reduced oxygen consumption in a concentration-dependent manner in both normal (maximum, 36±3%) and B 2 −/− mice (28±3%). This was also true for the endothelium-dependent vasodilator substance P (10 −10 to 10 −7 mol/L; 22±7% in normal mice and 20±4% in B 2 −/− mice). Bradykinin (10 −7 to 10 −4 mol/L), ramiprilat (10 −7 to 10 −4 mol/L), and amlodipine (10 −7 to 10 −5 mol/L) all caused concentration-dependent decreases in MVo 2 in normal mice. At the highest concentration, tissue O 2 consumption was decreased by 18±3%, 20±5%, and 28±3%, respectively. The reduction in MVo 2 to all 3 drugs was attenuated in the presence of N G -nitro-l-arginine-methyl ester. However, in the B 2 −/− mice, bradykinin, ramiprilat, and amlodipine had virtually no effect on MVo 2 . Therefore, nitric oxide, through a bradykinin-receptor–dependent mechanism, regulates cardiac oxygen consumption. This physiological mechanism is absent in B 2 −/− mice and may be evidence of an important therapeutic mechanism of action of angiotensin-converting enzyme inhibitors and amlodipine.

Antiadrenergic and Hemodynamic Effects of Ranolazine in Conscious Dogs

Effects of ranolazine alone and in the presence of phenylephrine (PE) or isoproterenol (ISO) on hemodynamics, coronary blood flow and heart rate (HR) in the absence and presence of hexamethonium (a ganglionic blocker) were studied in conscious dogs. Ranolazine (0.4, 1.2, 3.6, and 6 mg/kg, intravenous) alone caused transient (<1 minute) and reversible hemodynamic changes. PE (0.3-10 μg/kg) caused a dose-dependent increase in blood pressure and decrease in HR. ISO (0.01-0.3 μg/kg) caused a dose-dependent decrease in blood pressure and an increase in HR. Ranolazine at high (11-13 mM), but not at moderate (4-5 mM) concentrations partially attenuated changes in mean arterial blood pressure and HR caused by either PE or ISO in normal conscious dogs. However, in dogs treated with hexamethonium (20 mg/kg) to cause autonomic blockade, ranolazine (both 4-5 and 11-13 μM) significantly attenuated both the PE- and ISO-induced changes in mean arterial blood pressure. The results suggest that a potential antiadrenergic effect of ranolazine was masked by autonomic control mechanisms in conscious dogs but could be observed when these mechanisms were inhibited (eg, in the hexamethonium-treated dog). Ranolazine, at plasma concentrations <10 μM and in conscious dogs with intact autonomic regulation, had minimal antiadrenergic (α and β) effects.

Regadenoson, a novel pharmacologic stress agent for use in myocardial perfusion imaging, does not have a direct effect on the QT interval in conscious dogs.

Our goal was to determine the effect of regadenoson (a novel A2A adenosine receptor agonist) on the QT interval in conscious dogs. Sixteen mongrel dogs were chronically instrumented for measurements of blood pressure and ECG. Regadenoson (2.5, 5, and 10 μg/kg, IV) caused a dose-dependent QT interval shortening (ΔQT: 14 ± 3, 24 ± 5, and 27 ± 5 ms, mean ± SEM; n = 7 to 11; all P < 0.05) associated with significant increases in HR (Peak HR: 114 ± 9, 125 ± 6, and 144 ± 7 bpm). Atrial pacing (135, 150, and 165 bpm) also caused a frequency-dependent shortening of the QT interval (ΔQT: 15 ± 3, 22 ± 3, and 39 ± 5 ms; n = 6 to 7; all P < 0.05). Regadenoson- and pacing-induced shortenings in the QT interval were significantly correlated with the R-R interval (r = 0.67 and 0.8, both P < 0.05). Regadenoson at 5 and 10 μg/kg did not cause a significant change in HR or QT interval either during atrial pacing at 165 bpm or after administration of propranolol and atropine to prevent HR from changing or after treatment of dogs with hexamethonium to block autonomic ganglia. Regadenoson (5 to 10 μg/kg) caused no significant changes of QT interval in the heart in which HR was kept constant via physiological or pharmacological procedures, indicating that regadenoson has no direct effect on the QT interval.

Potential role of eNOS in the therapeutic control of myocardial oxygen consumption by ACE inhibitors and amlodipine

OBJECTIVES Our aim was to investigate the potential therapeutic role of endothelial nitric oxide synthase (eNOS) in the modulation of cardiac O(2) consumption induced by the angiotensin converting enzyme (ACE) inhibitor ramiprilat and amlodipine. METHODS Three different groups of mice were used; wild type, wild type in the presence of N-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/l) or genetically altered mice lacking the eNOS gene (eNOS -/-). Myocardial O(2) consumption was measured using a Clark-type O(2) electrode in an air-tight stirred bath. Concentration-response curves to ramiprilat (RAM), amlodipine (AMLO), diltiazem (DIL), carbachol (CCL), substance P (SP) and S-nitroso-N-acetyl-penicillamine (SNAP) were performed. The rate of decrease in O(2) concentration was expressed as a percentage of the baseline. RESULTS Baseline O(2) consumption was not different between the three groups of mice. In tissues from wild type mice, RAM (10(-5) mol/l), AMLO (10(-5) mol/l), DIL (10(-4) mol/l), CCL (10(-4) mol/l), SP (10(-7) mol/l) and SNAP (10(-4) mol/l) reduced myocardial O(2) consumption by -32+/-4, -27+/-10, -20+/-6, -25+/-2, -22+/-4 and -42+/-4%, respectively. The responses to RAM, AMLO, CCL and SP were absent in tissues taken from eNOS -/- mice (-7.1+/-4.3, -5.0+/-6.0, -5.2+/-5.1 and -0.4+/-0.2%, respectively). In addition, L-NAME significantly (P<0.05) inhibited the reduction in O(2) consumption induced by RAM (-9.8+/-4.4%), AMLO (-1.0+/-6.0%), CCL (-8.8+/-3.7%) and SP (-6.6+/-4.9%) in cardiac tissues from wild type mice. In contrast, NO-independent responses to the calcium channel antagonist, DIL, and responses to the NO donor, SNAP, were not affected in cardiac tissues taken from eNOS -/- (DIL: -20+/-4%; SNAP: -46+/-6%) or L-NAME-treated (DIL: -17+/-2%; SNAP: -33+/-5%) mice. CONCLUSIONS These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine.