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During heart failure, chronically decreased cardiac output can be treated with positive inotropes, but classic inotropes such as β-adrenergic receptor (βAR) agonists that increase cAMP-dependent Ca 2+ mobilization and contractility ultimately enhance patient mortality. Thus, an alternate approach would be to enhance cardiomyocyte contractility without alterations in cAMP and Ca 2+ levels, such as regulation of sarcomeric proteins. Recently, we demonstrated that a small lipidated pepducin designed from the 1 st intracellular loop of β2AR (ICL1-9) enhanced cardiomyocyte contractility in a Ca 2+ -independent, β-arrestin-dependent manner. We also showed that β2AR stimulation in hearts in vivo or neonatal rat ventricular myocytes (NRVM) in vitro activates RhoA in a βarr-dependent manner, therefore we sought to determine whether ICL1-9-dependent cardiomyocyte contractility is mediated downstream of RhoA. Using adult murine cardiomyocytes isolated from wild-type C57Bl/6J mice, we measured basal, ICL1-9- and isoproterenol (ISO, as a positive control)-promoted contractility either alone or in the presence of inhibitors of myosin light chain kinase (ML7), ROCK1 (Y-27632) and MEK (PD181452). Consistent with RhoA activation by ICL1-9, ROCK1 inhibition was able to attenuate ICL1-9-mediated contractility, as was inhibition of MLCK, though inhibition of MEK/ERK signaling had no effect. Through the use of GPCR kinase 5 knockout (GRK5KO) cardiomyocytes, we observed that ICL1-9 was unable to enhance contractility in the absence of GRK5 expression. Further, treatment of isolated cardiomyocytes with ICL1-9 increased phoshphorylation of the myosin light chain regulatory subunit (RLC). Therefore, ICL1-9 acts proximally via β2AR/GRK5/βarr-dependent engagement of RhoA/ROCK1 signaling to distally increase RLC phosphorylation, representing a new signaling paradigm for the enhancement of cardiomyocyte contractility.

We investigated the mechanism(s) responsible for the decreased cardiac output during continuous positive-pressure ventilation (CPPV). Seven dogs were anesthetized with chloralose-urethane, intubated, and ventilated using a volume ventilator. We measured heart rate, stroke volume, and the determinants of stroke volume: left and right ventricular end-diastolic volumes, isovolumic and ejection phase indices of myocardial contractility, and pulmonary and systemic arterial pressures. Myocardial blood flow was estimated using radioactive microspheres. Variables were measured during a control period of intermittent positive-pressure ventilation (IPPV), 8-20 minutes after the initiation of CPPV using 12 cm H2O positive end-expiratory pressure (PEEP), and 8-20 minutes after the removal of PEEP. CPPV decreased cardiac output but did not affect total or regional myocardial blood flow or the ratio of subendocardial to subepicardial blood flow. Isovolumic and ejection phase indices of myocardial cointractility, heart rate, and systemic arterial pressure did not change during CPPV. Right and left ventricular end-diastolic and end-systolic volumes decreased markedly during CPPV. We conclude that CPPV decreases cardiac output in accordance with Starling's law by decreasing preload.

Right auricular pressure, pulmonary "capillary" pressure (a measure of left auricular pressure) and cardiac output were measured at rest and during exercise in 14 patients with cardiovascular disease affecting primarily the left ventricle. In five patients these measurements were normal at rest, in nine abnormal. In all physiologic abnormalities developed on exercise in the sequence: increased pulmonary "capillary" pressure, increased right auricular pressure, decreased cardiac output. Definite abnormalities of left ventricular function were demonstrable when right ventricular function was entirely normal. These results are discussed in relation to the clinical status of the patients.

The systemic and coronary hemodynamic effects of relatively large doses of propranolol have been studied following its infusion into intact anesthetized dogs at rest and during simulated exercise. At rest, the administration of propranolol was associated with decreased cardiac output and ventricular work and increased peripheral, pulmonary, and coronary vascular resistances. Coronary blood flow and coronary sinus oxygen content decreased while myocardial oxygen consumption and the index of cardiac efficiency were unchanged. The usual hemodynamic response to mild exercise was obtained, with increased cardiac output, cardiac work, body oxygen consumption, and a modest but insignificant increase in coronary blood flow. When propranolol was given and the same exercise continued, body oxygen consumption, cardiac output, and left ventricular work significantly decreased. Insignificant decreases occurred in coronary blood flow, left ventricular oxygen usage, and coronary sinus oxygen content. The present observations are consistent with the thesis that beta-adrenergic blockade induced by propranolol decreases cardiac work at rest and reduces the cardiovascular response to exercise.

SUMMARY Decreased cardiac output, coronary blood flow, and systemic oxygen transport in polycythemia are attributed to increased blood viscosity and regarded as potentially harmful. We studied the effects of isovolemic polycythemia on these variables as well as on myocardial oxygen consumption and regional myocardial blood flow in 31 anesthetized dogs, seven with cannulated left main coronary arteries. Measurements were made at rest, during hypoxemia or adenosine infusions, and with aortic stenosis, pacing, or an aorto-atrial fistula. When hematocrit increased from 42% to 66%, it reduced cardiac output by 36% and systemic oxygen transport by 8%; with hypoxemia, cardiac output rose in polycythemic dogs. Normoxemic polycythemia decreased myocardial blood flow by 46% and increased mean coronary resistance by 54%, slightly decreased myocardial oxygen transport and consumption, and did not alter coronary sinus oxygen tension or myocardial oxygen extraction. Cardiac stress, hypoxemia, and adenosine infusion lowered coronary resistance in polycythemic dogs. Left ventricular myocardial oxygen transport was dependent on pressure work and not on arterial oxygen content or hematocrit. With maximal coronary vasodilation, coronary vascular resistance at hematocrits of 66% was 1.5 times that at 42%. Polycythemia per se did not alter the even distribution of flows across the left ventricular wall, but subendocardial underperfusion began at higher perfusion pressures in polycythemic than in normocythemic dogs. We conclude that autoregulation plays a role in regulating flows and oxygen transport in polycythemia. With maximal coronary vasodilation, however, the increased viscosity of polycythemic blood could be an important factor reducing the amount of myocardial blood flow and oxygen transport. THE EFFECTS of polycythemia on the circulation depend in part on whether there is an associated increase in blood volume 1 which is usually elevated in most forms of polycythemia in man. 2 " 5 Because of the raised blood volume, cardiac output is usually increased, unless there is heart failure. Systemic oxygen transport (cardiac output times arterial oxygen content) is therefore increased above normal when arterial oxygen saturation is normal 4 and may be normal or only moderately reduced when