Nancy M. Buckley

Effects of angiographic contrast media on cardiac function

Abstract Alterations in cardiovascular dynamics after intravenous administration of angiographic media suggested that these effects might be due to the high sodium concentration of these agents. Experiments were performed on dog heart-lung preparations and intact dogs. Stroke volume, ventricular, atrial and arterial pressures, and serum osmolarity were measured. Responses were recorded to (1) conventional angiographic agents containing 2,000 to 2,500 milliosmols/ liter, (2) angiographic agents containing the same base but no sodium, (3) hypertonic glucose solutions and (4) hypertonic sodium solutions of equivalent osmolar concentrations. After injection of hyperosmolar sodium chloride or sodium-containing angiographic agents into the aortic root or left ventricle, left ventricular end-diastolic, left atrial and pulmonary arterial pressures increased and myocardial contractile force decreased for 10 to 15 minutes. Injection of hypertonic glucose solutions or angiographic agents containing no sodium produced no significant cardiovascular changes. Total serum osmolarity was similar after administration of each agent. These studies demonstrate that administration of hypertonic sodium solutions produces significant transient alterations in cardiovascular function and that it is one mechanism for changes observed with sodium-containing angiographic agents.

Age-related cardiovascular effects of catecholamines in anesthetized piglets.

We studied cardiac and peripheral circulatory effects of graded doses of catecholamines (0.05-1.0 μkg) in piglets aged £ 1 day, 2-4 days, 1 week, 2 weeks, and 2.5-3 months, under anesthesia with pentobarbital. We evaluated cardiovascular function from simultaneous recordings of aortic pressure, ventricular pressure and its first derivative, heart rate, and phasic carotid and femoral blood flows. We calculated vascular resistance as the ratio of mean aortic pressure to mean flow. The age of onset of a given cardiovascular response was determined, and magnitudes of each type of response were compared among the age groups. Norepinephrine elevated the blood pressure at all doses in piglets of all ages, elicited reflex bradycardia only in older piglets, and increased carotid resistance. Epinephrine elevated the blood pressure at all doses in piglets less than 1 week old, but low doses lowered the blood pressure in piglets older than 1 week of age; resistance changes in the femoral and carotid circulations were variable except in the 2.5-3 month age group. Isoproterenol increased cardiac contractility at all doses in piglets of all ages and increased heart rate at low doses in piglets older than 2 days of age; however, blood pressure and femoral resistance decreases were age and dose dependent. There were age-related differences in the catecholamine dose required to elicit a given cardiac or peripheral circulatory effect and age-related differences in the direction and magnitude of such effects. These results provide evidence for differing rates of postnatal maturation of cardiovascularα and β adrenergic mechanisms in swine. Ore Res 45: 282-292, 1979

Maturation of circulatory system in three mammalian models of human development

The review surveys the literature on maturation of vasoconstrictor and vasodilator functions in cerebral, renal and intestinal circulations of three non-primate models of human development. An ovine model has been refined for use at both fetal and neonatal stages of development. Important variables controlling regional circulations in the lamb fetus at term include arterial O2 content and pCO2 (brain), angiotensin-II (kidney) and norepinephrine (small intestine). Blood flow autoregulation to decreasing perfusion pressure has been inferred for the renal circulation of the neonate. A canine model has been employed in the postnatal period, usually later than the first week after birth. Important variables controlling regional circulations in the young puppy include arterial pO2 and pCO2 (brain) and epinephrine and angiotensin-II (kidney). Blood flow autoregulation to decreasing pressure has been demonstrated in the cerebral circulation at birth and in the renal circulation at one week thereafter. The intestinal circulation has not been studied with respect to blood flow control. A porcine model has been examined from birth through at least two months of postnatal life. Important variables controlling regional circulations in swine at birth include adrenergic nerve stimulation, arterial pCO2 (brain), angiotensin-II (kidney) and norepinephrine (kidney and small intestine). Blood flow autoregulation to decreasing perfusion pressure has been demonstrated in the brain by the fourth day, in the kidney by the end of the second week and in the small intestine by the end of the first month after birth. The advantage of each model for further investigation of functional maturation of regional circulatory control is summarized.

Inotropic Effects of Purines and Pyrimidines on the Isolated Heart

Hypoxanthine, guanine, thymine, and uracil were found to be positively inotropic for failing left ventricle preparations of the dog heart. Inosine, guanosine, thymidine, uridine, and their corresponding bases were found to be positively inotropic for failing rabbit hearts perfused with an artificial medium. Adenosine and cytidine and their corresponding bases were found to be negatively inotropic. Inosine, guanosine, uridine, and their constituent bases, and thymine were found to be positively inotropic for nonfailing rabbit hearts perfused with an artificial medium. Compounds that had hydroxyl groups in addition to one in the six position (xanthine, uric acid, 5-hydroxyuridine, barbituric acid and alloxan) had no consistently positive inotropic effects. The methylated purine, caffeine, was always positively inotropic. Compounds containing other substituents in the four or six position (6-mercaptopurine; 6-chloropurine; 2,4,6-trichloropyrimidine; 4-carboxypyrimidine) had no consistently positive inotropie effects. The carboxy derivative of uracil, orotic acid, was always a positive inotrope. Parent ring compounds such as purine, pyridine, and benzene had no consistent inotropic effects, while pyrimidine was always positively inotropic. Four consistently negative inotropic substances were found among all these compounds: xanthine, alloxan, 6-chloropurine, and 4-carboxypyrimidine. It was concluded that the constituent bases of naturally occurring nucleosides have cardiac effects similar to those of the nucleosides and that their inotropic effects are characteristic in both failing and nonfailing hearts.

Effect of Nucleosides on Acute Left Ventricular Failure in the Isolated Dog Heart

The effect of nucleosides on acute left ventricular failure was studied in 15 isolated dog hearts. The unilateral failure was produced by exposure of the isolated left ventricle to elevated aortic pressure. Parameters of left ventricular function used to evaluate the control, failure and nucleoside periods included ventricular stroke work and output, contractility and distensibility. Adenosine and cytidine were found to be negative inotropic substances. Guanosine, inosine, thymidine and uridine were found to he positive inotropic substances, restoring the control level of ventricular function.

Metabolism of Perfused C14-Labeled Nucleosides and Bases by the Isolated Heart

The cardiac metabolism of C14-labeled nucleosides and bases was investigated in isolated rabbit hearts perfused with a glucose-electrolyte medium. Records of contractile force, heart rate and coronary drainage were taken at intervals before, during, and after perfusion with a labeled compound. Contractile force was increased in the presence of inosine, uridine, guanosine, and hypoxanthine; and decreased in the presence of adenine. Determination of radioactivity of aliquots of perfusate during C14 perfusion and washout periods showed generally constant uptake of the labeled compounds by the hearts, after an initial dilution by tissue water, and efficient washout of extracellular label before preparing myocardial extracts. Recirculation of inosine-C14 was accompanied by incorporation of radioactivity into cardiac nucleotides, chiefly adenine nucleotides but also inosinic acid (IMP) and guanine nucleotides. Labeled hypoxanthine was recovered from both heart and perfusate. Recirculation of uridine-C14 was accompanied by incorporation of radioactivity into cardiac uridine nucleotides, and the appearance of labeled uracil in the perfusate. In both groups of experiments, the ratio of labeled base to nucleoside in cardiac extracts exceeded the ratio in perfusates, indicating unequal cellular retention of base and nucleoside. Perfusion with guanosine-C14 led to limited incorporation of C14 into guanine nucleotides without interconversion to other cardiac nucleotides. Recirculation of C14-labeled hypoxanthine or adenine was accompanied by incorporation of radioactivity into cardiac purine nucleotides. Equivalent label distribution was found among adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate, indicating intracellular equilibrium among these compounds. Conversion of labeled adenine to hypoxanthine occurred in the perfusate of the adenine-C14 experiments. The cardiac metabolism of the perfused nucleosides and bases followed generally predictable sequences, and did not suggest a mechanism for the marked inotropic activity of these compounds.

The influence of left ventricular filling on postextrasystolic potentiation in the dog heart.

We studied the role of left ventricular filling on postextrasystolic potentiation (PESP) in the intact dog heart by calculating changes in end-systolic and end-diastolic volumes on a beat-to-beat basis from electromagnetic measurements of phasic mitral inflow and aortic outflow. In all, 161 extrasystolic sequences with compensatory pauses in 13 dogs were analyzed. The first postextrasystolic cycle showed an increased end-diastolic volume (EDV) in 94%, a decreased end-systolic volume (ESV) in 50%, and an estimated increased ejection fraction in 85% of the sequences. In the 91 sequences with a coupling index ⩽0.7, despite a 76% increase in filling time, there was during the compensatory pause only a 6% increase in filling volume when compared to control. The net filling volume, stroke volume, and diastolic filling period for the sum of the extra- and postextrasystolic cycles were, respectively, 78%, 80%, and 116% of the sum of two control cycles. This retarded filling rate is attributed to a lower left atrial pressure, a reduced left ventricular relaxation rate, and a relaxation to a higher pressure minimum, all of which decrease the amplitude of the atrioventricular pressure gradient. Nevertheless, in 98% of the postextrasystolic cycles, stroke volume was augmented when compared to control (ratio, 1.49 ± 0.26; mean ± SD), due in part to intrinsic mechanisms, to increased preload (EDV), and to decreased afterload. As a first approximation, the effects of increases in preload were separated from intrinsic increases in contractility following an extrasystole by defining potentiation in terms of decreased ESV and/or increased ejection fraction. With the former criterion, 50% of the sequences showed PESP; with the latter, PESP occurred in 85% of the sequences. Circ Res 44: 712-722, 1979

Cardiac Nucleotides and Derivatives in Acute and Chronic Ventricular Failure of the Dog Heart

The levels and proportionate distribution of nucleotides, nucleosides, and bases were determined in myocardial samples from two freshly excised hearts, three acutely failing left ventricle preparations in which the nonworking right ventricle served as control, and two hearts from dogs in which aortic regurgitation was produced surgically as a source of chronic overload of the left ventricle. Ventricular performance was evaluated from cardiac function studies, including measurements of cardiac output, stroke work, and contractility. The compounds identified by chromatographic resolutions were AMP, ADP, ATP, DPN, UPP, and GPP; inosine and hypoxanthine; and uridine and uracil. Qnantitative analyses revealed no consistent difference in specific composition of nonfailing and acutely or chronically failing ventricles.

Effects of Work Loads Applied at Various Times in the Cardiac Cycle of the Isolated Dog Heart

Effects of work loads imposed at various times in the cardiac cycle were studied in isolated left ventricle preparations of dog hearts. In six preparations, resistance loads were applied briefly at times in ventricular systole; in six, volume loads were applied briefly at times in ventricular diastole; in six, experimental aortic regurgitation was produced. Simultaneous recorc1s of left ventricular and aortic pressures and electrocardiograms were used to cletermilie the subdivisions of the cardiac cycle and to measure the rates of isometric contraction and relaxation for evaluation of changes in ventricular contractility. The results of many observations indicated that the rates of isometric ventricular contraction and relaxation were not fixed by prior events, that contraction and relaxation could be altered independently, and that aortic regurgitation loaded the left ventricle at a time critical for its relaxation. Accommodation to aortic regurgitation included maintenance of contractility without diastolic left ventricular pressure rise; failure of accommodation was characterized by loss of contractility at high diastolic ventricular pressure.

CARDIOVASCULAR RESPONSES TO BIOGENIC AMINES IN NEONATAL SWINE

Aortic pressure, heart rate, and femoral and renal flows were recorded in piglets aged 1–16 days under light anesthesia. Norepinephrine (NE, 0.5 μg/kg), isoproterenol (ISP, 0.1 μg/kg) and dopamine (D, 25 μg/kg) were tested before and after adrenergic receptor blockade. Evidence was obtained for differential postnatal development of responses to NE and ISP, and presence of D receptors in neonatal swine.