Chang-Seng Liang

Insulin Infusion in Conscious Dogs: EFFECTS ON SYSTEMIC AND CORONARY HEMODYNAMICS, REGIONAL BLOOD FLOWS, AND PLASMA CATECHOLAMINES

Cardiovascular actions of insulin were studied by intravenous infusions of insulin (4 and 8 mU/kg per min) in normal conscious dogs. This resulted in increases in cardiac output, heart rate, and left ventricular derivative of pressure with respect to time (dP/dt) and dP/dt/P, as blood glucose was reduced. The inotropic and chronotropic effects of insulin were not related to hypoglycemia, as they persisted even when blood glucose was restored to control values or when it was prevented from falling by a simultaneous infusion of glucose. These cardiac effects were accompanied by increases in plasma catecholamines, and were abolished by propranolol pretreatment. Both plasma epinephrine and norepinephrine increased during insulin hypoglycemia, but only norepinephrine increased during insulin infusion when euglycemia was maintained. Mean arterial blood pressure did not change significantly during insulin hypoglycemia, but rose if euglycemia was maintained, probably due to the selective increase in norepinephrine in the latter condition. A pressor response also occurred in propranolol-pretreated dogs during insulin hypoglycemia, but was abolished when the animals also had been pretreated with phentolamine, indicating that the vasoconstrictor action of insulin was mediated via alpha adrenergic receptors. Insulin infusion increased left ventricular work and myocardial blood flow in dogs with and without hypoglycemia. Myocardial blood flow, however, did not change significantly during insulin infusion in dogs pretreated with propranolol. As propranolol also diminished the inotropic response, it appears that the increase in myocardial blood flow caused by insulin in the normal dog is causally related to the increased myocardial metabolic demand. Insulin also produced vasomotor effects on other vascular beds. In skeletal muscle, blood flow was increased under all study conditions, except during insulin hypoglycemia after propranolol-pretreatment when unopposed alpha-mediated vasoconstriction was present. The persistent increase in flow during both alpha and beta adrenergic blockade suggests that insulin has a direct dilator effect on skeletal muscle vasculature. In the adrenal gland, flow was increased except during euglycemia, when no rise in plasma epinephrine was observed, suggesting coupling between adrenal flow and catecholamine release. In the splanchnic bed, flow was decreased during euglycemia, when plasma norepinephrine rose, and during beta adrenergic blockade with propranolol, when unopposed alpha-mediated vasoconstriction also predominated. A similar pattern was found in the kidney, except that renal blood flow also fell after combined alpha and beta adrenergic blockade. The results show that the vasomotor effects on regional flows are mediated both via adrenergic mechanisms, and in the case of skeletal muscle and kidney, via mechanisms unrelated to sympathetic stimulation.

Mineralocorticoid-Induced Hypertension in Patients with Orthostatic Hypotension

The mechanism of recumbent hypertension induced by fludrocortisone was studied in seven patients with orthostatic hypotension. All showed increases in blood pressure in the recumbent and standing positions, and hypertensive levels were achieved on recumbency in four of them. Hypertensive retinopathy developed in two patients and cardiomegaly in one. Initial blood-pressure elevations were associated with sodium retention and plasma-volume expansion. However, with long-term treatment, plasma volume decreased to control levels despite further blood-pressure increases. Treatment did not affect plasma levels of catecholamines but did enhance pressor responsiveness to infused norepinephrine in some subjects. Hemodynamic studies indicated that hypertension in the recumbent position was related to increases in total peripheral-vascular resistance and not to changes in cardiac output. Clinically, hypertension in the recumbent position is an important risk of fludrocortisone treatment in patients with orthostatic hypotension. This unusual model of chronic mineralocorticoid-induced hypertension is not volume dependent but is related to increased peripheral-vascular resistance.

Renin-Angiotensin System Inhibition in Conscious Sodium-Depleted Dogs: EFFECTS ON SYSTEMIC AND CORONARY HEMODYNAMICS

The role of the renin-angiotensin system in the regulation of the systemic and coronary circulations during sodium depletion was studied in conscious normotensive dogs by i.v. administration of teprotide (0.5 mg/kg), an angiotensin-converting enzyme inhibitor, and saralasin (0.05-5 mug/kg per min), an angiotensin-receptor antagonist. Sodium depletion was produced by administering a low sodium diet and furosemide for 5 days. Administration of both teprotide and saralasin lowered systemic arterial blood pressure and total peripheral vascular resistance. Simultaneously, cardiac output increased, but left ventricular end-diastolic pressure, dP/dt, and dP/dt/P did not change significantly. Furthermore, both agents reduced diastolic coronary vascular resistance and increased coronary blood flow, but did not affect myocardial oxygen consumption, left ventricular work, or myocardial efficiency. These systemic and coronary vasodilator effects of teprotide and saralasin, however, were not observed in normal dogs on a regular sodium diet; in this group, the only effect noted was a slight increase in arterial pressure during saralasin infusion. Arterial plasma concentration of norepinephrine did not differ between normal and sodiumdepleted dogs, nor did it change significantly after teprotide administration. These results suggest that, during salt depletion, angiotensin II exerts an active vasoconstrictor action on the systemic and coronary vessels, but has no significant effects on myocardial contractility or energetics. It also appears likely that the increase in cardiac output observed in sodiumdepleted dogs after angiotensin inhibition was caused, at least in part, by the decrease in systemic arterial pressure.

Conditioning Effects of Chronic Infusions of Dobutamine: COMPARISON WITH EXERCISE TRAINING

We studied the conditioning effects of chronic infusion of dobutamine and exercise training in three groups of chronically instrumented dogs. One group was infused with normal saline, a second group was infused with dobutamine (40 mug/kg per min), and the third group was exercised on a treadmill at 4 mph, up a 10 degrees incline. Each group was either infused or exercised for 2 h a day, 5 d a week for 5 consecutive wk. Resting heart rate and arterial blood lactate concentration, measured at weekly intervals, decreased progressively in the dobutamine and exercise groups, but not in the group that received normal saline infusion. Cardiovascular responses to submaximal treadmill exercise were not changed by 5 wk of normal saline infusion. However, the increases in heart rate, cardiac output, mean aortic blood pressure, arterial blood lactate, plasma renin activity, and norepinephrine concentration during exercise were significantly smaller after 5 wk of conditioning with either dobutamine or exercise training. After conditioning, the increases in arteriovenous oxygen difference during exercise were larger in the latter two groups, but the increases in total body oxygen consumption did not differ before and after conditioning. To assess ventricular function, we intravenously infused methoxamine both before and after conditioning. The slope of the line that related systolic aortic blood pressure and mean left atrial pressure increased in the animals conditioned with either dobutamine or exercise, indicating enhanced myocardial contractility. Left ventricular blood flow was lower in these two groups of animals than it was in the normal saline group. Left ventricular weight did not differ among the three groups. Our results show that chronic infusion of dobutamine produced cardiovascular and metabolic conditioning effects like those produced by exercise training, and further suggest that sympathetic stimulation during exercise plays a role in physical conditioning.

Renin-Angiotensin System Inhibition in Conscious Dogs during Acute Hypoxemia: EFFECTS ON SYSTEMIC HEMODYNAMICS, REGIONAL BLOOD FLOWS, AND TISSUE METABOLISM

The role of the renin-angiotensin system in mediating the circulatory and metabolic responses to hypoxia was studied in three groups of conscious dogs that were infused continuously with normal saline, teprotide (10 mug/kg per min), and saralasin (1 mug/kg per min), respectively. Hypoxia was produced by switching from breathing room air to 5 or 8% oxygen-nitrogen mixture. Plasma renin activity increased from 2.3+/-0.4 to 4.9+/-0.8 ng/ml per h during 8% oxygen breathing, and from 2.8+/-0.4 to 8.4+/-1.8 ng/ml per h during 5% oxygen breathing. As expected, cardiac output, heart rate, mean aortic blood pressure, and left ventricular dP/dt and dP/dt/P increased during both 5 and 8% oxygen breathing in the saline-treated dogs; greater increases occurred during the more severe hypoxia. Teprotide and saralasin infusion diminished the hemodynamic responses to 5% oxygen breathing, but did not affect the responses to 8% oxygen breathing significantly. In addition, the increased blood flows to the myocardium, kidneys, adrenals, brain, intercostal muscle, and diaphragm that usually occur during 5% oxygen breathing were reduced by both agents. These agents also reduced the increases in plasma norepinephrine concentration during 5% oxygen breathing, but had no effects on tissue aerobic or anaerobic metabolism. In dogs pretreated with propranolol and phentolamine, administration of teprotide (0.5 mg/kg) during 5% oxygen breathing reduced mean aortic blood pressure and total peripheral vascular resistance, and increased cardiac output and heart rate, but did not affect left ventricular dP/dt, dP/dt/P, and end-diastolic pressure. Simultaneously, renal and myocardial blood flows increased and myocardial oxygen extraction decreased, while myocardial oxygen consumption did not change significantly. These results suggest that the renin-angiotensin system plays an important role in the hemodynamic responses to severe hypoxia. It appears that angiotensin not only exerts a direct vasoconstrictor action, especially upon the coronary and renal circulations, but also potentiates the cardiovascular effects of sympathetic stimulation that occur during severe hypoxia.

Converting Enzyme Inhibition in Hypertensive Emergencies

The diagnostic and therapeutic value of the angiotensin converting enzyme inhibitor teprotide (SQ 20881) was assessed in 18 patients with hypertensive emergencies. Mean blood pressure fell 31 +/- 18 mm Hg in the 10 subjects who responded to 1 mg/kg body weight administered intravenously, whereas it fell 5 +/- 3 mm Hg in the eight nonresponders. In patients who had received no previous drug treatment, log baseline plasma renin activity and change in mean blood pressure after SQ 20881 correlated significantly (r = 0.651, P less than 0.05). After acute therapy with SQ 20881, the patients who had a satisfactory response to the drug were treated with propranolol and a relatively normal sodium intake (88 meq/day). Nonresponders were treated with diuretics and sodium restriction (10 meq/day), and intermediate responders were given combination therapy. Mean blood pressure responded favorably within 24 h to the chosen regimen for each group from 152 +/- 47 to 102 +/- 31 mm Hg. SQ 20881 allows prompt evaluation of the role of renin in hypertensive emergencies and permits early choice of appropriate therapy based on the prevailing mechanism.

Effects of Pinacidil on Myocardial Blood Flow and Infarct Size After Acute Left Anterior Descending Coronary Artery Occlusion and Reperfusion in Awake Dogs With and Without a Coexisting Left Circumflex Coronary Artery Stenosis

Summary: To determine whether partial stenosis of a second major coronary artery promoted vasodilator-induced coronary steal and increased infarct size after acute coronary artery occlusion, we produced acute myocardial infarction by 4-h left anterior descending coronary artery occlusion and 20-h reperfusion in awake dogs with and without a mild to moderate stenosis (33–72%) of the proximal left circumflex coronary artery. Dogs were randomized to receive intravenous (i.v.) normal saline or pinacidil, a new antihypertensive agent with a marked coronary dilator property, beginning 40 min after onset of coronary artery occlusion and continuing throughout the occlusion and the first hour of reperfusion. Pinacidil was titrated to decrease mean aortic pressure 25 mm Hg, which resulted in an increase in heart rate (HR), cardiac output (CO), and left ventricular (LV) dP/dt and LVdP/dt/P. Saline infusion had no effects. Blood flows to ischemic and remote myocardium did not differ between dogs with and without coronary stenosis. Pinacidil increased blood flow threefold in normal myocardium, but had no effect on infarct zone myocardial blood flow or infarct size (58 ± 4% of region at risk vs. 56 ± 4% in animals receiving normal saline) in dogs without coronary stenosis. In contrast, similar administration of pinacidil in dogs with coronary stenosis reduced infarct size zone myocardial blood flow and increased infarct size (69 ± 3% vs. 55 ± 5% in the saline group, p < 0.05). The data indicate that although neither myocardial blood flow nor infarct size is affected by a mild to moderate stenosis of a second major coronary artery, administration of an effective vasodilator during acute myocardial infarction can potentially further reduce infarct zone myocardial blood flow and increase infarct size.

Effects of milrinone on systemic hemodynamics and regional circulations in dogs with congestive heart failure: comparison with dobutamine.

Summary Milrinone is a new bipyridine inotropic agent with direct vasodilator properties. To determine the role of the vasodilator action in mediating systemic and regional hemodynamic responses to milrinone, we administered two equipotent inotropic doses of either milrinone or dobutamine to dogs with chronic congestive right heart failure produced by tricuspid avulsion and pulmonary artery stenosis. Similar increases in cardiac output, right and left ventricular dP/dt, and left ventricular dP/dt/P were produced by milrinone and dobutamine; however, heart rate increased and mean aortic pressure decreased only with milrinone infusion. In addition, while total peripheral vascular resistance decreased with both agents, the decrease was greater with milrinone. Regional blood flows were measured by a radioactive microsphere method. Milrinone and dobutamine produced similar increases in myocardial blood flow and left ventricular oxygen consumption. Dobutamine infusion decreased quadriceps muscle vascular resistance and had no effect on renal and splanchnic circulations. In contrast, milrinone infusion increased vascular resistance in quadriceps muscle and decreased it in renal and splanchnic beds. Thus, when milrinone was used in inotropic doses similar to those of dobutamine, the responses in systemic and regional hemodynamics in congestive heart failure differed. Milrinone produced a greater decline in total peripheral, renal, and splanchnic vascular resistances, probably resulting from its direct vasodilator action.

Effect of Nadolol in Treatment of Hypertension

Nadolol, a new beta-adrenergic blocking agent, was administered orally in gradually increasing single daily doses to 13 hospitalized patients with essential hypertension. Maximal doses ranged from 200 to 480 mg/day. Blood pressure was reduced in nine patients and heart rate was decreased in 11 patients. The decrease in blood pressure was either partial or temporary in five of the nine patients who responded. Concomitant administration of the diuretic chlorthalidone decreased blood pressure in a previously unresponsive patient. Nadolol effectively inhibited isoproterenol-induced tachycardia and decreased cardiac output by 18 per cent. Plasma renin activity and plasma aldosterone concentration were not changed significantly by the treatment. Body weight was not altered significantly. Blood pressure response was independent of the pretreatment renin levels or the change in renin induced by nadolol; it was also independent of the changes in cardiac output and heart rate but was more pronounced in patients with milder baseline hypertension. The decline in serum concentration of nadolol was consistent with the drugs reported half-life of 12.2 hours. The results indicate that single daily doses of nadolol alone can reduce blood pressure significantly with minimal cardiodepressant effects and no important side effects. The effectiveness of nadolol may be enhanced by the addition of a diuretic.

Contraction band necrosis : its modification by the free radical scavenger N-2-mercaptopropionyl glycine

Contraction band necrosis (CBN) may represent infarct extension from free radical generation during reperfusion. We sought to limit CBN with the free radical scavenger N-2-mercaptopropionyl glycine (MPG, 20 mg/kg). Sixteen chronically instrumented Beagles (8 control, and 8 MPG treated) underwent 90-min left anterior descending coronary artery (LAD) occlusion followed by 6-h reperfusion. Coronary blood flow (CBF) was measured by the radioactive microsphere technique. The dogs were killed, and the hearts were perfused with red and blue dyes to determine area at risk (AAR), stained with nitroblue tetrazolium for infarct localization, and sectioned for histologic analysis and BF measurements. In controls and MPG-treated animals, infarct/risk ratios were 40 +/- 5 and 38 +/- 6%, and epicardial collateral BFs were 0.21 +/- 0.037 and 0.15 +/- 0.034 ml/g/min, respectively (p = NS). Hemodynamic measurements did not differ between the two groups. However, CBN as a percentage of total infarct was reduced in controls (22 +/- 3%) as compared with MPG-treated animals (35 +/- 2%, p = 0.002). Thus, MPG altered the histologic composition of infarcts in this model, surprisingly increasing the amount of CBN without altering overall infarct size (IS). These results raise questions about the role of free radical scavengers in generation of CBN and suggest that a population of cells exists in which treatment with MPG may alter the mechanism of cell death.