Metabolic control of circulation. Effects of iodoacetate and fluoroacetate.

123

A B S T R A C T Chloralose-anesthetized dogs were infused intravenously with either Tris-acetate or Trispyruvate at 0.0375, 0.075, and 0.15 mmol/kg per min successively, each for 20 min. Acetate infusion increased cardiac output, left ventricular dP/dt and dPldt/P, and coronary blood flow, while pyruvate infusion did not. Infusions of either substance increased arterial blood and skeletal muscle concentrations of citrate and malate, but only acetate infusion increased the tissue AMP content and decreased the ATP:AMP ratio. The increase in cardiac output produced by acetate was accompanied by an increase in total body oxygen consumption and a decrease in the difference between arterial and mixed venous blood oxygen.Myocardial oxygen consumption increased during acetate infusion, but the decrease in myocardial oxygen extraction and the increase in coronary sinus blood oxygen saturation suggest that an active coronary vasodilation which was not a result of the increased cardiac work, occurred. The concentration of hypoxanthine in the coronary sinus and the content of myocardial adenosine increased, which suggests that the increase in coronary blood flow was caused by the vasodilator action ofadenosine released from the myocardium, and that adenosine production is not necessarily tied to Po2.These systemic and coronary hemodynamic changes also occurred when acetate (0.075 mmol/kg per min) was infused into conscious dogs. Acetate infusion also increased blood flow to the gastrointestinal tract, kidneys, intercostal muscle, and diaphragm. These changes were not affected by propranolol pretreatment, but were abolished by pretreatment with fluoroacetate which reduced acetate oxidation.These results suggest that the circulatory stimulation produced by acetate was not caused by increases in

Section: Introductionmentioning

confidence: 65%

Section: Methodsmentioning

confidence: 99%

Metabolic Control of the Circulation

Liang¹,

Lowenstein²

1978

123

“…Coronary blood flow was measured by a 4-aminoantipyrine indicator method (26,27). Diastolic Teprotide (0.5 mg/kg) was injected i.v., and systemic hemodynamic measurements were repeated at 5-min intervals for 30 min thereafter.…”

Section: Methodsmentioning

confidence: 99%

Renin-Angiotensin System Inhibition in Conscious Sodium-Depleted Dogs

Liang¹,

Gavras²,

Hood³

1978

A B S T R A C T 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 ,ug/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, 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. INTRODUCTIONSodium depletion increases plasma renin activity (PRA)l and blood angiotensin II concentration (1-3), indicating an activation of the renin-angiotensin system. This increase in 'angiotensin II concentration probably plays an important role in the maintenance of normal arterial blood pressure during salt depletion, because the arterial blood pressure decreases under these conditions after administration of saralasin (1-sarcosine-8-alanine-angiotensin II; P113) (2-7), teprotide (SQ 20,881) (7-10), and SQ 14,225 (11). Saralasin is a competitive receptor antagonist of angiotensin II (4, 12, 13), whereas the latter two agents inhibit angiotensin-converting enzyme, which converts angiotensin I to the biologically active angiotensin II (8,(13)(14)(15)(16). Because angiotensin II is one of the most potent vasoconstrictors known (17, 18), a decrease in arterial blood pressure after angiotensin inhibition presumably is due to elimination of the angiotensin-induced vasoconstriction. However, angiotensin II also exerts a positive inotropic action on the heart (19,20), the abolition of which may lower the arterial pressure. Previous investigators (9, 10) have shown that cardiac output de-

“…Regional organ blood flows were measured by a modification (22) of the radioactive microsphere method of Rudolph and Heymann (23). 500,000-1,000,000 microspheres, 15±3 grm in diameter, and labeled with cerium-141, tin-113, ruthenium-103, or scandium-46 at 10 mCi/g, sp act, were injected into the left atrial catheter, followed immediately by a flush of 10 ml of normal saline over a 30-s period.…”

Section: Methodsmentioning

confidence: 99%

Insulin Infusion in Conscious Dogs

Liang¹,

Doherty²,

Faillace³

et al. 1982

248

A B S T R A C T 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 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.