Positive hemodynamic interaction between amrinone and diltiazem in anesthetized dogs

The direct negative inotropic actions of calcium channel blockers limit the use of these otherwise effective systemic and coronary vasodilators in patients with heart failure. We studied the effects of amrinone pretreatment on the dose--hemodynamic response curve of diltiazem in order to test the hypothesis that amrinone might potentiate diltiazem's positive effects in anesthetized dogs. The control group (no pretreatment, n = 6) had a typical dose-related response to diltiazem (50, 100, and 150 micrograms/kg): coronary and systemic vasodilation, increased stroke volume, and no change in myocardial work and power. Amrinone pretreatment of the study group (n = 7) altered the hemodynamic response, thus maximal systemic vasodilation and stroke volume increase at a lower diltiazem dose, a 15 to 35% increase in myocardial work and power, and more profound coronary vasodilation. We propose that amrinone, by inhibiting phosphodiesterase, potentiates diltiazem vasodilation and reflexly secreted catecholamines' actions on the heart. This positive interaction may permit effective use of lower doses of diltiazem, thus circumventing its dose-limiting direct negative effects while still profitting from beneficial peripheral, reflex, and coronary actions.     

Effects of endothelin on renal hemodynamics and excretory functions in anesthetized dogs

The effects of endothelin on renal hemodynamics and excretory functions were investigated in anesthetized dogs. Infusion of endothelin at a rate of 1 ng/kg.min resulted in a slight but significant decrease in renal blood flow and an increase in renal vascular resistance and filtration fraction. Endothelin at doses higher than 10 ng/kg.min significantly decreased cardiac output, glomerular filtration rate, urine volume, and urinary sodium and potassium excretion, whereas it increased systemic vascular resistance. Mean arterial pressure and heart rate showed a transient decrease and increase, respectively, at doses higher than 50 ng/kg.min. Plasma renin activity and plasma aldosterone concentrations were increased only at the dose of 100 ng/kg.min. These effects lasted for more than 60 min. These results suggest that endothelin may have an important role in the modulation of renal functions as well as in the modulation of systemic hemodynamics.     

Effects of dopamine, noradrenaline and isoproterenol on pulmonary circulation in anesthetized dogs

Experiments were performed on 19 anaesthetized open-chest dog instrumented with polyethylene catheters inserted: into the aorta, in pulmonary artery and in left atrium and with an electromagnetic flow-transducer placed around the ascending aorta in order to record : systemic arterial and pulmonary pressures, mean left auricular pressure and phasic aortic flow. Heart rate, stroke volume, total systemic and pulmonary resistance, cardiac work were moreover calculated. Each dog was given intravenously by slow infusione : Dopamine (micrograms 5--10--20/kg/min/ 5 min), Isoproterenol (microgram 0.125--0.25--0.5/kg/min/5 min) and Norepinephrine (microgram 0.25--0.5--1 /kg/min/5 min). Results obtained on systemic hemodynamics agree with those reported by many other investigators. On pulmonary circulation : Isoproterenol, at the tested doses, elicited vasodilator effects, Norepinephrine increased total pulmonary resistance but not pulmonary vascular resistance, while Dopamine did not modify or slightly reduced vascular pulmonary tone.     

Effects of nifedipine and captopril on vascular capacitance of ganglion-blocked anesthetized dogs

The hemodynamic effects of nifedipine and captopril at doses producing similar reductions in arterial pressure were studied in pentobarbital-anesthetized ventilated dogs after splenectomy during ganglion blockade with hexamethonium. Mean circulatory filling pressure (Pmcf) was determined during transient circulatory arrest induced by acetylcholine at baseline circulating blood volumes and after increases of 5 and 10 mL/kg. Central blood volumes (pulmonary artery to aortic root) were determined from transit times, and separately determined cardiac outputs (right atrium to pulmonary artery) were estimated by thermodilution. Nifedipine (n = 5) increased Pmcf at all circulating blood volumes and reduced total vascular capacitance without a change in total vascular compliance. Central blood volume, right atrial pressure, and cardiac output were increased with induced increases in circulating blood volume. In contrast, captopril (n = 5) did not alter total vascular capacitance, central blood volume, right atrial pressure, or cardiac output at baseline or with increased circulating volume. Thus, at doses producing similar reductions in arterial pressure, nifedipine but not captopril increased venous return and cardiac output in ganglion-blocked dogs.     

Regional hemodynamic responses to nicotine in conscious and anesthetized dogs: comparative effects of pentobarbital and chloralose

This study was conducted in 12 dogs to evaluate regional hemodynamic responses during intravenous infusion of nicotine (36 micrograms/kg/min) in the conscious state and compare them with those in the same dogs following either pentobarbital (n = 6) or chloralose anesthesia (n = 6). Values for regional blood flow were obtained with 15-microns radioactive microspheres and used to calculate regional vascular conductance. In the conscious state, nicotine increased aortic pressure (+70%) and caused hyperventilation that reduced arterial PCO2 (-44%). These systemic effects were associated with decreases in vascular conductance in the renal cortex (-48%), pancreas (-81%), duodenum (-58%), and cerebral cortex (-55%), whereas no significant change in vascular conductance was evident in spleen, liver, or myocardium. Pentobarbital anesthesia blunted the increases in aortic pressure and respiratory activity and the reductions in vascular conductance in the renal cortex, pancreas, duodenum, and cerebral cortex during nicotine infusion. In contrast, chloralose anesthesia accentuated the increase in aortic pressure and the decrease in vascular conductance in the renal cortex during nicotine infusion, while it converted no change in vascular conductance in the spleen into a decrease and no change in vascular conductance in the myocardium into an increase. Chloralose anesthesia blunted nicotine-induced hyperventilation. These findings demonstrate that general anesthetic agents may have markedly different effects on cardiovascular reflex pathways. They emphasize the importance of considering the particular characteristics of the anesthetic agent used in interpreting results from studies of cardiovascular pharmacology and physiology in anesthetized animals.     

Effects of substance P on renin release and renal function in anesthetized dogs.

Substance P (SP), a naturally occuring undecapeptide with hypotensive, vasodilatory and smooth muscle stimulating properties, was infused intravenously or intrarenally into anesthetized dogs. Infusions of SP intravenously suppressed renin secretion rate (RSR) from 204±45 to 52±18 ng/min (p < 0.02) at an infusion rate of 0.5 ng/kg/min, and to 50±22 ng/min (p < 0.05) at 5 ng/kg/min. When the concentration of SP was further increased to 50 ng/kg/min, RSR increased to a level above the control value (728±81, p < 0.01). Intrarenal infusion of SP produced similar changes in renin release. At infusion rates of 0.5 ng/kg/min and 5 ng/kg/min, RSR was suppressed from 145±18 to 56±18 ng/min (p < 0.05) and to 26±8 ng/min (p < 0.01) respectively. At 50 ng/kg/min, RSR increased to 251±59 (p > 0.1). Both intravenous and intrarenal administration of the peptide significantly lowered arterial blood pressure at the highest two doses. Intrarenal infusion of SP resulted in a significant dose-related increase in urine volume, sodium and potassium excretion, and renal blood flow. In contrast, intravenous infusions did not alter these parameters. Thus SP suppresses renin release in the presence and in the absence of diuresis, natriuresis, and vasodilation.     

Vasorelaxing actions of molsidomine and its metabolites, in comparison with nitroglycerin

The effect of a novel antianginal agent, molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine) (SIN-10) and its metabolites, 3-morpholinosydnonimine (SIN-1) and N-nitroso-N-morpholinoaminoacetonitrile (SIN-1A) on isolated dog blood vessels were investigated. SIN-1 and SIN-1A elicited a concentration-dependent relaxation of prostaglandin F2 alpha, contracted strips, while SIN-10 was without effect even in a concentration of 10(-4) M. The mean effective concentration (EC50) values of SIN-1A were much lower than SIN-1 and other vasodilators including nitroglycerin. The time course of relaxation was more rapid and transient in response to SIN-1A than to SIN-1. Adrenergic and cholinergic blocking agents did not affect the relaxing responses to SIN-1 and SIN-1A. SIN-1A also attenuated the norepinephrine-, KCl-, Ca2+-, or electrical transmural stimulation-induced contractile response, but SIN-1A increased the [3H]norepinephrine release from the adrenergic nerve terminals in response to transmural stimulation. Methemoglobin, which reportedly binds nitric oxide, or methylene blue, an inhibitor of guanylate cyclase, attenuated the relaxing response to SIN-1A. These results indicate that the vasodilating action of molsidomine results from the direct action on the vascular smooth muscle and suggest that the action is caused by its metabolites, probably SIN-1A, which contains a nitric oxide-moiety in the molecule. The possible mechanism of vasorelaxing action of SIN-1A is discussed in comparison with that of nitroglycerin.     

Effects of hypoxia on the hemodynamic actions of prostaglandin E1

The effect of prostaglandin E₁ (PGE₁) on central and peripheral hemodynamics was studied in seven conscious dogs under conditions of normoxia and hypobaric hypoxia to ascertain if hypoxia attenuated the cardiovascular actions of PGE₁. Silastic catheters were chronically implanted in the pulmonary artery, left atrium, and aorta. Acute hypoxia was produced in a hypobaric chamber maintained at 446 mmHg pressure (14,000 feet). PGE₁ at sea level (normoxia) resulted in significant increases in heart rate, cardiac output, left ventricular stroke work and pulmonary blood volume as well as significant decreases in aortic, pulmonary arterial, and left atrial pressures. During hypobaric hypoxia, PGE₁ produced essentially identical effects on all hemodynamic parameters except pulmonary blood volume and pulmonary arterial pressure where marked attenuation of PGE₁ action occurred.Significant hypoxemia does not alter the peripheral and myocardial actions of PGE₁ in intact animals. Attenuation of the pulmonary hemodynamic actions of PGE₁ may be secondary to the effect of hypoxia on certain segments of the pulmonary vascular bed.     

Investigations on the circulation of anesthetized dogs.

In the present experiments arterial blood pressure, cardiac output, heart rate, oxygen consumption, AVO2 difference values and their changes were investigated in 64 anesthetized dogs in four periods for altogether 60 min. Blood flows of the renal, commune carotid and femoral arteries were measured in parallel and the changes were recorded throughout the 60 min of the experimental period. Urine was collected separately from both kidneys, in order to determine whether the measurement of the blood flow of the renal artery disturbed renal functions. Total peripheral vascular resistance and the vascular resistance of the territories of the commune carotid and femoral arteries were calculated from the parameters measured. In the present experiments the equation of the regression line between cardiac output and body weight was y = 0.102x + 0.9411. The equation of the regression line between cardiac output an body surface proved to be y = 2.996x + 0.653. The relationship between total oxygen consumption and body weight could be characterized by the y = 5.815x + 24.227 equation. Our data were in accordance with data of the Biology Data Book obtained in dogs anesthetized by pentobarbital. Our present data can be found but partially in the Biology Data Book, so the results obtained in the present study may serve as basis of future comparisons. In this work proper care was taken to maintain the same conditions and, thus ruling out possible artefacts. The experiments were carried out on mongrel dogs of different sexes; nevertheless, the animals were attempted to be kept under the same conditions for the 14 days preceding the experiments.     

Effect of acebutolol on plasma catecholamine concentrations in anesthetized dogs with ouabain-induced arrhythmias and its direct actions in vitro on the adrenal medulla

We have performed studies on blood hormone dynamics following intravenous administration of acebutolol, a newly synthesized beta-blocker, and its direct action on the adrenal medulla in vitro. Intravenous injection of acebutolol into anesthetized dogs almost doubled the plasma adrenaline and noradrenaline concentrations within 5 to 15 minutes, while renin activity was reduced to approximately two-thirds of the pre-administration level. When arrhythmia was induced in dogs with ouabain, the plasma adrenaline and noradrenaline levels increased to 220 +/- 109 and 392 +/- 84 pg/ml, respectively, from the basal levels of 44 +/- 24 and 140 +/- 43 pg/ml. The restoration of sinus rhythm following the administration of acebutolol was accompanied by a further increase in the plasma adrenaline and noradrenaline levels to 797 +/- 364 and 1226 +/- 263 pg/ml, respectively. A perifusion experiment indicated that acebutolol directly accelerated catecholamine release from the adrenal medulla in pigs.