Hemodynamic actions of endothelin in conscious and anesthetized dogs

The newly described endogenous peptide, endothelin, was administered to five chronically instrumented conditioned dogs. Endothelin produced significant and simultaneous increases in both heart rate (HR) and mean arterial pressure (MAP) in conscious dogs. Endothelin also produced significant increases in MAP in anesthetized animals. Ganglionic suppression induced by hexamethonium (10 mg/kg) and atropine (0.1 mg/kg) blocked HR responses and markedly inhibited the pressor responses to endothelin in conscious animals. These results suggest that endothelin in part acts to elevate blood pressure and heart rate through modification of autonomic nervous system tone. When endothelin and angiotensin II were administered in mole equivalent doses, angiotensin II produced a pressor response of greater magnitude than did endothelin in conscious animals.     

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 midline laparotomy on expiratory muscle activation in anesthetized dogs

Abdominal surgery has a marked inhibitory influence on the diaphragm, but its effect on the expiratory muscles is not known. Therefore, we have recorded the electromyograms of the triangularis sterni, abdominal external oblique, and transversus abdominis before and after a midline laparotomy in 10 anesthetized, spontaneously breathing dogs. Measurements were obtained during quiet breathing in the supine posture, during breathing against expiratory threshold loads, during head-up tilting, and during hyperoxic hypercapnia. Expiratory activation of the transversus abdominis in all conditions was considerably reduced after laparotomy. This reduction was real, as no change in the compound muscle action potential during single pulse stimulation was observed. In contrast, expiratory recruitment of either the triangularis sterni or the abdominal external oblique was maintained or increased. We therefore conclude that laparotomy inhibits not only activation of the diaphragm during inspiration but also activation of the transversus abdominis during expiration. Visceral afferents thus affect in concert the two respiratory muscles lining the peritoneum. The present findings also emphasize the important fact that the pattern of activation of a particular abdominal muscle is not necessarily representative of the entire abdominal musculature.     

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 dichloroacetate on hemodynamic responses to dynamic exercise in dogs.

To determine whether lactic acid production contributes significantly to the cardiac responses to muscular dynamic exercise, we administered intravenous sodium dichloroacetate (32 mumol.kg-1.min-1), a pyruvate dehydrogenase activator that facilitates lactate metabolism via the tricarboxylic cycle, in 12 dogs during two graded levels of treadmill exercise. Similar exercise was carried out in nine normal dogs receiving equimolar doses of NaCl. In the latter group, arterial lactate increased progressively from 0.80 +/- 0.11 (SE) mmol/l at rest to 2.13 +/- 0.28 mmol/l by the end of exercise. In contrast, arterial lactate did not change significantly (0.98 +/- 0.12 to 0.95 +/- 0.11 mmol/l) during exercise in dogs receiving dichloroacetate infusion. Dichloroacetate infusion also reduced the increases in plasma norepinephrine, heart rate, and left ventricular contractile indexes that occurred during exercise, suggesting that the sympathetic cardiac stimulation occurring during exercise may be related to the production of lactic acid. However, dichloroacetate affected neither the net increase in cardiac output nor the relationship between total body oxygen consumption and cardiac output that occurred during exercise. Thus we conclude that lactic acid production is not essential to the increase in cardiac output that occurs during mild-to-moderate exercise.     

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.     

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 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.     

Effects of acetaminophen and ibuprofen on renal function in anesthetized normal and sodium-depleted dogs

In certain conditions, renal prostaglandins (PGs) are importantdeterminants of kidney function. Under these "renal PG-dependent states," pharmacological inhibition of vasodilatory PG may result inexcessive renal vasoconstriction and adversely affect kidney function.The purposes of this study were to determine whether acetaminophen(Acet), a weak PG-synthesis inhibitor, influences kidney function inthe renal PG-dependent state of anesthesia and sodium depletion.Comparisons were made with ibuprofen (Ibu). Measurements ofPGE₂ excretion were used to assessrenal PG synthesis. Acet (15 mg/kg) and Ibu (10 mg/kg) both decreasedrenal blood flow and glomerular filtration rate by ~20-30% innormal, anesthetized, sodium-replete dogs. Although Acet producedsimilar changes in renal blood flow and glomerular filtration rate inthe low-sodium dogs, Ibu caused a significantly greater renalvasoconstriction (64 ± 10%) in these animals. Both Acet and Ibuinhibited urinary PGE₂ excretionin sodium-replete and low-sodium dogs. Ibu tended to have a greater andmore prolonged effect than did Acet. These results suggest that Acetalters PGE₂ excretion and kidneyfunction under renal PG-dependent conditions; the effects, however, are less severe than those seen with Ibu.