Selective vasoconstriction by alniditan in the carotid vascular bed of anaesthetized dogs.

In anaesthetized dogs, alniditan or (-)-(R)-N-[3,4-dihydro-2H-1- benzopyran-2-yl)methyl]-N'-(1,4,5,6-tetrahydro-2-pyrimidinyl)-1,3- propanediamine dihydrochloride, a new compound with 5-HT1-like receptor ligand effects, dose dependently (0.63-80 micrograms/kg i.v.) reduced common carotid arterial blood flow with comparatively little effect on other cardiovascular variables including coronary, mesenteric and renal arterial blood flow, systemic and pulmonary vascular resistance and airway resistance. The potency of alniditan was higher than that of sumatriptan and comparable to that of ergotamine (dose producing a 50% reduction: alniditan = 5.1 micrograms/kg i.v.; sumatriptan = 13.1 micrograms/kg i.v.; ergotamine = 4.6 micrograms/kg i.v.; median values). The reduction of carotid arterial blood flow by alniditan was accompanied by an increase of carotid arterial vascular resistance and correlated with the increase of the difference in oxygen saturation between arterial and jugular venous blood, suggesting a preferential reduction of extracerebral shunt flow by the compound via constriction of arteriovenous anastomoses in the carotid vascular region. The extent and duration of carotid arterial blood flow reductions after alniditan at 5 micrograms/kg i.v. were similar to those after sumatriptan 15 micrograms/kg i.v. but larger/longer after alniditan at 15 micrograms/kg i.v. than after sumatriptan at 15 micrograms/kg i.v. The dose-dependent increase of carotid arterial vascular resistance by alniditan was similar in dogs premedicated daily for 4 days with solvent or active compound (20 micrograms/kg i.v.), indicating absence of tolerance or resetting of sensitivity to the compound.

Cardiac and hemodynamic effects of intravenous R 80122, a new phosphodiesterase III inhibitor, in anesthetized and awake dogs.

R 80122 is a newly synthesized, selective phosphodiesterase III inhibitor. The cardiac and hemodynamic effects of this compound following intravenous administration were studied in closed-chest anesthetized as well as in conscious chronically instrumented dogs. The findings in the closed-chest anesthetized dogs indicate that R 80122 has positive inotropic and possibly moderate vasodilating properties [maximum increase in LV dp/dtmax/pd: 61%, and maximum decrease in systemic vascular resistance: 29% (a 12.5% decrease for the solvent)]. As a result, cardiac output maximally increased to 149% of the control value. The most striking effect of R 80122 was its positive lusitropic effect (maximal decrease in the time constant of relaxation [T] of 46%). This pronounced lusitropic effect of R 80122 can be regarded as beneficial, because of the increasing evidence that lusitropic defects play an important role in disorders related to heart failure. These effects of R 80122 were associated with only slight changes in arterial blood pressure. The effects of R 80122 lasted about 75 min after stopping the infusion. No ventricular arrhythmias were noted during and after infusion of the compound. The positive inotropic effects seen in anesthetized dogs were confirmed in conscious nonsedated dogs. It may be concluded that R 80122 has a clinically favorable cardiovascular profile for acute applications in heart failure, because its combined positive inotropic and positive lusitropic effects, and moderate vasodilating properties lead to a pronounced increase in cardiac output and only minimal changes in aortic blood pressure.

Electrophysiologic, antiarrhythmic and hemodynamic effects of transcainide.

Transcainide was selected as an antiarrhythmic drug with potential clinical application. In isolated dog, sheep and rabbit Purkinje fibres, in dog and guinea-pig trabecular preparations and in the guinea-pig right auricle, transcainide decreases the rate of rise of the transmembrane action potential, with no effect on normal spontaneous activity and calcium-mediated action potentials; it inhibits early after-depolarizations. The effect on the rate of rise is very slow in onset. In vivo a prolongation of QRS duration is observed. In dogs, the drug is effective against post-infarction and ouabain-induced ventricular arrhythmias, and abolishes acetylcholine and aconitine-induced atrial fibrillation; it elevates the threshold of electrically induced ventricular fibrillation. Hemodynamic studies in anaesthetized and unaesthetized dogs indicate that transcainide moderately decreases contractility, while slightly increasing frequency. No major side effects are seen. Preliminary data on the pharmacokinetics suggest that in the dog the observed effects after i.v. infusion are related to the parent drug. Transcainide is an antiarrhythmic of the local anaesthetic type, with very slow kinetics. It is characterized by a good oral absorption and a long duration of action.

Cardiovascular and some respiratory effects of high doses of alfentanil in dogs.

The cardiovascular and some respiratory effects of alfentanil, a potent and short-acting morphinomimetic, were studied in conscious (n = 6) and anaesthetized, artificially ventilated dogs (n = 7). The compound was injected intravenously in increasing doses of 12.5, 12.5, 25, 50, 100, 200, 400 and 800 micrograms X kg-1 in the conscious dogs and of 0.16, 0.32, 0.64, 1.25, 2.5 and 5 mg X kg-1 in the anaesthetized animals. In the conscious dogs, the heart rate decreased significantly reaching a maximum decrease after the injection of 400 micrograms X kg-1 X PCO2 and arterial and venous lactate concentrations increased, while PO2, pH and base excess decreased significantly. At higher dose levels (100-400 micrograms X kg-1) short periods of convulsions were seen. The most pronounced change in the anaesthetized dogs was a significant fall in LVdP/dt max and LV dP/dt max/P, associated with a rise in left ventricular end-diastolic pressure following the injection of 5 mg X kg-1, suggesting negative inotropic properties at this high dose level. Most of the animals showed A-V dissociations which disappeared at higher doses. All animals survived. These findings indicate that alfentanil is a safe analgesic as far as the effects on the cardiovascular system are concerned. High doses are tolerated well, especially when the animals are artificially ventilated. The short periods of convulsions, seen only in the awake dogs, may have been facilitated by the low PO2 levels reached (median value: 9 kPa).

Propagation velocity and reflection of pressure waves in the canine coronary artery.

In this study the pressure wave velocity in the anterior descending branch of the left coronary artery (LADC) of the dog was measured by determining the delay time between pressure pulses along this artery. This method can only be applied if reflections of the pressure wave distal to the sites of pressure measurement are insignificant. From araldite casts of the coronary arteries the following relation between the diameter proximal to (dprox) and distal to (ddist 1, ddist 2) a bifurcation was found: dprox2.55 = ddist12.55 + ddist 22.55, indicating that reflections at a bifurcation areminimal. In dogs reflections were studied by inducing during diastole a pressure pulse in the aorta and measuring pressure and volume flow proximal to and pressure distal to a segment of the LADC at various levels of the coronary peripheral resistance. Reflection of high-frequency components (greater than 7 Hz) was found to be insignificant, allowing application of the above-mentioned method for measuring the wave-front velocity, which is insensitive to low-frequency reflection. At a pressure in the LADC of 13.3 kPa this velocity was 8.6 +/- 1.4 m.s-1 (mean +/- SD). The calculated dynamic cross-sectional stiffness (deltaP/(deltaA/A)) of the LADC was 97 +/- 11 kPa (mean +/- SE) at an arterial pressure of 13.3 kPa.

Acute effect of fentanyl on haemodynamics and myocardial carbohydrate utilization and phosphate release during ischaemia.

The effect of fentanyl 25 micrograms/kg body weight i.v. on left ventricular haemodynamics, myocardial carbohydrate utilization and phosphate release during ischaemia in dogs was investigated. A reproducible degree of ischaemia could be obtained by partial occlusion (stenosis) of the interventricular artery, using an inflatable cuff. Inducing stenosis twice made it possible to use the animal as its own control. Arterio-local venous differences of glucose increased during ischaemia and lactate and inorganic phosphate were released from the ischaemic myocardium. Fentanyl administered before the second stenosis reduced heart rate and, to a lesser extent, mean aortic pressure and left ventricular dP/dt max. The release of lactate and inorganic phosphate was diminished during the period of ischaemia. These findings suggest that fentanyl prevents excessive breakdown of energy-rich phosphates and high anaerobic production rate of lactate by decreasing the energy demand of the ischaemic myocardium.

A chronically implantable catheter-tip micromanometer (JSI 0400) that can be calibrated after implantation.

This paper describes a catheter-tip micromanometer for chronic left ventricular pressure measurements which can be calibrated in the animal after implantation. The calibration curves are linear, both in vitro and in vivo. Good zero-stability is reached after 1 week of implantation. The duration of function of the device is 3 to 6 months.

An improved animal model for studying the effect of drugs on myocardial metabolism during ischemia.

An improved dog model to study the effect of drugs on myocardial metabolism during ischemia is described. A reproducible degree of ischemia could be obtained by partial occlusion of the anterior descending branch of the left coronary artery (LAD), using an inflatable cuff with a micrometer. The possibility of inducing the stenosis twice in the same animal has the advantage that the animal can be used as its own control. The reproducibility of the degree of ischemia was demonstrated by the nonsignificant differences in local venous lactate, inorganic phosphate, and glucose concentrations after the first and second stenosis. The mean pressure difference over the stenosis was used to express the degree of coronary artery narrowing. In this model, one does not have to rely on the collateral circulation in collecting local venous blood. Moreover, it is very likely that this blood is obtained from the most pronounced ischemic area, which was localized with radioactive microspheres. At this degree of stenosis, left ventricular function was not affected too much, as was demonstrated by the slight changes in dP/dt max, and systolic and diastolic aortic pressure after induction of the stenosis. The usefulness of our model to evaluate the activity of drugs is demonstrated by the effect of fentanyl, a potent morphine-like analgesic, on the poststenotic local venous lactate and inorganic phosphate concentrations.

The radioactive microsphere method for the assessment of regional myocardial blood flow after coronary artery occlusion. Inaccuracies due to variations in the diameter distribution of the spheres.

In this study, we have tried to determine the magnitude of the inaccuracy of the radioactive microsphere method - due to variations in the diameter distribution of the spheres - for measuring regional myocardial blood flow after coronary artery occlusion. In 5 mongrel dogs, three types of 15 mum microspheres, labelled with 125I, 141Ce or 85Sr, were injected simultaneously after the descending branch of the left coronary artery had been ligated. Myocardial samples wert taken from the left ventricle and divided into four groups according to the number of spheres per sample. The radioactivity of the various isotopes per gram tissue was expressed as percentage of their activity per milliliter of the reference sample. The diameter distribution of microspheres, labelled with each of the isotopes, was determined light-microscopically in suspensions belonging to three different batches. The relative error, as determined from the difference in relative radioactivity of the various types of microspheres in the tissue samples, was higher than the theoretical error for each of the number of spheres per sample. It is very likely that this discrepancy is caused by the differences in diameter distribution of the various types of microspheres, resulting in non-random error. The smaller spheres tended to go to low flow areas and the larger ones to high flow areas. Because of the non-randomness, the error due to diameter variations in the spheres can be diminished by randomizing the order of injection of the various isotopes. The present study indicates that the relatively high degree of accuracy of the microsphere method for the determination of blood flow to large parts of the myocardium with an unimpeded coronary circulation, as was described in literature, cannot be extrapolated to the determination of regional myocardial blood flow after coronary artery occlusion, when the combination of small tissue samples, variations in the diameter distribution of the spheres and an unevenly distributed myocardial blood flow unfavourably affect the accuracy of the method.