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We studied the effects of intravenous injections of three β-adrenoceptor antagonists on cardiac automaticity in conscious dogs after sinoatrial node (SAN) excision. Injections were repeated for 60 days post-operatively. In controls, mean corrected sinoatrial node recovery time (CSNRT) was 535 ± 24 ms. One milligram per kilogram of dl-propranolol did not modify heart rate but raised CSNRT (p< 0.01). One-half milligram per kilogram of dl-pindolol raised heart rate (p< 0.05) and reduced CSNRT (p< 0.05). Ten milligrams per kilogram of dl-practolol were needed to significantly reduce heart rate and raise CSNRT (p< 0.01). In dogs after SAN excision, 0.1 mg/kg and 0.5 mg/kg of dl-propranolol lowered heart rate on days 3, 30, 43, and 60. Corrected recovery time (CRT) at a cumulative dose of 0.5 mg/kg rose to 9015 ± 1028 ms on day 3 and to 3064 ± 810 ms on day 30 (p< 0.001). dl-Pindolol stabilized the rhythm. With 0.1 mg/kg, heart rate and CRT were not modified significantly on days 9 and 46. dl-Practolol at cumulative doses of 1 and 5 mg/kg lowered heart rate significantly on days 7 and 46. On day 12, the same doses did not modify heart rate but raised CRT (p < 0.05). This suggests that of the β-adrenoceptor antagonists studied here, pindolol may be preferable in treatment of certain supraventricular arrhythmias.

The vasoactive effects of calcium antagonist drugs were compared using a multi-organ functional imaging technique with thallium-201 (Tl-201). Four drugs were tested at two different doses: nifedipine (10 and 25 μ/kg), verapamil (100 and 250 μg/kg), diltiazem (100 and 250 μg/kg), and bepridil (2.5 and 10 mg/kg). Tl-201 was injected at three different times after drug administration to examine the time course of the effects of the drugs. The regions studied were heart, liver, kidneys, shoulder skeletal muscles, and lungs. The results showed marked changes in Tl-201 biodistribution in anesthetized dogs after administration of calcium antagonists. The major increases in count density were observed in heart and skeletal muscles, but the drug effects differed in intensity and duration. Nifedipine induced the largest variations in the doses used (136 and 153 in the heart 2 min after 10 and 25 μg/kg doses, respectively). Diltiazem and verapamil were most efficient at 250 μg/kg (134 and 115 at 2 min after injection, respectively). With bepridil the increases of cardiac and muscular uptakes of Tl-201 were transient and the 2.5 mg/kg dose induced a decrease of myocardial count density (84 at 5 min). The effects were less reproducible in the other organs studied.

The electrophysiologic effects of diproteverine were studied in the conscious nonsedated chronically instrumented dog. Diproteverine at 0.25–0.75 mg/kg (i.e., at plasma levels within the assumed therapeutic range) dose-relatedly decreases heart rate, increases corrected sinus node recovery time, and decreases Wenckebach point. These effects are observed at plasma levels ranging between 16.2 ± 4.1 and 144.7 ± 12.5 ng/ml. After cholinergic blockade with N-methyl-scopolammonium, diproteverine lowers heart rate (≥=0.25 mg/kg), increases corrected sinus node recovery time, and decreases Wenckebach point (≥=0.5 mg/kg). After propranolol, diproteverine only significantly reduces corrected sinus node recovery time 5 min after the third administration (0.75 mg/kg). After pharmacologie autonomie blockade by N-methylscopolammonium propranolol combination, diproteverine lowers intrinsic heart rate (≥=0.25 mg/kg) and Wenckebach point (≥=0.5 mg/kg). Diproteverine does not modify mean blood pressure. These results show that diproteverine administered with and without pharmacologie autonomie blockade in the conscious dog causes dose-related depressant effects on sinus node function and atrioventricular conduction without producing significant vasodilatation.

Grisorixin and alborixin are two monocarboxylic ionophores of the nigericin group which carry potassium preferentially over sodium. We studies their cardiovascular effects in anesthetized digs. Grisorixin (2 mg/kg) and alborixin (1 mg/kg) produced a dramatic increase in ventricular contractile force (+250 and +320, respectively) and in systolic and diastolic arterial pressures. At the same time, they induced a marked increase in plasma potassium in the coronary sinus and hepatic vein and a lesser increase in the renal and deep femoral veins. The concomitant modifications of the electrocardiogram were similar to those usually described in hyperkalemia, reflecting the effect of grisorixin and alborixin on plasma potassium. The parallel decrease in plasma sodium in the coronary sinus was more marked with alborixin than with grisorixin. These results suggest that the ionophores alter the intracellular ionic state of the myocardium, which may partly explain their positive inotropic effect and the greater effect of alborixin.

The antinociceptive effect of the octapeptide vapreotide, an analog of somatostatin, was studied after systemic injection in normal mice using the hot plate and abdominal stretching assays, and in normal rats using the paw pressure analgesiometric assay. Vapreotide was ineffective at 1 microgram/kg s.c. in the hot plate test in mice, but 30 min after injection it induced an antinociceptive effect at s.c. injected doses of 8, 64, 512 and 4096 micrograms/kg, with an ED50 of 213 +/- 5 micrograms/kg. For the three highest doses this effect persisted 24 hr after the injection (maximal increase: +80 +/- 23% for 512 micrograms/kg) and disappeared at 48 hr. In the phenylbenzoquinone stretching test, in mice, the ED50 was 186 +/- 6 micrograms/kg (maximal decrease: -63 +/- 5%); the effect persisted 24 hr only for the same two highest doses. Using the paw pressure test, in rats, a dose-dependent increase in paw withdrawal and vocalization thresholds was observed for 21 and 24 hr, respectively, after s.c. injections of 16, 64 and 512 micrograms/kg. Global scores obtained for vocalization thresholds were significantly increased (vs. paw withdrawal thresholds) for 64 and 512 micrograms/kg. Carrageenan-induced nociception in rats was reduced for 21 hr by 64 and 512 micrograms/kg s.c.; scores of the contralateral noninflamed paw were also increased. Vapreotide administered locally in the inflamed paw was inactive. No change in edema volume was obtained after systemic injection of vapreotide.(ABSTRACT TRUNCATED AT 250 WORDS)

The known vagolytic effect of quinidine has been termed "atropine-like." This effect was studied in vitro and in vivo. Unlike atropine, quinidine was not found to exert any competitive antagonism to acetylcholine at the muscarine-sensitive cholinoceptors of isolated guinea-pig atria. In the narcosed dog subjected to vagal stimulation, the effects of slow perfusion of quinidine (0.5 mg/kg/min for 120 min) were also different in several ways from those of atropine. The tachycardia induced by quinidine was not concomitant with an inhibition of the cardiomoderation caused by vagal stimulation. Tachycardia appeared at low plasma levels, whereas reduction of vagal influence only occurred at high concentrations. Even then, the effects of vagal stimulation were never totally suppressed. After propranolol, quinidine had no tachycardiac action. This could not be attributed to any difference in metabolism because plasma levels of quinidine were the same in dogs pretreated or not with propranolol. Evidence reported here suggests that the cardioacceleration induced by quinidine is not due to a direct vagolytic action. The slight lowering of vascular resistance and arterial pressure observed cannot fully account for this effect either. An adrenergic mechanism involving beta receptors seems likely. In any case, to describe the effects of quinidine on heart rate as atropine-like is evidently inappropriate and misleading.

THIS work studies the antinociceptive effect of a sustained (7day) release dosage form of vapreotide, a peptidic analogue of somatostatin, in rats submitted to a nociceptive mechanical stimulus (paw pressure). One intramuscular injection (0.6 mg/animal) induced a significant antinociceptive effect for 7complete days with a maximal increase in vocalization thresholds of 68 ± 5 and a plateau of activity during the first 4 days. This action was totally inhibited by naloxone (1 mg kg−1, s.c.) injected 24 h or 6 days after vapreotide, suggesting an opioidergic involvement throughout the antinociceptive effect. These findings suggest potential interest in human therapy.

One-hundred and fifty non-diabetic patients with stage II chronic oclusive arterial disease (COAD), were tested for red blood cell filterability (RBF). At the same time, glycaemia, uricaemia, plasma cholesterol and triglycerides, fibrinogen, haematocrit, and white blood cells (granulocytes and lymphocytes) count, mean corpuscular volume, were measured. Thirty healthy people, tested for the same biological parameters, were used as controls. RBF was performed, using the Reid & Dormandy technique, with the same batch of filters (Nucle-pore 5 μm, No. 54 A8 A25) for patients and controls. Filtration time was expressed in s.ml-1. Values obtained in patients (41.967 ± 0.889) were significantly different (P< 0.005) from controls (32.1 ± 1.329). RBF alteration was correlated (P<0.05) with white blood cells count, haematocrit and plasma fibrinogen values. No correlation was observed with other biological parameters.