Centrally mediated enhancement of ouabain cardiotoxicity by angiotensin II in dogs.

The effect of angiotensin II (Ang II) infusion on the doses of ouabain required to induce ventricular arrhythmias and death was investigated in anesthetized dogs. Tritiated ouabain was infused alone i.v. (1 microgram/kg per min) to establish the control toxic doses and the level of ouabain in the heart at death. When Ang II and ouabain were co-infused i.v. the doses of ouabain needed to induce arrhythmias and death were significantly reduced. Spinal transections performed at C-1 prior to drug infusions prevented the effect of Ang II to enhance the toxicity of ouabain. Thus, the action of Ang II to augment ouabain toxicity appeared to be related to its effects on the sympathetic nervous system. To confirm that Ang II was acting within the brain rather than at peripheral sites of the sympathetic system, Ang II was infused into the vertebral artery of spinal cord intact dogs. The infusion rate of Ang II needed to produce a significant enhancement of ouabain toxicity was much lower when given into the vertebral artery than into the femoral vein. These data indicate that Ang II enhances the cardiotoxicity of ouabain via an action produced within the brain and mediated by the sympathetic nervous system.

Selective additive effect of phenylephrine to the inotropic action of isoproterenol on rabbit left atria.

The chronotropic and inotropic effects of isoproterenol, adrenaline and phenylephrine were examined in isolated right and left rabbit atria. 1. Spontaneous right atrial rate (RAR) and left atrial contractile force (LACF) (electrically stimulated at 2 Hz) were monitored during separate concentration-response curves to all 3 agonists. The order of potency for both parameters was isoproterenol greater than adrenaline greater than phenylephrine. 2. At maximum agonist effect, adrenaline produced the greatest LACF increase, followed in order by isoproterenol and phenylephrine. 3. When phenylephrine (6.0 x 10(-5) M) was added to the left atria maximally stimulated with isoproterenol, an additional 32% increase in LACF was recorded, but an additive effect was not noted when phenylephrine was added to atria maximally stimulated with adrenaline. The LACF achieved by a combination of isoproterenol and phenylephrine approximated the maximum LACF induced by adrenaline alone. 4. At maximum agonist effect, isoproterenol and adrenaline produced a greater RAR increase than phenylephrine. Further, phenylephrine did not increase the maximum RAR effect of isoproterenol or adrenaline. 5. Adrenergically mediated chronotropic increases appear to be mediated by a beta adrenoceptor and the maximum response to agonists of full intrinsic activity can not be further increased by agonist combinations. However inotropic increases appear to be mediated by 2 adrenoceptor types which may be simultaneously stimulated to produce additive effects. The two adrenoceptors mediating inotropic change are probably alpha and beta.

Loss of H2 histamine receptor activity in rabbit aorta after maturity.

The activity of H1 and H2 histaminergic receptors was studied in aortic strips taken from young (6 weeks) and mature (7-8 months) rabbits. H1-mediated contractile activity was similar in both age groups, but H2 receptor relaxant activity was greatly diminished in mature rabbits. H2 receptor activity was evaluated with two experimental approaches: its modifying effect on blockade of H1 receptors by diphenhydramine (DPN), and its capacity to directly relax precontracted strips. Schild plot evaluation of DPN blockade revealed that the slope of the plot was below 1.0 in strips from young rabbits (0.77), but not in strips from mature rabbits (0.94). Propranolol pretreatment did not increase the Schild plot slope (0.66) of young aortic strips, but metiamide pretreatment did (0.92). Metiamide treatment did not further in crease slope of mature strips (0.95). When the slopes of the plots were near 1.0, as in the mature and metiamide-treated mature and young strips, the pA2 of DPN was very close (7.51, 7.70, and 7.65). Lost H2 receptor activity in maturity was confirmed by relaxing norepinephrine-precontracted strips with histamine or dimaprit. Histamine-induced relaxation of precontracted strips was slightly diminished in mature strips, while the relaxing activity of dimaprit was greatly reduced in mature tissue. The same strips relaxed vigorously when exposed to nitroglycerin or NaNO2, demonstrating that the strips were capable of relaxing. Therefore, it appears that H2 receptor activity in rabbit aorta is greatly diminished as the animal matures.

Increased automaticity and decreased inotropism of ouabain in dogs with furosemide-induced hypomagnesemia.

Unusual cardiac glycoside toxicity has been reported during hypomagnesemia, but the underlying cause remains unexplained. Therefore, we characterized and compared the effects of ouabain in normo- and hypomagnesemic dogs with and without induced heart block. Hypomagnesemia (30% reduction in plasma magnesium) was induced with 7 days of furosemide treatment (20 mg/kg, p.o.). Following potassium replacement, ouabain was infused at 1 microgram/kg/min and changes in contractile force (strain gauge), electrocardiogram (ECG), ventricular automaticity, and cardiac conduction were monitored. The inotropic response, sustained ventricular arrhythmias, and death all occurred at significantly lower ouabain doses in hypomagnesemic dogs with and without heart block. The changes observed were specifically related to magnesium depletion, and not to potassium depletion. Ouabain activity was not different from control when both magnesium and potassium were replaced. Ouabain-induced increases in automaticity were enhanced during hypomagnesemia and contributed to the development of sustained ventricular arrhythmias at lower ouabain doses. Although the inotropic response occurred at smaller ouabain doses in hypomagnesemia, the overall increase in contractile force was diminished. Thus, increased glycoside toxicity appears related to enhanced automaticity development at doses which are normally subtoxic.

Histaminergic mechanisms involved in the centrally mediated effects of ouabain.

The role of central histaminergic mechanisms in cardiac glycoside toxicity was evaluated in chloralose-urethane anesthetized cats. Cardiac rhythm, blood pressure and sympathetic nerve activity were monitored during continuous i.v. infusion of ouabain (1 microgram/kg/min). Histamine administered into the fourth cerebral ventricle decreased significantly the dose of ouabain necessary to produce ventricular arrhythmias and fibrillation. Toxicity potentiation was associated with enhancement of sympathetic efferent activity. Dimaprit, a specific H2 receptor agonist, produced a similar, but slightly greater, potentiation of ouabain activity than histamine when similarly administered. Intracerebroventricular (i.c.v.) pretreatment of cats with cimetidine, an H2 receptor antagonist, provided a dose-dependent protective effect against ouabain-induced toxicity. Central administration of diphenhydramine, an H1 receptor antagonist, had no effect on cardiotoxic actions. These results suggest a role for central histaminergic mechanisms in cardiac glycoside toxicity which is mediated through an H2 receptor process. Furthermore, it is suggested that ouabain stimulates central histaminergic neurons which impinge on hypothalamic areas and such excitement results in a centrogenic activation of sympathetic centers which is responsible for cardiac glycoside cardiotoxicity.

Pulmonary vascular responsiveness to histamine: exquisite sensitivity of small intrapulmonary arteries.

The contractile responses of cylindrical segments of the central and peripheral pulmonary arteries of the rabbit and the guinea pig to norepinephrine and histamine were studied. Concentration-response curves demonstrated that the relative sensitivity of the pulmonary arteries of both species to the 2 agents increased as the internal diameter of the arterial segments decreased, except in very small arterial rings obtained from the rabbit, which did not respond at all to norepinephrine, but responded quite vigorously to histamine. These data suggested that histamine and other vasoactive substances may play an important role in the regulation of blood flow in the periphery of the lung, and, perhaps, in the response of the peripheral vasculature to hypoxia.

Myocardial depression associated with effective refractory period prolongation after pentobarbital and procainamide but not after dantrolene.

Effective refractory period (ERP) and contractile force (CF) of isolated rabbit left atria were monitored before and during cumulative concentration-response curves to procainamide, pentobarbital and dantrolene. CF reductions and ERP increases were observed after addition of pentobarbital or procainamide. Dantrolene, however, atypically reduced CF without affecting ERP. The prolonged ERP correlated with simultaneous CF reductions during pentobarbital and procainamide activity. These results suggest that the sarcolemmal stabilizing effects of pentobarbital and procainamide could be related to CF reductions while the cardiac depression of dantrolene is unrelated to this action and, as in skeletal muscle, may result from intracellular activity.

Suitability of the rabbit for hypothyroid studies.

New Zealand white rabbits were thyroidectomized, then examined for hypothyroidism after 6 to 8 weeks. Serum thyroxine levels were reduced 77% after surgery. This occurred without apparent calcium homeostatic imbalances even though no calcium supplementation was added to the food or water. The advantages of using the animal and procedure are discussed.

Barbiturate and amphetamine activity in rats fed a magnesium-deficient diet.

Hexobarbital hypnosis and d-amphetamine toxicity were observed in rats fed a commercially available rat food preparation (lab chow) and in another two groups fed complete nutritionally defined diets with or without magnesium. Neither hexobarbital sleeping time nor hexobarbital blood concentration at awakening were affected after 4, 8 or 12 days of feeding the deficient diet. However, increased sensitivity to d-amphetamine was observed after 11 days of feeding the same magnesium deficient diet to other rats. The LD50 of d-amphetamine in magnesium deficient rats was less than 0.5 that recorded for the groups fed lab chow or the nutritionally defined diet with a magnesium supplement.

Quinidine-like activity of atropine in rabbit atria.

Direct effects of atropine and quinidine on contractile force, overdrive suppression, and effective refractory period was studied in rabbit atria. Left atrial contractile force at normal CaCl2 concentration (2.2 mM) and the contractile force response to elevated CaCl2 (5 mM) were unchanged over 30 min. Atropine exposure (1.7 X 10(-5) M) for 30 min significantly reduced contractile force at both normal and elevated CaCl2 levels. Quinidine exposure (6.2 X 10(-6) M) for 30 min produced similar but statistically insignificant changes. At 4 h, control contractile force at 2.2 mM CaCl2 decreased to the post-atropine level, but the response to 5 mM CaCl2 was unchanged. The asystolic interval of right atria following overdrive (for 2 min at 3 rates) was increased after 30 min by 4% for controls, 14% after atropine (1.7 X 10(-5) M) and 45% after quinidine. The effective refractory period of left atria (evaluated by paired pulse stimulation) was unchanged after 30 min for controls, but increased by 20% after atropine and 45% after quinidine.

Left ventricular mural force changes as reflections of induced alterations in myocardial pump performance.

Strain gauge measurements of changes in left ventricular mural force seen during the ejection phase of the cardiac cycle were examined for a relation to ventricular emptying efficiency. Left ventricular pressure and mural force were recorded at aortic valve opening and closing, then residual fractions were calculated using (a) a representative radius determined from the LaPlace formula (MF = pi PR2), (b) mural force recordings alone, and (c) intraventricular pressure recordings alone. These fractions were compared to other residual fractions simultaneously obtained by thermodilution. Comparisons were made during changes in blood pressure, heart rate, and cardiac contractility. Findings were: 1. Significant correlation is seen when residual fractions, calculated from mural force alone or representative radii (mural force and left ventricular pressure) are regresed against the residual fraction obtained by thermodilution. 2. No relation is seen when residual fraction, calculated from intraventricular pressure, is similarly regressed against the residual fraction obtained by thermodilution. 3. It follows that mural force changes occurring during ventricular ejection do reflect ventricular dimension changes during this period. Moreover, directly recorded mural force can be used to calculate representative ventricular radii which more accurately reflect ventricular size changes. On the other hand, intraventricular pressure, which does not necessarily determine ventricular size, does not reflect ventricular emptying efficiency.