Prolonged Blockade Research Articles

British pilot study of exercise therapy. I. Middle-aged men.

The physiological and biochemical effects of a carefully graduated course of vigorous gymnasium training with two or three weekly exercise sessions lasting only 15 minutes have been studied in middle-aged London business men. Activity diaries and psychological questionnaires indicated that these men had a positive attitude to exercise which was probably greater than average. The gymnasium exercises caused a large oxygen debt and considerable rises in plasma catecholamines and lactate levels. A close correlation was found between the pulse rate during exercise and the Borg scale of perceived exertion, so that both could be used to ensure that short periods of exercise were sufficiently vigorous to produce a training effect, and protect against over-exertion. The acceptability of this particular exercise regime was shown by the low fall-out and injury rate. It is suggested that this exercise training programme possesses many features which are advantageous if increased physical activity is to be more widely used as a method of reducing some of the risk factors in coronary heart disease.

Renal Pelvic Pacemaker Arrhythmias Induced by Pentothal Anesthesia

The influence of Pentothal anesthesia in blocking the mechanism intimating ureteral peristalsis in the dog is examined. Pressure measurements of pacemaker rhythmicity were made through renal cortical catheterization of the renal pelvis. Simultaneously, ureteral recordings were made by extracellular electromyography of the ureteral smooth muscle wall. It is shown that Pentothal anesthesia transiently blocks the spontaneous and rhythmic contractions of the renal pelvis and inhibits the generation of ureteral peristaltic contractions. It is demonstrated that repeated or prolonged pacemaker blockade results in an open ureteropelvic junction and aperistalsis. A discussion of the possible implication of these observations is given.

TIME COURSE OF CHANGES IN PLASMA RENIN AFTER BLOCKADE OF THE RENIN‐SYSTEM.

Inhibition of the angiotensin I converting enzyme with SQ 20.881 results in a 2 to 35 fold increase in plasma renin concentration in normal rats and in spontaneously hypertensive rats. The effect is transient, lasting for 1 to 3 hours even in the presence of prolonged blockade. The relative increase is independent of the pretreatment plasma renin concentration. The blood pressure is unchanged in conscious rats in which the effect of SQ 20.881 on plasma renin is believed to be due to a blockade of the negative feedback of angiotensin II on renin release. In anaesthetized rats, SQ 20.88) has an additional hypotensive effect which augments the increase in plasma renin. Saralasin is without effect on blood pressure and plasma renin in conscious normal rats and in spontaneously hypertensive rats, while it causes a transient 3 to 27 fold increase in plasma renin concentration in anaesthetized rats. It is suggested that this increase is hardly due to an interception of the feedback, but to the concomitant fall in blood pressure, as a similar hypotension and increase in plasma renin is produced by dihydralazine. It is furthermore found that Saralasin blocks renin release induced by SQ 20.881. This demonstrates that Saralasin is bound to the receptors in the juxtaglomerular cells and has slight, agonistic properties there. Both in conscious rats and in anaesthetized adrenalectomized rats substituted with DOCA and salt, SQ 20.881 as well Saralasin causes transient increases in plasma renin concentration. If such rats are only substituted with salt and not with DOCA, the effects of both blockers are in the form of severe hypotension and a permanent elevation of plasma renin.

Selective inhibition by des-1-Asp-8-lle-angiotensin ii of the steroidogenic response to restricted sodium intake in the rat.

Angiotensin III (des-1-Asp-angiotensin II) is a potent steriodogenic agent in many species. The effects of the heptapeptide in the adrenal zona glomerulosa are resistant to blockade by C-terminally substituted analogues of angiotensin II (1-Sar-8-Ile- or 1-Sar-8-Ala-octapeptides). For this reason, the effects of 7-Ile-angiotensin III, a C-terminally substituted analogue of the heptapeptide, and 1-Sar-8-Ile-angiotensin II on aldosterone biosynthesis in rabbit adrenal cortical cell suspensions and on urinary aldosterone excretion in sodium-deprived rats were studied. In the vitro studies, 7-Ile-angiotensin III was a better antagonist of angiotensin II- or angiotensin III-induced steroidogenesis than was 1-Sar-8-Ile-angiotensin II. In the rats, subcutaneously administered 1-Sar-8-Ile-angiotensin II (0.9 mumoles/kg) produced prolonged blockade of the pressor responses to exogenous angiotensin II. 70Ile-angiotensin III (0.9 mumoles/kg) had no effect on resting blood pressure or on blood pressure responses to angiotensin II infusions. At the doses studied, however, 7-Ile-angiotensin III caused a marked decrease (50%) in aldosterone excretion in sodium-deprived rats, but 1-Sar-8-Ile-angiotensin II had no effect on aldosterone excretion. In the sodium-deprived rats, the administration of 7-Ile-angiotensin Ile was not associated with an acute increase in plasma renin activity, but treatment with 1-Sar-8-Ile-angiotensin II resulted in a sixfold increase in plasma renin activity, but otensin III was not associated with an acute increase in plasma renin activity, but treatment with 1-Sar-8-Ile-angiotensin II resulted in a sixfold increase in plasma renin activity. These results are consistent with a role for angiotensin III in the control of aldosterone biosynthesis.

Supersensitivity to dopaminergic agonists induced by haloperidol.

Haloperidol caused a significant reduction in the spontaneous locomotor activity of mice when added to their diet for 11 days. Upon removal of the drug from their diet these mice exhibited withdrawal hyperactivity for several days that was characterized by an increase in activity over control or pre-halopericol values. Similar results were obtained when mice were fed a diet containing pimozide. Withdrawal hyperactivity was not detected after 1 or 3 days of haloperidol containing diet, but was maximal after 6 days of this diet. Dose-response curves of apomorphine-stimulated motor activity and rearing behavior were shifted to the left when determined in mice during the period of withdrawal hyperactivity. Dopaminergic agonists (apomorphine, piribedil, L-DOPA and d-amphetamine) induced gnawing at lower doses in mice removed from a chronic haloperidol-containing diet for 2 days than in mice maintained on a control diet. These results support the hypothesis that prolonged blockade of central dopaminergic receptors by neuroleptics causes subsequent behavioral effects that may be due to the development of enhanced receptor sensitivity.

Action of several -adrenoceptor blocking drugs in the pregnant sheep and foetus.

1. The effect of several beta-adrenoceptor blocking drugs on the pregnant ewe and foetus were studied. Bunolol, butidrine, oxprenolol, propranolol and USVP65-24 all crossed the ovine placenta and produced a beta-adrenoceptor blockade in the ovine foetus. AH3474, AY21011 and sotalol did not cross the ovine placenta as assessed by the absence of a beta-blockade in the foetus when these compounds were administered to the pregnant ewe.2. Of the beta-blocking compounds tested, only propranolol and oxprenolol produced a prolonged blockade in the foetus. The beta-blockade with propranolol was of 3 h duration in the ewe and 10 h duration in the foetus. Oxprenolol produced a beta-blockade of 3 h duration in the ewe and 8 h in the foetus.3. The beta-blocking drugs which did cross the ovine placenta were more soluble in organic solvents (ether, chloroform, corn oil and olive oil) than those which did not cross the ovine placenta.

Ganglionic and cardiac actions of batrachotoxin.

Abstract Batrachotoxin (BTX), the purified active principle from the Colombian Arrow Poison Frog (Phyllobates aurotaenia), blocked transmission in the in situ rabbit superior cervical ganglion preparation when administered intraarterially in doses of 0.3 to 1.3 μg. The initial ganglionic potential was more susceptible to BTX depression than the late potential; the positive afterpotential was abolished and even reversed. At higher doses (1.0 μg or more), the poison caused a prolonged blockade of the ganglionic transmission; a partial recovery of only the late spike was observed within two hours following the administration of BTX. These actions of BTX on the ganglion were partly due to its effect on the impulse conduction in the preganglionic sympathetic nerve in which the poison differentially blocked the initial spake of the preganglionic antidromically evoked action potential. Both the failure of ganglionic transmission and of nerve conduction occuring after BTX were functions of the dose and frequency of stimulation. In most experiments during the blockade of the ganglionic transmission produced by BTX, the ganglion cells were responsive to the depolarizing agents, nicotine, acetylcholine and potassium chloride. The poison also produced a large variety of cardiac arrhythmias including A-V block, multifocal ventricular ectopic beats, ventricular tachycardia and fibrillation.

RETICULOENDOTHELIAL BLOCKADE PRODUCED BY ANTILYMPHOCYTE SERUM

Injection of antiserum to mouse lymphocytes (A.L.S.) was found to impair clearance from the bloodstream of colloidal carbon and microaggregated human serum-albumin in mice. Intravenous injection of A.L.S. produced immediate, profound, and prolonged blockade of the reticuloendothelial system and was more effective than the same dose administered intraperitoneally.

THE EFFECTS OF A BETA-ADRENERGIC BLOCKING AGENT, PRONETHALOL, ON DIGITALIS-INDUCED VENTRICULAR ARRHYTHMIAS

Abstract The ability of pronethalol, a beta-adrenergic blocking agent, to protect against and to reverse digitalis-induced ventricular arrhythmias has been studied. Pronethalol quickly and permanently reverses arrhythmias due to acetylstrophanthidin. The dose of pronethalol required to restore promptly a sinus mehcanism was far in excess of that which produced acute beta-adrenergic blockade. Pretreatment with pronethalol, in a dose that yielded effective and prolonged beta-adrenergic blockade, failed to protect dogs against acetylstrophanthidin-induced arrhythmias in these experiments. Pretreatment with reserpine or guanethidine did not alter the ability of pronethalol to restore a sinus mechanism. It is concluded that the ability of pronethalol to reverse ventricular arrhythmias due to digitalis is not related to its action as an adrenergic blocking agent, but may be a function of its quinidine-like effect.

Studies on the Immune Response of Guinea Pigs to the Envelope Substance of Pasteurella Pestis

Summary Given a weight-adjusted dose, mice excreted an excess of Fraction I two to three times faster than guinea pigs, which explains former difficulties in detecting immunounresponsiveness in mice. The rapidity of elimination of further Fraction I by immunounresponsive guinea pigs 90 days after a primary excess in oil may prevent further stimulation of antibody production in some animals, thus resulting in partial, rather than complete, immunity. Hyperimmune animals were not easily made immunounresponsive. Immunity to Fraction I once established was solid and not easily overwhelmed. Serologic response of guinea pigs to graded doses of Fraction I approaching excess 21 days after injection or over a long period after a single large excess indicates a limited plateau of antibody production to excess Fraction I. This and previous studies indicate immunounresponsiveness of guinea pigs to excess Fraction I in oil adjuvant to be a temporary long delay in immunity resulting from a prolonged blockade of elements of the RES by finely divided state of the antigen, producing a saturation of a limited plateau of antibody production by this system. These inhibiting factors are partially overcome 3 to 6 months later by a gradually appearing antibody excess stimulated from within or by booster inoculation from without. Complete immunity was not obtained because of the rapidity of excretion of later immunizing doses, appearing slowly from the encapsulated injection site or as booster injections.