A one-week introductory course in clinical biochemistry and research based on renal function testing in man.

A one-week introductory course in clinical biochemical and research techniques was devised to provide a brief but concentrated experience for interested persons. Urinary creatinine concentrations were measured to demonstrate acceptable degrees of precision of a method (co-efficients of variation, 0.5-2.4%), and to give confidence by favourable comparison with routine laboratory results (day 2, mean 0.95 vs 0.94 mg/ml). Subjects then submitted themselves to one-day renal function testing, and subsequently measured their own urinary acid-base parameters by autotitrimetry and glomerular filtration rates by spectrophotometry. The values obtained for the latter fell within the normal range (85-124% of normal, corrected for age and surface area). Finally, statistical methods and a small desk-top computer were employed to compute linear regression equations, correlation coefficients, and t tests from the week's data. The course contained a number of features which stimulated learning, including active participation by the learner, and the use of meaningful materials to induce both desire for success and tolerance of mistakes.

Haemodynamic interactions between alpha- and beta-adrenoceptor antagonists in conscious or anaesthetized rats.

1. The alpha-adrenoceptor antagonist, phentolamine, was administered intravenously, to conscious or anaesthetized rats, before or after the beta-adrenoceptor antagonist, propanolol. 2. The bradycardia which followed the combined administration of propranolol and phentolamine exceeded that induced by propranolol alone, yet the hypotensive effect of phentolamine was attenuated by propranolol. 3. The results are compatible with the concept that a significant part of the hypotensive effect of phentolamine is mediated by stimulation of vascular beta-adrenoceptors.

Studies in the rat on endralazine, a new antihypertensive drug structurally related to hydralazine.

1. The effects on blood pressure, heart rate and plasma renin activity of a new hydralazine congener, endralazine, were evaluated in anaesthetized rats. Dose-response relationships for endralazine, hydralazine and diazoxide, administered intravenously, were compared, and the interactions of endralazine with the ganglionic blocking agent, pentolinium, or with adrenaline, noradrenaline and angiotensin II were examined. 2. In the dose range 0.05 to 1.0 mg/kg, endralazine produced prompt dose-related reductions in systolic and diastolic blood pressure, with relatively little effect on heart rate. The drug had a pronounced dose-related renin stimulating effect. 3. Endralazine retained approximately 80% of its hypotensive activity after pretreatment with pentolinium, and caused no significant attenuation of pressor responses to adrenaline, noradrenaline or angiotensin II. 4. Endralazine was an effective hypotensive agent, with a prompt onset of action, a prolonged and stable effect, and a potency at least twice that of hydralazine and 20 to 25 times that of diazoxide. The data are consistent with a predominantly direct vasodilator mode of action.

Studies in the rat on the haemodynamic overshoot response to withdrawal of guanfacine or clonidine treatment.

1. Normal rats were injected intramuscularly twice daily for either 3 days or 3 weeks with guanfacine (0.1 or 1.0 mg/kg), clonidine (0.01 or 0.1 mg/kg) or 0.9% saline. All were anaesthetized at various times before or after the last injection, and their arterial pressures and heart rates were monitored via a carotid artery catheter. 2. Overshoots in systolic and diastolic pressure and heart rate, reaching peak values as soon as 16 h after the last injection, occurred in all rats withdrawn from guanfacine or clonidine treatment, but in no control rats. 3. Post-withdrawal blood pressures and heart rates of rats which had received the low dose of guanfacine or clonidine were as great as those of rats which had received the ten-fold greater dosage. Moreover, withdrawal responses were as great in rats which had been treated for only 3 days as in those treated for 3 weeks. 4. The dosages and duration of treatments used in these experiments thus did not influence the magnitude of the haemodynamic overshoots provoked by withdrawal of guanfacine or clonidine. However, all groups of rats from which guanfacine was withheld exhibited significantly greater peak overshoots in systolic and diastolic pressure than did those withdrawn from clonidine treatment.

Interactions between prazosin, clonidine and direct vasodilators in the anaesthetized rat.

1. Prazosin, clonidine, hydrallazine and diazoxide were administered intravenously, alone or in various combinations, to anaesthetized rats. 2. Prazosin and clonidine were equipotent. Their combined hypotensive effects in no instance exceeded the maximum effect attainable with either agent alone. The hypotensive effects of hydrallazine or diazoxide were, in contrast, additive to those of either prazosin or clonidine. 3. Pressor responses to clonidine were antagonized by prazosin. Prazosin may prove useful in hypertensive crises provoked by clonidine.

Effects of prazosin on blood pressure and plasma renin activity during onset and withdrawal of action in the anaesthetized rat.

1. The effects of single intramuscular injections of prazosin, 0.1 mg/kg, upon blood pressure, heart rate and plasma renin activity, were studied, over 24 h, in groups of anaesthetized rats, control rats receiving 0.9% saline. 2. Within 6 min of prazosin administration, heart rate fell by 50 beats/min (s.e.m = 19) and blood pressure by 40 mmHg (s.e.m. = 8). Starting levels were regained within 90 min and 16 h of injection, respectively, and thereafter both parameters remained unaltered. Plasma renin activity showed a slight though insignificant rise during the initial hypotension, but subsequently fell to 32% of the control level. 3. The hypotensive response to prazosin, unlike that to the centrally acting agents clonidine or guanfacine, was not followed by overshoots in blood pressure, heart rate or plasma renin activity. Instead, suppression of plasma renin activity was demonstrable after re-establishment of control blood pressure.

Profile of a new prazosin congener, BL-5111A. Studies in the rat.

1. The effects on blood pressure and heart rate of prazosin and a structurally-related congener, BL-5111A, were compared in conscious and anaesthetized rats. 2. Both agents induced dose-related falls in systolic and diastolic blood pressure, with relatively little effect on heart rate. The hypotensive potency of prazosin was twenty-fold greater than that of BL-5111A. 3. The hypotensive activity of prazosin was abolished by pretreatment with the ganglionic blocking agent, pentolinium, or the alpha-adenoceptor blocking agent, phentolamine, whereas BL-5111A retained significant hypotensive activity (up to 28%) after either pretreatment. 4. Both prazosin and BL-5111A attenuated pressor responses to noradrenaline, and reversed the responses to adrenaline, prazosin being, in this respect, 6 times more potent than BL-5111A. There was a highly significant relationship between the alpha-adrenoceptor blocking activity of either agents and its hypotensive effect. 5. BL-5111A differed from prazosin in possessing, in addition to its predominant alpha-adrenoceptor blocking action, a minor component of action attributable to direct vasodilatation.

Studies in the rat on bucindolol, a new antihypertensive agent with beta-adrenoceptor blocking properties.

The properties of a new antihypertensive agent, bucindolol, were studied in the anaesthetized rat. When administered intravenously in the dose range 0.03 to 1.0 mg/kg, bucindolol evoked dose-related decreases in mean arterial blood pressure wtih relatively little change in heart rate. Bucindolol retained nearly 50% of its hypotensive activity after ganglionic blockage with pentolinium. When administered intravenously in a dose of 0.25 mg/kg, bucindolol caused approximately 1000-fold and 100-fold shifts to the right in the dose-response curves for isoprenaline-induced chronotropic activity and hypotensive activity, respectively. The same dose of bucindolol caused a decrease in pressor responsivity to angiotensin II, no significant change in that to noradrenaline, and an increase in that to adrenaline. Bucindolol was an effective hypotensive agent, which under the conditions of test, had relatively little effect on basal heart rate, exhibited no significant alpha-adrenoceptor blocking activity in the dose range tested, had potent beta-adrenoceptor blocking properties, and exhibited an apparent direct relaxant effect on vascular smooth muscle.

Alpha blocking action of the antihypertensive agent, prazosin.

The vasodilatory and alpha adrenergic blocking properties of prazosin were studied in anesthetized rats and compared with the direct-acting vasodilator, diazoside. The hypotensive activity of diazoxide was unimpaired after ganglion blockade with pentolinium or alpha adrenoreceptor blockade with phentolamine; diazoxide also significantly attenuated angiotensin II pressor responses. In contrast, the hypotensive action of prazosin was completely abolished, over a 10(4)-fold dose range, after ganglion or alpha adrenoreceptor blockade, and this agent failed, even in maximal hypotensive doses, to attenuate angiotensin II pressor responses. In addition, prazosin was shown to possess potent alpha adrenoreceptor blocking properties, significantly attenuating norepinephrine pressor responses and causing reversal of epinephrine pressor responses. These studies in the rat indicate that the hypotensive action of prazosin is not due to a direct relaxant effect upon vascular smooth muscle, but is attributable to alpha adrenoreceptor blockade.

Haemodynamic effects of prazosin.

Parzosin, 0.001 to 10 mg/kg, was administered intravenously to anesthetized normal rats. In the dose range 0.001 to 0.01 mg/kg, the drug induced highly significant, dose-related falls in blood pressure, pulse pressure and heart rate. With doses above 0.01 mg/kg, there was a plateau in hypotensive efficacy and a diminution in negative chronotropic activity. Both actions of prazosin (0.01 mg/kg) were unaffected by vagal blockade with atropine, while hypotensive potency was unimpaired after beta-adrenoreceptor blockade. The vasodilator, diazoxide, lowered blood pressure, widened pulse pressure and caused tachycardia in rats pre-treated with pentolinium. In contrast, all effects of prazosin were abolished by ganglion blockade. These findings, together with the absence of compensatory tachycardia or gross renin hypersecretion during prazosin-induced hypotension, are compatible with an antisympathotonic mode of action for the drug. However, consistent with its effects on cyclic nucleotide distribution, prazosin appears to enhance isoprenaline-induced beta-receptor stimulation.

The beta-adrenoceptor controlling renin release.

The beta-adrenoceptor antagonists, atenolol, metoprolol and propranolol, administered intravenously to anaesthetized rats in doses producing equal beta1-adrenoceptor blocking effects, caused comparable suppression of plasma renin activity (PRA) despite the fact that, at these doses, atenolol and metoprolol exhibited no beta2-adrenoceptor blocking properties. Practolol, an agent specific for beta1-adrenoceptors but possessing intrinsic sympathomimetic activity, caused less marked suppression of PRA. When doses of atenolol, metoprolol, propranolol and butoxamine were selected to achieve equal beta2-blocking effects, PRA was again significantly suppressed by atenolol and metoprolol but not by propranolol or butoxamine. These results do not support the concept that adrenergic release of renin is mediated by beta2-adrenoceptors, but are compatible with the involvement of a beta1-adrenoceptor-mediated mechanism.

Withdrawal of clonidine: effects of varying dosage or duration of treatment on subsequent blood pressure and heart rate responses.

The influence of the dosage or duration of treatment on the incidence and severity of clonidine withdrawal responses was examined in normotensive rats. Clonidine (0.01 or 0.1 mg/kg i.m.) was administered either in single doses, or twice daily for 3 days or 3 weeks. Rats were then anesthetized and arterial catheters were inserted. Significant overshoots in blood pressure and heart rate, reaching peak values 16 to 26 hr after the last injection, occurred in all clonidine-treated rats, but in no control rats. The overshoots after single injections of clonidine were as great as those after suspension of sustained treatment. Moreover, withdrawal responses were as great after the low dose as they were after the 10-fold greater dose. Only plasma renin activity showed a significantly greater elevation during withdrawal of the high dose of clonidine. Since ganglionic blockade reduced blood pressures and heart rates to the same levels in rats with clonidine withdrawal hypertension as in control rats, the withdrawal overshoots appear to be nervously mediated. Neither the dosage nor the duration of treatment could be shown to determine the magnitude of the response to withdrawal of clonidine.

Comparative haemodynamic effects of clonidine administered intramuscularly or intravenously to anaesthetized rats.

1. The acute haemodynamic effects of clonidine, 0.001-1.0 mg/kg, administered intramuscularly or intravenously, were studied in anaesthetized rats. 2. The direct pressor potency of clonidine was 100-fold greater following intravenous administration than after intramuscular injection, but hypotensive efficacy was equal by either route.

Comparative haemodynamic effects of clonidine and guanfacine.

Dose-response relationships were established for the acute effects on arterial pressure and heart rate of the antihypertensive agents, clonidine and guanfacine, administered intravenously or intramuscularly to anaesthetized rats. The intramuscular route appeared to be preferable to the intravenous, for the direct pressor potency of each drug was thereby greatly reduced in relation to the hypotensive efficacy. The potency of clonidine was 10-20 times that of guanfacine, but the same maximal fall in blood pressure was obtained with either agent administered by either route. Both agents caused a marked, dose-related suppression of plasma renin activity. When either clonidine or guanfacine was administered twice daily for 3 weeks and then discontinued, a phase of blood pressure overshoot with tachycardia commenced within 24 hr of the last injection. These withdrawal effects were more evident in guanfacine-treated rats than in clonidine-treated rats.