In 17 normal subjects we studied the changes evoked by five levels of expiratory pressure (EP) ranging from 2.5 to 30 mmHg in a number of circulatory variables during the last 10 s of a 30-s Valsalva maneuver. Variables studied included mean arterial (MAP) and pulse (PP) pressures; right atrial (RAP) and peripheral vein (PVP) pressures; cardiac output (CO); total peripheral resistance (TPR) and heart rate (HR). EP-circulatory response curves were obtained in each subject a) before autonomic block; b) after cardiac effector block (atropine + propranolol); c) after "total" autonomic block (atropine + propranolol; guanethidine + phentolamine). Mechanical effects were determined from results during "total" autonomic block. They included EP-related rises in RAP and PVP each to about 0.7 mmHg/mmHg applied EP, and falls in CO, MAP, and PP to levels of approximately 50%, 70%, and 80% of resting respectively at EP 30 mmHg, but no changes in TPR and HR. Reflex effects included EP-related rises in HR and in TPR and in MAP, to levels of 160%, 160%, and 115% of resting respectively at EP 30 mmHg. The afferent input profile is probably complex, and the role of the different receptor groups may vary at the different levels of EP.

1.The haemodynamic and heart rate responses to graded expiratory pressures were studied during Valsalva manoeuvres of standard 30 s duration in two groups of normotensives in the upper (n = 10) and lower (n = 9) halves of the 'normal' blood pressure range, and in a group of essential hypertensive subjects with minimal complications (n = 10). Haemodynamic variables were arterial, atrial and peripheral vein pressures, cardiac output and total peripheral resistance.2. Reflex and mechanical effects of the manoeuvre were assessed in each subject from changes in the relationship between the expiratory pressure and circulatory responses before autonomic blockade, after cardiac effector block and after 'total' blockade.3. The relationships between expiratory pressure and central and peripheral vein pressures were not changed by autonomic blockade, indicating that they depended on mechanical factors. In hypertensives the rise in venous pressures per unit expiratory pressure was significantly smaller than in normotensive subjects.4. The expiratory pressure-related rise in total peripheral resistance was reflex and was similar in magnitude in all groups before autonomic blockade. However, after cardiac effector blockade the rise was greatest in the hypertensive subjects. The sensitivity of the constrictor response was related t o the subjects' resting total peripheral resistance index when measurements from all subjects were included. 5.The reflex heart rate responses of the hypertensives showed: (i) accentuation of the bradycardia at the start of forced expiration; (ii) an increased threshold for eliciting tachycardia during the latter part of the manoeuvre; and (iii) attenuation of the 'overshoot' bradycardia following release of expiratory pressure.6. The differences between the responses of hypertensives and normotensives were relatively small and probably depended at least partly on differences in venous filling, structural differences of resistance vessels and different afferent inputs through arterial and cardiopulmonary baroreceptors.

I A study was made of the influence of hydralazine on the oral availability of a sustained release formulation of propranolol (Inderal LA®). Sustained release propranolol 160 mg was given orally either alone or in combination with oral hydralazine 25 mg on separate occasions to six healthy volunteers. Blood and urine samples were collected post-dosing over 34 h. 2 Peak concentrations of propranolol, time to peak and area under the plasma concentration-time curve (AUC) were not altered by co-administration of hydralazine with sustained release propranolol. 3 Similarly, there was no change in recovery of '4C-labelled propranolol and metabolites in those individuals to whom tracer label was given. 4 These results contrast with previous reports of marked interaction between the conventional formulation of propranolol and hydralazine or food. 5 Interactions were confirmed between hydralazine and conventional propranolol in three subjects who had been studied previously with sustained release propranolol. Analysis of metabolite profiles in one of these subjects established that the major metabolites do change under hydralazine stimulus. 6 These results indicate that substrate delivery rates may determine presystemic drug interactions, suggesting capacity limitations of hydroxylation processes or short-term flow redistribution following hydralazine, resulting in functional shunting past the hydroxylation enzymes. 7 These results exclude global or lasting enzyme inhibition by hydralazine or simple flow-sensitivity of presystemic clearance.

for evoking graded reflex constrictor responses in 1. A Valsalva-like manoeuvre was used to elicit graded rises in total peripheral resistance (TPR) in conscious rabbits. The rises were reflex and mediated through sympathetic constrictors. Propranolol infused at different rates reaching plasma concentrations up to 240 (SEM 33) ng/ml had no effect on this reflex but reduced mean arterial pressure. However, the response was attenuated by clonidine in a dose-dependent manner. 2.Valsalva manoeuvres were used to elicit graded sympathetically mediated rises in TPR index in twenty-nine subjects with mean arterial pressure ranging from 75 to 165 mmHg. Absolute sensitivity of the constrictor response increased with rising resting TPR index, resulting in some enhancement of constrictor responses in the hypertensive subjects. It seems likely that non-autonomic factors (e.g. vessel structure) rather than hyperactive neural constrictor effects are involved in the enhanced constrictor responses in essential hypertension.

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