B. F. Robinson

Relation of Heart Rate and Systolic Blood Pressure to the Onset of Pain in Angina Pectoris

Arterial pressure was recorded directly and continuously in 15 patients with angina pectoris while pain was repeatedly induced by exercise of various types and severity. In every case, the precipitation of angina could be consistently related to the level reached by the product of heart rate and systolic blood pressure (corrected when necessary for changes in ejection time). This relationship persisted even when there were large variations in the type, intensity, and duration of the exercise and was also maintained in a patient in whom spontaneous and emotional episodes of pain were observed. A substantial improvement in exercise tolerance occurred in one patient and this was completely accounted for by a reduction in the circulatory response to exercise.It was concluded that the precipitation of angina is normally the result of a rise in the work of the myocardium to a critical level which is essentially fixed in each patient. The varying ease with which pain is provoked on different occasions can usually be explained by variations in circulatory response to the precipitating stress.

Measuring Forearm Blood Flow and Interpreting the Responses to Drugs and Mediators

Venous occlusion plethysmography has been widely used to study forearm blood flow. The principle of the technique is straightforward: the rate of swelling of the forearm during occlusion of venous return is used to assess the rate of arterial inflow. Provided that perfusion pressure (arterial blood pressure) remains constant, changes in flow reflect changes in smooth muscle tone in small arteries and arterioles. Local infusion into the brachial artery allows assessment of the direct effect of drugs on vascular tone and has been used to probe the roles of endogenous mediators. The technique is at its most powerful when dose-response relationships to different drugs or mediators within a single study are being compared but can also be used for comparison of responses to drugs between healthy control subjects and patient populations. However, when responses between groups are being compared, it is important to take into account the starting conditions of baseline blood flow and pressure. This article describes venous occlusion plethysmography, discusses the presentation and analysis of data (dose of drug or concentration? forearm blood flow or resistance?), and highlights certain potential problems and limitations of the technique as a means of studying disease states.

REDUCTION OF PRESSOR EFFECTS OF ANGIOTENSIN I IN MAN BY SYNTHETIC NONAPEPTIDE (B.P.P.9a OR SQ 20,881) WHICH INHIBITS CONVERTING ENZYME

Abstract A synthetic nonapeptide (B.P.P. 9a , SQ 20,881) which blocks angiotensin-converting enzyme in animal preparations in vitro and in vivo, reduces the pressor activity of angiotensin in man. This nonapeptide may be useful for the diagnosis and treatment of some forms of hypertension.

Mode of action of nitrglycerin in angina pectoris. Correlation between haemodynamic effects during exercise and prevention of pain.

Nitroglycerin isgenerallyagreed tobethemost effective drugavailable forthetreatment ofangina pectoris, butitsmodeofaction remains uncertain. Two mainexplanations havebeenputforwird. Thefirst suggests that itactsbylowering thearterial pressureandsoreducing cardiac work;thesecond thatitactsbydilating thecoronaryarteries andso improving themyocardial bloodsupply. Formany yearsthecoronarydilator action ofthedrughas beenwidely accepted astheprobable mechanism for itstherapeutic effect, anditsaction inreducing blood pressurehasbeenregarded asofsecondary importance, ifnotactually harmful. Attempts to demonstrate a beneficial effect on coronaryflowin patients withischaemic heartdisease, however, havemetwith no success,anditappearsthatsublingual nitroglycerin isunable toincrease themyocardial bloodsupply whenthecoronaryarteries are diseased (Gorlin etal., 1959; Bernstein etal., 1966). Thisfailure toconfirm thecoronarydilator theory hasledtorenewed interest inthepossibility that the drugactsbyreducing cardiac work,buttheevidencetosupportthisviewisinconclusive. Most studies oftheeffect ofnitroglycerin on thecirculatory responsetoexercise haveshownthat thedrug reduces arterial pressurebothinnormalsubjects and in patients withischaemic heartdisease (Eldridge etal., 1955;MullerandR0rvik, 1958; Christensson, Karlefors, and Westling, 1965; Najmi etal., 1967).Innoneofthese investigations, however, havethechanges inthecirculatory response beencorrelated withthealteration in capacity forexercise. Inconsequence,though itis generallyaccepted thatnitroglycerin doescause some attenuation ofthecirculatory responseto exercise, ithasbeenimpossible toassesstheextent

Clinical investigation of an antagonist at α‐ and β‐adrenoceptors‐AH 5158A

1 The α‐ and β‐adrenoceptor blocking action of AH 5158A was investigated in man using the veins of the hand, the arterial bed of the forearm, and certain responses of the circulation as a whole. 2 In the veins, locally infused AH 5158A resulted in specific and competitive antagonism of the constrictor response to locally infused noradrenaline and of the dilator response to isoprenaline. 3 Brachial artery infusions of AH 5158A resulted in competitive antagonism of the arterial blood flow changes produced by local infusions of noradrenaline and isoprenaline. 4 Systemic infusion of AH 5158A (0·5–0·9 mg/kg) produced clear blockade of the heart rate response to systemic infusion of isoprenaline. It also attenuated the response to exercise at 80 watts for 4 min; mean arterial pressure during exercise was reduced by 16% and heart rate by 18%. Blockade lasted at least 1 hour. 5 AH 5158A caused small changes in arterial pressure and heart rate at rest supine, but had no effect on the response of pressure and rate to tilting.

THE CAROTID PULSE I: DIAGNOSIS OF AORTIC STENOSIS BY EXTERNAL RECORDINGS

The brachial pulse is unreliable in the diagnosis of aortic stenosis as it may fail to show distinctive changes (Hancock and Abelmann, 1957; Hancock and Fleming, 1963). The carotid pulse should be more satisfactory for this purpose, since it reflects central events more clearly and external recordings reproduce the pressure pulse simply and adequately (Robinson, 1963). In 1956 Duchosal et al. reported the use ofextemal carotid pulse recordings in the diagnosis of aortic stenosis. Daoud, Reppert, and Butterworth (1959) and Smith et al. (1959) also found the method valuable, but these investigators relied on clinical diagnosis in most of their patients, and each group used a different method to analyse the pulse. The present study is an attempt to define reliable diagnostic criteria, and patients with aortic stenosis have been included only when the diagnosis has been proved by left heart catheterization, operation, or necropsy. Their pulse tracings have been compared with those from healthy people and patients with a wide variety of cardiovascular disorders.

THE CAROTID PULSE II: RELATION OF EXTERNAL RECORDINGS TO CAROTID, AORTIC, AND BRACHIAL PULSES

As it passes from the proximal aorta to the periphery, the normal pulse undergoes striking changes, mainly due to peripheral reflections, which result in it becoming sharper and increased in amplitude (Kroeker and Wood, 1955; McDonald and Taylor, 1959). The abnormal pulse is also subject to change, and alterations in the central pulse may, as a result, become either more or less obvious in the periphery. Thus the characteristic pulse of aortic regurgitation is made more obvious by transmission (Wright and Wood, 1958). The typical central pulse of aortic stenosis, on the other hand, may be so altered by transmission that the brachial fails to show a diagnostic pattern (Hancock and Fleming, 1960). As a result of the inadequacy of the brachial pulse in diagnosis, the carotid pulse, recorded by external means, is now increasingly used as a guide to central events (Duchosal et al., 1956; Daoud, Reppert, and Butterworth, 1959; Robinson, 1963). The present study is an attempt to assess how closely external carotid tracings reflect the central aortic pulse and in what ways they are superior to brachial pulse recordings. The relation of external carotid tracings to simultaneous carotid pressure recordings will first be established, and various types of external carotid will then be compared with the aortic and brachial pulse.

Verapamil and Bendrofluazide in the Treatment of Hypertension: A Controlled Study of Effectiveness Alone and in Combination

SummaryThe effects of verapamil and bendrofluazide used singly and in combination were examined in patients with primary hypertension in a patient blind, partly observer blind placebo controlled study of parallel group design; there were ten subjects in each arm of the trial.Verapamil 160 mg twice daily caused supine mean arterial pressure to fall by 21 mm Hg; this reduction was significantly greater (p<0.05) than that induced by bendrofluazide 5 mg daily which caused a fall of only 10 mm Hg.The addition of verapamil 160 mg twice daily to bendrofluazide 5 mg daily caused a further fall in pressure of 18 mm Hg (p<0.005), but the reduction in pressure when bendrofluazide was added to verapamil was only 1 mm Hg and not significant.Bendrofluazide therapy caused a fall in plasma potassium concentration and an increase in plasma urate concentration; urinary calcium excretion was reduced. Verapamil caused no detectable biochemical alterations in plasma or urine.

Comparison of blockade at α‐adrenoceptors by thymoxamine and phentolamine in peripheral arteries and veins of man

1 The antagonism at α‐adrenoceptors by thymoxamine and phentolamine of the response to noradrenaline was investigated in the limb veins and arteries of man. 2 Brachial artery infusions of thymoxamine (40 μg/min) produced rises in resting arterial flow of up to 100%. When infused mixed with noradrenaline, thymoxamine (40 μg/min) attenuated the blood flow response to noradrenaline. Blockade was of a similar degree to that which occurred following a 10 min infusion of phentolamine (40 μg/min). 3 Local intravenous infusion of thymoxamine (400–2,000 ng/min) mixed with noradrenaline attenuated the venoconstrictor response to noradrenaline. The degree of attenuation was similar to that seen after a 10 min infusion of phentolamine (500 ng/min). Blockade after thymoxamine did not last longer than 16 minutes. Neither thymoxamine nor phentolamine altered resting venous compliance. 4 Local intravenous infusions of thymoxamine (500 ng/min) and phentolamine (500 ng/min) abolished the sympathetically mediated venoconstriction produced by overbreathing. 5 Systemic injection of thymoxamine (0·1 mg/kg) did not block the reduction in forearm arterial flow produced by locally infused noradrenaline. In two out of three experiments, however, it produced some antagonism of noradrenaline induced venoconstriction. Systemic phentolamine (5 mg) blocked the effect of noradrenaline in the arterial bed, but antagonized its actions in the veins in only one out of three experiments.

Functional differences in blood vessels determined from studies with calcium-channel blockers: Functional changes in forearm resistance vessels of men with primary hypertension

Vascular smooth muscle is activated through 2 major systems. One, which can be inhibited by calcium-entry blocking agents, involves the influx of calcium through potential-sensitive channels. The other, which can be inhibited by sodium nitroprusside, involves the entry of calcium through agonist-controlled channels and probably its mobilization from within the cell as well. Human veins, muscular arteries and resistance vessels show differing patterns of response to agents that selectively inhibit the 2 activation systems. The responses indicate that physiologic contractions of cutaneous veins and muscular arteries depend on the agonist-controlled system; contractions of veins induced by high concentrations of potassium depend on the potential-sensitive system as, probably, does local spasm in arteries. The tone of resistance vessels depends on a balance between the potential-sensitive and agonist-controlled systems. The forearm resistance vessels of men with primary hypertension respond to verapamil with larger-than-normal dilatation compared with that induced by nitroprusside. This is interpreted as showing an increased contribution to resistance vessel tone from the potential-sensitive system. This functional abnormality does not depend on the inhibition of sodium pump activity that is known to occur in hypertension, because it cannot be reproduced by local infusion of ouabain. It probably results from a primary disorder of calcium handling by the cell membrane.