COMPARISON OF EFFECTS OF TOLMESOXIDE (RX71 107), DIAZOXIDE, HYDRALLAZINE, PRAZOSIN, GLYCERYL

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1 Br. J. clin. Pharmac. (978),5,35-44 COMPARISON OF EFFECTS OF TOLMESOXIDE (RX7 07), DIAZOXIDE, HYDRALLAZINE, PRAZOSIN, GLYCERYL TRINITRATE AND SODIUM NITROPRUSSIDE ON FOREARM ARTERIES AND DORSAL HAND VEINS OF MAN J.G. COLLIER, R.E. LORGE & B.F. ROBINSON Clinical Pharmacology Unit, Department of Pharmacology, St George's Hospital Medical School, London SW 7 OQT I Dilator drugs used in treatment of hypertension and angina pectoris vary greatly in their clinical effects. The action of selected drugs of this group on the human forearm arterial bed and dorsal hand veins has been studied in an attempt to account for these differences. 2 Arterial responses were studied by infusing the drug into the brachial artery and measuring changes in forearm blood flow by plethysmography. Venous responses were studied by local infusion of the drug into a dorsal hand vein preconstricted by infusion of noradrenaline or other constrictor agent and measuring changes in vein size at a standard congesting pressure. 3 Tolmesoxide (RX7 07), diazoxide, prazosin, glyceryl trinitrate and sodium nitroprusside produced dose dependent increases in forearm flow which had a rapid onset and waned quickly when the drug was discontinued. The response to hydrallazine was delayed and reached a maximum about 30 min after completion of short infusions. 4 Tolmesoxide, diazoxide, prazosin, glyceryl trinitrate and sodium nitroprusside all produced dilatation of the constricted hand vein. Hydrallazine had a weak dilator effect in some subjects but the responses were inconsistent. 5 Tolmesoxide was approximately equipotent in dilating arteries and veins, and diazoxide behaved similarly. Prazosin, glyceryl trinitrate and sodium nitroprusside were relatively more effective in the veins than the arteries. Hydrallazine was much more effective in arteries than veins. 6 The relative effectiveness of these drugs on peripheral arteries and veins can be correlated with their action on the circulation as a whole and with their clinical effectiveness. Introduction Drugs which have a direct relaxant effect on vascular smooth muscle are used in the treatment of both arterial hypertension and angina pectoris. However, the comparative effectiveness of different drugs in these disorders varies greatly and they are, in general, only of use in one of the two conditions; some drugs such as hydrallazine, which are effective in hypertension, may even aggravate angina pectoris (Judson, Hollander & Wilkins, 956). These differences might result from differing actions on peripheral arteries and veins. We have therefore studied the effects on the human forearm arterial bed and dorsal hand veins of a number of dilator drugs including diazoxide, hydrallazine, prazosin, glyceryl trinitrate and sodium nitroprusside. In addition, we have investigated the effects of a new peripheral dilator and potential antihypertensive drug, tolmesoxide ((4,5-dimethoxy-2- methylphenyl) methyl sulphoxide, RX707), which has not previously been studied in man. Methods Studies were carried out in normal volunteers, all except one of whom were male; ages ranged from 2-46 years. The Ethical Committee of St George's Hospital approved the investigation, and informed consent was obtained from each subject. Experiments were performed with the subjects supine; laboratory temperature was maintained essentially constant during any one study, but varied between C on different occasions.

2 36 J.G. COLLIER, R.E. LORGE & B.F. ROBINSON Forearm arterial studies Forearm blood flow was measured by venous occlusion plethysmography using a temperature compensated mercury-in-rubber strain gauge (Whitney, 953) with a Devices amplifier and recorder. A wrist occlusion pressure of mmhg was used and a collecting cuff pressure of mmhg; flows were recorded for 0 s in every 5 seconds. Drugs were dissolved in 0.5 M sodium chloride solution and infused into the brachial artery of one arm while the other arm served as a control. Infusions were made through a 26 SWG unmounted needle introduced under local anaesthesia (% lignocaine), and connected via a Portex remote injection catheter to a syringe driven by a Harvard constant rate infusion pump. The initial dose of each drug was infused for 4 min and the dose was then doubled at 3 min intervals to obtain a cumulative dose response curve. The mean of the last five measurements of flow at each dose was taken as the response. The order in which the drugs were given was varied when possible, but drugs with a delayed or prolonged action necessarily had to be given last. Saline was infused between drugs for a minimum of 0 min to allow forearm flow to return to pre-infusion levels. Dorsal hand vein studies Changes in compliance of a dorsal hand vein were measured using a modification of the technique developed in this laboratory (Nachev, Collier & Robinson, 97). In brief, the veins of the hand were distended by maintaining a constant pressure of 25 mmhg in a cuff around the upper arm. Changes in size of a selected dorsal hand vein were recorded by means of a lever connected to a Harvard displacement transducer with a Devices amplifier and recorder. The congesting cuff was deflated at intervals and the vein allowed to empty; the change in vein size between the congested and collapsed state was taken as the index of distensibility at the selected pressure. Drugs were dissolved in 0.5 M sodium chloride solution and infused through a 23 SWG butterfly needle (Abbotts) at 0.25 ml/min by means of Harvard constant rate infusion pump. The needle was introduced without local anaesthesia and positioned with its tip 5-0 mm upstream from the point of measurement. Each dose of drug was infused for 6 min with the cuff inflated. The cuff was then deflated and distensibility measured. In some studies, further measurements were made at the same dose. The rate of infusion of the drug was increased at intervals of not less than 6 min, and measurements of distensibility made at each dose. Since hand veins have no resting tone in the fully relaxed and warm subject, the veins were preconstricted by continuous infusion of noradrenaline, 5-hydroxytryptamine (Collier, Nachev & Robinson, 972), or prostaglandin F2< (Robinson, Collier, Karim & Somers, 973) before infusion of dilator drugs. At the end of the infusion of each dilator, the vein was allowed to reconstrict before another dilator drug was given. The order in which the short acting drugs was given was varied, but those with prolonged action had to be given last. Drugs Drugs used were tolmesoxide (RX707, Reckitt & Colman), diazoxide (Eudemine, Allen & Hanbury), glyceryl trinitrate, hydrallazine hydrochloride (Apresoline, Ciba), 5-hydroxytryptamine (Burroughs Wellcome), lignocaine hydrochloride (Lidothesin, Willows Francis), noradrenaline acid tartrate (Levophed, Winthrop), prazosin hydrochloride (Hypovase, Pfizer), prostaglandin F2a (Prostin F, Upjohn) and sodium nitroprusside. Glyceryl trinitrate and sodium nitroprusside were prepared in a form suitable for parenteral use by the pharmacy at St George's Hospital and were diluted immediately before use. Ascorbic acid (Evans Medical) at a final concentration of 5-0 ig/ml was added to noradrenaline solutions to prevent oxidation. The doses of those drugs formulated as salts were calculated as the base with the exception of sodium nitroprusside. Results Effects onforearm arterialflow Tolmesoxide produced a dose dependent increase in forearm flow over the range ,g/min in 4 experiments in 2 subjects. At each dose level, flow increased to reach a steady state by the third minute of infusion and did not show any significant further increase in experiments continued up to 8 min; when the infusion was discontinued, flow fell rapidly over -2 min, and had usually regained control values within 5-0 min. Experiments in which the same dose was given on more than one occasion showed no evidence of tachyphylaxis. The mean response at 400,g/min was an increase in flow of 88% (range %, 4 experiments), at 800 gg/min it was 50% (range %, 3 experiments) and at 600 gg/min it was 20% (range 56-23%, 5 experiments). Tolmesoxide ( gg/min) antagonized the constrictor effect of both noradrenaline (50-00 ng/min) and angiotensin ( ng/min) in the forearm arterial bed (2 experiments). The dilator effect of tolmesoxide was not attenuated by prior intra-arterial infusion of propranolol ( and 2 mg given over 5 min); when the degree of P-adrenoceptor blockade was assessed after tolmesoxide had been given, the response to isoprenaline (00 and 200 ng/min) was still partially attenuated after mg of propranolol and almost completely so after 2 mg. Diazoxide produced a dose dependent increase in

3 VASODILATORS IN HUMAN ARTERIES AND VEINS 37 forearm flow over the range jg/min in 5 subjects. The time course of the onset and disappearance of the response was rapid and similar to that of tolmesoxide, but the variation in response between subjects was greater. The mean response at 400 jg/min was an increase of 2% (range 0-45%) and at 800 jig/min it was 78% (range 0-67%). Hydrallazine caused an increase in forearm flow, but the response was much delayed compared to tolmesoxide and diazoxide. When 00 jg/min was infused for 2 min there was no increase in flow until towards the end or shortly after the infusion. Flow then increased progressively over the next 5-30 min and in some subjects there was a further slow increase up to 60 min; it then gradually fell and in one subject had almost regained control levels at 90 min but in two others it was still substantially elevated when the study was discontinued after 20 minutes. The maximum increase in flow, which occurred between 5 and 60 min, averaged 94% (range 5-275% in five subjects). In one subject, given a total dose of 800 jg over 4 min, the maximum increase was 708%, and in another given 2000 jg over 7 min the increase was 200%. In the one subject in whom flow returned close to the control level, a repeat infusion of hydrallazine showed no evidence of tachypylaxis. In two subjects the infusion of hydrallazine was repeated after infusion of propranolol (2 mg over 5 min); no significant reduction in the dilator response was seen when flow was followed for 30 and 40 min respectively. In a subject pretreated with indomethacin (25 mg over the preceding 20 h), the response to hydrallazine (200 jig over 2 min) was within the normal range. Prazosin caused a dose dependent increase in forearm flow over the range ng/min (five subjects). In three subjects in whom a constant dose was infused for 0-2 min, the response showed no further increase after the third minute in two; in the third subject, however, it continued to increase up to the tenth minute. The response waned slowly when the drug was discontinued and in most subjects a major part of the response was still present after 0 minutes. The mean response in five subjects during the third minute of infusion at 00 ng/min was an increase of 7% (range 0-28%), at 200 ng/min it was 50% (range 25-9%) and at 400 ng/min it was 90% (range 50-22%). Glyceryl trinitrate produced a dose dependent increase in forearm flow over the range ng/min in seven subjects. At each dose level, flow increased rapidly to reach a steady state by the third minute; the response waned rapidly when the infusion was stopped and had returned to control values within about 0 min. The mean response at 00 ng/min was an increase of 34% (range 0-65%) and at 200 ng/min it was 58% (range 5-85%). Sodium nitroprusside produced a dose dependent increase in forearm flow over the range ng/min in five subjects. The pattern of response was similar to that produced by glyceryl trinitrate. The mean response at 00 ng/min was an increase of 40% (range 23-75%) and at 200 ng/min it was 67% (range 44-00%). The relative potencies as arterial dilators of tolmesoxide, diazoxide, prazosin, glyceryl trinitrate and sodium nitroprusside were assessed by comparing cumulative dose response curves obtained by measurement during the third minute of infusion in each subject. The ratios of dose rates required to produce an equal increase in forearm flow (taking tolmesoxide as the arbitrary standard) are shown in Table. Diazoxide was of the same order of potency as tolmesoxide. Glyceryl trinitrate, sodium nitroprusside and prazosin were all more than 000 times as potent as tolmesoxide. It is possible that the potency of prazosin has been slightly underestimated as the response may not have reached maximum in all subjects by the third minute. Hydrallazine cannot be directly compared with the other drugs as the pattern of response is so different. However, the delayed steady state response to the infusion of 200 jg over 2 min would be equivalent to that produced by a continuous infusion of tolmesoxide at about 450 jig/minute. Effects on dorsal hand vein distensibility Tolmesoxide produced a dose dependent dilatation of the noradrenaline constricted hand vein in the dose range 0-80 jg/min (5 experiments in thirteen subjects). The response usually reached its maximum within 4-5 min and waned over a similar interval of time when the infusion was discontinued. The response to 20 jg/min in the steady state was an increase in size of the constricted vein of 6% (range 3-25%; 5 experiments) and at 40 jg/min it was 0% (range 55-73%; 5 experiments). Tolmesoxide also caused dilatation in the same dose range when infused into veins preconstricted by 5-hydroxytryptamine (3 experiments) and PGF2a (4 experiments). In two subjects the effect of doubling the infusion rate was studied. A dilator response to infusion of tolmesoxide at 0 jg/min was demonstrated during infusion of noradrenaline at 6 ng/minute. The rate of infusion was then increased from 0.25 to 0.5 ml/min and the concentration of drugs in the infusate was halved. The responses were not significantly altered. Diazoxide produced a dose-dependent dilatation of the noradrenaline constricted hand vein in the dose range jg/min (six subjects). The time course of the appearance and disappearance of the response was similar to that of tolmesoxide. The average response to 20 jg/min was an increase in size of the constricted vein of 44% (range 36-50%; 4 experiments), and at 40 gg/min it was 82% (range 5-75%; 6 experiments). The drug also caused

4 38 J.G. COLLIER, R.E. LORGE & B.F. ROBINSON Table Dose ratios relative to tolmesoxide for dilator action in forearm arterial bed and noradrenaline constricted hand vein of diazoxide, hydrallazine, prazosin, glyceryl trinitrate and sodium nitroprusside. The arterial dose ratio for hydrallazine has been assessed by estimating the total dose of tolmesoxide required to cause the same duration of dilatation as a single dose of hydrallazine; the venous dose ratio has been assessed from the observed transient responses. Statistical significance has been calcuiated for the difference between the arterial/venous dose ratio of each drug and that for tolmesoxide (see text) Subject J.G. S.B. B.R. N.S. D.S. J.R. J.C. S.L. B.R. J.G. S.A. Mean N.S. P.G. J.R. B.L. B.R. D.S. J.G. P.K. J.w. S.L. B.R. J.H. S.S. P.C. Mean Arterial/ venous dose ratio Significance Tolmesoxide >2.5 8 > >2.6 Diazoxide > NS Hydrallazine Arterial [<0.06] Venous Prazosin.6x x x x 0-4 lo.ox 0-4 Glyceryl trinitrate 3.5x O'" 2.9x 0-4.8x 0-4 Sodium nitroprusside 6. x x x x x x0-4.7 x x x x x x x 0-4.0x x O'4 0.9x 0o' 0.3 x x x x x 0-4.5x 0-4.0x 0-4.5x 0-4 [> x x x 0-4 [< P<0.00 P<0.00 P<0.00 dilatation over the same dose range when infused into veins preconstricted by 5-hydroxytryptamine (2 experiments) and PGF2 (3 experiments). Hydrallazine was infused into the noradrenaline constricted vein in the dose range gg/min in six subjects. In four of them, no dilator response was seen; in the other two, partial dilatation was produced. The response was followed for up to 0 min after the infusion, and in those subjects in whom a partial response had been seen, it had always waned within that time. In two further subjects given 80 gg/min for 0 min and followed for 60 min, partial dilatation was seen during the infusion in both but had waned within 6 min of discontinuing the drug. In one there was no evidence of dilatation over the following hour; in the other the noradrenaline induced constriction relaxed moderately after 30 min, but this was not progressive. Prazosin caused dilatation of the noradrenaline constricted hand vein in the dose range -0 ng/min (eight subjects). When low doses were infused, the response usually did not begin until the sixth to eighth min and took up to 20 min to reach a maximum; because of the long time taken to reach a steady state, cumulative dose response curves could not be obtained. The average steady state response to ng/min was an increase in size of the noradrenaline constricted vein of 32% (range %; 4 experiments); in 2 experiments, however, the response to

5 VASODILATORS IN HUMAN ARTERIES AND VEINS 39 Noradrenaline (6ng/min) - Sodium nitroprusside (2ng/min) mm 0 I N rm (vi Figure Effect of sodium nitroprusside on noradrenaline constricted hand vein. The continuous recording shows the size of the congested hand vein; it is interrupted twice by deflation of the congesting cuff to establish the baseline. The vein is constricted by a continuous infusion of noradrenaline at 6 ng/min. Infusion of sodium nitroprusside at 2 ng/min leads to gradual relaxation of the tonic contraction with the appearance of phasic contractions at about 5/min. V ng/min was maximal and the average response gives an underestimate of potency. Glyceryl trinitrate produced a dose dependent dilatation of the noradrenaline constricted hand vein in the dose range -5 ng/min (seven subjects). The response usually reached its maximum in 4-5 min and waned over a similar period. In 6 out of 2 experiments, phasic contractions appeared at about 5/min during infusion of glyceryl trinitrate and disappeared when it was stopped. The average response to I ng/min was an increase in size of the constricted vein of 67% (range 2-0%; 5 experiments), and at 2 ng/min it was 4% (range %; 4 experiments). The drug caused dilatation over the range 2-0 ng/min when infused into veins constricted by 5- hydroxytryptamine (3 experiments) and PGF2a(2 experiments). In one subject the constrictor response to noradrenaline, 6 ng/min, was shown to be unchanged by doubling the infusion rate to 0.5 ml/min and halving the concentration of the drug; administration of nitroglycerin ng/min at the increased infusion rate caused a large dilator response. Sodium nitroprusside produced a dose dependent dilatation of the noradrenaline constricted hand vein in the dose range -8 ng/min (six subjects). The response appeared and disappeared at a similar rate to that produced by glyceryl trinitrate; phasic contractions similar to those caused by glyceryl trinitrate were seen in 3 out of 8 experiments (Figure ). The average response to infusion of ng/min was an increase in size of the constricted vein of 73% (range %; 5 experiments) and at 2 ng/min it was 05% (range %; 5 experiments). The relative potencies as venodilators of tolmesoxide, diazoxide, glyceryl trinitrate and sodium nitroprusside were assessed by comparing cumulative dose response curves in each subject; the potency of prazosin was assessed from the steady state response at a single dose rate. The ratios of dose rates required to cause an equal degree of relaxation of the noradrenaline constricted vein are shown in Table. Diazoxide was of the same order of potency as tolmesoxide; glyceryl trinitrate, sodium nitroprusside and prazosin were all about 0,000 times more potent than tolmesoxide. The results with hydrallazine were too inconsistent for precise quantitation, but it was clearly much less potent than tolmesoxide. Comparison ofpotencies in arteries and veins The ratio of the arterial to the venous dose ratio provides an index of the relative effectiveness of each drug in arteries and veins compared to tolmesoxide (Table ); values greater than indicate that the drug is relatively more effective in the veins, and less than that it is more effective in the arteries. Diazoxide was not significantly different from tolmesoxide in its effects on arteries and veins. Glyceryl trinitrate and sodium nitroprusside were on average more than five times as potent in the veins as in the arteries relative to tolmesoxide; prazosin was also much more effective in veins than arteries. The arterial venous ratio for each of these drugs was found to be significantly different from that for tolmesoxide (P <0.00) when the null hypothesis that the ratio was unity was examined by t- test on the log dose-ratio values. The ratio for hydrallazine is not stictly comparable with that for the other drugs as the methods were different, but it sets an approximate upper limit; the drug is clearly much more effective in arteries than veins compared to tolmesoxide. Discussion The results demonstrate the direct effect of the drugs studied in the forearm arterial bed and dorsal hand veins in man. The method used to assess arterial

6 40 J.G. COLLIER, R.E. LORGE & B.F. ROBINSON responses has been widely employed in the investigation of vasoactive substances (Whelan, 967). The technique used to assess venous responses permits quantitation of the direct effect of drugs on veins and has been applied to a wide range of vasoactive agents (Collier et al., 972; Robinson et al., 973; Aellig, 974; White & Udwadia, 975; Ghose, Gifford, Turner & Leighton, 976). Local effects ofdilators in arteries and veins Tolmesoxide lowers arterial pressure in several animal species and has a direct dilator effect in arterial beds (Doxey & Green, personal communication). Our experiments show that it has a dilator effect in the forearm arterial bed and dorsal hand veins in man; the results are consistent with the view that it acts by a direct effect on the contractile process. The threshold concentration in the forearm arterial bed can be estimated by calculating the mean threshold dose rate from the pooled data and dividing it by the average total forearm flow in the control state (assuming a forearm volume of 600 ml); this yields a value of approximately 2.5,ug/ml whole blood. The threshold concentration in the veins is more difficult to assess as the flow is unknown. The mean threshold infusion rate was 7 gg/min which corresponds to a concentration in the infusate of 28 gg/ml. The experiments in which the infusion rate was doubled to 0.5 ml/min suggest that at the normal rate of infusion the solution was mixed with at least its own volume of blood and an upper limit of 4 g.g/ml whole blood can be set for the threshold concentration. Considerations based on hand blood flow suggest a lower limit for the concentration of about 5-6 gg/ml. Tolmesoxide thus appears to be approximately equipotent as a dilator in the arterial and venous beds studied. For this reason, it was used as the standard against which the other drugs were compared. Diazoxide was of the same order of potency as tolmesoxide, and, like that drug, was approximately equipotent in dilating the forearm arterial bed and hand veins. These results are in agreement with previous studies of the effect of diazoxide on arterial beds in both animals (Rubin, Roth, Taylor & Rosenkilde, 962; Rubin, Zitowitz & Hausler, 963; Powell, Green, Whiting & Sanders, 97; Ogilvie & Mikulic, 972), and man (Thirwell & Zsoter, 972). Conflicting reports have appeared of the effect on veins: a venodilator effect in dogs was noted in one study (Ogilvie & Mikulic, 972), but not in another (Rubin et al., 963). In the only previous study in man, forearm venous tone showed a small but statistically insignificant reduction during systemic administration (Thirwell & Zsoter, 972); the absence of any definite response in this study may have been due to complete, or almost complete, relaxation of the forearm veins in the control state so that little or no further relaxation was possible. Glyceryl trinitrate dilates peripheral arteries and veins when given sublingually in man, but interpretation of these findings is complicated since responses to systemic administration may be greatly modified by reflex effects (Mason & Braunwald, 965). The direct effects of the drug on resistance and capacitance vessels have not previously been studied in man, but our findings are in general agreement with studies of sodium nitrite in both animals and man (Ablad & Mellander, 963; Ablad & Johnsson, 963). Our results indicate that (relative to tolmesoxide) glyceryl trinitrate is nearly seven times more effective in dilating veins than arteries (Table ). Calculation of threshold concentrations confirms that the sensitivity of hand veins to glyceryl trinitrate is greater than that of forearm arteries: the upper limit for the threshold in the veins (calculated as for tolmesoxide) is 0.8 ng/ml whole blood, whereas the threshold in the forearm arterial bed is 3-4 ng/ml whole blood. Sodium nitroprusside relaxes both resistance and capacitance vessels in animals (Page, Corcoran, Dustan & Koppanyi, 955) and intravenous infusion lowers peripheral resistance in man (Palmer & Lasseter, 975). In our experiments, sodium nitroprusside behaved in all respects like glyceryl trinitrate. The results conflict with those of Miller, Vismara, Williams, Amsterdam & Mason (976) who reported that sodium nitroprusside had a balanced action on forearm resistance and (unconstricted) capacitance vessels compared to the predominantly venous action of glyceryl trinitrate. This discrepancy may be due to administration of the drugs by different routes in their experiments coupled with the differing time course of the response in veins and arteries. Sodium nitroprusside and glyceryl trinitrate were the only drugs studied which led to the appearance of phasic activity in the veins as they dilated. This is consistent with previous reports that sodium nitroprusside is much more effective in antagonizing tonic than phasic contractions in smooth muscle (Kreye, Baron, Luth & Schmidt-Gayk, 975). It also raises the possibility that sodium nitroprusside and glyceryl trinitrate have a mechanism of action which is common to each other but different from that of the other dilators. Prazosin dilates arterial beds in animals (Constantine, McShane, Scriabine & Hess, 973), but a venodilator action has not previously been demonstrated. Prazosin was of the same order of potency as glyceryl trinitrate and sodium nitroprusside and resembled those drugs in being relatively more effective in veins than arteries. Despite this similarity of effect, its mechanism of action is quite different, and it is thought to act at least in part by interfering with a-adrenoceptor function (Constantine etal., 973). Hydrallazine has a dilator effect in the forearm arterial bed with a delayed onset and long duration; it has little or no effect on the veins. These results are in

7 VASODILATORS IN HUMAN ARTERIES AND VEINS 4 general agreement with previous findings (Ablad, Johnsson & Henning, 96; Ablad & Johnsson, 963). Ablad (963) suggested that the delayed onset might reflect accumulation in the vessel wall of an active metabolite of the drug or of an endogenous dilator substance. If a dilator accumulates it is unlikely to be a prostaglandin since the response occurs after pretreatment with indomethacin. Comparative effects of dilator drugs on arteries and veins in relation to action on the circulation as a whole Difference in the circulatory effects of dilator drugs have been thought to be due, at least in part, to differences in their action on arteries and veins. The demonstration of the relative potencies of a number of these drugs in arteries and veins enables the patterns of activity found to be correlated with the effects of the drugs on the circulation as a whole. The drugs studied fall clearly into three groups; tolmesoxide and diazoxide are approximately equipotent as dilators in arteries and veins; glyceryl trinitrate, sodium nitroprusside and prazosin are, by comparison, at least five times more potent in veins than arteries; hydrallazine is much more effective in arteries than veins. This grouping of the vasodilators was achieved by comparison with tolmesoxide but the drugs can also be grouped independently by calculation either of the ratio of threshold doses in arteries and veins, or of the ratio of doses required to cause a 50% relaxation (Table 2). The effects of the drugs on the circulation as a whole are in accordance with what would be expected if the effects on forearm arteries and hand veins are representative of the effects on resistance and capacitance beds elsewhere. A drug whose sole effect was to cause arteriolar dilatation would have as its primary circulatory effect a fall in peripheral resistance. This would lead to a rise in cardiac output with a small fall in arterial pressure. Reflex tachycardia, and possibly venoconstriction, would contribute to increasing cardiac output; postural hypotension would not be expected. A drug whose sole effect was to cause dilatation in the systemic venous bed with a resultant increase in venous capacitance would have as its primary circulatory effect a fall in central venous pressure. This would lead to a fall in cardiac output which would be most marked in the upright position. There would a be a fall in arterial pressure secondary to the fall in output, but this would be offset to some extent by reflex arterial constriction; postural hypotension might occur as a result of venous pooling in the upright position. Our results suggest that the effects of hydrallazine in usual clinical doses would be confined almost entirely to reducing arterial resistance. The circulatory effects of intravenous doses are in agreement with what would be expected of a pure arterial dilator: peripheral resistance and arterial pressure fall; central venous pressure is unchanged, and both heart rate and cardiac output rise (Ablad, 963). Glyceryl trinitrate in clinically used doses can produce blood levels in excess of 3 ng/ml (Bogaert & Rosseel, 972), and it should therefore have a large venodilator effect with, in addition, a small (and shorter-lived) effect on arterial resistance; the pattern of circulatory changes that result from sublingual administration would be expected to vary rapidly with time. Its reported effects are what would be expected of a drug with a dominant effect on the venous bed: there is a fall in ventricular filling pressures and stroke volume; reflex tachycardia may prevent a fall in cardiac output in the supine position, but, at least during exercise, there is a significant fall in output in the upright position; arterial pressure falls and this is usually the result of a reduction in both cardiac output and peripheral resistance (Eldridge, Hultgren, Stewart & Proctor, 955; Brachfeld, Bozer & Gorlin, 959; Christensson, Nordenfeldt, Westling & White, 969); postural hypotension is well recognized clinically. Similar circulatory effects have been reported for sodium nitroprusside (Palmer & Lasseter, 975). Prazosin has a similar pattern of activity to glyceryl trinitrate in arterial and venous beds and would therefore be expected to have similar acute effects on the circulation. The circulatory effects of intravenous prazosin are in agreement with this expectation (Safar, Weiss, London & Milliez, 974). Diazoxide has a balanced action on arterial and venous beds and the acute circulatory effects would be expected to be somewhere between the two extremes. The reported effects resemble those of hydrallazine more than glyceryl trinitrate: both peripheral resistance and arterial pressure fall; right atrial pressure is unchanged, but Table 2 Ratios of mean dose ratio in arteries and veins at threshold and at 50% dilatation. Data are not available for hydrallazine or for the 50% dilatation ratio with prazosin (see text) Tolmesoxide Diazoxide Prazosin Glyceryl trinitrate Sodium nitroprusside Threshold ratio (arteries/veins) 2 34 > % dilatation ratio (arteries/veins)

8 42 J.G. COLLIER, R.E. LORGE & B.F. ROBINSON heart rate and cardiac output rise (Wilson & Okun, 963). The effects of long term administration of drugs may differ from those of acute administration. Nevertheless, the clinical effects of the dilator drugs studied correlate well with their acute circulatory actions and hence with their pattern of activity in arteries and veins. Diazoxide and hydrallazine are effective in the treatment of hypertension and lower arterial pressure without reducing cardiac output (Wilson & Okun, 963; Judson, Hollander & Wilkins, 957); they do not cause postural hypotension. Hydrallazine frequently provokes angina when given intravenously to patients with ischaemic heart disease (Judson et al., 956); this probably results from the disproportionately large increase in heart rate relative to the fall in arterial pressure which, in the absence of venodilatation to reduce ventricular volume, would be expected to cause an increase in left ventricular work and oxygen requirements. The clinical usefulness of drugs acting on the veins appears to depend on their duration of action and method of administration. Short acting glyceryl trinitrate is, of course, highly effective in the prophylaxis or relief of angina pectoris; the reduction in left ventricular work that results from its combined action on both resistance and capacitance beds provides an adequate explanation for its therapeutic effects (Robinson, 968). Sodium nitroprusside has very similar circulatory actions but is not suitable for selfmedication and its effects in angina have not been studied. It has, however, been given by continuous infusion in acute myocardial infarction when it lowers lft ventricular filling pressure and arterial pressure but increases cardiac output (Chatterjee, Parmley, Ganz, Forrester, Walinsky, Crexells & Swan, 973), and it has similar effects in cardiac failure (Miller et al., 976). These changes are what would be expected from a combination of venodilatation and reduction of peripheral resistance when left venctricular function is severely impaired. Sodium nitroprusside is also used in the management of hypertensive emergencies when its effects are again consistent with its actions on the peripheral vessels; it lowers arterial pressure with moderate changes in cardiac output in either direction (Schlant, Tsagaris & Robertson, 962). In contrast to its acute action, prazosin has either no significant effect on cardiac output or may even lead to an increase when given long term to patients with hypertension (Safar et al., 974; Masoni, Tommasi, Baggioni and Bagni, 974); this suggests that the venodilator effect is either decreased or partially compensated for during chronic administration. A postural drop in arterial pressure is, however, a feature of the clinical action of the drug, and it has been found to have the unexpected side-effect of occasionally causing syncope after the initial dose. The finding that the drug is strongly venoselective provides a possible explanation for this side effect; syncope is well recognized with glyceryl trinitrate and is probably a predictable risk wherever a venoselective dilator is given acutely to predisposed subjects exposed to the stress of the upright position. The clinical effects and unwanted actions of the Table 3 Correlation of relative activity of dilator drugs in resistance and capacitance vessels with circulatory and clinical effects Arterioselective (hydrallazine) Non-selective (diazoxide) Venoselective (prazosin. glyceryl trinitrate, sodium nitroprusside) Cardiac output t t Supine-little change Upright I Arterial pressure Supine I Upright-greater fall Central venous pressure no change no change Pulmonary arterial pressure t Clinical effects Effective in hypertension. May aggravate angina Effective in hypertension. Rarely aggravate angina Effective in hypertension; may cause postural hypotension and syncope. Effective in angina and left ventricular failure when given acutely.

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