Br. J. clin. Pharmac. (1980), 10, 115S- 121S ACUTE ACTION OF GUANFACINE ON PERIPHERAL CIRCULATION IN HYPERTENSIVE PATIENTS: MEASUREMENTS OF ARTERIAL FLOW OF THE CALF AND OF THE FOREFOOT, OF VENOUS CAPACITY OF THE CALF, OF THE BLOOD PRESSURE AND OF THE HEART RATE H. EHRINGER, G. BERGER, H. INGERLE, U. KONECNY & A. WOSS Division of Angiology, Department of Internal Medicine, University of Vienna, Austria 1 The acute action of an intravenous infusion (5 min) of guanfacine in doses of 0.01, 0.02 and 0.04 mg/kg on peripheral circulation was studied in five hypertensive patients and compared with a placebo in a randomized study. The observations were combined for 2 h after drug administration. 2 Two phases of drug action were seen during and immediately after the administration of guanfacine; a dose-dependent decrease in blood flow mainly of the forefoot but also in the calf was combined with an increase in systolic and diastolic blood pressures and a decrease in heart rate. Peripheral resistance was increased in this phase. Later, an increase in blood flow to the foot combined with a tendency towards a decrease in blood pressure were observed. 3 These preliminary results show that this second phase of action of guanfacine is dependent on the dose given. Introduction THE aim of this study was to evaluate the acute action of guanfacine on the peripheral circulation and its dependence on dose in hypertensive patients. Methods The study was carried out in five hypertensive patients (one male, four female) with a mean age of 41.2 + 13.4 yr, a mean weight of 61.0 + 6.6 kg, and a mean height of 160.8 + 4.2 cm. No patient suffered from heart failure, peripheral arterial occlusive disease or varicose veins. No other antihypertensive treatment was given at the same time. Patients served as their own controls and there were four treatment periods. The following doses of guanfacine were compared in random order with a placebo (P); dose A: 0.01, B: 0.02 and C: 0.04 mg/kg respectively. The drug was infused intravenously over 5 min using a motor pump. During the whole period of observation, before and after administration of the drug, the same volume of saline 2.0 ml/min was infused intravenously. In one patient dose C was not given because of pronounced bradycardia with dose B. The interval between the different treatments in each patient was 72 h or more. The investigation was carried out at a constant room temperature of 25 C 0306-5251/80/130115-07 $01.00 following a period of adaptation of 60 min in the supine position. Blood flow in the calf and forefoot was measured simultaneously and automatically every 15 s using a strain gauge plethysmograph (Gutmann) and an automatic venous occlusion device developed in our laboratory (Ehringer, Ehringer & Deutsch, 1968). The gauges were placed on the forefoot and at the maximal circumference of the calf. The collecting cuffs were situated at the ankle and at the proximal calf, respectively. The venous capacity of the right calf was measured using a water-filled plethysmograph and final cuff pressure of 50 mmhg above the effective venous pressure 0 according to the technique originally described by Wood & Eckstein (1958) and Ehringer & Deutsch (1968). The values are given as venous capacity per 50 ml or ml tissue and were measured once per period of observation. Blood pressure was taken on the left arm every minute, at least three times per observation period. At the same time, heart rate was counted from the ECG record. The time and duration of the periods of measurements and drug administration are shown in Figures 3-8. The drug was given during the middle 5 min of the period of 15 min of continual assessment. For each treatment an individual mean was Macmillan Journals Ltd. 1980.
116S H. EHRINGER, G. BERGER, H. INGERLE, U KONECNY & A. WOSS 0-n. 90 L 50L 180-2 160 O14Q II oe I 0E 120-0- I 80 ~~~~~~~Guanfacine E 41 o o r z =5 0 5 3 5 4 55 70 851 00 115 130 145 Figure 1 Acute effects of guanfacine 0.04 mg/kg on peripheral circulation in one hypertensive patient. Pulse rate, blood pressure, blood flow in the left calf (0) and foot (@).and 'venous capacity 50' are shown. acd 90r fl 70[- 5 L- 160, _ 140- a. E 120 -il s 11 Is t V PU - 80 - ET 6 i*e 4 -o 2 ci 0 2 a 0 Venous capacity 4 - (mi/1o0m)l 3L 0 1-15 30 35 40 55 70 85 115 130 145.. I I.... I.s..... Figure 2 Acute effects of placebo on peripheral circulation in the same hypertensive patient as in Figure 1. Pulse rate, blood pressure, blood flow in the left calf (0) and foot (@), and 'venous capacity 50' are shown.
ACUTE ACTION ON PERIPHERAL CIRCULATION 117S 3a 23- [TX 1A 2 -A E 2t I I VA I I I I E11p E 2 1 o 2 C RlS rusn n P H P fln n wn,tfln 1 fl wfl. R o 20 40 60 80 120 140 Figure 3 Acute action of guanfacine intravenously (a 0.01 mg/kg, hatched columns; b 0.02 mg/kg, solid columns; c 0.04 mg/kg, cross-hatched columns) and placebo (d stippled columns) on blood flow in the calf. Columns represents mean results (n= 5, n =4) and the vertical line the s.e.mean. calculated. On the basis of this mean value, mean values for all five patients (dose C, four patients only) per treatment and period of measurement were calculated. Due to the small number of patients involved, the results were not analysed statistically. Results A typical response to the acute action of guanfacine administered intravenously to one hypertensive patient is shown in Figure 1. During and immediately after infusion of the drug the following effects were observed: (1) a decrease in pulse rate, blood flow of the calf and especially of the foot; (2) a simultaneous increase in systolic and diastolic blood pressures. These effects started about 90 s after the beginning of the drug infusion and lasted until a few minutes after the end of it. Later on, during the 2 h period of observation, a sustained increase in blood flow of the foot and a tendency towards a decrease in blood pressure was observed. There was no change in 'venous capacity 50' after drug administration. During the administration of placebo to the same hypertensive patient, these effects on pulse rate, blood flow and blood pressure were not observed (Figure 2). There was some tendency for a spontaneous increase in the blood pressure over the 2 h period of the observations after placebo. Figures 3-8, show the spontaneous variation in baseline readings from the values before drug administration in each group and from the placebo group. The small decrease in blood flow of the calf during or after drug administration shows little dependence on dose (Figure 3). Figure 4 shows the most pronounced decrease in blood flow of the foot during the infusion of the drug and its dependence on dose. After administration of the lowest dose of guanfacine (0.01 mg/kg), the most pronounced 'afterdilation' was observed. A dose-dependent decrease in heart rate occurred, and is shown in Figure 5. Systolic blood pressure was increased during and immediately after drug administration, but not during the administration of placebo (Figure 6). After infusion a tendency towards a decrease in systolic blood pressure was observed, which was most pronounced with the highest dose of guanfacine (0.04 mg/kg). A similar effect was observed for diastolic blood pressure. A dose-dependent increase during and immediately after infusion of guanfacine was followed by a tendency to decrease later (Figure 7). These effects were not observed in the placebo group. There was no drop in 'venous capacity 50' after the infusion of guanfacine (Figure 8). Measurements of venous capacity during the infusion were not made.
118S H. EHRINGER, G. BERGER, H. INGERLE, U. KONECNY & A. WOSS 0 6-5 - 4-3 - 2-1 - L L1 j 'pi 2,M h h 0 20 40 60 80 120 140 Figure 4 Acute action of guanfacine intravenously (key as in Figure 1) and placebo on blood flow in the foot. Columns represent the mean results (n 5, n =4) and the vertical line the s.e.mean. b E 8 60 - L~~~~~~~~~~~I d (D 80- ol 60[ 10 -n 0 20 40 60 80 120 140 Figure 5 Acute action of guanfacine intravenously (key as in Figure 1) and placebo on pulse rate. Columns represent the mean results (n= 5, n = 4) and the vertical line the s.e.mean.
ACUTE ACTION ON PERIPHERAL CIRCULATION 119S a 180 160 ii h I h E E 180, 140111 i II b. II.0 l60fj dii k 0, 140- o 180 n160 140H i - h. i o 200 406-0 10 2 4 K l!.'.~ 0 0 40 60 80 120 140 Figure 6 Acute action of guanfacine intravenously (key as in Figure 1) and placebo on systolic blood pressure. Columns represent the mean results (n =5, n = 4) and the vertical line the s.e.mean. a 120 110 0) 90 I EE 120b 0D 110 Uo 0. 90 00 120 C > 110 o -.X 90L 0.m 1101 90 F I I 11f I 1i II. 11 h h A 0 h h R. 3i. i1. 0 20 40 60 80 120 140 Figure 7 Acute action of guanfacine intravenously (key as in Figure 1) and placebo on diastolic blood pressure. Columns represent the mean results (n = 5, n = 4) and the vertical line the s.e.mean.
120S H. EHRINGER, G. BERGER, H. INGERLE, U. KONECNY & A. WOSS a 6 4 -b 6 - Er~~~~,0 10.0 Figure 8 Acute action of guanfacine intravenously (key as in Figure 3) and placebo on venous capacity. a, guanfacine 0.01 mg/kg; b, 0.02 mg/kg; c, 0.04 mg/kg; d, placebo. Columns represent the mean results (n=5, n=4) and the vertical line the s.e. mean. Measurements of venous capacity were not made during infusion. Discussion Some of the actions of guanfacine on peripheral circulation are very similar to those described earlier for other centrally acting hypotensive drugs such as clonidine, that is, a dose dependent vasoconstriction due to a direct peripheral action during the infusion followed by a pronounced dilatation especially in the foot after the end of drug administration (Ehringer, 1968). The transient increase in blood pressure during the infusion of guanfacine and the decrease in heart rate are also similar to findings with clonidine (Bock, Heimsoth, Merguet, Schonermark & Ehringer, 1966). After infusion of guanfacine no decrease in venous tone as measured by 'venous capacity 50' could be observed during the 2 h which contrasts with results for clonidine (Ehringer, 1968). The increase in blood flow in to the foot combined with some decrease in blood pressure means a substantial decrease in peripheral resistance. This might provide some but not all of the rationale for the initial phase of the hypotensive action of the drug. A change in cardiac output, which was not measured in this study, might also play a major role. Alteration in cardiac output was documented for clonidine (Grabner, Michalek, Pokorny, & Vormittag, 1966; Schneider, 1968; Stenberg, Homberg, Naets & Varnauskas, 1968; Vorburger, Buttikofer & Reubi, 1968). References BOCK, K.D., HEIMSOTH, V. MERGUET, P. & SCHONERMARK, J. (1966). Klinische und klinischexperimentelle Untersuchungen mit einer neuen blutdrucksenkenden Substanz: Dichlorphenylaminoimidazol. Dtsch. med. Wschr., 91, 1761. EHRINGER, H. (1968). Die akute Wirkung von Catapresan auf die periphere Haemodynamik. In Hochdrucktherapie. Ed. Heilmayer, L., Holtmeier, H.J. & Pfeiffer, E.F. Pp. 39-49. Stuttgart: G. Thieme Verlag. EHRINGER, H. (1969). Differenzierte simultane Durchblutungsmessung konsekutiver Extremitatensegmente (gleichseitiger Unterschenkel und Fuss) mit einem automatisch registrierenden Venenverschlussplethysmographen: Zur Frage der Okklusionstechnik. Ztschr.f. Kreislaufforsch., 58, 500-509. EHRINGER, H. & DEUTSCH, E. (1968). Zur Wirkung von Raubasin auf Venentonus und Venenkapazitat des Unterschenkels Z. Kreisl. Forsch. 57, 1099-1105. GRABNER, G., MICHALEK, P., POKORNY, P. & VORMITTAG, E. (1966). Klinische und experimentelle Untersuchungen mit der neuen blutdrucksenkenden Substanz 2 (2,6-Dichlorphenylamino)-2-imidazolinhydrochlorid. Arzneimnittel-Forschung, 16, 1174. SCHNEIDER, K.W. (1968). Cardiale Haemodynamik im
ACUTE ACTION ON PERIPHERAL CIRCULATION 121S akuten Versuch, nach chronischer Behandlung und im Belastungstest mit St 155. In Hochdrucktherapie. Ed. Heilmeyer, L., Holtmeier, H.J. & Pfeiffer, E.F. Pp. 78-83. Stuttgart: G. Thieme Verlag. STENBERG, J., HOMBERG, S., NAETS, F. & VARNAUSKAS, E. (1968). Hemodynamic effects of catapresan: central circulation at rest and during exercise. In Hochdrucktherapie. Ed. Heilmeyer, L., Holtmeier, H.J. & Pfeiffer, E.F. Pp. 68-75. Stuttgart: G. Thieme Verlag. VORBURGER, C., BUTTIKOFER, E. & REUBI, F. (1968). Die akute Wirkung von St 155 auf die cardiale und renale Haemodynamik. In Hochdrucktherapie. Ed. Heilmeyer, L., Holtmeier, H.J. & Pfeiffer, E.F. Pp. 86-94. Stuttgart: G. Thieme Verlag. WOOD, J.E. & ECKSTEIN, J. (1958). A tandem forearm plethysmograph for study of acute responses of the peripheral veins of man: The effect of environmental and local temperature change, and the effect of pooling blood in the extremities. J. clin. Invest. 37, 41.