Increased forearm vascular resistance after dopamine blockade

Transcription

1 Br. J. clin. Pharnac. (1984), 17, Increased forearm vascular resistance after dopamine blockade D. MANNERING, E.D. BENNE7T, N. MEHTA & F. KEMP Department of Medicine 1, St George's Hospital Medical School, London SW17 ORE 1 The peripheral haemodynamic effects of a 4 mg intravenous injection of domperidone (a dopamine antagonist) have been studied in 1 normal subjects. In four subjects domperidone was infused directly into the brachial artery and the effects on forearm blood flow were measured. 2 When administered systemically, domperidone significantly decreased forearm blood flow by 9% (P <.1) and significantly increased calculated forearm vascular resistance by 11% (P <.1). 3 The drug produced no measurable changes in forearm blood flow at any dose when infused directly into the brachial artery. 4 A further study was carried out into the effects of a systemic injection of domperidone on peripheral sympathetic tone. Reduction of sympathetic tone in the forearm was achieved by passively raising the legs of eight recumbent subjects. 5 Before domperidone administration, passive leg elevation significantly increased forearm blood flow by 39% and decreased forearm vascular resistance by 13%. After drug administration the absolute values of vascular resistance increased and the changes between the supine and elevated position values when compared with those of the corresponding values prior to drug administration were significantly lower. 6 These results suggest that the role of domperidone in increasing peripheral vascular tone is unlikely to be mediated by a direct local effect on peripheral resistance vessels. Any effect the drug may have is suggested to be mediated via a central control mechanism. Keywords domperidone dopamine forearm vascular resistance Introduction The role of a dopaminergic mechanism in the regulation of peripheral vascular tone has not been fully established. Previous studies have shown that dopaminergic agonists, such as bromocriptine have been successfully used to lower blood pressure in patients with essential hypertension and have been shown to induce hypotension in normotensive adults (Kolloch et al., 1981). This study was thus designed to investigate the effects of a dopaminergic antagonist on both the central and peripheral circulation. Domperidone has been demonstrated in in vitro experiments to be a potent antagonist of striatal dopamine receptors (Laduron & Leyson, 1979). Unlike many neuroleptic drugs, domperidone 373 does not cross the blood-brain barrier and is devoid of any central dopaminergic activity other than the effects it is known to have on the hypothalamus. Investigations into two possible mechanisms by which domperidone may be effective were carried out. Firstly, a direct infusion into the brachial artery to assess any local effects of dopamine blockade. Secondly, since it has been demonstrated that administration of bromocriptine reduces noradrenaline levels and sympathetic tone in man (Francis et al., 1983), to investigate any attenuating effect of domperidone on reflex inhibition of sympathetic tone in the forearm as a result of passively elevating the legs of a recumbent subject.

2 374 D. Mannering et al. Methods Systemic study The study was performed on 1 normal volunteer subjects, five male and five female of age range years (mean age 25 ± 3 years). Each subject was informed of the nature of the study and his or her consent was obtained before each individual study took place. The studies were performed in a double-blind manner; for each subject there was an active and a placebo study. The identity of each study was revealed only after analysis of all the results were complete. The ambient room temperature was maintained at C throughout each study. A 'butterfly' needle was inserted into an antecubital vein in the right arm and the subject was allowed to rest in the supine position for 4 min. A 4 mg intravenous injection of domperidone or.9% saline placebo was given over 5 min preceded by two control measurements separated by a period of 1 min of which the mean of the two values was recorded. Measurements were then taken at 2, 1, 15, 3, 45 and 6 min. Forearm blood flow (FBF) was measured by venous occlusion plethysmography using a temperature compensated mercury-in-silastic strain gauge and expressed in ml/1 ml-' of tissue min-'. Brachial arterial pressure was measured by conventional sphygmomanometry using the fourth Korotkov phase as the diastolic pressure. Mean arterial pressure (MAP) was calculated as the mean diastolic pressure plus one-third of the pulse pressure. Forearm vascular resistance (FVR) was calculated as the mean arterial pressure divided by the forearm blood flow and expressed in kpa/ml.s. Student's paired t-tests were used to determine the significance of any difference between the control period and the post injection periods. Local infusion study The effect of an intra-arterial infusion of domperidone on forearm blood flow was performed on four of the above volunteers. A fine needle attached by way of a catheter to an infusion pump was inserted into the right brachial artery. The subject was allowed rest for 15 min before doses of 12.5, 25, 5 and 1,ug/min of domperidone were infused into the artery for 15 min per dose. Forearm blood flow was measured in both forearms simultaneously by venous occlusion plethysmography, the left arm being used as a control. The corresponding values of blood flow for the left (control) and right forearms were compared using paired t-tests for each infused dose at the recorded time intervals. Leg elevation study The effects of domperidone on the release of vasoconstrictor tone were carried out on eight normal volunteer subjects. Each subject quietly rested on a bed for 15 min. Measurements were then taken at 15 min intervals for 6 min, firstly with the subject in the supine position and then repeated immediately after passively raising the subject's legs to an angle of approximately 9 degrees and undergoing head down tilt of 1 degrees. The procedure was then repeated after administration of a 4 mg intravenous injection of domperidone. Forearm blood flow, mean arterial pressure and forearm vascular resistance were determined as have previously been described. Student's paired t-tests were used to determine firstly, any significant difference in the variables discussed following leg elevation in the control period and secondly, to see whether administration of domperidone had any significant effect on this response. Results Systemic study The results are shown in Tables 1 and 2 as the absolute values + s.e. mean. Forearm blood flow decreased 8.9% from the control value, falling from ml min- '1 ml- Ito ml min-i 1 ml-' at 1 min (P <.1) post drug administration. Forearm vascular resistance increased 11.7% at 1 min (P <.1) and 14% (P <.5) at 6 min from a control value of kpa/ml.s to kpa/ml.s at 1 min and kpa!ml.s at 6 min. No significant changes were observed in mean arterial pressure. No significant changes or trends were observed in any of the variables during the placebo studies. In order to assess any inter-relationships between the drug, subjects and time on the variables discussed, three-way analysis of variance was applied to the data. Domperidone significantly decreased forearm blood flow (P <.1) and increased forearm vascular resistance (P <.1) during the study period. Time however was not found to be a significant factor throughout the study.

3 Table 1 Increased vascular resistance and dopamine blockade Mean values (+ s.e. mean) of all measured variables; during active (Act) and placebo (Plac) runs. Heart rate Forearm bloodflow MAP Forearm vascular resistance (beatslmin) (ml 1 ml- min') (mm Hg) (kpa/ml.s) Control Act 67 ± ± t.29 Plac Post-injection time (min) 2 Act t t.3 Plac t.27 1 Act ± t.34 Plac 64 t t t Act 62± ± ± ±.37 Plac 64 ± ± ± ±.32 3 Act 68 ± ± ±.36 Plac Act 62± ± ± ±.32 Plac 63 ± ± ± ±.33 6 Act Plac 64 ± ± ± ±.21 Ps.5, *OP Intra-arterial study The results are shown in Table 2. Incremental increases in drug concentration produced no significant changes or observable trend during the study and there were no significant differences in blood flow between the forearms. Leg elevation study The results are shown in Table 3 as the absolute values + s.e. mean. Over the 1 h control period before drug administration, passive leg elevation significantly increased FBF by a mean value of 39%. MAP was significantly increased during every period of leg elevation, increasing by a mean of 5% over the control period. FVR decreased by a mean of 13%, significant at 15 and 6 min. After domperidone administration, FBF was significantly lower by a mean value of 27% in the supine position and with elevated legs, but a mean value of 14% when compared with the values obtained during the control period. Further, the percentage increases in FBF with leg elevation when compared to those previous to drug administration over the full 6 min Table 2 Mean values (+ s.e. mean) of forearm blood flow accompanying intra-arterial infusion of domperidone. Forearm blood flow (ml 1 ml-l min-') Dose (.Agilmin) Drug infused arm (right) Control arm (left) Control 3.7± ± (5 min) 3.9 ± (1 min) ±.73 (15 min) 3.9 ± ± (5 min) 4. ± ±.67 (1 min) 3.7 ± ±.59 (15 min) (5 min) 4.3 ± ±.78 (1 min) 4.2 ± ±.85 (15 min) (5 min) 4.2 ± ±.63 (1 min) 4.5 ± ±.87 (15 min)

4 376 D. Mannering et al. 4)..S: -o 66o +1 tl +1 tlt tl- period were significantly lower with a mean increase of 2% compared with 39% (P <.5); and the mean decrease in FVR was 6.8% compared with 13% (P <.5). There were no significant accompanying increases in MAP after domperidone administration. cu 4-4) co 4) 4). 4) $ +. cis ci Cd 4) +l ~s --Z :3 E Q ~j E L. s ' ok I. I.E "4)4 - : Q 4Z) Q o N tn N kt efn % -,..-- r- ) N e N 'IC o o Ci (e N. o; o o 'IC 'oo 'It o o~ tl tl tl t co o6^ tl +1 tli tl t+1 oo m %l Ifl N- o t cc- Cie -. - t \ 'fl Ci Cl) N- o oo oi cl N 14 en t- C. vi v to o;t 'IC o o UN on o, C +l +l oo ON W: en t +1 +l ' %-C- % ci % - 'n ' ' ' e en n en en Tr +l +l +l +l +l +l +l +l 4)2 4) 4W) 2 I) u CaC coc CaC - n- >- >u'- P Q G 4) CL4 4 4 VI. VI Discussion This study has shown in normotensive subjects domperidone increases forearm vascular tone as reflected by the decrease in forearm blood flow. Furthermore, this response does not appear to be a direct effect on forearm vascular tone, however the drug does attenuate the forearm blood flow response to leg elevation, implying a centrally mediated mechanism. The intravenous dose of domperidone used was based on a pilot dose response study in which administration of less than 4 mg produced little or no effect. The intra-arterial doses used were calculated so that the plasma levels at the lowest dose of 12 ug/min were within the range that would be obtained in the forearm at the 4 mg systemic dose. Experimental studies have demonstrated the presence of peripheral post-ganglionic sympathetic nerve terminals that possess dopaminergic receptors (Steinsland & Heible, 1978). When stimulated these receptors inhibit the release of noradrenaline. Studies carried out on isolated artery preparations have demonstrated dopamine agonists to inhibit noradrenaline release by stimulation of pre-synaptic receptors. Further studies on dopamine rich brain tissue have suggested dopaminergic antagonists may compete with dopamine for dopaminergic receptors within the cellular membrane (Ziegler et al., 1979). This present study has shown domperidone to significantly increase forearm vascular tone when administered systematically, however the intra-arterial infusion which at higher doses would be expected to produce local plasma levels considerably greater than the systemic dose produced no measurable responses in forearm blood flow. These results suggest the mechanism of action of domperidone is not at a local level at the pre-synaptic receptors. Bromocriptine, a dopamine receptor agonist is known to lower plasma noradrenaline levels in humans (Francis et al., 1983) and may thus have an effect on reducing sympathetic nervous system activity. It follows that a dopaminergic antagonist may increase sympathetic activity. In order to assess the effects of domperidone on sympathetic activity, the passive leg elevation study was carried out.

5 Previous studies have shown passively raising the legs of a recumbent subject to significantly increase forearm blood flow with paralleled decreases in vascular resistance (Roddie & Shepherd, 1956). The increase in forearm blood flow either by passive leg elevation or by lower body positive pressure is abolished by nerve block to the forearm and by sympathectomy (Roddie et al., 1957, 1958). This vasodilator reflex appears to be sympathetically mediated, that is by a reduction in sympathetic tone. The results obtained in this study have confirmed that a significant increase in forearm blood flow occurs as a result of leg elevation. The effect of domperidone was to decrease forearm blood flow both in the supine and elevated leg positions. Further, domperidone significantly reduced the magnitude of the increase in forearm blood flow that occurred upon passive leg elevation. The fact that it has been established that the increase in forearm blood flow upon leg elevation is achieved through a reduction in sympathetic tone to the forearm vasculature these results suggest domperidone may be increasing vascular tone by increasing sympathetic activity. The effects of changes in ambient temperature on forearm blood flow is well recognised and for this reason the laboratory was maintained at a constant temperature of C throughout all studies. Studies have proposed that a central dopaminergic system is involved in the regulation of peripheral vascular tone and that reduced central dopaminergic activity may be an important factor in the maintenance of essential hypertension (Stumpe et al., 1977). Furthermore, domperidone has been demonstrated to increase serum prolactin levels; the drug acting primarily at the hypothalamus to increase prolactin Increased vascular resistance and dopamine blockade 377 secretion (Hiroshi et al., 198) and it is therefore suggested that dopamine exerts its inhibitory effects on prolactin secretion at the hypothalamus (Donoso et al., 1971). Treatment of essential hypertensive patients with bromocriptine has been shown to decrease blood pressure and plasma prolactin concentrations (Stumpe et al., 1977) and they concluded that reduced dopaminergic activity is involved in the production of hyperprolactinaemia as well as hypertension. Manku et al., (1973) suggest plasma prolactin at least in vitro may play a role in the modification of the response of arteriolar smooth muscle to noradrenaline. This suggests an indirect mechanism by which domperidone may increase peripheral vascular tone by increasing plasma prolactin levels and thus increasing vascular smooth muscle sensitivity to noradrenaline. However, the effects of in vitro plasma prolactin administration may be overshadowed by contamination of prolactin with vasopressin and thus further studies would be required in order to elucidate any such observations. In conclusion, these results suggest the increase in vascular tone as reflected by the observed decrease in forearm blood flow resulting from dopamine blockade with domperidone is attributable to the actions of the drug on the central nervous system as no forearm responses were achieved by local infusions. However, from this study it is not possible to establish at what level or the specific mechanism by which dopamine blockade increases peripheral vascular tone; either via sympathetic mediation or by indirectly increasing release of vasoconstrictive agents. Further studies would be required to identify the specific central mechanisms of action of domperidone. References Donoso, A. O., Bishop, W., Fawcett, C. P. & McCann, S. M. (1971). Effects of drugs that modify brain monoamine concentrations on plasma gonadotrophin and plasma prolactin levels in the rat. Endocrinology, 89, Francis, G. S., Parks, R. & Cohn, J. N. (1983). The effects of bromocriptine in patients with congestive heart failure. Am. Heart J., 16, Hiroshi, K., Toshio, F., Shojiro, A., Koresawa, M., Saburo, Y. & Tadashi, T. (198). The role of domperidone in the regulation of prolactin release in rats. Life Sci., 26, Kolloch, R. E., Stumpe, K. O., Ishmer, U., Kletzky,. & Dequattro, V. (1981). Central dopaminergic mechanisms in young patients with essential hypertension. Clin. Sci., 61, 231s-234s. Laduron, P. M. & Leysen, J. E. (1979). Domperidone, a specific in vitro dopamine antagonist, devoid of in vivo central dopaminergic activity. Biochem. Pharmac., 28, Manku, M. S., Nassar, B. A. & Horrobin, D. F. (1973). Effects of prolactin on the responses of rat aortic and arteriolar smooth muscle preparations to noradrenaline and angiotensin. Lancet, H, Roddie, I. C. & Shepherd, J. T. (1956). The reflex nervous control of human skeletal muscle blood vessels. Clin. Sci., 15, Roddie, I. C., Shepherd, J. T. & Whelan, R. F. (1957). Reflex changes in vasoconstrictor tone in human skeletal muscle in response to stimulation of receptors in a low pressure area of the intrathoracic vascular bed. J. Physiol., 139, Roddie, I. C., Shepherd, J. T. & Whelan, R. F.

6 378 D. Mannering et al. (1958). Reflex changes in human skeletal muscle blood flow associated with intra-thoracic pressure changes. Circulation Res., 6, Steinsland,. S. & Hieble, J. P. (1978). Dopaminergic inhibition of adrenergic neurotransmission as a model for studies on dopamine receptor mechanisms. Science, 199, Stumpe, K. O., Kolloch, R. E., Higuchi, M., Kruck, F. & Vetter, H. (1977). Hyperprolactinaemia and antihypertensive effect of bromocriptine in essential hypertension: identification of abnormal dopamine control. Lancet, Ui, Ziegler, M. G., Lake, C. R., Williams, A. C., Teychenne, P. F., Shoulson, I. & Steinsland,. (1979). Bromocriptine inhibits noradrenaline release. Clin. Pharmac. Ther., 25, (Received September22, 1983, accepted December 14, 1983)