Br. J. Pharmacol. (1990), 100, 277-282

Nimodipine has no effect on the cerebral circulation inconscious pigs, despite an increase in cardiac output

1W.J. van der Giessen, D.J. Duncker, *P.R. Saxena & P.D. Verdouw

Departments of Cardiology (Thoraxcenter) and *Pharmacology, Erasmus University Rotterdam, P.O. Box 1738, 3000 DRRotterdam, The Netherlands

1 We studied the effects of four doses of nimodipine (0.5, 1, 2 and 4pgkg- min 1) on systemic haemo-dynamics and on regional vascular beds, in particular the cerebral circulation, in conscious pigs.2 Nimodipine caused dose-dependent, probably reflex-mediated, increases in heart rate (42% with thehighest dose) and cardiac output (54%), while arterial blood pressure was only minimally affected. Leftventricular end-diastolic pressure and systemic vascular resistance decreased dose-dependently (35-40% atthe highest dose) while stroke volume remained unchanged.3 Total brain blood flow was not affected by the drug. Furthermore, we could not demonstrate any

regional cerebral differences, as blood flows to both cerebral hemispheres as well as the diencephalon,cerebellum and brain stem remained unchanged.4 Blood flow to the kidneys, liver, small intestine and skin also did not change. Nimodipine causeddose-dependent increases in blood flow to the stomach (95%), myocardium (97%) and adrenal glands(102%), while blood flow to skeletal muscles (267%) increased most.

5 It is concluded that in the conscious pig, nimodipine is an arterial vasodilator which shows some

selectivity for the skeletal muscle vasculature but does not increase total or regional cerebral blood flow.

IntroductionThe calcium channel blockers exhibit considerable heter-ogeneity with respect to their effects on the heart and differentvascular smooth muscle preparations (Cauvin et al., 1983;Fleckenstein, 1983; Nayler, 1983; Katz & Leach, 1987). The 1,4-dihydropyridine derivative, nimodipine, appears to have apreferential action on cerebral vessels in vitro (Towart, 1981;Towart & Perzborn, 1981; Towart et al., 1982; Kazda &Towart, 1982; White et al., 1982). Results of in vivo studies,however, are variable. In conscious rabbits the drug was report-ed to have a greater effect on cerebral blood flow than onperfusion of other organs and tissues (Haws et al., 1983).However, we failed to confirm these observations in anaes-thetized pigs as nimodipine like the related compound nisoldi-pine (Duncker et al., 1986a), did not affect cerebral blood flowbut more than doubled skeletal muscle blood flow (Dunckeret al., 1986b). The decrease in arterial blood pressure is muchmore pronounced in anaesthetized than in conscious pigs afteracute administration of systemic vasodilators apparently dueto a lack of reflex tachycardia and concomitant increase incardiac output in the anaesthetized animals (Duncker et al.,1988). It is therefore possible that this pronounced decrease inblood pressure elicited by nimodipine in anaesthetized pigsnegated the expected increase in cerebral blood flow. In orderto eliminate possible complications introduced by the use ofanaesthetic drugs, we have investigated the vascular responsesin various tissues to nimodipine in conscious instrumentedpigs. Particular attention has been devoted to regional cere-bral blood flows in view of growing clinical evidence that thedrug may exert a beneficial effect on a number of cerebralvascular disorders (Auer et al., 1982; Grotenhuis et al., 1984;Kostron et al., 1984; Gelmers et al., 1988) and in the treatmentof migraine headaches (Gelmers, 1983; Meyer & Hardenberg1983).

MethodsAnimal model

Experiments were performed in conscious, Landrace x York-shire cross-bred pigs (18-24kg, n = 14), which were instru-

Author for correspondence.

mented by methods described earlier by Duncker et al.(1987a). The investigations were performed according to theGuide for the Care and Use of Laboratory Animals (DHEWpublication No. (NIH) 80-23, 1980). Briefly, the animals weresedated with ketamine HCI (30mgkg-1) and connected to aventilator after endotracheal intubation. Anaesthesia wasmaintained with enflurane (1-4 vol%), added to a mixture of02. N20 (1:2, v/v). Under sterile conditions, cannulae wereplaced in the superior vena cava (via the right jugular vein)and the thoracic aorta (via the common carotid artery), for theadministration of drugs and the measurement of arterialblood pressure, respectively. After a left lateral thoracotomy,an electromagnetic flow probe (13-15 mm, Skalar, Delft, TheNetherlands) was positioned around the ascending aorta. Atip-manometer pressure transducer (Konigsberg InstrumentsInc., Pasadena, CA, USA) was implanted through the apexinto the left ventricle of the heart. The left atrium was cannu-lated for recording of left atrial pressure which, together withthe aortic blood pressure, was used for calibration of theKonigsberg transducer signals. A second left atrial cannulawas used for the injection of tracer microspheres (diameter15 + 1pM; 14'Ce, 113Sn, 103Ru, "Nb or 46Sc labelled; NENChemicals GmbH, Dreieich, F.R.G.) for the measurement oforgan blood flows (Saxena et al., 1980; Saxena & Verdouw,1982). Catheters and wires were externalized subcutaneouslyvia the back or the neck. The thorax was then closed and theanimals allowed to recover from surgery. Catheters wereflushed daily with heparinized saline and antimicrobialprophylaxis was obtained with amoxycillin (500mg daily). Atleast 6-8 sessions were held to adapt the animals to theexperimental and laboratory conditions. When haemo-dynamic parameters remained stable for at least 90min theanimals were regarded as being suitable to enter the experi-mental protocol. All experiments were carried out while theanimals were quietly resting in a constraining jacket.

Experimental protocol

After baseline recordings had been made of arterial pressure,aortic blood flow, left ventricular pressure and its first deriv-ative (LVdP/dt), approximately 1 million microsphereslabelled with one of the isotopes were injected while anarterial reference blood sample (8.8 ml min -1) was withdrawn,

%(--I Macmillan Press Ltd, 1990

278 WJ. VAN DER GIESSEN et al.

starting 10s before the injection of the microspheres andlasting up to 60s after completion of the injection. All mea-surements were repeated at the end of each of four consecutive10 min i.v. infusions of nimodipine (0.5, 1, 2 and4 Mg kg 1 min 1; n = 7) or equivalent volumes of the solvent(n = 7). After the last measurements, the animals were killedwith an overdose of pentobarbitone sodium and the organsremoved for the determination of regional blood flows. Theheart was fixed in formaldehyde (10%) for later dissection ofthe left ventricular wall into three layers of equal thickness(epicardium, mesocardium and endocardium). All otherorgans were dissected without fixation. The brain was dividedinto cerebral hemispheres, diencephalon, cerebellum and brainstem. Both iliopsoas muscles were dissected for the analysis ofskeletal muscle blood flow. Full details of the procedures andthe calculation of flow data with this technique have beendescribed earlier (Saxena et al., 1980; Duncker et al., 1986b).In our laboratory the variability of repeated measurements isless than 6% (Schamhardt, 1980).

Vascular resistances in the particular organs were calcu-lated as the ratio between the mean arterial blood pressureand the corresponding organ blood flow. Left ventricular 02demand was estimated by the product of the heart rate andsystolic left ventricular blood pressure.

Drugs

Nimodipine (Bay e 9736; Bayer AG, Wuppertal, F.R.G.) wasdissolved at 0.2mgml-1 in a mixture of glycerol (60g), H20(100g) and polyethylene glycol 400 (to 1129g) and this stocksolution was diluted with 0.9% w/v NaCl solution imme-diately before use and administered while protected from light.

Statistical analysis

Data are expressed as mean + s.e.mean. The significance ofthe effects of nimodipine was evaluated by Duncan's newmultiple range test, after two-way analysis of variance hadrevealed that the samples represented different populations.Only values of P < 0.05 (two-tailed) were considered sta-tistically significant.

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Results

Systemic haemodynamics

Infusion of the solvent did not affect systemic haemodynamicvariables (Figure 1). Nimodipine caused a dose-dependentincrease in cardiac output (from 2.4 + 0.2 at the baseline to3.7 + 0.41 min-1 at the highest dose; + 54%) which wasalmost entirely due to an increase in heart rate (from 124 + 6to 176 + 2 beats min-'; + 46%). Mean arterial blood pressuredecreased (from 108 + 8 to 97 + 7 mmHg; -9%), with thedecrease in systolic arterial blood pressure (5mmHg at thehighest dose; P < 0.05) being considerably smaller than thatof diastolic arterial blood pressure (14mmHg; P < 0.05). Sincethe blood pressure response was accompanied by an increasein cardiac output, calculated systemic vascular resistancedecreased substantially (by 39%) at the highest dose. Althoughboth left ventricular filling pressure and diastolic arterial pres-sure decreased, there was a marked increase in LVdP/dt,,(60%) at the highest dose.

Left ventricular bloodflow

In the solvent-treated animals, myocardial 02 demand, esti-mated by the product of heart rate and left ventricular systolicblood pressure, did not change (15 + 1 mmHgmin- 103 atthe baseline and 17 + 1 mmHgmin 103 at the end of thelast infusion). This was also reflected by the unchanged trans-mural left ventricular blood flow (Figure 2). The increase inleft ventricular 02 demand in the nimodipine-treated animals(from 15 + 1 mmHgmin-1 103 at the baseline to21 + lmmHgmin-1103 at 4pgkg-'min-1; +40%) was sta-tistically significant compared to the solvent-treated animals,but the rise in myocardial blood supply (80%; Figure 2),which was uniformly distributed over the different layers, wasfar in excess of that required to meet the increased demand.Consequently, there was an appreciable decrease (from 86 + 8to 64 + 6mmHgmlP1 00g) in the ratio between 02 demandand blood supply.

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REGIONAL VASODILATOR EFFECTS OF NIMODIPINE 279

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Cerebral bloodflow

Total cerebral blood flow was not affected by nimodipine.Analysis of the flows to the different parts of the brain(hemispheres, diencephalon, cerebellum and brain stem)revealed that no redistribution had occurred in favour of anyof these parts (Figure 3). Vascular conductances in the differ-ent brain areas were also not affected.

Bloodflows to other organs

During administration of the incremental doses of nimodipine,blood flow to the kidneys, liver, small intestine and skinremained unchanged (Figure 4). Perfusion of the spleenincreased, but this change was not dose-dependent. Bloodflows to the stomach, adrenal glands and skeletal muscle also

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Discussion

Systemic haemodynamics

In the present study the effects of four incremental dosages ofnimodipine on systemic haemodynamics and the regional dis-tribution of cardiac output in conscious pigs were comparedwith those of its solvent. Nimodipine caused dose-dependentdecreases in left ventricular filling pressure as well as in sys-temic vascular resistance. Cardiac output increased by morethan 50% at the highest rate of infusion, probably because ofa baroreflex-mediated increase in heart rate. Accordingly,mean arterial blood pressure decreased only 9% at the highestdose of nimodipine. These effects are comparable with the sys-temic haemodynamic actions of other dihydropyridines inconscious pigs (Duncker et al., 1988). In anaesthetized pigs,however, nimodipine (in a comparable dose-range) causedmarked decreases in mean arterial blood pressure, heart rateand cardiac output (Duncker et al., 1986b), apparentlybecause of suppression of baroreceptor reflex effects by theanaesthetic drugs used. The reduction in cardiac outputobserved in the latter study was due to a closure of arterio-venous anastomoses, as the nutrient part of cardiac outputremained unaffected.

Myocardial bloodflow

In the present investigation nimodipine caused dose-dependent increases in myocardial blood flow. As the ratiobetween °2 demand and °2 supply decreased by up to 25%,this higher myocardial blood flow cannot be explained by anautoregulatory process because of a higher °2 demand. Ittherefore seems likely that nimodipine elicits 'active' vasodila-tation in the coronary vascular bed.

Bloodflows to other organs

A small part of the increase in aortic blood flow was directedto the spleen, stomach and adrenals. Vasodilatation was mostpronounced in the iliopsoas muscle as blood flow increasedmore than two fold. This observation was also made in anaes-thetized pigs with nimodipine and nisoldipine (Duncker et al.,1986a,b). Interestingly, Haws et al. (1983) reported selectiveincreases in cerebral and coronary blood flow after nimodi-pine administration in conscious rabbits. In fact, at doses of0.1 and 1.Opgkg-1min-1, the drug induced 70+ 25% and110 + 25% increases in cerebral blood flow, respectively,whereas masseter muscle blood flow was enhanced by50 + 50% and 450 + 320%, respectively. Although the latterresponses did not reach statistical significance, it is possiblethat nimodipine might have elicited a greater response in theskeletal muscle vasculature compared to the cerebral circula-tion in some rabbits.

Cerebral bloodflow

Contrary to the general belief, but in agreement with ourexperiments in anaesthetized pigs (Duncker et al., 1986b),nimodipine in the doses used in this study did not increasetotal or regional cerebral blood flows (That is, flows to thehemispheres, midbrain, cerebellum and brain stem). Bloodflow measurements with microspheres depend, among otherthings, on complete trapping of spheres by the tissue underinvestigation. Since we did not detect any increase in cerebralblood flow, it might be argued that nimodipine dilated smallblood vessels to the extent that microspheres escaped to the

venous side and, therefore, flow increases remained unde-tected. For several reasons this possibility is highly unlikely:(i) increases in blood flow to the extent of up to 20 to 30 fold,at least in the skeletal muscles (Hof, 1983; Bolt & Saxena,1984; Duncker et al., 1986ab; 1987b; present study) and skin(Saxena & Verdouw, 1982; 1985; Duncker et al., 1987b), canbe detected with 15 ym spheres; (ii) if tracer microspheres wereescaping to the venous side, lung radioactivity should haveincreased after calcium antagonists but, as found earlier(Bolt & Saxena, 1984; Duncker et al., 1986a,b; 1987b) and inthe present study 'lung' blood flow tended to decrease (from34 + 4 to 46 + 9 ml min 1 100g-1 after solvent infusion andfrom 35 + 8 to 24 + 4mlmin- 1 100g- I after the highest doseof nimodipine) and (iii) even after the administration of micro-spheres directly into the carotid artery, thus avoiding theirentry into the lungs via the bronchial arteries, local infusionsof both nimodipine and nifedipine decreased (not increased)cephalic shunting of microspheres (see Duncker et al., 1987b).

Results in the literature on the effects of nimodipine oncerebral blood flow thus far are equivocal (Table 1). In anaes-thetized rats, rabbits, cats, dogs and baboons an increase incerebral blood flow has been reported (Harper et al., 1981;Kazda et al., 1982; Haws et al., 1983; Mohamed et al., 1984;McCalden et al., 1984). In anaesthetized pigs no such increasein flow could be observed (Duncker et al., 1986b). In consciousrabbits (Haws et al., 1983), and conscious hypertensive rats(Grabowski & Johansson, 1985) nimodipine increased cerebralblood flow, but in conscious normotensive rats, as well as indogs, no changes were observed (Grabowski & Johansson,1985; Kanda & Flaim, 1986; Forsman et al., 1986). Withrespect to the study by Kanda and Flaim, it must be kept inmind that the studies were performed 3 h after recovery fromsurgery and that the baseline flows were twice as high as intheir anaesthetized rats. It could be argued that, in this prep-aration, further vasodilatation could hardly be expected. Theauthors, however, also showed that further cerebral vasodila-tation was possible when the animals were exercised (treadmillrunning). Our results in conscious pigs are in agreement withthe latter studies. An explanation for the discrepancy in theresults between anaesthetized and conscious animals may bethe effect of anaesthesia on brain blood flow. Indeed, anaes-thetic agents like barbiturates and fentanyl lower total brainflow (Nilsson & Siesjo, 1975; Carlsson et al., 1982), which mayresult in greater susceptibility of the cerebral circulation to thevasodilator actions of nimodipine. Another variable may beintroduced by opening the skull, which was done in severalexperimental studies (see Table 1). It has been shown thatnimodipine infusion increases basal blood flow only in pri-mates with a craniotomy, but not when the skull remainsclosed (Harris et al., 1982). In vitro studies conducted onarteries from several species, including man, showed thatnimodipine was a more potent dilator of the large conduc-tance vessels of the cerebral circulation than of other conduc-tance vessels (Towart, 1981; Cauvin et al., 1983;Miiller-Schweinitzer & Neumann, 1983). Therefore it is pos-sible that, under physiological conditions, nimodipine dilatesthe larger cerebral vessels (vertebral and basilar arteries)without dilatation of the smaller cerebral arterioles and thus iswithout an effect on cerebral blood flow. However, in patho-logical conditions, where vasoconstrictor mediators act on thecerebral vasculature, or during anaesthesia, the effects ofnimodipine may be different. Indeed, in experiments involvingligation of a cerebral artery (Steen et al., 1983; Smith et al.,1983; Mohamed et al., 1985; Newberg Milde et al., 1986) orexperimental subarachnoid haemorrhage (McCalden et al.,1986) impairment of cerebral blood flow, due to an increase invasomotor tone in the post-ischaemic or post-haemorrhagicphase, can be alleviated by nimodipine. However, negativereports have also been published (Barnett et al., 1986; Schuier& Ulrich, 1987; Sahlin et al., 1987; Berger & Hakim, 1988).From the present and other studies the question ariseswhether the differences in results can be explained by differ-ences in preparations only (conscious versus anaesthetized,

REGIONAL VASODILATOR EFFECTS OF NIMODIPINE 281

Table 1 Cerebral blood flow and vascular resistance responses to intravenous or intracarotid administration of nimodipine in animalswith an intact cerebral circulation

CerebralRate of Cumulative Cerebral blood Mean arterial vascular

Animal administration dose flow blood pressure resistancespecies (pgkg-1min-1) (ugkg1) (% increase) (% decrease) (% increase)

AnaesthetizedHarper et al., 1981 Baboon bolus injection 3-10 NC NC NC

Baboon (os) 2.0 100 25 10 30Harris et al., 1982 Baboon 0.6 i.c. 27 NC 10 10

Baboon (os) 0.6 i.c. 27 25 10 30McCalden et al., 1984 Baboon 0.1-1000 2-22222 NC 0-20 0-25Haws & Heistad, 1984 Monkey 1.0 5 NC NC NCKazda et al., 1982 Cat 0.3-3.2 6-118 20-60 10-20 25-50Haws & Heistad, 1984 Cat (os) 0.5-1.0 2.5-7.5 NC NC NCMohammed et al., 1984 Rat 1.0-4.0 30-210 0-30c 10-25 10-40Kanda & Flaim, 1986 Rat 0.4-4.0 6-66 10-60 25-40 25-60Haws et al., 1983 Rabbit 0.1-1.0 0.5-5.5 25-100 20 35-60Kazda et al., 1982 Dog bolus injection 1-111 19-54 8-31 23-55Duncker et al., 1986b Pig 0.05-6.25 0.5-7.8 0-35 5-60 5-40

ConsciousHaws et al., 1983 Rabbit 0.1-1.0 0.05-5.5 25-110 5-35 25-70Grabowski & Johansson, 1985 Rat (WKY) 0.75-7.5a 27.5-275 NC 10-38 10-50

Rat (SHR) 0.75-7.5' 27.5-275 0-30 10-46 10-40Kanda & Flaim, 1986 Rat 0.4-4.0 6-90 NC 5-20 NCForsman et al., 1986 Dogb (os) 0.1-3.0 1.5-66 NC 10-45 0-40Present study Pig 0.5-4.0 5-75 NC 0-10 NC

WKY = Wistar-Kyoto rats; SHR = spontaneous hypertensive rats; a bolus injection of 5-S50.gkg-' followed by an infusion of 0.75-7.5 jug kg -min-1; b spinal anaesthesia was employed to circumvent effects of general anaesthesia on the brain; C cerebral blood flowincreased only in 9 out of 31 brain regions; total cerebral blood flow responses have been estimated from the regional data; NC = nochange. Only in the study by Harris et al. (1982) was intracarotid (i.c.) administration used. Most studies were performed in animals witha closed skull, for those in which open skull preparations were employed this has been indicated in parentheses (os).

open versus closed skull) or that differences in species may bethe dominant factor. Furthermore it should be kept in mindthat maintenance of cerebral blood flow when arterial bloodpressure decreases does not necessarily mean a drug-inducedvasodilatation since Harper et al. (1981) have shown that cere-bral 02-consumption does not change in anaesthetizedbaboons. We feel that further studies are needed to show fromwhich species the results of the studies on the cerebral effectsof calcium antagonists can be most reliably extrapolated tothat of man.The question raised above seems to be appropriate as the

results of clinical studies point towards a beneficial effect ofnimodipine in patients with cerebrovascular disease (Gelmers,

1983; Meyer & Hardenberg 1983; Grotenhuis et al., 1984;Kostron et al., 1984; Gelmers et al., 1988). Though we grantthat it remains difficult to extrapolate animal data to clinicalsituations, our results do question the assertion that nimodi-pine exerts its beneficial effects by enhancement of cerebralblood flow (Smith et al., 1983; Sahlin et al., 1987; Berger &Hakim, 1988; Lyden et al., 1988).

Nimodipine was generously supplied by Bayer AG, Wuppertal, FRG.The authors would like to thank the staff of the Laboratory forExperimental Surgery for their skilful assistance during surgery andthe post-surgical period. Ms Marjo van Ee is thanked for help in thepreparation of this manuscript.

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(Received November 13, 1989Revised February 2, 1990

Accepted February 21, 1990)