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In vivo and in vitro effects of lead on vascular reactivity in rats R. CLINTON WEBB, RAYMOND J. WINQUIST, WINONA VICTERY, AND ARTHUR J. VANDER Department of Physiology, University ofMichigan Medical School, Ann Arbor, Michigan 48109 We b b , R. Cl in t o n , Ra y mo n d J. Win q u is t , Win o n a Vic - treatment in their drinking water beginning 1 wk after t e r y , a n d ARTHUR J. Va n d e r . In vivo and in vitro effects of conception. During the 7-mo treatment period, body lead on vascular reactivity in rats. Am. J. Physiol. 241 (Heart Circ. Physiol. 10): H211-H216, 1981.--The effects of lead on vascular responsiveness were examined in rats. Adult rats, which had received levels of lead acetate intheir drinking water to produce blood levels similar to those seen in some urban human populations, consistently had higher systolic blood pres sures compared to age-matched controls. Helical strips of tail arteries from the lead-treated rats displayed a greater force generating ability in response to the cumulative addition of methoxamine to the muscle bath. There were no differences in weights were monitored, and systolic blood pressures were measured in the unanestheti2ed state by the tailcuff technique. An additional group of untreated adult male Wistar rats (7-9 mo old) were used to study the effects of lead added in vitro on vascular reactivity. These rats received tap water for drinking. All rats were main tained on a diet of Teklad laboratory chow. The rats were killed by either a blow to the head or by decapitation. Tail arteries (0.8-1.0 mm OD) were excised, EDao between the two groups. Similar results were obtained when norepinephrine was used. The calcium-entry blocker, D 600, was less effective in reducing contractions induced by methoxamine in lead-treated rats than in controls. There were no differences between the two groups in responses to KC1 or electrical stimulation of nerve endings. Contractile responses to norepinephrine, methoxamine, KC1, and nerve stimulation in arteries from untreated rats were unaltered by addition of lead acetate to the muscle bath. These results demonstrate that hypertension induced by moderate levels of lead intake is dissected free of loose connective tissue, and cut helically into strips (0.8 x 10 mm) under a dissecting microscope. The helical strips were mounted vertically on either a glass or plastic holder in a tissue bath containing physi ologic salt solution (PSS; described below). The upper end of each strip was connected to a force transducer (Grass FT .03). Before the start of experiments, the strips were allowed to equilibriate for 60-90 min in PSS, main tained at 37C, and aerated with a mixture of 95% 02-5% associated with an increased vascular responsiveness to a-ad- C02. At the end of the equilibration period, the resting renergic agonists. tension of each strip was adjusted so that it produced a maximum active tension in response to a standard dose norepinephrine; D 600; methoxamine; vascular smooth muscle; of methoxamine. PSS composition was as follows (in tail artery mM): NaCl 130, KC1 4.7, KH2PO< 1.18, MgS0-7H20 1.17, CaCl2-2H20 1.6, NaHCOs 14.9, dextrose 5.5, Ca- a c o n s id e r a b l e c o n t r o v e r s y exists concerning the possible role of lead in the etiology of human hyperten sion (see Ref. 1 for example). In an extensive study (15) of rats exposed chronically (beginning in utero) to a relatively modest amount of lead, we observed that rats drinking 100 ppm lead (which produced blood lead con centrations of --40 pg/di) developed a chronic significant 15- 20-mmHg elevation in systolic blood pressure. This study was designed to investigate one possible mecha nism for this hypertension: increased vascular respon siveness to pressor agents. The experiments were per formed on isolated tail arteries from lead-treated and control rats. Na2-EDTA 0.03 (pH 7.4). Higher concentrations of po tassium (10-130 mM) in the bathing medium were achieved by equimolar substitution of NaCl with KC1. Strips of tail artery were electrically stimulated by the use of two platinum wire electrodes placed parallel to the preparations. Electrical impulses consisted of square waves (12 V, 0.3 ms) provided by a Grass stimulator (SM6). In experiments designed to investigate the in vitro effects of lead on vascular responsiveness, the arterial strips were allowed to equilibriate in PSS containing either lead acetate (1(T9 to 10-3 M) or sodium acetate (10-9 to 10~3 M) for 15 min before the addition of vaso active agents or transmural nerve stimulation. METHODS Drugs used were: norepinephrine bitartrate (Winthrop Laboratories), methoxamine hydrochloride (Burroughs Experiments were performed on adult male Wistar rats Wellcome), D 600 (methoxy derivative of verapamil, that were given drinking water containing 100 ppm lead Knoll AG), and phenotlamine mesylate (C1BA Pharma (as lead acetate) or sodium acetate (supplying an identi ceutical). All drug concentrations were expressed in cal amount of acetate) for 7 mo. The rats had been terms of the base. weaned from nursing mothers that had received a similar The results of these experiments were analyzed by 0363-6135/81/0000-0000$01.25 Copyright 1981 the American Physiological Society H2U TEH 0350329 N36717 DU P 050298966 H212 WEBB. WlNQflST. VICTEKY. AND VANDEK several statistical procedures. Concentration-response TABLE 1. EDm for dose-response curves curves were calculated as geometrical means (data for each arterial strip were normalized to its maximal re sponse to pressor agent to allow interpretation of results Agonist ED,. IM) orEF,. (Hz) Maximum Response (mg) in terms of vascular reactivity and sensitivity). Paired Sodium acetate-treated rata and unpaired t tests, analysis of variance, chi-square analysis, and curve-fitting procedures (logit transforma tion) were performed. P < 0.05 was considered statisti cally significant. Methoxamine in <= 8) Norepinephrine in *= 6) Potassium In = 6) 2.1 X 30~hM 6.0 x 10"" M 3.6 X KT- M` 1,736 179 2.190 181 799 87 RESULTS The systolic blood pressures of rats treated with 100 ppm lead acetate were significantly higher than those treated with 100 ppm sodium acetate (at time of death, lead-treated rats weighed 147 4 mmHg and control rats weighed 133 4 mmHg; P < 0.05). Chronic exposure to Nerve stimulation In = 6) Methoxamine <n=9> Norepinephrine <n *> 9) 5.2 Hz Lead acetate-treated rats 1.6 x 10- M 5.2 X 10- M 1,249 396 2,243 111' 2,612 121" lead treatment had no effect on body weight (lead-treated rats 527 7 g, control rats 496 12 g). The blood levels of lead were higher in rats treated with lead acetate compared to the controls (lead-treated rats 40.4 1.4 fig/ dl, control rats 2.2 0.3 pg/dl; P < 0.05). Concentration-response to methoxamine and norepi nephrine. Cumulative addition of methoxamine (2.2 x Potassium In- 7) Nerve stimulation In- 6) 3.9 X 10"-' M 5.6 Hz 664 96 1,450 126" Values are means SE; n, no. of rats. Concentration-response and frequency-response curves were calculated as geometrical means. The concentration of an agonist that produced a half-maximal contraction (ED) was determined by logit transformation. The frequency that 10~s to 10_< M; Fig. 1 and Table 1) <h norepinephrine (10"s to 1(T5 M; Table 1) to the muscle bath produced contractile responses in tail-artery strips from rats treated with lead acetate or with sodium acetate. The produced a half-maximal contraction (EF) was estimated from graphic representations of individual curves. * Statistically significant dif ferences between rats treated with lead acetate and those treated with sodium acetate (P < 0.05; unpaired t test). maximal contractile response to either agonist was sig nificantly greater in arterial strips from lead-treated rats (P < 0.05). There was no difference in the 50% effective doses (EDm) for norepinephrine or methoxamine be tween the two groups of rats when the dose-response curves were normalized to their respective maximal re sponses. Effect of D 600 and methoxamine. Treatment of arte rial strips for 10 min with 10-6 M D 600 (before addition of methoxamine) decreased the magnitude of contractile responses induced by 2.2 x 10"5 M methoxamine (Fig. 2). The absolute change in tension was similar for both groups of rats (785 83 mg for lead acetate-treated rats and 647 60 mg for sodium acetate-treated rats; Fig. 2A). When the methoxamine contraction in the presence of D 600 was normalized to its respective control re sponse, the contractions of arterial strips from rats treated with lead acetate were less affected by the drug than were those treated with sodium acetate (Fig. 2B). Nerve stimulation. Cumulative frequency-response curves in tail-artery strips were performed subsequent to obtaining reproducible contractions with a 4-Hz test stimulus. Stimulation began at 1 Hz with the frequency increasing stepwise to 2, 4, 8, 16, and 32 Hz when the contractile response to the previous stimulation fre quency had reached a maximum (Fig. 3). Contractile responses were abolished by 1.3 x 10~6 M phentolamine. Maximal contractile responses to electrical stimulation in the tail-artery strips from lead-treated rats were sig nificantly greater than sodium-treated rats (Table 1). However, when responses were normalized to the maxi mum response to exogenous norepinephrine to eliminate differences in force-generating ability, there were no sig nificant differences (Fig. 3). f ig . 1. Concentration-response curve to methoxamine. Helical strips of tail artery from rats treated with sodium acetate (NaAc) or lead acetate (PbAc) were made to contract ia response to cumulative addition of methoxamine to muscle bath. Arterial strips from PbActrested rats developed more force in response to all concentrations of methoxamine than did those from control rate. Values are means SE; n, no. of rats. "Statistically significant difference between groups at P < 0.05 (unpaired t test). Relaxation after methoxamine and electrical stimu lation. Strips of tail artery from rats treated with lead or sodium were contracted with either 2.2 x 10"5 M meth oxamine or 32-Hz electrical stimulation. After the con tractile response had reached a maximum level, the strips were immediately rinsed twice and then rinsed at 2-min intervals until the level of tension returned to base line. TEH 0350330 DUP050298967 VASCULAR r e a c t iv it y in l e a d -t r e a t e d r a t s 2400 Uj I CL 1600 | ^ 800 vj Na Ac IPb Ac B Co 40 - I Ju ^20 I (CONTROL) + r' tt 0 000 S0 1 H213 FIG. 2. D 600 and contraction in duced by methoxamine. Helical strips of tail artery from rats treated with sodium acetate (NaAc) and lead acetate (PbAc) were made to contract in response to 2.2 X 10_t M methoxamine in presence and absence of I0"6 M D 600. In absence of D 600, arterial strips from PbAc-treated rats developed more force than those from control rats. In presence of D 600, contractile responses in both groups of rats were depressed; but absolute mag nitude of depression was similar for both groups (A). Normalisation of contractile responses in presence of D 600 to their respective control responses indicated that arterial strips from PbAc-treated rats had a smaller component of total contraction that was sensitive to cal cium-entry blocker (B). Values are means SE for 5 rats in each group. Statistically significant difference be tween rats treated with NaAc and PbAc at P < 0.05 (unpaired t test). +Statistically significant difference between untreated condition (control without D 600) and treatment with 1CT6 M D 600 within each group of rats at P < 0.05 (paired t test). [KCl ] (mM) FREQUENCY (Hz ) f ic . 3. Frequency-response relationship. Helical strips of tail artery from rats treated with sodium acetate (NaAc) and lead acetate (PbAc) were made to contract in response to electrical-field stimulation of adrenergic nerve endings. Arterial strips from both groups of rats responded similarly at all frequencies of stimulation when contractile responses ofeach arterial strip were normalized to its maximal response to exogenous norepinephrine. Values are means SE; n, no. of rats. The period of time required to reach half-maximal relax ation ((1/2) was significantly greater in strips from leadtreated rats [after methoxamine (n = 16) fi/2 = 5.6 0.2 min, after 32-Hz electrical stimulation (n = 6) (1/2 = 20 + 2 s] compared to those from control rats [after meth oxamine (ri *= 14) h/2 = 4.7 0.2 min, after 32-Hz electrical stimulation (n = 5) tiJ2 = 15 1 s]. Concentration-response to elevated potassium. Tailartery strips from lead-treated and sodium-treated rats were made to contract in response to the cumulative addition of potassium to the muscle bath in the presence f ig . 4. Concentration-response curve to KCl. Helical strips of tail artery from xats treated with sodium acetate (NaAc) and lead acetate (PbAc) were made to contract in response to KCl. Desired concentra tion of KCl was achieved by equimolar substitution of NaCl and KCl. Arterial strips from both groups of rats responded similarly to all concentrations of KCl. Values are means SE; n, no. of rats. of 1.3 X 1CT6 M phentolamine. There was no difference in the contractile responses of tail artery strips from leadtreated rats to potassium and those from sodium-treated rats (Fig. 4 and Table 1). Spontaneous activity. Some arterial strips used in these experiments exhibited spontaneous activity (Fig. 5). Phasic contractions were observed in tail-artery strips from both groups, the incidences being similar. These contractions were characteristically small in amplitude (10-100 mg), and their frequency ranged from 2 to 6 contractions/min. These spontaneous phasic contrac tions never continued throughout an entire experiment (4-6 h) and, when present, were always observed during the 60- to 90-min equilibration period. Nine out of 28 arteries from lead-treated rats exhibited phasic contrac- TEH 0350331 DUP050298968 4- H214 WEBB. WlNQl'lST. VJCTERY. AND YANDEK tions superimposed on a tonic contraction during the t a b l e 2. In vitro effects of lead acetate equilibration period. These tonic contractions were large in magnitude (200-500 mg), disappeared by the end of the equilibration period, and were also inhibited by 1.3 x 10~ M phentolamine. Tonic contractions were never observed in tail arteries from sodium-treated rats. The total incidence of spontaneous activity (phasic or a com bination of tonic and phasic) was significicantly greater in lead-treated rats. The incidence of phasic contractions alone was similar in both groups of rats, and the incidence of phasic contractions superimposed on tonic contrac tions was greater in lead-treated animals (Fig. 5). In vitro effects of lead. The direct effects of lead were tested in tail arteries from rats that received tap water for drinking. Control studies were performed using an equilmolar concentration of sodium acetate. The strips were allowed to equilibriate in a solution of either lead acetate (10~8 to 10~3 M) or sodium acetate (10-B to 1CT3 M) for 15 min before addition of norepinephrine or transmural nerve stimulation. The addition of lead ace tate had no effect on contractile responses to either exogenous norepinephrine or electrical stimulation (Ta Concn Agonist ED,. (M) or EFv. <Hzt Maximum Ke&pons* (mg). Control 10" M lead acetate 10" M lead acetate 10"* M lead acetate 10"J M lead acetate Norepinephrine <n 14) Nerve stimulation in=* 6) N orepinephrine (n = 4) Norepinephrine <n *= 10* Nerve stimulation in 6) Norepinephrine in 4) Norepinephrine (n *= 41 6.5 X 10 " M 5.2 Hz 7.3 X 10" M 6.3 x 10" M 5.2 Hz 7.1 X 10" M 9.5 x 10" M 1,857 161 913 * 190 1,985 330 * 1.936 241 917 153 1.763 153 1,708 * 133 Values are means SE; n. no. of rats. Concentration-response and frequency-response curves were calculated as geometrical means. The concentration of an agonist that produced a half-maximal contraction (EDi) was determined by logit transformation. The frequency that produced a half-maximal contraction (EFso) was estimated from graphic representations of individual curves. Statistical comparisons were made by analysis of variance between groups. ble 2). DISCUSSION Cumulative addition of lead acetate (10 9 to 10 3 M) to the muscle bath did not alter tension in unstimulated preparations. Contractions induced by 2.2 X 10~s M methoxamine, 100 mM KC1, or 2.0-Hz electrical stimu lation were not altered by the cumulative addition of lead acetate (1(T9 to MT M) to the muscle bath during the plateau phase of the response. The major goal of this investigation was to compare the reactivity of vascular smooth muscle obtained from normotensive rats and rats with lead-induced hyperten sion. The increased force-generating ability in response to a-adrenergic agonists (norepinephrine and methoxa mine) of arterial strips from lead-treated rats was a striking and consistent observation. This result contrasts with an earlier study (19) in which bolus injections of norepinephrine in lead-treated rats produced increases in mean arterial pressure similar to those seen in untreated controls. However, there are many differences between our study and that of Williams et al. (39). The rats used by Williams et al. (19) received lead via maternal milk for only 21 days, whereas our rats were treated for a much longer period of time. The lead concentration in the drinking water in our study was 100 ppm, whereas Williams et al. (19) used a concentration of 2,000 ppm. Additionally, the rats used by Williams et al. (19) were not hypertensive. It should also be pointed out that, because these investigators only measured systemic blood pressure responses to norepinephrine, they could not determine whether the blood pressure response was due to a change in vascular reactivity or to a change in cardiac output (or both). In our studies, we measured changes in vascular reactivity (or responsiveness) in iso lated tail-artery segments. This preparation has been shown to be a useful model for studies of vascular reac tivity in other forms of hypertension. For instance, the vascular changes observed in isolated resistance arteries FIG. 5. Incidence of spontaneous activity in tail arteries.. Some tailartery strips used in these experiments developed spontaneous activity. Phasic contractions were observed in strips from both sodium acetate- treated (NaAc) and lead acetate-treated (PbAe) rats. Phasic activity superimposed on a tonic contraction was observed in arterial strips from PbAc-treated rats only. Addition of 1.3 X10 * M phentolamine to muscle bath inhibited phasic and tonic contractions. 'Statistically significant difference between groups at P< 04 (chi-square analysis). Numbers above each column, no. of strips showing spontaneous activ ity/total no. of strips. (150 pm ID) from spontaneously hypertensive rats (9,18) are very similar to those reported for tail arteries from the same rats (6,17). It is doubtful that the difference in response to aadrenergic agonists is caused by a difference in the amount of preload (i.e,, existence of hypertension) or passive tension placed on the arterial strips from the two groups of rats. The optimum passive force for maximum response to methoxamine was similar for arterial strips tEH 0350332 DUP050298969 VASCrLAK REACTIVITY IN LEAD TREATED HATS H215 from lead-treated and control rats (-600 mg). Further enous norepinephrine or to endogenously released nor more, there was no difference between the two groups in epinephrine. The reasons for the differences between this the maximum force-generating ability in response to high study and that by Cooper and Steinberg (4) in terms of potassium concentrations. A difference in the length- nerve-mediated responses are not evident. tension relationship would be predicted to result in a The increased maximum force-generating ability of generalized change in contractility. Thus, the experimen tail-artery strips from lead-treated rats appears to be tal observations suggest that a specific change in force related to an alteration in the intracellular pool of acti generating ability in response to activation of c-adrener- vator calcium. The basis for this conclusion is that nor gic receptors occurs in blood vessels of lead-treated rats. epinephrine and potassium chloride depend .on two dif One possible explanation of the increased responsive ferent mechanisms to produce contraction. Increased ness of arterial strips from lead-treated rats is a decreased potassium concentration causes membrane depolariza /3-adrenergic component. The total tension development tion, and the contractile response is the result of an influx of a vascular preparation to norepinephrine is the sum of of extracellular calcium into the cell (see Ref. 3 for two receptor-mediated events: 1} -adrenergic receptor- review). In contrast, norepinephrine-induced contrac mediated contraction, and 2) /3-adrenergic receptor-me tions are caused by an initial release of intracellularly diated relaxation. A decrease in the number or affinity of bound calcium followed by an increased cellular mem /S-adrenergic receptors could result in an increased con brane permeability to the cation. Contractile responses tractile response if the number and affinity of o-adrener- to elevated potassium concentrations were similar in the gic receptors remained constant. However, this is an two groups of rats, whereas contractions induced by unlikely explanation for our results, because a change in norepinephrine and methoxamine were greater in the receptor number or affinity usually produces a change in lead-treated animals, suggesting an increased intracellu agonist sensitivity manifested by a shift in the normalized lar pool of activator calcium in lead-treated animals. concentration-response curve. It should also be noted Further support for this hypothesis is the observation that the increased responsiveness of arterial strips from that treatment with D 600, a calcium-entry blocker, lead-treated rats was evident when methoxamine was inhibited contractile responses to methoxamine in lead- used as the a-adrenergic agonist; this drug has insignifi treated rats to a lesser extent (percent basis) than those cant ^-adrenergic receptor activity (2). Finally, we ob in control rats. An enlarged intracellular calcium pool served no qualitative or quantitative differences in relax may also be partly responsible for the decreased relaxa ation produced by isoproterenol in arterial strips from tion (indicated by increased <i/a) after contraction in lead-treated rats and control animals (3 expt on KCI- duced by methoxamine and transmural nerve stimulation contracted strips in presence of phentolamine; data not in tail arteries from lead-treated rats. shown). Further evidence suggesting a change in the intracel Another possible cause of the difference in a-adrener lular pool of activator calcium is obtained from the work gic responsiveness (for norepinephrine) is a decrease in of Piccinini et al. (10). These investigators observed that the neuronal uptake mechanism of nerve endings present in vitro treatment with lead increased the tissue content in the arterial walls of lead-treated rats. Neuronal uptake of radioactive calcium in rat-tail artery. The half-life of of norepinephrine plays an important role in transmitter the slow component of the radioactive calcium washout disposition in vascular smooth muscle (14), and a de (which probably represents the discharge of calcium from crease in its activity could lead to an enhanced receptor the cytosolic compartment) was retarded in the presence activation and an increased contractile response. Our of lead, suggesting that intracellular calcium binding sites results do not support this hypothesis for the following are involved in the action of this element in vascular reasons: 1) methoxamine is not taken up by the nerve smooth muscle. Although we did not observe contraction endings (2), 2) changes in neuronal uptake activity are of tail-artery segments in response to in vitro treatment not usually accompanied by changes in the maximum with lead, it must be remembered that a change in force-generating ability of the vascular preparation (16), Tadioactive calcium uptake or efflux does not necessarily 3) changes in the function of adrenergic nerves are usu reflect contraction, because calcium may not be made ally associated with changes in catecholamine sensitivity available to the contractile proteins. (14, 16, 17), and 4) the experiments with transmural In the present study, arterial strips from lead-treated nerve stimulation also argue against any significant rats exhibited a greater incidence of spontaneous activity change in adrenergic nerve endings in lead-treated rats. than did those from control rats. These spontaneous The experiments on the effects of in vitro lead treat contractions were only apparent during the equilibration ment on vascular reactivity suggest that the change in period of the experiment and were probably due to the maximum force-generating ability is not an acute alter spontaneous leakage of norepinephrine from nerve end ation but requires chronic exposure to the trace element; ings in the vessel wall (14, 16). Other investigators have however, it is also possible that exposure of the vessels to also noted phasic activity in rat-tail artery to be inhibited lead for only 15 min was not long enough to permit lead by phentolamine (16), but the development of a tonic uptake and alteration of tissue function. In rabbit saphe contraction appears to be unique to arterial strips from nous artery (4), administration of lead to the perfusate lead-treated rats. The reasons for this phenomenon in inhibited nerve-mediated increases in perfusion pressure, lead-treated animals are not apparent but suggest that whereas responses to exogenous norepinephrine were not lead may have an action on the spontaneous leakage of altered. In our experiments, we observed no acute lead- the neurotransmitter. Alternatively, the amount of spon induced changes in contractile responses to either exog taneous leakage is similar in lead-treated and control TEH 0350333 DUP0502 98970 H216 WEBB. W1NQU1ST, VICTEHY. AND VANDER rats, but the difference in force-generating ability ac counts for the spontaneous contractions. The results of these experiments suggest a mechanism whereby chronic exposure to moderate levels of lead could cause hypertension. A portion of the increased blood pressure may be due to the increased reactivity of the vasculature to a-adrenergic-receptor activation. The mechanism of this increased reactivity appears to be related to a larger pool of intracellular calcium available for activation of contraction. Finally, it should be empha sized that increased vascular responsiveness to pressor agents may be only one of several factors contributing to the development of hypertension. Abnormalities in car diac function have been noted in patients with clinical existence of lead intoxication (13) and in rats (7). Rats treated with lead during the first 5 wk of life show an increased susceptibility to the arrhythmogenic action of norepinephrine (18). Chronic lead exposure has also been shown to elicit an increase in the urinary excretion of catecholamine metabolites (11) and to enhance adrener gic function in the central nervous system (12). Altera tions in the renin-angiotensin system have also been noted after both acute and chronic exposures to lead (S, 8). The authors express their sincere appreciation to Dr. M, A. Schork and R. Burnside (Dept, of Biostatistics, Univ. of Michigan) for their assistance in statistical evaluation of the experimental data. These studies were supported by grants from the Michigan Heart Association, Michigan Memorial Phoenix Project, National Heart, Lung, and Blood Institute Grants HL-16575 and HL-06080 National Institute ofOccupational Safety and Health Grants ROI-OH-00913 and 01141 and National Institute of Environmental Health and Safety Grant 05126. Received 12 December 1980; accepted in final form 30 March 1981. REFERENCES 1. Be e v e r s , D. G., E. Er s x in , a n d M. Ro b e r t s o n . 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Adrenergic neurotransmission in vascular smooth muscle from spontaneously hypertensive rats. Hypertension 3: 93-103,1981. 18. Wh a LL, C. IV., M. M. My er s , a n d W. Ha l p e r n . Norepinephrine sensitivity, tension development and neuronal uptake in resistance arteries from spontaneously hypertensive and normotensive rats. Blood Vessels 17:1-15,1980. 19. Wil l ia ms , B. J., W. H. Gr if f it h , C. N. Al b r e c h t , J. H. Pir c h , a n d M. R. Ha j t ma n c ir . Effects of chronic lead treatment on some cardiovascular responses to norepinephrine in the rat. Toxicol. Appl. Pharmacol. 40:407-413,1977. TEH 0350334 DUP050298971