Humoral regulation of vascular resistance 30 days of pulmonary artery constriction

after

RICHARD F. McNAMARA, PHILLIP G. SCHMID, JENNIE A. SCHMIDT, DONALD D. LUND, AND RANBIR K. BHATNAGAR The Cardiovascular Division, Departments of Internal Medicine, Biochemistry, and Pharmacology, the Cardiovascular Center, University of Iowa College of Medicine, and the Veterans Administration Hospital, Iowa City, Iowa 52240 MCNAMAF~A, RICHARD F., PHILLIP G. SCHMID, JENNIE A. The goal of the present study was to assess and comSCHMIDT, DONALD D. LUND, AND RANBIR K. BHATNAGAR. pare the influence of circulating catecholamines, angio-

Hwnoral regulation of vascular resistance after 30 days of puhnonawy artery constriction. Am. J. Physiol. 236(6): H866H872, 1979 or Am. J. Physiol.: Heart Circ. Physiol. 5(6): H866H872,1979.-In an earlier study of guinea pigs with constriction of the pulmonary artery (PA) for 30 days, hindquarters’ vascular resistance was maintained primarily by humoral mechanisms. In the present study, we investigated the contribution of circulating catecholamines, angiotensin II, and other constrictor stimuli to hindquarters’ vascular resistance by observing vasodilator responses to specific competitive antagonists. Pressureflow curves indicated vascular resistances in isolated, perfused, sympathectomized hindquarters of anesthetized guinea pigs. Phentolamine produced significantly greater (P < 0.05) vasodilatation in animals with constriction of pulmonary artery than in sham animals. [Sari-Ala8]angiotensin II produced no vasodilation in either group. After cr-adrenergic blockade, papaverine produced similar vasodilatation and similar final perfusion pressures in both groups. It appears that circulating catecholamines and augmented vasoconstrictor responsiveness to norepinephrine are totally responsible for the increased humoral regulation of vascular resistance in this experimental model of right ventricular hypertrophy. guinea pigs; neurogenic; II; catecholamines

nonneurogenic;

structural;

angiotensin

WHEN FUNCTION OF THE HEART IS compromised, regional vascular resistances may increase and alter the distribution of cardiac output (2). Neurogenic, humoral, and structural factors regulate these vascular changes; however, the relative importance of each factor appears to differ in experimentally induced left and right heart disease (15). In guinea pigs with left ventricular stress produced by severe, chronic (30 days) constriction of the ascending aorta, an increased neurogenic influence is predominantly responsible for the maintenance of hindquarters’ vascular resistance (15). In contrast, guinea pigs with right ventricular stress produced by corresponding constriction of the pulmonary artery have an increased humoral influence that predominates in the regulation of vascular resistance (15). However, the specific factors that might be primarily responsible for this increased humoral influence in right ventricular stress have not been identified.

H866

tensin II, and other humoral constrictor stimuli on hindquarters’ vascular resistance in guinea pigs with right ventricular hypertrophy and failure produced by chronic constriction of the pulmonary artery. Catecholamines and angiotensin were chosen for analysis because they have potent vasoconstrictor effects, and circulating levels reportedly increase in association with stresses that produce heart failure (3, 7, 8, 12, 17). In addition, we previously observed increased vascular responsiveness to angiotensin and catecholamines in guinea pigs with pulmonary artery constriction and right ventricular hypertrophy and failure (15). Thus, even normal levels of angiotensin and catecholamines in conjunction with increased vascular responsiveness to these agents might lead to increases in vascular resistance. In the present study, we have quantitated and compared the vasodilator responses to antagonists that inhibit the constrictor effects of catecholamines, angiotensin II, and other humoral stimuli. We have also determined plasma norepinephrine and renin levels to determine whether the contributions to hindquarters’ vascular resistance of these factors might be related to increased plasma concentrations or to altered vascular reactivity to the stimuli. METHODS

Preparatory surgery. Anesthesia was induced in guinea pigs, 400-600 g, with halothane (Fluothane, Ayerst) and maintained with sodium pentobarbital (Nembutal, Abbott), 15 mg/kg iv. An injection of atropine sulfate (Inenex), 0.2 mg/kg im, was given to control pulmonary secretions. Succinylcholine chloride (Squibb), 5 mg/kg ip, a neuromuscular blocking agent, was administered to facilitate control of respiration. Ventilation through a tracheal cannula was maintained with a rodent respirator (Harvard Apparatus). A tidal volume of 4 ml of 40% 02 was delivered at a rate of 6O/min. The pulmonary artery (PA) was exposed through an incision in the left fourth intercostal space, the pericardial sac was opened, and the pulmonary artery was isolated from the aorta. The pulmonary artery of each animal in the banded group was then constricted with a band 1.8

0363-6135/79/0000-0000$01.25

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0 1979 the American

Physiological

Society

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mm in diameter. Animals in the sham group underwent the same operation, but without the final constriction of the vessel. This banding produced a consistent 85% reduction in cross-sectional area. Techniques of producing and quantitating the pulmonary artery constriction have been reported previously (15). After surgery the guinea pigs were caged and given food and water ad libitum until the studies of vascular control were performed 30 days later. Ten of 13 guinea pigs with pulmonary artery constriction survived for 30 days and 7 completed the perfusion studies. This corresponds to the mortality in our previous study (15). Studies of humoral regulation of hindquarters’ vascular resistance. Guinea pigs were anesthetized and ven-

tilated as described above. The right carotid artery was cannulated with PE-90 tubing and connected to a pressure transducer (P23De Statham) to monitor systemic arterial pressure. Heart rate was determined from the phasic pressure recording. Blood for perfusion of the hindquarters was obtained from the proximal abdominal aorta and flow was controlled using a roller pump (Holter, model 911). The distal abdominal aorta was cannulated with PE-90 tubing just above the bifurcation to deliver the heparinized blood to the hindquarters. Flow was maintained at 3.5 ml/mm except as noted. Pressure-flow relationships were established by measuring the perfusion pressure at various levels of flow (1.8,3.5,5.3 ml/min). At any given rate of flow, a decrease in perfusion pressure reflected a decrease in vascular resistance. The vasodilator responses to interventions were normalized by averaging the decreases in perfusion pressure at the different levels of arterial perfusion (1.8, 3.5, 5.3 ml/min) for the seven guinea pigs in each of the two groups (15). The vasodilator responses produced by four interventions were determined. First, the component of hindlimb vascular resistance mediated by the sympathetic nervous system was determined by transection of both right and left lumbar sympathetic chains at the Lz-L4 vertebral level. Sympathectomy eliminated neurogenic control and allowed us to investigate humoral control more specifically. Second, the component of the hindlimb vascular resistance mediated by angiotensin II was determined by the intraarterial administration of [Sar’-Ala8]angiotensin II (Beckman), a competitive antagonist of angiotensin II (6, 9). This was infused at a rate of 0.21 pg/min for 5 min. This dose of antagonist produced effective blockade when tested again&la 400~ng dose of angiotensin II (see RESULTS). Increasing the dose of antagonist to 0.42 pg/ min produced no additional change in perfusion pressure. Third, the contribution of circulating catecholamines to hindquarters’ vascular resistance was determined by infusing phentolamine (Regitine, Ciba) intraarterially at a rate of 50 pg/min until a constant base-line pressure was obtained. This dosage produced effective blockade when tested against a 16.pg injection of phenylephrine (see RESULTS). Increasing the dosage of phentolamine to 100 &nin produced no additional change in perfusion pressure. We considered the possibility that the contribution of catecholamines to vascular resistance might be

H867

overestimated because a nonspecific vasodilator action has been reported with phentolamine, in addition to its cr-adrenergic blocking activity (14). We therefore compared the vasodilator effects of phentolamine to that of dibozane [ 1,4-bis (1,4)-benzodioxan-2-ylmethyl) piperazine], another a-adrenergic blocking agent, which has no nonspecific vasodilator activity (14). In two guinea pigs, dibozane was infused intra-arterially to the hindquarters at a rate of 150 pg/min until a constant perfusion pressure was reached; this dose of dibozane produced effective blockade of a-adrenergic receptors comparable to that achieved with phentolamine when tested against 16 pg of phenylephrine. After the infusion of dibozane, perfusion pressures were allowed to return toward base line and then phentolamine was infused as described above. Fourth, the remaining humoral, local myogenic, and metabolic contributions to hindquarters’ vascular resistance were determined by inducing maximal vasodilatation with papaverine (Lilly), 0.41 mg/min. The residual or minimal resistance after papaverine was assumed to reflect the structural influence of vascular and perivascular tissues. The interval between induction of anesthesia and the first intervention, sympathectomy, was relatively long (60 min) compared to the interval from the first intervention to completion of the study (30 min). Each intervention was assessed over a short interval: 4 min elapsed between sympathectomy and the start of saralasin; 15 min elapsed between the start of saralasin and the start of phentolamine; 7 min elapsed between the start of phentolamine and the administration of papaverine. On completion of each study, a sample of arterial blood was taken for determination of blood gases and hematocrit. The hearts were excised and weights of the right ventricle and the left ventricle plus septum were recorded. Two additional series of experiments were performed to determine plasma catecholamines, plasma renin activity, and the tyrosine hydroxylase activity in lumbar sympathetic chains of guinea pigs with pulmonary artery constriction and sham surgery with the same surgical and postsurgical care described above. In the first series, nine PA-banded and eight sham guinea pigs were decapitated, and blood was collected from the trunk of each animal. In the second series, seven PA-banded and six sham guinea pigs were anesthetized with halothane and blood was obtained by direct cardiac puncture. The blood was collected in chilled test tubes (both series), and the lumbar chains (first series only) were immediately removed and stored in liquid nitrogen. In the blood from the first series, the analysis of plasma norepinephrine was performed using a radioisotope assay (16). Plasma renin activity was determined by radioimmunoassay as described by Cohen (4). The tyrosine hydroxylase activity was determined using the method of Coyle (5). In the second series of experiments, plasma norepinephrine, epinephrine, and dopamine were determined in duplicate in each sample (16). RESULT6

Base-line data. Guinea pigs with PA constriction gained less weight than sham animals in the 30 days

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McNAMARA

following surgery (Table 1). PA-constricted animals also displayed signs of severe right ventricular stress with significant increases in right ventricular weights (123%) and, in two of the guinea pigs, ascites. Vascular resistance. The pressure-flow curves were shifted significantly (P < 0.05) toward the pressure axis in the PA group, indicating a higher hindquarters’ vascular resistance both before and after lumbar sympathectomy compared to the sham group (Fig. 1). Vasodilator responses. The vasodilator response to sympathectomy was greater (P c 0.05) in the PA group (20 & 3 mmHg) than in the sham group (7 + 3 mmHg) (Fig. 1). This represents the neurogenic contribution to vascular resistance. Also, the sum of the vasodilator responses to phentolamine and papaverine, which reflected the nonneurogenic contribution to vascular resistance, was greater in the PA group (59 mmHg) than in the sham group (41 mmHg) (Fig. 2). Role of angiotensin II. The major goal of this study was to investigate the humoral factors that might account for the high nonneurogenic vascular influence in the PA group. In the sympathectomized hindquarters, [Sar’Ala’]angiotensin failed to produce a decrease in perfusion pressure. In the sham group, normalized perfusion pressure increased 3.9 f 2.1 mmHg; in the PA group, pressure increased 7.4 + 1.9 mmHg. This dose of the antagonist reduced the pressor responses to 400 ng of angiotensin II to 3 + 1 mmHg in the PA group, and 2 f 0.5 mmHg in Intact

m m 0

ET

AL.

I-Sar-E-Ala A JJ Phentolamine Papaverine

Catecholamines

Vasoconstricto

After Sympathectomy L

1---a -

PA Constriction Sham

C(7) 8’

Sham

PA Constriction

FIG. 2. Vascular responses to [Sk’-Ala’]angiotensin II, phentolamine, and papaverine. Responses were normalized by averaging changes in perfusion pressure at different levels of arterial perfusion (L&3.5,5.3 ml/min) for guinea pigs in the two groups. The group with PA constriction had significantly greater (P < 0.05) vasodilatation than the sham group during close intraarterial administration of phentolamine, 50 I.rg/min. Therefore, circulating catecholamines appears to contribute more to the maintenance of hindquarters’ vascular resistance in guinea pigs with PA constriction than in the sham group.

8’ 8’ . / E r’ /

(7)

9

I

I

1

,

1.8

3.5

5.3

I

1.8

1

I

3.5

5.3

Flow, ml/min 1. Pressure-flow curves for sham group with PA constriction (dashed line). Constriction ciated with a significantly higher (P < 0.05) resistance both before and after sympathectomy, in the P-F curves towards the pressure axis. FIG.

(solid line) and group of the PA was assohindquarters’ vascular as indicated by shifta

the sham group, thus demonstrating effective blockage of angiotensin receptors in the hindquarters’ vasculature. Role of catecholamines. Phentolamine, the antagonist for cu-adrenergic receptors, infused at a rate of 50 pg/min, produced significantly greater (P < 0.05) vasodilatation in the hindquarters of the PA-banded group than in the sham group (Fig. 2). This dose of phentolamine reduced pressor responses to 16 pg of phenylephrine to 3 + 1 mmHg in the PA group, and 2 + 0.5 mmHg in the sham group, demonstrating effective blockade of a-adrenergic receptors. Alpha-adrenergic receptor blockade resulted in the same plateau in hindquarters’ perfusion pressures in the two groups (40 mmHg). In two guinea pigs, dibozane, an a-adrenergic receptor blocking agent without nonspecific vasodilating activity, produced responses comparable to those produced by phentolamine. In a sham guinea pig, dibozane and phentolamine produced decreases in perfusion pressure of 19 and 20 mmHg, respectively; after the initial decreases, perfusion pressures plateaued at 63 and 58 mmHg, respectively. In a guinea pig with pulmonary artery con-

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FIG. 3. PA-constricted (n = 9) and sham-operated (n = 8) animals did not difTer significantly with respect to plasma norepinephrine levels (A ) , plasma renin activity (B ), and tyrosine hydroxylase activity in lumbar sympathetic chains (C). Values are means k SE.

Sham

PA

0

Sham

PA

striction, the corresponding decreases m perfusion pressure with dibozane and phentolarnine were 41 and 44 mmHg, respectively, and the plateaus were 59 and 58 mmHg, respectively. Role of structural factors. Subsequently, the infusion of papaverine, 0.4 mg/min, produced a similar level of maximal vasodilation in both groups. The normalized minimal perfusion pressures achieved with papaverine averaged 15.8 * 1.1mmHg in sham guinea pigs and 16.1 t 0.8 mmHg in PA guinea pigs (P > 0.1). Plasma levels of norepinephrine and renin activity and tyrosine hydroxylase activity in lumbar sympathetic ganglia and chains. The additional guinea pigs in the first series of experiments representing sham-operated and PA-constricted groups had RV/BW values of 0.61 t 0.02 (n = 8) and 1.18t 0.08 (n = 9) g/kg, respectively (P < 0.05). These animals did not differ in this respect (RV/BW) from the guinea pigs that were used for hemodynamic studies. The sham and PA groups did not differ with respect to plasma norepinephrine levels, plasma renin activity, and tyrosine hydroxylase activity in the lumbar sympathetic ganglia and chains (Fig. 3). Plasma levels of norepinephrine, epinephrine, and dopamine. The additional guinea pigs in the second series of experiments representing sham operated- and pulmonary artery-constricted groups had RV/BW values of 0.649 t 0.03 (n = 6) and 1.26 t 0.09 (n = 7) g/kg, respectively (P c 0.05). These animals also did not differ in this respect (RV/BW) from the guinea pigs that were used for hemodynamic studies. Plasma norepinephrine averaged 32.2 t 7.2 and 34.0 t 7.0 rig/ml, respectively, in the sham- and PA-banded animals in this series (P > 0.1). Plasma epinephrine averaged 28.8 t 5.8 and 40.3 t 8.8 rig/ml (P > 0.05). Plasma dopamine averaged 2.09 t 0.18 and 2.90 t 0.27 rig/ml (P < 0.05).

Sham

PA

DISCUSSION

A previous study in our laboratory has indicated that, in guinea pigs with constriction of she pulmonary artery for 30 days, there is an increased humoral vascular influence that predominates in the regulation of hindquarters’ resistance (15). The present study confirms this finding because the differences in the vascular resistances between sympathectomized and maximally vasodilated hindquarters were greater (P < 0.05) in guinea pigs with pulmonary artery constriction. The major goal of the present study was to determine the relative contributions of catecholamines, angiotensin II, and other constrictor stimuli to vascular regulation after 30 days of pulmonary artery constriction. Catecholamines accounted totally for the increased humoral influence on vascular tone. In contrast, there was no detectable influence of angiotensin II. Constrictor stimuli other than catecholamines and angiotensin II appeared to contribute equally to vascular regulation in the two groups. The influence of other factors that might have affected this experiment was considered. The two groups were similar with respect to blood gases and pH (Table 1). Therefore, none of the differences between the groups can be attributed to these. The experimental design for this study required that the intraarterial administration of [Sar’-Ala’langiotensin II precede that of phentolamine because the vascular action of the angiotensin antagonist was very transient, whereas the vascular action of phentolamine tended to be prolonged. If there was any interaction between these two antagonists, we would have expected it to be similar for the sham and PA groups. Therefore, none of the differences between the groups have been attributed to the order of administering drugs. Furthermore, there was

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H870 TABLE

McNAMAR.A

1. Base-line

data Sham

n Weight, g At operation At time of death RWW

g/kg

MAP, mmHg Heart rate, beats/min Hct, % PO2 PC02 PH

7 525 f: 26 745k16 0.539 * 0.025 56*5 287 zk 6 42 k 1 124 k 8 26 =1=2 7.43 * 0.03

PA Constriction

7 508 ct 630*29’ 1.202 k 55 * 259 * 41* 129 * 21 * 7.36 zt

24 0.65* 7 14 1 11 1.2 0.03

Guinea pigs with pulmonary artery constriction gained less weight and had significantly greater right ventricular weights than the sham group. The groups were similar with respect to other variables. PA, pulmonary artery; RV, right ventricle; BW, body weight; MAP, mean arterial pressure; Hct, hematocrit. * P < 0.05.

no detectable effect of [Sar’-Ala’]angiotensin II, so the effects of phentolamine were assessed in sympathectomized, but otherwise relatively unperturbed vascular beds. Role of angiotensin II. Our previous results indicated a selective, l&fold augmentation of the vasoconstrictor effects of angiotensin II after 30 days of pulmonary artery constriction (15). On the basis of this and other information, it seemed possible that levels of circulating angiotensin II, even in the normal range, could account for some of the increase in humorally mediated vascular tone. To assess the role of angiotensin II in vascular regulation, we investigated the vasodilator effects of the competitive antagonist, [Sa.r’-Ala’langiotensin II (6, 9). The results indicate that angiotensin II contributed minimally to vascular resistance in the PA-banded group. Perfusion pressure did not decrease during infusion of the antagonist despite effective blockade of angiotensin receptors, which was demonstrated by the nearly complete inhibition of the vasoconstrictor effects of exogenous angiotensin II, 400 ng. In fact, during administration of [Sar’-Ala’langiotensin II to the hindquarters, there were slight increases in perfusion pressure in both groups; this is consistent with the reported slight agonistic activity of this analogue (9). The absence of an inhibitory effect of [Sar’-Alas]angiotensin II, and the detection of a slight agonistic effect in both groups support the conclusion that circulating levels of angiotensin II contributed little, if any, to hindquarters’ vascular resistance in either sham animals or those with chronic PA constriction. Plasma renin activity was similar in both PA-constricted and sham animals, providing indirect evidence that angiotensin II activity may also have been similar in both groups. In our previous study, we speculated that the markedly increased responsiveness to exogenous angiotensin II in the PA guinea pigs resulted from low levels of circulating angiotensin II and thus, a greater availability of angiotensin II receptor sites (15). However, because the present data indicate that plasma renin activity was similar in the two groups, it is also possible that the previously observed increased responsiveness to angiotensin II was the result of either an increased number of receptors or an increased affinity of angiotensin II receptors for agonist.

ET AL.

The contention that angiotensin II has minimal influence in increasing vascular resistance in this model of right ventricular stress is consistent with other reports that suggest that the acute stage of uncompensated heart failure may be associated with activation of the reninangiotensin-aldosterone system (7, 8, 17), whereas the chronic stage of compensated right heart failure may be characterized by normal activity of this system (17). RoZe of catecholamines. In our previous study (15), there was a threefold augmentation of the vasoconstrictor effects of cr-adrenergic stimuli 30 days after PA constriction. To assess the role of circulating catecholamines, we investigated the vasodilator effects of the competitive antagonist, phentolamine. This produced a greater vasodilatation in the sympathectomized hindquarters of PA guinea pigs than in comparably prepared sham guinea pigs (P < 0.05). Thus, catecholamines would appear to be a significant vascular influence in right ventricular hypertrophy and failure produced by chronic pulmonary artery constriction. We considered the possibility that the contribution of catecholamines to vascular resistance might have been overestimated because a nonspecific vasodilator action has been reported with phentolamine, in addition to its a-adrenergic blocking activity (14). Therefore, the response to phentolamine was compared to the response to dibozane, another cr-adrenergic blocking agent lacking nonspecific vasodilator activity (14). In the two animals tested, one with sham surgery and one with PA constriction, both the vasodilatation and final perfusion pressure after administration of dibozane were identical to the corresponding responses seen with phentolamine. This suggests that the vasodilatation observed with phentolamine is due to its cu-adrenergic blocking properties and accurately reflects the contribution of circulating catecholamines to vascular resistance. It was necessary to consider whether an increase in catecholamines per se or increased vascular responsiveness to adrenergic stimuli was responsible for the increased adrenergic contribution to vascular resistance in the sympathectomized hindquarters of PA guinea pigs. In two separate groups with PA constriction, the levels of circulating norepinephrine and epinephrine was not increased above that in the sham group. This suggests that increased vascular responsiveness to adrenergic stimuli accounted for much of the increased adrenergic influence. Consistent with this reasoning, increased vascular responsiveness to norepinephrine was observed in our previous study of PA guinea pigs (15). We considered the possibility that the data on plasma catecholamines might not be representative of the circulating levels in those initial guinea pigs undergoing hemodynamic studies and possibly subjected to greater stress. In the first additional series of guinea pigs with sham surgery and PA constriction, plasma norepinephrine averaged about 3 rig/ml in both groups. In the second series, plasma norepinephrine averaged about 30 rig/ml in both groups. Plasma epinephrine levels in the latter series were correspondingly high. These results indicate that, with respect to plasma catecholamines (norepinephrine and epinephrine), sham and PA-constricted guinea pigs were similar over a wide range of

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adrenergic activity. It seems unlikely that the stress of Role of other constrictor stimuli. With the infusion of phentolamine, perfusion pressures in the hindquarters hemodynamic studies could have resulted in catecholamine levels outside of these values, especially because were reduced to the same absolute levels in PA-consevere stress produces catecholamine levels in other spe- stricted and sham-operated guinea pigs. Subsequently, cies (3) that correspond closely to those values reported with the infusion of papaverine, perfusion pressures were reduced further and to the same minimal levels in both here. The surprising finding was a significantly higher (P < groups. The difference between the perfusion pressures achieved with phentolamine and those achieved with 0.05) circulating level of dopamine in PA-constricted guinea pigs than in sham-operated guinea pigs. The papaverine represented the vasoconstrictor influence of values in the two groups are not strikingly different, stimuli other than catecholamines and angiotensin II however, so the significance of this difference in terms of (Fig. 2). These other, as yet unidentified factors, contribvascular regulation are not entirely clear. Again, it is uted equally to vascular regulation in both groups of worth emphasizing that levels of plasma dopamine in guinea pigs. rats subjected to “restraint stress” (3) approach values Role of structural factors. The maximal vasodilatation similar to those identified in guinea pigs in this study. evoked by papaverine, which would have been limited by Future studies will explore in greater detail the signifistructural changes in vascular and perivascular tissues, cance and mechanisms of elevated plasma dopamine in were similar in both experimental groups in this study as in our previous study (15). PA-constricted guinea pigs. Although nonneurogenic influences on vascular resistThese results demonstrate that the increased nonneuance predominated in both the present and previous rogenic vascular tone associated with chronic right venstudy of PA guinea pigs (15), we also noted a significant tricular stress, produced by constriction of the pulmonary artery for 30 days, result from a selective increase in the increase in sympathetic neurogenic influence as reflected by the augmented vasodilator response to sympathecvascular influence of catecholamines. There was no increase in the the contributions of angiotensin II, other tomy. To determine if this increased sympathetic influconstrictor stimuli, and structural factors to vascular ence was associated with other evidence of a primary increase in sympathetic activity to the hindquarters, we resistance in this experimental model. Because levels of circulating norepinephrine and epinephrine were not dedetermined a biochemical index of sympathetic activity, the activity of tyrosine hydroxylase, the rate-limiting tectably increased, the increased nonneurogenic vascular enzyme in norepinephrine biosynthesis. We found normal tone has been ascribed chiefly to augmented vasoconstrictor responsiveness to catecholamines. These obserlevels of tyrosine hydroxylase in the sympathetic lumbar chains and ganglia, which does not rule out sympathetic vations raise further questions about whether primary alterations occur in vascular smooth muscle of guinea activation but suggests that it was not marked and that increased responsiveness to adrenergic stimuli may have pigs with PA constriction or, as in hypertensive models, been partially responsible for the increased vasodilator sensitizing factors appear in the circulation (10, 11, 13). response to sympathectomy. In support of this, in our We thank Howard Mayer and Judy Donnell for technical assistance previous study, there was a significant increase in vas- and Barbara Nolte and Carol Huffman for secretarial assistance. cular responsiveness to electrical stimulation of the symThis work was supported by Grants HL-20768, NS-11316, and NS12121, and Program Project Grant HL-014388 from the Public Health pathetic lumbar chains and exogenous norepinephrine Service, Grant MRIS-7737 from the Veterans Administration, and a (15). Thus, there could have been an increased sympaUniversity of Iowa Student Fellowship to R. F. McNamara. thetic neural influence, even without elevated efferent Received 13 February 1978; accepted in final form 6 February 1979. sympathetic nervous system activity. REFERENCES 1. BELLEAU, L., H. MIOR, S. SIMARD, P. GRANGER, E. BERTANOU, W. NOWACZYNSKI, R. BOUCHER, AND J. GENEST. Studies on the mech-

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1617, 1976.

1977.

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Humoral regulation of vascular resistance after 30 days of pulmonary artery constriction.

Humoral regulation of vascular resistance 30 days of pulmonary artery constriction after RICHARD F. McNAMARA, PHILLIP G. SCHMID, JENNIE A. SCHMIDT,...
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